piperidines and Schizophrenia

Schizophrenia significantly limits social functioning with positive and negative symptoms and cognitive dysfunction. Blonanserin (LONASEN®), a novel second-generation antipsychotic approved for treating schizophrenia in Japan in 2008, reportedly shows beneficial effects on cognitive function as well as positive and negative symptoms, with potential for improving social functioning. To understand the safety and effectiveness of blonanserin in the real clinical practice, five Japanese post-marketing surveillances have been conducted and published to date. In this article, we reviewed all the Japanese post-marketing surveillances and discussed the clinical usefulness of blonanserin in patients with schizophrenia having diverse clinical characteristics. Adverse drug reactions, such as akathisia and extrapyramidal symptoms, were common in all surveillances. However, those specific to second-generation antipsychotics, such as weight gain and abnormalities in glycometabolism or lipid metabolism, were rarely observed. In addition, no adverse drug reactions apart from clinical trial results were found. Brief Psychiatric Rating Scale total scores in all surveillances significantly lowered at the last evaluation than at baseline. These results were consistent through 1-year of treatment, suggesting that effectiveness is maintained even after long-term use. In conclusion, blonanserin is considered a beneficial drug in real clinical practice for patients with schizophrenia having diverse characteristics.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Akathisia, Drug-Induced; Antipsychotic Agents; Basal Ganglia Diseases; Child; Female; Humans; Japan; Male; Middle Aged; Piperazines; Piperidines; Product Surveillance, Postmarketing; Safety; Schizophrenia; Treatment Outcome; Young Adult

The dose-response relationships of antipsychotic drugs for schizophrenia are not well defined, but such information would be important for decision making by clinicians. The authors sought to fill this gap by conducting dose-response meta-analyses.. A search of multiple electronic databases (through November 2018) was conducted for all placebo-controlled dose-finding studies for 20 second-generation antipsychotic drugs and haloperidol (oral and long-acting injectable, LAI) in people with acute schizophrenia symptoms. Dose-response curves were constructed with random-effects dose-response meta-analyses and a spline model. The outcome measure was total score reduction from baseline on the Positive and Negative Syndrome Scale or the Brief Psychiatric Rating Scale. The authors identified 95% effective doses, explored whether higher or lower doses than the currently licensed ones might be more appropriate, and derived dose equivalencies from the 95% effective doses.. Sixty-eight studies met the inclusion criteria. The 95% effective doses and the doses equivalent to 1 mg of oral risperidone, respectively, were as follows: amisulpride for patients with positive symptoms, 537 mg/day and 85.8 mg; aripiprazole, 11.5 mg/day and 1.8 mg; aripiprazole LAI (lauroxil), 463 mg every 4 weeks and 264 mg; asenapine, 15.0 mg/day and 2.4 mg; brexpiprazole, 3.36 mg/day and 0.54 mg; haloperidol, 6.3 mg/day and 1.01 mg; iloperidone, 20.13 mg/day and 3.2 mg; lurasidone, 147 mg/day and 23.5 mg; olanzapine, 15.2 mg/day and 2.4 mg; olanzapine LAI, 277 mg every 2 weeks and 3.2 mg; paliperidone, 13.4 mg/day and 2.1 mg; paliperidone LAI, 120 mg every 4 weeks and 1.53 mg; quetiapine, 482 mg/day and 77 mg; risperidone, 6.3 mg/day and 1 mg; risperidone LAI, 36.6 mg every 2 weeks and 0.42 mg; sertindole, 22.5 mg/day and 3.6 mg; and ziprasidone, 186 mg/day and 30 mg. For amisulpride and olanzapine, specific data for patients with predominant negative symptoms were available. The authors have made available on their web site a spreadsheet with this method and other updated methods that can be used to estimate dose equivalencies in practice.. In chronic schizophrenia patients with acute exacerbations, doses higher than the identified 95% effective doses may on average not provide more efficacy. For some drugs, higher than currently licensed doses might be tested in further trials, because their dose-response curves did not plateau.

Topics: Acute Disease; Administration, Oral; Antipsychotic Agents; Aripiprazole; Clozapine; Delayed-Action Preparations; Dose-Response Relationship, Drug; Haloperidol; Humans; Imidazoles; Indoles; Isoxazoles; Lurasidone Hydrochloride; Olanzapine; Paliperidone Palmitate; Piperazines; Piperidines; Quetiapine Fumarate; Quinolones; Risperidone; Schizophrenia; Schizophrenic Psychology; Thiazoles; Thiophenes

The use of the blonanserin patch (BLO-P) for schizophrenia treatment was approved in Japan in 2019. This systematic review of trials in Japan assessed the efficacy and safety profile of BLO-P compared with other antipsychotics.. The systematic review included 6-week, double-blind, randomized, placebo-controlled, phase 3 trials in Japan that included patients with acute schizophrenia. Pooled data for patients receiving BLO-P 40 and 80 mg/day (BLO-P40+80) were compared with pooled data for patients receiving asenapine 10 and 20 mg/day (ASE10+20) and data for those receiving brexpiprazole 2 mg/day (BRE2) and paliperidone extended-release 6 mg/day (PAL-ER6).. All the investigated treatments were superior to placebo in reducing the Positive and Negative Syndrome Scale (PANSS) total score; the Hedges' g values (95% confidence interval) for BLO-P40+80, ASE10+20, BRE2, and PAL-ER6 were-0.40 (-0.58,-0.22),-0.61 (-0.79,-0.42),-0.33 (-0.60,-0.07), and-0.69 (-0.93,-0.45), respectively. There were differences among the antipsychotics in the incidence of various individual adverse events.. BLO-P40+80 may have a good efficacy/safety/tolerability profile for the treatment of patients with acute schizophrenia.

Topics: Acute Disease; Administration, Cutaneous; Antipsychotic Agents; Clinical Trials, Phase III as Topic; Double-Blind Method; Humans; Japan; Piperazines; Piperidines; Randomized Controlled Trials as Topic; Schizophrenia

Schizophrenia has a prevalence of approximately 1% in the general population, with 15.2 per 100,000 persons affected. Iloperidone is a second-generation antipsychotic drug approved for the treatment of schizophrenia in adults. It acts primarily by D2/5HT2a receptor antagonism, with greater affinity for the 5HT2a receptor than for the D2 receptor.. This article discusses iloperidone and aims to provide useful information for clinicians to determine which circumstances would best suit the use of iloperidone to treat schizophrenic patients. In this review, the authors briefly discuss schizophrenia and its treatment, before they discuss properties of iloperidone, its indications, approval process, and adverse effects. Finally, the authors review the specific strengths and weaknesses of the medication.. Iloperidone would be an attractive option in patients who are particularly prone to EPS, or who are showing prominent negative symptoms, as well as cognitive deficits. Its availability only in an oral formulation makes it a better option for patients with good medication adherence, and though it could be useful in patients prone to weight gain or hepatic dysfunction on other second generation antipsychotics, it should be used with caution in patients prone to side effects related to alpha adrenergic blockade.

Topics: Antipsychotic Agents; Humans; Isoxazoles; Piperidines; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Schizophrenia; Weight Gain

We conducted an updated systematic review and meta-analysis of randomized controlled trials (RCTs) comparing blonanserin with other antipsychotics (amisulpride, aripiprazole, haloperidol, paliperidone, and risperidone).. Weighted mean difference (WMD), risk ratio, and number needed to harm (NNH) with 95% confidence intervals (95% CIs) were calculated using random-effects model.. The current meta-analytic study did not update the comparison of blonanserin vs. haloperidol because there were no new RCTs. Our results suggest that the efficacy of blonanserin for schizophrenia is comparable with that of other antipsychotics, and blonanserin seems to be well tolerated.

Topics: Antipsychotic Agents; Humans; Piperazines; Piperidines; Randomized Controlled Trials as Topic; Schizophrenia

Positive allosteric modulation of mGlu2 has attracted much interest as an alternative approach to classical orthosteric receptor activation. Two mGlu2 PAMS have advanced into the clinic. The results obtained in schizophrenia and MDD phase 2 clinical trials have tempered the high expectations put on selective mGlu2 receptor activation for treating these conditions; nevertheless, the search for novel therapeutic indications and novel chemotypes continues to be an active field of research.. 2013-2018 patent literature on mGlu2 receptor PAMs.. After a decade of intensive research, the mGlu2 PAM field has seen a deceleration in the last five years. Negative phase 2 schizophrenia clinical trials with JNJ-40411813 and AZD8529 seem to have tempered the high expectations of the scientific community on the utility of mGlu2 PAMs for the treatment of schizophrenia. Nevertheless, novel therapeutic indications continue to be explored and AZD8529 is currently in a phase 2 study for smoking cessation. The advances in medicinal chemistry and in pharmacology, with novel indications such as epilepsy, have set the stage in the field of mGlu2 receptor PAMs. Ongoing preclinical and clinical studies will contribute to define their optimal therapeutic indication and potential to become novel therapeutic agents.

Topics: Allosteric Regulation; Animals; Depressive Disorder, Major; Humans; Indoles; Oxadiazoles; Patents as Topic; Piperidines; Pyridones; Receptors, Metabotropic Glutamate; Schizophrenia

Cognition deficit is one of the most common symptoms of schizophrenia, including abstract thinking and memory, and attention deficits. Previous studies have suggested that the improvement of cognition is very important for the recovery of disease and social function for the patients. Recent studies indicated that two new atypical antipsychotics, blonanserin and lurasidone, are expected to improve the cognitive impairment in patients with schizophrenia. This review introduces pathogenesis of cognitive impairment in schizophrenia, mechanisms of blonanserin and lurasidone in the improvement of cognitive impairment and progress in their clinical application for schizophrenia. We hope that this review could guide clinical use of antipsychotics and provide new directions for future studies.. 认知功能障碍是精神分裂症常见症状之一，主要表现为抽象思维、记忆、注意等方面的障碍。认知功能的改善对患者疾病康复、社会功能恢复具有至关重要的意义。近来研究表明新型非典型抗精神病药物布南色林和鲁拉西酮具有独特的受体作用机制，有望使患者认知功能障碍得到更好的改善。笔者从精神分裂症患者认知功能障碍的病因机制入手，综述布南色林和鲁拉西酮改善精神分裂症患者认知功能的作用机制；介绍两种药物的临床应用进展，以便更好地指导临床用药，为进一步研究提供新方向。.

Topics: Antipsychotic Agents; Cognition Disorders; Humans; Lurasidone Hydrochloride; Piperazines; Piperidines; Schizophrenia; Schizophrenic Psychology

Although there has been more than 50 years of development, there remains a great need for better antipsychotic medications. This article looks at the recent advances in treatment of schizophrenia. New hypotheses have been suggested that may replace or complement the dopamine hypotheses. The article explores the different novel drugs that impact some of the key neurotransmitter systems currently. Phosphodiesterase 10A inhibitors and α-7 neuronal nicotinic acetylcholine receptor modulators constitute the majority. The marketing of these medications eventually may result in change about how schizophrenia is treated.

Topics: Antipsychotic Agents; Drug Approval; Excitatory Amino Acid Agents; Glycine Agents; Humans; Minocycline; Nicotinic Agonists; Phosphodiesterase Inhibitors; Piperazines; Piperidines; Schizophrenia

Parkinson´s disease (PD) is a synucleinopathy that affects millions of people worldwide and leads to progressive disability. Psychosis is highly prevalent in PD patients and is associated with poor prognosis. Until April 2016, there were no licensed drugs available in the United States of America (USA) for the treatment of PD psychosis (PDP). Pimavanserin is the first Food and Drug Administration approved medicine for the treatment of hallucinations and delusions associated with PDP.. A MEDLINE literature search, publicly available information provided by ACADIA Pharmaceuticals, and expert opinion were used for this review. A review of PDP, its current treatment and limitations is followed by the rationale for development of pimavanserin. The mechanism of action, preclinical data, pharmacokinetics, pharmacodynamics, and clinical data supporting the efficacy and safety of pimavanserin in PDP are reviewed. We also describe the potential benefits of pimavanserin in other contexts such as schizophrenia and sleep disorders.. Pimavanserin is an antipsychotic with a unique mechanism of action (5-HT2A receptor inverse agonist) and no measurable dopaminergic activity; it has been demonstrated to be efficacious, well tolerated and safe for the treatment of PDP. The development of pimavanserin as an antipsychotic represents a major breakthrough in the pharmacotherapy of psychotic symptoms associated with PD.

Topics: Antipsychotic Agents; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Schizophrenia; Serotonin 5-HT2 Receptor Agonists; Urea

Medicinal chemistry is continually developing and testing new drugs and drug candidates to satisfactorily address the needs of patients suffering from schizophrenia. In the last few years, some significant additions have been made to the list of widely available atypical antipsychotics. In particular, iloperidone, asenapine and lurasidone have been approved by the USA's Food and Drug Administration in 2009-10. In this paper, the most notable metabolic characteristics of these new drugs are addressed, with particular attention to their potential for pharmacokinetic interactions, and to the respective advantages and disadvantages in this regard. Moreover, current perspectives on the therapeutic drug monitoring (TDM) of the considered drugs are discussed. Since TDM is most valuable when it allows the personalisation and optimisation of therapeutic practices, it is even more interesting in the case of novel drugs, such as those discussed here, whose real impact in terms of side and toxic effects on very large populations is still unknown. Some analytical notes, related to TDM application, are included for each drug.

Topics: Animals; Antipsychotic Agents; Dibenzocycloheptenes; Drug Approval; Drug Design; Drug Monitoring; Heterocyclic Compounds, 4 or More Rings; Humans; Isoxazoles; Lurasidone Hydrochloride; Piperidines; Schizophrenia; United States; United States Food and Drug Administration

Iloperidone is a novel antipsychotic medication approved for the treatment of schizophrenia in adults with efficacy similar to its class counterparts. The purpose of this article is to describe the safety profile of iloperidone and its clinical implications.. A PubMed search was undertaken on May 10, 2013, using the keyword iloperidone. Of the 121 articles that resulted, those with primary sources of information, along with secondary sources with an emphasis on drug safety, were included in this article. Iloperidone was found to have lower extrapyramidal symptom (EPS) and akathisia rates compared to haloperidol and risperidone. Twelve percent of patients experienced clinically significant weight gain, largely during initiation phase of treatment. No other clinically significant metabolic abnormalities were observed. QTc interval was increased by 10 ms, comparable to the effect observed with ziprasidone. QTc prolongation was heightened under inhibition of CYP2D6 and CYP3A4. Orthostatic hypotension was a common effect seen in the first week of treatment.. The favorable EPS and akathisia profile of iloperidone makes it an attractive choice for patients whose compliance is limited by these effects. However, the slow titration schedule adapted to reduce orthostasis may limit the use of this agent in an acute setting.

Topics: Antipsychotic Agents; Humans; Isoxazoles; Piperidines; Schizophrenia; Treatment Outcome

The present study aimed to evaluate cardiometabolic risks [weight gain, blood lipid levels (total cholesterol and triglycerides), blood glucose levels, hemoglobin A1c (HbA1c) levels, and corrected QT interval (QTc) prolongation] associated with the use of blonanserin and perospirone versus other antipsychotics in the management of patients with schizophrenia.. We conducted a systematic review and meta-analysis of patient data from randomized controlled trials comparing blonanserin or perospirone with other antipsychotics.. In total, 4 blonanserin studies (n = 1080) were identified [vs. risperidone (2 studies, n = 508); vs. haloperidol (2 studies, n = 572)]. Blonanserin produced less weight gain compared with risperidone (weighted mean difference = -0.86, 95% confidence intervals = -1.36 to -0.36, p = 0.0008; 2 studies, 480 patients). However, no significant differences were observed in blood lipid, glucose, and HbA1c levels or QTc prolongation between blonanserin and risperidone or haloperidol. For perospirone studies, 5 studies [562 adult patients with schizophrenia randomized to perospirone (n = 256), olanzapine (n = 20), quetiapine (n = 28), risperidone (n = 53), aripiprazole (n = 49), haloperidol (n = 75), or mosapramine (n = 81)] were identified. Perospirone did not differ from other antipsychotics with regard to weight gain and total cholesterol levels.. Our results suggest that blonanserin is associated with a lower of weight gain compared with other antipsychotics. Because the number of studies was small, additional controlled clinical trials with larger number of patients are indicated.

Topics: Adult; Antipsychotic Agents; Blood Glucose; Double-Blind Method; Glycated Hemoglobin; Heart; Humans; Isoindoles; Piperazines; Piperidines; Randomized Controlled Trials as Topic; Risk; Schizophrenia; Thiazoles; Weight Gain

The management of schizophrenia has seen significant strides over the last few decades, due to the increasing availability of a number of antipsychotics. Yet, the diminished efficacy in relation to the negative and cognitive symptoms of schizophrenia, and the disturbing adverse reactions associated with the current antipsychotics, reflect the need for better molecules targeting unexplored pathways.. To review the salient features of the recently approved antipsychotics; namely, iloperidone, asenapine, lurasidone and blonanserin.. We discuss the advantages, limitations and place in modern pharmacotherapy of each of these drugs. In addition, we briefly highlight the new targets that are being explored.. Promising strategies include modulation of the glutamatergic and GABAergic pathways, as well as cholinergic systems.. Although regulatory bodies have approved only a handful of antipsychotics in recent years, the wide spectrum of targets that are being explored could eventually bring out antipsychotics with improved efficacy and acceptability, as well as the potential to revolutionize psychiatric practice.

Topics: Antipsychotic Agents; Dibenzocycloheptenes; Drug Discovery; Heterocyclic Compounds, 4 or More Rings; Humans; Isoindoles; Isoxazoles; Lurasidone Hydrochloride; Piperazines; Piperidines; Schizophrenia; Thiazoles

Blonanserin was developed in Japan in 2008 as an antipsychotic drug. It has high affinity for dopamine D2/3 and serotonin 5-HT2A receptors, but shows low affinity for adrenergic alpha1, histamine H1, and muscarinic M1 receptors. Several short-term double-blind trials demonstrated that blonanserin was well tolerated and had equal efficacy to haloperidol and risperidone in terms of positive symptoms and depressive symptoms in patients with chronic schizophrenia. It was also superior to haloperidol in improving negative symptoms. We have recently reported that blonanserin may improve some types of cognitive function associated with the frontal lobe activity in patients with first-episode schizophrenia. Taken together, blonanserin may be a promising candidate for a first-line antipsychotic for patients with first-episode and chronic schizophrenia.

Topics: Antipsychotic Agents; Cognition; Humans; Japan; Piperazines; Piperidines; Quality of Life; Schizophrenia; Treatment Outcome

Serotonin (5-hydroxytryptamine, or 5-HT) receptors mediate a plethora of physiological phenomena in the brain and the periphery. Additionally, serotonergic dysfunction has been implicated in nearly every neuropsychiatric disorder. The effects of serotonin are mediated by fourteen GPCRs. Both the therapeutic actions and side effects of commonly prescribed drugs are frequently due to nonspecific actions on various 5-HT receptor subtypes. For more than 20 years, the search for clinically efficacious drugs that selectively target 5-HT receptor subtypes has been only occasionally successful. This review provides an overview of 5-HT receptor pharmacology and discusses two recent 5-HT receptor subtype-selective drugs, lorcaserin and pimavanserin, which target the 5HT2C and 5HT2A receptors and provide new treatments for obesity and Parkinson's disease psychosis, respectively.

Topics: Benzazepines; Diabetes Mellitus, Type 2; Heart Valve Diseases; Humans; Molecular Structure; Obesity; Parkinson Disease; Piperidines; Receptors, Serotonin; Schizophrenia; Serotonin; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Urea

There is uncertainty about the efficacy and tolerability of blonanserin in schizophrenia.. PubMed, the Cochrane Library databases, PsycINFO, and Google Scholar were searched up to September 2012. A systematic review and meta-analysis of individual patient data from randomized, controlled trials comparing blonanserin with other antipsychotics were conducted. The risk ratio (RR), 95% confidence intervals (CI), numbers-needed-to-harm (NNH), and weighted mean difference (WMD) were calculated.. Four studies (total n = 1080) were identified (vs. risperidone studies [n = 508], vs. haloperidol studies [n = 572]). Comparing blonanserin with other pooled antipsychotics, there were no significant differences in the Positive and Negative Syndrome Scale (PANSS) total score (p = 0.75), PANSS positive (p = 0.41), PANSS negative (p = 0.09), and PANSS general psychopathology subscale scores (p = 0.96), and response rate (p = 0.72). However, blonanserin showed greater efficacy in PANSS negative subscale scores compared with haloperidol (WMD = -1.29, CI = -2.29 to -0.30, p = 0.01, I(2) = 0%). No significant differences were found in discontinuation rates between blonanserin and other pooled antipsychotics (due to any cause: p = 0.29, inefficacy: p = 0.32, adverse events: p = 0.56). Blonanserin had a 0.31 lower risk of hyperprolactinemia than the other pooled antipsychotics (CI = 0.20-0.49, NNH = not significant). While dizziness (RR = 0.47, CI = 0.23-0.93, NNH = not significant) and akathisia (RR = 0.54, CI = 0.32-0.90, NNH = 7) occurred significantly less often with blonanserin than with haloperidol, blonanserin had a 1.62 higher risk of akathisia than risperidone (CI = 1.18-2.22, NNH = 8) [corrected].. Our results suggest that although blonanserin has a more beneficial effect on negative symptoms than haloperidol, there was a significant difference in the adverse events profile between blonanserin and other antipsychotics.

Topics: Antiparkinson Agents; Double-Blind Method; Humans; Piperazines; Piperidines; Psychiatric Status Rating Scales; PubMed; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome

Even though cognitive impairment is manifested in almost all patients with schizophrenia, the Clinical Antipsychotic Trials for Intervention Effectiveness (CATIE) study showed no significant difference between first- and second-generation psychotropic drugs in improving cognitive abilities. Discovering new drugs that can improve impaired cognition, thus, is an attractive treatment target for patients with schizophrenia.. This article briefly reviews about donepezil, a highly selective (IC(50) = 6.7 nM) centrally acting reversible acetylcholinesterase inhibitor that has been approved by FDA for treating cognitive deficit states such as in Alzheimer's disease and its uses in clinical trials for the treatment of schizophrenia. The literature search included PubMed and Cochrane library with the following words: donepezil, schizophrenia and cognitive impairments.. The results of several clinical trials utilizing donepezil as an adjunct to second-generation antipsychotic drugs targeting cognitive deficits in schizophrenia subjects have been disappointing and would not lead clinicians to consider this as a potential treatment option. While longer randomized controlled trials, increase dosage and selected groups of patients at different stage of cognitive impairment may provide a better understanding of the potential for this drug in addressing cognitive deficits, results to date have not been encouraging.

Topics: Binding Sites; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Donepezil; Humans; Indans; Models, Molecular; Molecular Structure; Piperidines; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

This article reviews the pharmacological profile and published efficacy and tolerability/safety data of iloperidone, asenapine and lurasidone, the most recent atypical antipsychotics to be approved in the USA for the treatment of schizophrenia. All three agents are similar in terms of overall efficacy and low propensity for clinically significant weight gain or adverse changes in glycemic or lipid profile. However, these agents differ from one another in terms of formulations, pharmacokinetics, and dosing and nonmetabolic adverse effect profile. For each drug, comparative and real-world effectiveness studies are lacking, as are effectiveness and safety data in elderly, young and pregnant/nursing patients. As such, the exact place of iloperidone, asenapine and lurasidone within the broader antipsychotic armamentarium is currently difficult to establish.

Topics: Antipsychotic Agents; Dibenzocycloheptenes; Drug Approval; Heterocyclic Compounds, 4 or More Rings; Humans; Isoindoles; Isoxazoles; Lurasidone Hydrochloride; Piperidines; Schizophrenia; Thiazoles

When schizophrenia patients have insufficient response to clozapine, pharmacological augmentation is often applied. This meta-analysis summarizes available evidence on efficacy of pharmacological augmentation of clozapine treatment in schizophrenia spectrum disorder.. Only double-blind randomized controlled studies were included. Primary outcome measure was total symptom severity, and secondary outcome measures were subscores for positive and negative symptoms. Effect sizes were calculated from individual studies and combined to standardized mean differences (Hedges's g).. Twenty-nine studies reporting on 15 different augmentations were included. Significant better efficacy than placebo on total symptom severity was observed for lamotrigine, citalopram, sulpiride, and CX516 (a glutamatergic agonist). The positive effect of lamotrigine disappeared after outlier removal. The other positive findings were based on single studies. Significantly better efficacy on positive symptom severity was observed for topiramate and sulpiride. The effect of topiramate disappeared after outlier removal. Results for sulpiride were based on a single randomized controlled trial. Citalopram, sulpiride, and CX516 showed better efficacy for negative symptoms than placebo, all based on single studies.. Evidence for efficacy of clozapine augmentation is currently scarce. Efficacy of lamotrigine and topiramate were both dependent on single studies with deviating findings. The effect of citalopram, sulpiride, and CX516 were based on single studies. Thus, despite their popularity, pharmacological augmentations of clozapine are not (yet) demonstrated to be superior to placebo.

Topics: Antipsychotic Agents; Brief Psychiatric Rating Scale; Citalopram; Clozapine; Dioxoles; Double-Blind Method; Drug Synergism; Drug Therapy, Combination; Fructose; Humans; Lamotrigine; Piperidines; Psychiatric Status Rating Scales; Psychotropic Drugs; Randomized Controlled Trials as Topic; Schizophrenia; Schizophrenic Psychology; Sulpiride; Topiramate; Treatment Outcome; Triazines

Antipsychotic medication remains the mainstay of treatment for schizophrenia and has been in use for a long time. As evidenced by ongoing research and partial effectiveness of the antipsychotics on cognitive and negative symptoms, the search is on for drugs that may improve these domains of functioning for someone suffering from schizophrenia. Acetylcholinesterase inhibitors have long been in use for treating cognitive symptoms of dementia.. The aim of the review was to evaluate the clinical effects, safety and cost effectiveness of acetylcholinesterase inhibitors for treating people with schizophrenia. We searched the Cochrane Schizophrenia Group's Register (February 2009), and inspected the references of all identified studies for further trials.. We included all clinical randomised trials comparing acetylcholinesterase inhibitors with antipsychotics or placebo either alone, or in combination, for schizophrenia and schizophrenia-like psychoses.. We extracted data independently. For dichotomous data, we calculated risk ratios (RR) and their 95% confidence intervals (CI) on an intention-to-treat (ITT) basis based on a random-effects model. For continuous data, we calculated mean differences (MD), again based on a random-effects model.. The acetylcholinesterase inhibitor plus antipsychotic showed benefit over antipsychotic and placebo in the following outcomes.1. Mental state - PANSS negative symptoms average end point score (2 RCTs, n = 31, MD -1.69 95% CI -2.80 to -0.57), PANSS General Psychopathology average end point score (2 RCTs, n = 31, MD -3.86 95% CI -5.40 to -2.32), and improvement in depressive symptoms showed at least by one short-term study as measured by CDSS scale (data skewed).2. Cognitive domains - attention, (1 RCT, n = 73, MD 1.20 95% CI 0.14 to 2.26), visual memory (2 RCTs, n = 48 , MD 1.90 95% CI 0.52 to 3.28), verbal memory and language (3 RCTs, n = 42, MD 3.46 95% CI 0.67 to 6.26) and executive functioning (1 RCT, n = 24, MD 17.10 95% CI 0.70 to 33.50).3. Tolerability - EPSE: AIMS, (1 RCT, n = 35, MD 1.50 95% CI 1.04 to 1.96).No difference was noted between the two arms in other outcomes. The overall rate of participants leaving studies early was low (13.6 %) and showed no clear difference between the two groups.. The results seem to favour the use of acetylcholinesterase inhibitors in combination with antipsychotics on a few domains of mental state and cognition, but because of the various limitations in the studies as mentioned in the main text, the evidence is weak. This review highlights the need for large, independent, well designed, conducted and reported pragmatic randomised studies.

Topics: Antipsychotic Agents; Cholinesterase Inhibitors; Donepezil; Galantamine; Humans; Indans; Phenylcarbamates; Piperidines; Psychotic Disorders; Randomized Controlled Trials as Topic; Rivastigmine; Schizophrenia; Schizophrenic Psychology

Iloperidone is a second-generation "atypical" antipsychotic whose primary mechanism of action is within the subclass of combined D2/5HT2A antagonism. Iloperidone was approved by the FDA in May 2009 for the treatment of schizophrenia. This review is a comprehensive synthesis of the history and clinical trials data leading up to approval, and evaluates iloperidone within the clinical context of how it compares with other available antipsychotics.

Topics: Ambulatory Care; Antipsychotic Agents; Basal Ganglia Diseases; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Approval; Hospitalization; Humans; Isoxazoles; Piperidines; Schizophrenia; Schizophrenic Psychology; Secondary Prevention; Treatment Outcome

Three newer atypical antipsychotic drugs were FDA-approved in 2009 and 2010 in the following order: iloperidone, asenapine and lurasidone. The three drugs are indicated for the treatment of acute schizophrenia. Asenapine is also approved for treatment of manic or mixed episodes associated with bipolar I disorder, for the maintenance treatment of schizophrenia and as an adjunctive therapy with lithium or valproate for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults.. This review compares and contrasts the current preclinical, clinical, safety and tolerability profiles of the three newer drugs, as reported in published preclinical and clinical studies, product labels, poster presentations and press releases.. Preclinical studies have reported that the three drugs have variable affinities for a wide range of neurotransmitter receptors, and are active in animal models predictive of antipsychotic activity. Asenapine is the first antipsychotic to be administered sublingually, whereas iloperidone requires titration to minimize orthostatic hypotension. Asenapine and lurasidone are associated with dose-related akathisia, whereas iloperidone is not. The three drugs appear to have relatively benign metabolic profiles. The availability of the three novel antipsychotics should provide additional options for improved treatment of schizophrenia and other psychotic disorders.

Topics: Adult; Animals; Antipsychotic Agents; Bipolar Disorder; Dibenzocycloheptenes; Drug Approval; Heterocyclic Compounds, 4 or More Rings; Humans; Isoindoles; Isoxazoles; Lurasidone Hydrochloride; Piperidines; Schizophrenia; Thiazoles; United States; United States Food and Drug Administration

The introduction of second-generation antipsychotics (SGAs) over the past 2 decades generated considerable optimism that better antipsychotic treatments for schizophrenia and bipolar disorder were possible. SGAs offer several tolerability benefits over first-generation antipsychotics (FGAs), particularly with respect to extrapyramidal symptoms. However, SGAs can induce serious metabolic dysregulations, especially in drug-naive, first-episode, and child and adolescent populations, with olanzapine and clozapine having the highest propensity to cause these abnormalities. In this context, newer SGAs were developed to further improve the adverse effect burden of available agents. However, until now, the metabolic risk profile of the newly approved SGAs - asenapine, iloperidone, lurasidone and paliperidone (paliperidone extended release and paliperidone palmitate) - has not been compared.. The objective of this systematic review and exploratory meta-analysis was to assess the effects of asenapine, iloperidone, lurasidone and paliperidone on body weight and other metabolic parameters (cholesterol, triglycerides and glucose), as this information is relevant to guide clinical decision making.. A systematic literature search (1966-March 2012), using the Cochrane Central Register of Controlled Trials and MEDLINE, CINAHL and EMBASE databases, was conducted for randomized, placebo-controlled and head-to-head clinical trials of asenapine, iloperidone, lurasidone and paliperidone. Published and unpublished data on changes in body weight and glucose and lipid metabolism parameters were extracted. For placebo-controlled, short-term (≤12 weeks) and longer-term (>12 weeks) trials with available data on ≥7% weight increase compared with pre-treatment weight, or mean weight change with standard deviation, a formal meta-analysis was performed, estimating the pooled effect size (represented as relative risk [RR], numbers-needed-to-harm [NNH] and weighted mean difference [WMD]). An exploratory meta-analysis was also performed for the other metabolic variables (cholesterol, triglycerides and glucose). Data from active- and placebo-controlled studies were used for a pooled comparison of simple mean changes in weight, cholesterol, triglyceride and glucose levels.. Fifty-six trials (n = 21 691) in schizophrenia (N = 49, n = 19 299) or bipolar disorder (N = 7, n = 2392) were identified (asenapine: N = 9, iloperidone: N = 11, lurasidone: N = 8, paliperidone: N = 28). Most of the trials (64.3%) were of ≤12 weeks' duration. In the short-term trials, compared with placebo, a ≥7% weight increase was statistically significantly (p < 0.05) most prevalent for asenapine (5 trials, n = 1360, RR = 4.09, 95% confidence interval [CI] 2.25, 7.43, NNH = 17), followed by iloperidone (4 trials, n = 1931, RR = 3.13, 95% CI 2.08, 4.70, NNH = 11) and paliperidone (12 trials, n = 4087, RR = 2.17, 95% CI 1.64, 2.86, NNH = 20). The effect of lurasidone on body weight (6 trials, n = 1793, RR = 1.42, 95% CI 0.87, 2.29) was not statistically significant. Short-term weight gain was statistically significantly (p < 0.001) greater than placebo with iloperidone (1 trial, n = 300, +2.50 kg, 95% CI 1.92, 3.08), paliperidone (15 trials, n = 3552, +1.24 kg, 95% CI 0.91, 1.57), asenapine (3 trials, n = 751, +1.16 kg, 95% CI 0.83, 1.49), as well as with lurasidone (5 trials, n = 999, +0.49 kg, 95% CI 0.17, 0.81, p < 0.01). Sufficient meta-analysable, longer-term, weight change data were only available for asenapine and paliperidone, showing statistically significantly (p < 0.001) greater weight gain versus placebo for both drugs (asenapine, 3 trials, n = 311, +1.30 kg, 95% CI 0.62, 1.98; paliperidone, 6 trials, n = 1174, +0.50 kg, 95% CI 0.22, 0.78). Although statistically significant, in general, no clinically meaningful differences were observed between the four newly approved SGAs and placebo regarding the mean change from baseline to endpoint in cholesterol levels in short-term trials, with the exception of iloperidone for total cholesterol (1 trial, n = 300, +11.60 mg/dL, 95% CI 4.98, 18.22, p ≤ 0.001), high-density cholesterol (1 trial, n = 300, +3.6 mg/dL, 95% CI 1.58, 5.62, p < 0.001) and low-density cholesterol (1 trial, n = 300, +10.30 mg/dL, 95% CI 4.94, 15.66, p < 0.001) and with the exception of lurasidone for high-density cholesterol (5 trials, n = 1004, +1.50 mg/dL, 95% CI 0.56, 2.44, p < 0.01). Asenapine increased total cholesterol statistically significantly (p < 0.05) during longer-term treatment (1 trial, n = 194, +6.53 mg/dL, 95% CI 1.17, 11.89). Regarding triglycerides, only short-term (3 trials, n = 1152, +1.78 mg/dL, 95% CI 0.40, 3.17, p < 0.01) and longer-term treatment with paliperidone (4 trials, n = 791, -0.20 mg/dL, 95% CI -. While preliminary data suggest the lowest weight gain potential with lurasidone and potentially relevant short-term metabolic effects for asenapine and iloperidone, data are still too sparse to comprehensively evaluate the metabolic safety of the newly approved SGAs. Therefore, there is a clear need for further controlled studies to evaluate whether these agents are less problematic regarding treatment-emergent weight gain and metabolic disturbances than other currently available antipsychotics.

Topics: Antipsychotic Agents; Bipolar Disorder; Blood Glucose; Dibenzocycloheptenes; Heterocyclic Compounds, 4 or More Rings; Humans; Isoindoles; Isoxazoles; Lipid Metabolism; Lurasidone Hydrochloride; Paliperidone Palmitate; Piperidines; Pyrimidines; Randomized Controlled Trials as Topic; Schizophrenia; Thiazoles; Weight Gain

The pharmacology, pharmacokinetics, pharmacogenomics, clinical efficacy, and safety and tolerability profile of iloperidone for the treatment of schizophrenia are reviewed.. Iloperidone is an atypical antipsychotic that recently received marketing approval from the Food and Drug Administration for the acute treatment of schizophrenia. Iloperidone is a pure antagonist and the first antipsychotic to have pharmacogenomic studies indicate predictive response based on six identified polymorphisms. Pharmacokinetic studies have determined that iloperidone is well absorbed orally, with a bioavailability of 96%. Phase II and III clinical trials have shown iloperidone to improve symptoms of schizophrenia, based on the Positive and Negative Symptom Scale, Brief Psychiatric Rating Scale, and Clinical Global Impressions-Severity scores (p < 0.05). Iloperidone has established tolerability at recommended dosages of up to 24 mg daily; however, the dosage must be slowly increased over seven days, and twice-daily administration is required to avoid orthostatic hypotension. The most common adverse effects associated with iloperidone were dizziness, dry mouth, fatigue, nasal congestion, orthostatic hypotension, somnolence, tachycardia, and weight gain. Safety studies have also found that iloperidone increases the risk of Q-Tc interval prolongation, similar to that seen with ziprasidone. Minimal changes in glucose and lipid abnormalities were seen in short-term (4- and 6-week) and long-term (52-week) studies, indicating a low chance of metabolic disturbance with iloperidone.. Iloperidone may be a viable and safe option for the treatment of schizophrenia in adult patients, especially for patients who cannot tolerate other antipsychotic agents. However, iloperidone lacks a clear benefit over other antipsychotic agents.

Topics: Antipsychotic Agents; Drug Administration Schedule; Drug Interactions; Humans; Isoxazoles; Piperidines; Polymorphism, Single Nucleotide; Randomized Controlled Trials as Topic; Schizophrenia

Three new second-generation antipsychotics were approved by the US Food and Drug Administration in 2009 and 2010: iloperidone, asenapine, and lurasidone. All 3 agents are approved for the treatment of acute schizophrenia in adults, and asenapine is also approved for the maintenance treatment of schizophrenia and as a monotherapy or as an adjunct to lithium or valproate for the treatment of bipolar manic or mixed episodes. The expectation is that these new agents will be less problematic regarding treatment-emergent weight gain and metabolic disturbances, which unfortunately can occur with several other second-generation antipsychotics. Asenapine is a sublingual preparation, in contrast to iloperidone and lurasidone, which are swallowed. Iloperidone and asenapine are dosed twice daily, in contrast to lurasidone, which is dosed once daily with food. Both asenapine and lurasidone can be initiated at a dose that is possibly therapeutic, but iloperidone requires 4 days of titration to reach its recommended target dose range. Although both asenapine and lurasidone can be associated with dose-related treatment-emergent akathisia, iloperidone is essentially free of extrapyramidal adverse effects or akathisia throughout its recommended dose range. Sedation and/or somnolence have been reported with each medication. They are the most common adverse events associated with asenapine treatment, and are clearly dose-related for lurasidone. In contrast, no therapeutic dose response for iloperidone, asenapine, or lurasidone is clearly evident from short-term clinical trials. Longer-term and naturalistic studies will be helpful in evaluating these agents and their role in the psychiatric armamentarium.

Topics: Akathisia, Drug-Induced; Antipsychotic Agents; Dibenzocycloheptenes; Heterocyclic Compounds, 4 or More Rings; Humans; Isoindoles; Isoxazoles; Lurasidone Hydrochloride; Piperidines; Schizophrenia; Thiazoles

Iloperidone is a second-generation antipsychotic drug approved in May 2009 by the US Food and Drug Administration (FDA) for the acute treatment of schizophrenia in adults. It is a piperidinyl-benzisoxazole derivative with mixed serotonin (5HT2A) and D2 dopamine antagonist properties.. The purpose of this article was to review the pharmacology, pharmacokinetics, efficacy, safety, and role in treatment for iloperidone in schizophrenia.. Scientific and clinical data were collected through searches of PubMed, ClinicalTrials.gov, International Pharmaceutical Abstracts, and the FDA, using the search term iloperidone, and limited to English-language articles. Reference lists were reviewed for additional publications. Dates included the beginning of the database through 2010. No limits were placed on study design.. In a 4-week Phase III trial, iloperidone 12 mg twice daily lowered the Positive and Negative Syndrome Scale (PANSS) total scores to a significantly greater extent than did placebo (-12 vs -7.1; P < 0.01). The ziprasidone active control also separated from placebo (-12.3 vs -7.1; P < 0.05). A pooled analysis of 3 Phase III trials compared iloperidone in divided doses to placebo. The primary outcome was reduction in PANSS scores. Study 1 included iloperidone 4, 8, or 12 mg/d, haloperidol as an active control, and placebo. The PANSS reduction in the 12 mg/d group was significantly greater at end point versus baseline when compared with placebo (-9.9 vs -4.6; P = 0.047). Study 2 included iloperidone 4 to 8 mg/d or 10 to 16 mg/d, risperidone 4 to 8 mg/d, or placebo. The primary efficacy measure was change from baseline to end point in the Brief Psychiatric Rating Scale (BPRS). Improvement from baseline on all iloperidone doses was significantly greater than with placebo (4-8 mg/d group: -6.2, P = 0.012; 10-16 mg/d group: -7.2, P = 0.001; placebo, -2.5). Study 3 included iloperidone 12 to 16 mg/d, risperidone 6 to 8 mg/d, and placebo. The results on the primary efficacy variable, reduction in the BPRS score, was not significant for the 12 to 16 mg/d group versus placebo (-7.1 vs -5.0; P = 0.09), but was significant for the 20 to 24 mg/d iloperidone group (-8.6 vs -5.0; P = 0.01) and for the risperidone group (-11.5 vs 5.0; P < 0.001). A 52-week maintenance trial included iloperidone versus haloperidol as an active control. The primary efficacy variable was time to relapse. Comparison of mean time to relapse of the 2 arms showed no significant difference. The most common adverse events (AEs) associated with iloperidone were dizziness (5.1%-23.2%), dry mouth (5.2%-10.4%), somnolence (4%-13%), and dyspepsia (4.8%-7.8%). AEs appeared dose related. Prescribing information recommends a starting dosage of 1 mg twice daily and then titrated over 7 days to reach a target dosage of 12 to 24 mg/d. The titration is necessary to reduce the risk of orthostatic hypotension-related dizziness.. Data support that when titrated slowly to a therapeutic dosage, iloperidone is generally well tolerated, has a favorable safety profile, and is an effective treatment option in patients with schizophrenia. Its place in therapy and performance in a typical patient population remain to be established. Slow initial titration and twice-daily dosing are potential disadvantages.

Topics: Adult; Antipsychotic Agents; Clinical Trials as Topic; Humans; Isoxazoles; Piperidines; Schizophrenia; Treatment Outcome

All approved antipsychotic drugs share an affinity for the dopamine 2 (D(2)) receptor; however, these drugs only partially ameliorate the symptoms of schizophrenia. It is, therefore, of paramount importance to identify new treatment strategies for schizophrenia.. Preclinical, clinical and post-mortem studies of the serotonin 5-HT(2A) system in schizophrenia are reviewed. The implications of a combined D(2) and 5-HT(2A) receptor blockade, which is obtained by several current antipsychotic drugs, are discussed, and the rationale for the development of more selective 5-HT(2A) receptor antagonists is evaluated. Moreover, the investigational pipeline of major pharmaceutical companies is examined and an Internet search conducted to identify other pharmaceutical companies investigating 5-HT(2A) receptor antagonists for the treatment of schizophrenia.. 5-HT(2A) receptor antagonists appear to assume an intermediate position by being marginally superior to placebo but inferior to conventional antipsychotic drugs. Three previous 5-HT(2A) receptor antagonists have been discontinued after Phase II or III trials, and available Phase IIa data on the remaining 5-HT(2A) receptor antagonist will need substantial additional validation to be approved as a new treatment strategy against schizophrenia.

Topics: Antipsychotic Agents; Brain; Fluorobenzenes; Humans; Phenols; Piperidines; Positron-Emission Tomography; Receptor, Serotonin, 5-HT2A; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Urea

Iloperidone is a new second-generation (atypical) antipsychotic medication approved for the treatment of schizophrenia in adults. The target dose of 6 mg bid can be achieved in 4 days, with titration recommended to minimize postural hypotension. The maximum recommended dose is 12 mg bid. The tolerability profile of iloperidone is noteworthy in terms of modest weight gain, no medically important changes in lipid and glucose levels, little in the way of prolactin elevation, and absence of extrapyramidal side effects, including akathisia. However, iloperidone can prolong the QTc interval on electrocardiogram. Iloperidone may be best suited for patients who are sensitive to akathisia or who are unable to tolerate the sedation and weight gain that can occur more frequently with other antipsychotics.

Topics: Antipsychotic Agents; Electrocardiography; Heart Rate; Humans; Isoxazoles; Long QT Syndrome; Piperidines; Schizophrenia; Treatment Outcome; Weight Gain

Oral blonanserin (Lonasen) is an atypical antipsychotic agent indicated for use in patients with schizophrenia in Japan and Korea. It is effective in the treatment of patients with schizophrenia, providing short- and long-term efficacy against both the positive and negative symptoms of the disorder in several randomized and noncomparative trials. Notably, in two randomized, double-blind trials of 8 weeks' duration, blonanserin was noninferior to haloperidol or risperidone for primary endpoints, although it appeared to be better than haloperidol in improving negative symptoms. Blonanserin is generally well tolerated and appears to have an acceptable profile in terms of bodyweight gain. Potential tolerability benefits of the drug in short-term trials included fewer extrapyramidal symptoms than haloperidol and fewer reports of prolactin level increases or hyperprolactinaemia than risperidone. Nevertheless, extrapyramidal symptoms and hyperprolactinaemia were among the most common adverse reactions associated with blonanserin in noncomparative long-term studies. Further prospective and long-term comparative studies are required in order to definitively position blonanserin with respect to other antipsychotic agents. In the meantime, available clinical data suggest that blonanserin is an effective and generally well tolerated option for the short-term treatment of schizophrenia and for those requiring longer-term therapy.

Topics: Antipsychotic Agents; Clinical Trials as Topic; Drug Interactions; Humans; Piperazines; Piperidines; Schizophrenia; Schizophrenic Psychology

Delta(9)-Tetrahydrocannabinol (Delta(9)-THC), the principal psychoactive constituent of the Cannabis sativa plant, and other agonists at the central cannabinoid (CB(1)) receptor may induce characteristic psychomotor effects, psychotic reactions and cognitive impairment resembling schizophrenia. These effects of Delta(9)-THC can be reduced in animal and human models of psychopathology by two exogenous cannabinoids, cannabidiol (CBD) and SR141716. CBD is the second most abundant constituent of Cannabis sativa that has weak partial antagonistic properties at the CB(1) receptor. CBD inhibits the reuptake and hydrolysis of anandamide, the most important endogenous CB(1) receptor agonist, and exhibits neuroprotective antioxidant activity. SR141716 is a potent and selective CB(1) receptor antagonist. Since both CBD and SR141716 can reverse many of the biochemical, physiological and behavioural effects of CB(1) receptor agonists, it has been proposed that both CBD and SR141716 have antipsychotic properties. Various experimental studies in animals, healthy human volunteers, and schizophrenic patients support this notion. Moreover, recent studies suggest that cannabinoids such as CBD and SR141716 have a pharmacological profile similar to that of atypical antipsychotic drugs. In this review, both preclinical and clinical studies investigating the potential antipsychotic effects of both CBD and SR141716 are presented together with the possible underlying mechanisms of action.

Topics: Animals; Antipsychotic Agents; Arachidonic Acids; Cannabidiol; Endocannabinoids; Humans; Memory; Piperidines; Polyunsaturated Alkamides; Proto-Oncogene Proteins c-fos; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Schizophrenia; Sensory Gating

The optimal treatment of schizophrenia poses a challenge to develop more effective treatments and safer drugs, to overcome poor compliance, discontinuation and frequent switching with available antipsychotics. Iloperidone is a new dopamine type 2/serotonin type 2A (D(2)/5-HT(2A)) antagonist structurally related to risperidone, expected to give better efficacy with less extrapyramidal symptoms than D(2) receptor antagonist antipsychotics. In double-blind phase III trials iloperidone reduced the symptoms of schizophrenia at oral doses from 12 to 24 mg. It was more effective than placebo in reducing positive and negative syndrome total score and Brief Psychiatric Rating scale scores; it was as effective as haloperidol and risperidone in post-hoc analysis. Its long-term efficacy was equivalent to that of haloperidol. The most common adverse events were dizziness, dry mouth, dyspepsia and somnolence, with few extrapyramidal symptoms and metabolic changes in short- and long-term studies in adults. Akathisia was rare, but prolongation of the corrected QT (QTc) interval was comparable to haloperidol and ziprasidone, which is of particular concern. Further comparative studies are needed to clarify the benefit/risk profile of iloperidone and its role in the treatment of schizophrenia.

Topics: Antipsychotic Agents; Clinical Trials as Topic; Humans; Isoxazoles; Piperidines; Schizophrenia

To review the pharmacology, pharmacokinetics, efficacy, and safety data of iloperidone for the treatment of schizophrenia.. Data were selected by searching Pre-MEDLINE, MEDLINE, and International Pharmaceutical Abstracts (1966-January 2010). Abstracts, scientific posters, and unpublished data provided by the manufacturer in the English language were also assessed.. All published data including pharmacologic, pharmacokinetic, pharmacodynamic, and clinical studies related to iloperidone were considered for inclusion. Selected studies included randomized controlled trials, abstracts, and posters presented at national scientific meetings providing pertinent data.. Iloperidone is a benzisoxazole phenylethanone with a higher affinity for serotonin-2a than dopamine-2 receptors. The recommended therapeutic total daily dose is 12-24 mg divided in 2 doses titrated over 1 week to avoid orthostasis. Acute, 6-week, randomized, placebo-controlled, and active-controlled studies demonstrated iloperidone's efficacy in reducing psychotic symptoms according to changes in the total positive and negative symptom scale (PANSS-T) score from baseline. A long-term maintenance trial demonstrated similar efficacy with haloperidol in preventing time to relapse. Pharmacogenomic studies reported possible single nucleotide polymorphisms related to QT interval prolongation and efficacy with iloperidone. Common adverse effects included dizziness, dry mouth, and sustained orthostasis occurring more frequently with higher doses. Weight gain is possible at any dose. Additionally, studies showed that QTc interval prolongation may be dose related. The incidence of extrapyramidal symptoms appears to be low across all dosage ranges; however, akathisia may be more frequent with higher doses.. Iloperidone demonstrated efficacy in acute exacerbations and long-term maintenance in adults with schizophrenia. Caution may be warranted in elderly patients and patients with cardiac disease, due to orthostasis. Further studies regarding pharmacogenomic testing related to the drug's efficacy and tolerability are needed to justify its routine use in practice.

Topics: Antipsychotic Agents; Humans; Isoxazoles; Piperidines; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome

No existing antipsychotic adequately controls all symptoms associated with schizophrenia. Also, no antipsychotic adequately benefits most patients with this disorder. Finally, the safety and tolerability of each antipsychotic frequently dictate the choice of agent.. The mechanism of action of iloperidone, its efficacy and its safety and tolerability when used to treat patients with schizophrenia.. An appreciation of the potential advantages and disadvantages of iloperidone when used for the treatment of schizophrenia.. Iloperidone is a recent addition to the current group of second-generation antipsychotics. While it may share many qualities with other agents in this class, its unique neuroreceptor signature and adverse-effect profile may prove beneficial in clinical practice.

Topics: Animals; Antipsychotic Agents; Dopamine Antagonists; Drug Approval; Humans; Isoxazoles; Pharmacogenetics; Piperidines; Schizophrenia; Serotonin Antagonists; Treatment Outcome

Visual hallucinations occur in various neurological diseases, but are most prominent in Lewy body dementia, Parkinson's disease and schizophrenia. The lifetime prevalence of visual hallucinations in patients with schizophrenia is much more common than conventionally thought and ranges from 24% to 72%. Cortical acetylcholine (ACh) depletion has been associated with visual hallucinations; the level of depletion being related directly to the severity of the symptoms. Current understanding of neurobiological visual processing and research in diseases with reduced cholinergic function, suggests that AChEI's may prove beneficial in treating visual hallucinations. This offers the potential for targeted drug therapy of clinically symptomatic visual hallucinations in patients with schizophrenia using acetylcholinesterase inhibition.. A systematic review was carried out investigating the evidence for the effects of AChEI's in treating visual hallucinations in Schizophrenia.. No evidence was found relating to the specific role of AChEI's in treating visual hallucinations in this patient group.. Given the use of AChEI's in targeted, symptom specific treatment in other neuropsychiatric disorders, it is surprising to find no related literature in schizophrenia patients. The use of AChEI's in schizophrenia has investigated effects on cognition primarily with non cognitive effects measured more broadly.. We would suggest that more focused research into the effects of AChEI's on positive symptoms of schizophrenia, specifically visual hallucinations, is needed.

Topics: Cholinesterase Inhibitors; Donepezil; Galantamine; Hallucinations; Humans; Indans; Phenylcarbamates; Piperidines; Rivastigmine; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Iloperidone is a recently approved antipsychotic agent indicated for the acute treatment of schizophrenia in adults. Iloperidone is characterized as a serotonin 5-HT(2A) and dopamine D(2) receptor antagonist, which makes its core mechanism of action similar to other second-generation antipsychotic agents. The affinity (or lack thereof) of iloperidone for other receptors (e.g., histamine, muscarinic, α(1)-adrenoceptors, serotonin) results in a unique side effect and perhaps response profile that may make it an additional option for patients who have previously not tolerated or adequately responded to other available agents. Iloperidone has been studied in over 3,200 patients throughout its development. Its efficacy appears to be similar to haloperidol, risperidone and ziprasidone. It appears to be safe with minimal extrapyramidal side effects, weight gain and prolactin elevation. A cautious dosing and titration schedule is recommended at the initiation of therapy due to the potential for orthostatic hypotension and dizziness. Drug interactions through the CYP3A4 and CYP2D6 enzymes, along with the potential for QT prolongation, may influence its use in certain patients. Genetic studies conducted during drug development may facilitate the clinical use of pharmacogenomic tests to aid clinicians in optimizing the risk-benefit ratio of iloperidone. The purpose of this review is to summarize the chemistry, pharmacology and clinical aspects of iloperidone, with the goals of identifying key scientific and clinical issues for its use, as well as assessing the potential utility of iloperidone for the treatment of schizophrenia.

Topics: Animals; Antipsychotic Agents; Drug Interactions; Evidence-Based Medicine; Humans; Isoxazoles; Pharmacogenetics; Piperidines; Precision Medicine; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Iloperidone is a newly commercialized second-generation (atypical) antipsychotic approved for the acute treatment of schizophrenia in adults.. the purpose of this review is to describe the pharmacokinetic profile of iloperidone and its clinical implications in the treatment of schizophrenia. Background information is also provided regarding chemistry, pharmacodynamics, clinical efficacy and safety data, and regulatory affairs.. the reader will have an understanding of the pharmacokinetics and overall metabolism of iloperidone within the context of efficacy and safety.. time to peak plasma concentration occurs in 2 - 4 h but elimination half-life is 18 h for extensive CYP2D6 metabolizers and 33 h for poor CYP2D6 metabolizers, suggesting that once or twice daily dosing would be feasible. Dizziness and/or postural hypotension are the limiting factors for how fast iloperidone can be titrated, and is explained by iloperidone and its metabolites' norepinephrine alpha 1 antagonism. Efficacy of iloperidone appears similar to that for ziprasidone and haloperidol, but iloperidone may be inferior in efficacy to risperidone. Iloperidone can prolong the ECG QT interval. The tolerability profile of iloperidone is noteworthy in terms of modest weight gain, no medically important changes in lipid and glucose, little in the way of prolactin elevation, and an absence of extrapyramidal adverse effects, including akathisia.

Topics: Adult; Animals; Antipsychotic Agents; Cytochrome P-450 CYP2D6; Half-Life; Humans; Isoxazoles; Piperidines; Receptors, Adrenergic, alpha-1; Schizophrenia

The new mixed dopamaine D(2)/serotonin 5-HT(2A) antagonist, Fanapt (iloperidone), was approved by the FDA on May 6th, 2009 for the treatment of schizophrenia in adults.

Topics: Antipsychotic Agents; Clinical Trials, Phase III as Topic; Device Approval; Dopamine Agonists; Humans; Isoxazoles; Piperidines; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; United States; United States Food and Drug Administration

The aim of the study was to describe the efficacy and safety of iloperidone for the treatment of schizophrenia.. The pivotal registration trials were accessed by querying http://www.pubmed.gov, http://www.fda.gov and http://www.clinicaltrials.gov for the search term 'iloperidone'.. Four published primary reports of phase III studies were identified as well as preclinical animal and receptor affinity studies that describe potential mechanisms of action and pharmacogenomic studies that identify potential genetic biomarkers for efficacy and tolerability. Product labelling provided additional data.. Descriptions of the principal results and calculation of number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were extracted from the study reports. Additional safety outcomes subject to NNH analysis were obtained from product labelling.. Iloperidone is a second-generation antipsychotic agent indicated for the acute treatment of schizophrenia in adults. Iloperidone has been evaluated in several double-blind placebo-controlled clinical trials. The oral formulation has demonstrated efficacy in reducing the symptoms of acute schizophrenia at fixed daily doses ranging from 12 to 24 mg. Data reported for categorical definitions of response using the Positive and Negative Syndrome Scale were limited to one study and specifically to rates of achieving a > or = 20% decrease in the positive subscale from baseline; significantly more patients receiving iloperidone 24 mg/day (72%) than placebo (52%) met this criterion, yielding a NNT of five. Iloperidone should be titrated slowly to avoid orthostatic hypotension, potentially delaying the achievement of a therapeutic dose level. There appears to be a dose relationship for adverse events such as dizziness, somnolence and dry mouth; for example NNH vs. placebo for somnolence was 25 for iloperidone 10-16 mg/day and 10 for 20-24 mg/day. There is a possibility of a therapeutic dose response as well. Iloperidone is essentially free of extra-pyramidal side effects. Iloperidone is associated with weight gain comparable with risperidone. Long-term double-blind maintenance studies have demonstrated iloperidone's non-inferiority to haloperidol for relapse prevention. Product labelling includes a warning about the potential for QT interval prolongation. At present there are no efficacy studies available that are powered to directly compare iloperidone with other second-generation antipsychotics. The development of a depot formulation of iloperidone as well as efforts to identify genetic biomarkers for prediction of both efficacy and tolerability are in progress.. Aside from paliperidone, iloperidone is the first new second-generation antipsychotic to be commercialised in the USA since 2002. From the limited registration data, iloperidone appears to be relatively well tolerated once titrated to a therapeutic level and can be a useful option to consider. The development of a depot formulation and potential for genetic biomarkers may make this agent compelling. Further comparisons with other available agents among patients with schizophrenia in the 'real world' are needed.

Topics: Antipsychotic Agents; Clinical Trials, Phase III as Topic; Drug Labeling; Humans; Isoxazoles; Piperidines; Randomized Controlled Trials as Topic; Sample Size; Schizophrenia; Treatment Outcome

Iloperidone is an atypical antipsychotic that is approved for the treatment of adult patients with schizophrenia. In several large (n > 570 per trial), 4- or 6-week, double-blind, multinational, multicentre trials in adult patients with schizophrenia, recommended target dosages of oral iloperidone (6-12 mg twice daily) generally showed better efficacy than placebo, in terms of improvements in Positive and Negative Syndrome Scale (PANSS) total scores or Brief Psychiatric Rating Scale (BPRS) scores (primary endpoints) and also for most secondary endpoints, including PANSS subscale scores. In addition, pharmacogenomic studies identified single nucleotide polymorphisms (SNPs) that were associated with an enhanced response to iloperidone during acute treatment of schizophrenia. More limited data also support the role of these SNPs in enhancing responses to iloperidone during longer-term treatment. In a pooled analysis of three 52-week, double-blind, multinational, multicentre trials (n = 473), iloperidone treatment was shown to be equivalent to that with haloperidol, based on Kaplan-Meier estimates of the time to relapse (primary endpoint). Iloperidone was generally well tolerated and was associated with few extrapyramidal symptoms or changes in metabolic parameters in short- and longer-term clinical trials in adult patients with schizophrenia.

Topics: Humans; Internationality; Isoxazoles; Multicenter Studies as Topic; Piperidines; Randomized Controlled Trials as Topic; Schizophrenia; Schizophrenic Psychology

Schizophrenia is a debilitating condition associated with high morbidity and mortality. While currently available atypical antipsychotic agents have significantly advanced the treatment of schizophrenia, there is still a great unmet need for new, effective and better-tolerated therapies. Iloperidone, a D(2)/5-HT(2) receptor antagonist, has been recently approved by the US FDA for the acute treatment of schizophrenia in adults. Iloperidone has been shown to be effective in the treatment of schizophrenia in four short-term (4-6 weeks) and three long-term (52 weeks) studies with over 3000 patients exposed to treatment. Results also indicated a reassuring safety profile, particularly regarding extrapyramidal symptoms, akathisia and prolactin elevation, with a modest effect on weight gain and no medically important changes in cholesterol, triglycerides and glucose. As other antipsychotics, iloperidone has been shown to prolong the QTc interval. Since none of the current therapies work for every patient, a pharmacogenetic approach was used to identify genetic markers associated with increased response to iloperidone, suggesting a personalized therapeutic option for this drug. In addition, a long-term 4-week injectable formulation is being developed that may assist with patient compliance. Key development findings for iloperidone are presented here.

Topics: Antipsychotic Agents; Brief Psychiatric Rating Scale; Clinical Trials as Topic; Confidence Intervals; Humans; Isoxazoles; Kaplan-Meier Estimate; Longitudinal Studies; Piperidines; Schizophrenia

Pimavanserin tartrate is the first 5-HT(2A) inverse agonist to enter clinical trials as a treatment for L-dopa-induced psychosis in Parkinson's disease and for augmentation of low-dose risperidone treatment in schizophrenia. Pimavanserin is also being evaluated as a possible anti-insomnia drug.. To discuss the potential of pimavanserin to fill multiple therapeutic needs.. The problems with currently approved antipsychotics and sleep agents are explored to highlight how pimavanserin might address some longstanding issues in the treatment of psychosis and insomnia.. In Phase II clinical trials, pimavanserin seemed to be safe, well-tolerated and efficacious in treating L-dopa-induced psychosis without worsening motor symptoms. Pimavanserin also potentiated the therapeutic effects of low-dose risperidone, reduced haloperidol-induced akathisia, and increased slow-wave sleep in older individuals.

Topics: Clinical Trials as Topic; Humans; Molecular Structure; Parkinson Disease; Piperidines; Schizophrenia; Serotonin 5-HT2 Receptor Agonists; Treatment Outcome; Urea

Topics: Animals; Antidepressive Agents, Second-Generation; Cognition Disorders; Dopamine D2 Receptor Antagonists; Double-Blind Method; Drug Discovery; Drug-Related Side Effects and Adverse Reactions; Humans; Piperazines; Piperidines; Randomized Controlled Trials as Topic; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Treatment Outcome

Patients with schizophrenia suffer from cognitive deficits which are important predictors of functional outcome. Alterations such as reduced muscarinic and nicotinic receptors in the central cholinergic system in patients with schizophrenia may contribute to these cognitive impairments. Because such deficits do not respond to neuroleptic treatment, different approaches have been developed regarding pharmacological treatments that enhance central cholinergic transmission, e.g. with acetylcholinesterase inhibitors. In this review the pathophysiology of cognitive impairment in schizophrenia, results of studies using acetylcholinesterase inhibitors (donepezil, rivastigmine, physostigmine, and galantamine), and future research strategies are presented. Till now randomized, placebo-controlled studies exist only for donepezil and rivastigmine, and none could replicate the positive results of previous trials with open designs. More trials with higher numbers of patients are needed, particularly for substances with more complex mechanisms of action (e.g. galantamine).

Topics: Antipsychotic Agents; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Galantamine; Humans; Indans; Phenylcarbamates; Physostigmine; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Iloperidone is a new-generation atypical antipsychotic agent, acting as a serotonin/dopamine (5-HT(2A)/D(2)) antagonist, under development by Vanda Pharmaceuticals for the treatment of schizophrenia, bipolar disorder and other psychiatric conditions. Chemically, iloperidone is a benzisoxazole, like risperidone, and shows a multiple receptor binding profile, sharing this feature with the other atypical antipsychotic agents. Administered orally, the drug is highly bound to plasma proteins and extensively metabolised. Several clinical trials have been carried out, to check efficacy, safety and side effects. In order to introduce iloperidone as an agent for the treatment of schizophrenia, a short overview of the disease and of the most important antipsychotic drugs available or under development will be reported. Iloperidone pharmacokinetics and pharmacodynamics are presented herein, together with an evaluation of clinical safety and efficacy results.

Topics: Animals; Antipsychotic Agents; Clinical Trials as Topic; Drug Design; Drug Evaluation, Preclinical; Humans; Isoxazoles; Marketing; Piperidines; Receptors, Adrenergic; Receptors, Dopamine; Receptors, Serotonin; Schizophrenia; Structure-Activity Relationship

Iloperidone, a mixed D2/5-HT2 antagonist, is currently in clinical development for the treatment of schizophrenia. This article assesses the short-term safety of iloperidone using a pooled analysis of 3 phase 2, short-term acute schizophrenia studies conducted between 1998 and 2002 (N = 1943). Patients exposed to 3 dose ranges of iloperidone, another antipsychotic, or placebo were compared on rates of serious adverse events (SAEs), adverse events (AEs), extrapyramidal symptoms, akathisia, prolactin, weight and metabolic parameters, QTc, and other standard safety parameters. The most common treatment-related AEs observed with iloperidone were dizziness, headache, dry mouth, nausea, and insomnia. Discontinuation due to AEs was 4.8% for iloperidone, 7.6% for haloperidol, 6.2% for risperidone, and 4.8% for placebo. Iloperidone groups showed better overall performance on the Extrapyramidal Symptom Rating Scale and Barnes Akathisia Scale than risperidone or haloperidol groups. Patients taking iloperidone experienced a mild weight increase (range, 1.5-2.1 kg) similar to that of risperidone (1.5 kg), whereas those on haloperidol and placebo showed mean weight loss (-0.1 kg and -0.3 kg, respectively). QTc interval significantly increased across all iloperidone groups (least squares mean change from baseline to end point, 2.9-9.1 msec) and for haloperidol (5.0 msec). No significant QTc changes occurred in the risperidone or placebo groups. Iloperidone was associated with no change from baseline in total cholesterol, mild elevation in serum glucose, and slight decrease in triglycerides. Prolactin levels decreased with iloperidone and increased significantly with risperidone and haloperidol. These short-term trials suggest that iloperidone has a reassuring safety profile in many of the areas that are of potential concern, including relatively low dropout rates because of AEs, low extrapyramidal symptoms, akathisia, and prolactin elevation, and a modest short-term effect on weight gain.

Topics: Adolescent; Adult; Aged; Akathisia, Drug-Induced; Antipsychotic Agents; Basal Ganglia Diseases; Double-Blind Method; Female; Humans; Isoxazoles; Long QT Syndrome; Male; Middle Aged; Patient Dropouts; Piperidines; Prospective Studies; Psychotic Disorders; Randomized Controlled Trials as Topic; Schizophrenia; Weight Gain

This research compared the long-term efficacy and safety of iloperidone with those of haloperidol in individuals with schizophrenia. Data were pooled from 3 prospective multicenter studies, each with 6-week stabilization followed by 46-week double-blind maintenance phases. Patients were randomized to iloperidone 4 to 16 mg/d or haloperidol 5 to 20 mg/d. Patients included in this analysis completed the initial 6-week phase with at least 20% reduction in Positive and Negative Syndrome Scale (PANSS) total score at weeks 4 and 6, had 7-item Clinical Global Impressions of Change (CGI-C) scores less than 4, received 1 or more doses of long-term phase medication, and had 1 or more efficacy/safety assessments during the long-term phase. The primary efficacy variable was time to relapse, defined as a 25% or more increase in PANSS total score, including at least a 10-point change; discontinuation because of lack of efficacy; aggravated psychosis with hospitalization; or 2-point increase in the 7-item CGI-C after week 6. Of 1644 patients randomized and 1326 completing the 6-week phase, 473 (iloperidone, n = 359; haloperidol, n = 114) were included in the long-term efficacy analysis, and 489 (iloperidone, n = 371; haloperidol, n = 118) in the safety analysis. Iloperidone was equivalent to haloperidol in time to relapse. The most common adverse events were insomnia (18.1%), anxiety (10.8%), and schizophrenia aggravated (8.9%) with iloperidone, and insomnia (16.9%), akathisia (14.4%), tremor (12.7%), and muscle rigidity (12.7%) with haloperidol. The Extrapyramidal Symptoms Rating Scale scores improved with iloperidone and worsened with haloperidol. Metabolic changes were minimal for both groups. Mean changes in Fridericia's QT interval correction were 10.3 msec (iloperidone) and 9.4 msec (haloperidol) at end point. Iloperidone demonstrated long-term efficacy equivalent to haloperidol and a favorable long-term safety profile, potentially making this agent a suitable option as maintenance therapy for schizophrenia.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Double-Blind Method; Drug Administration Schedule; Female; Haloperidol; Humans; Isoxazoles; Male; Middle Aged; Piperidines; Prospective Studies; Randomized Controlled Trials as Topic; Schizophrenia

This review discusses the laboratory and clinical research supporting the rationale for the efficacy of donepezil (Aricept USA) in enhancing cognition in autism, Alzheimer disease, Down syndrome, traumatic brain injury, Attention Deficit Hyperactivity Disorder (ADHD), and schizophrenia. While preliminary animal models have shown effective, human studies exclusive of Alzheimer disease are sparse. Although attention and memory are unlikely a sole operation of the cholinergic system, evidence indicates a promising direction for further examination of this hypothesis in autism. Studies that examine changes in operationally defined behaviors and reliable and valid measure of changes in attention and memory are needed.

Topics: Alzheimer Disease; Animals; Attention; Attention Deficit Disorder with Hyperactivity; Autistic Disorder; Brain Injuries; Donepezil; Down Syndrome; Humans; Indans; Learning Disabilities; Memory Disorders; Mental Recall; Nootropic Agents; Piperidines; Schizophrenia; Treatment Outcome

A growing body of evidence suggests that activation of the glutamatergic system, particularly N-methyl-D-aspartate (NMDA) receptor function, may be a viable approach to the treatment of schizophrenia, and potentially other cognitive disorders. The excitotoxicity associated with direct NMDA receptor agonists limits their therapeutic potential, and the glycine modulatory site of the NMDA receptor has received growing interest as a therapeutic target. One approach to enhance NMDA receptor function is to increase the availability of the necessary co-agonist glycine at this modulatory site through inhibition of glycine reuptake from the synapse via glycine transporter-1 (GlyT1). Both preclinical and clinical evidence provide support for this approach, as do recent findings demonstrating the regulation of dopaminergic neurotransmission by GlyT1 inhibition. As a result, several groups have focused on the development of novel GlyT1 inhibitors. In addition, recent electrophysiological findings and data from transgenic mouse models suggest that GlyT1 might also play a role in terminating the actions of glycine at strychnine-sensitive glycine receptors, and therefore GlyT1 antagonists also have potential for the treatment of conditions where activation of inhibitory pathways in the central nervous system might be beneficial.

Topics: Animals; Benzamides; Central Nervous System; Clinical Trials as Topic; Dopamine; Drug Evaluation, Preclinical; Glycine; Glycine Plasma Membrane Transport Proteins; Humans; Neurons; Piperidines; Receptors, N-Methyl-D-Aspartate; Sarcosine; Schizophrenia; Synaptic Transmission

Multiple lines of evidence suggest that a dysfunction in the glutamatergic neurotransmission via the N-methyl-D-aspartate (NMDA) receptors contributes to the pathophysiology of psychiatric diseases including schizophrenia. The potentiation of NMDA receptor function may be a useful approach for the treatment of diseases associated with NMDA receptor hypofunction. One possible strategy is to increase synaptic levels of glycine by blocking the glycine transporter-1 (GlyT-1) in glia cells, since glycine acts as a co-agonist site on the NMDA receptor. In this article, the author reviews the recent important patents on GlyT-1 inhibitors for treatment of schizophrenia and other psychiatric diseases associated with the NMDA receptor hypofunction.

Topics: Animals; Benzamides; Glutamic Acid; Glycine; Glycine Plasma Membrane Transport Proteins; Humans; Piperidines; Schizophrenia

To evaluate the efficacy of glutamatergic drugs, acting agonistically on the N-methyl-D-aspartate (NMDA) or the non-NMDA receptors, in schizophrenia.. All relevant randomized controlled trials of glutamatergic drugs for schizophrenia were obtained from the Cochrane Schizophrenia Group's Register of Trials without any language or year limitations. Trials were classified according to their methodological quality. For binary and continuous data, relative risks and weighted (WMD) or standardized mean differences (SMD) were calculated, respectively.. Eighteen short-term trials with 343 randomized patients were included in the meta-analysis. In all of these trials, glycine, D-serine, D-cycloserine or ampakine CX516 was used to augment antipsychotics. NMDA receptor co-agonists glycine and D-serine are effective in reducing negative symptoms (N = 132, fixed effect model SMD = -0.66, 95% CI -1.02 to -0.29, p = 0.0004) of schizophrenia, the magnitude of the effect is moderate. D-Cycloserine, a partial agonist of NMDA receptors, is less effective towards negative symptoms (N = 119, fixed effect model SMD = -0.11, 95% CI -0.48 to 0.25, p = 0.6). Positive symptoms fail to respond to glutamatergic medication. Available derived data on cognitive functioning do not indicate a significant effect of glycine or D-serine (N = 80, random effect model WMD = -2.79, 95% CI -6.17 to 0.60, p = 0.11).. In the current limited data set, a moderate amelioration of negative symptoms of schizophrenia was found, but no other statistically significant beneficial effects on symptoms of schizophrenia.

Topics: Clozapine; Cycloserine; Dioxoles; Drug Synergism; Drug Therapy, Combination; Excitatory Amino Acid Agents; Glycine; Humans; Hydro-Lyases; Molindone; Piperidines; Schizophrenia

Positive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) modulators enhance glutamate transmission via the AMPA receptor by altering the rate of desensitization; alone they have no intrinsic activity. They are the only class of compounds known that may pharmacologically separate AMPA subtypes.. This manuscript will review preclinical work on positive AMPA modulators, with clinical examples where relevant.. The activity of these compounds appears to be determined by the AMPA receptor subunit composition. Studies have shown that splice variant and/or subunit combinations change the desensitization rate of this receptor. Also, these subunits are heterogeneously expressed across the central nervous system. Therefore, the functional outcome of different positive AMPA modulators could indeed be different. The origins of this pharmacological class come from hippocampal long-term potentiation studies, so quite naturally they were first studied in models of short- and long-term memory (e.g., delayed match to sample, maze performance). In general, these agents were procognitive. However, more recent work with different chemical classes has suggested additional therapeutic effects in models of schizophrenia (e.g., amphetamine locomotor activity), depression (e.g., forced swim test), neuroprotection (e.g., NMDA agonist lesions) and Parkinson's disease (e.g., 6-hydroxydopamine lesion).. In conclusion, positive modulation of AMPA may offer numerous therapeutic avenues for central nervous system drug discovery.

Topics: Alzheimer Disease; Animals; Benzothiadiazines; Cognition; Dioxoles; Humans; Long-Term Potentiation; Memory; Neuroprotective Agents; Piperidines; Protein Subunits; Receptors, AMPA; Schizophrenia

Although current antipsychotic drugs are effective at treating the psychotic (positive) symptoms of schizophrenia, they have one or more serious side effects, including extrapyramidal symptoms, weight gain, cardiovascular liabilities and type II diabetes. However, recent data from clinical trials of selective neurokinin 3 (NK(3)) receptor antagonists in schizophrenia - osanetant and talnetant - have shown significant improvement in positive symptoms, with no major side-effects reported as yet. Here we discuss the preclinical and clinical evidence that indicates that NK(3) receptor antagonists might represent a new approach to the treatment of schizophrenia and possibly other neuropsychiatric disorders.

Topics: Animals; Antipsychotic Agents; Humans; Piperidines; Receptors, Neurokinin-3; Schizophrenia

This article reviews the piperidine derivative, donepezil hydrochloride (E2020, Aricept), a reversible central acetylcholinesterase inhibitor currently approved for treatment of mild-to-moderate Alzheimer's disease. Donepezil is well absorbed orally, unaffected by food or by time of administration; it reaches therapeutic levels in doses of 5-10 mg/day and peak plasma concentrations are obtained 3-4 h after oral administration. A single bedtime dose is recommended due to the long elimination half-life of the drug (70 h). Donepezil does not cause liver toxicity or significant drug interactions and is relatively well-tolerated. Initial side effects include nausea, vomiting, diarrhoea, insomnia, muscle cramps, fatigue, anorexia and syncope. Caution is advised in patients with bradycardia. Long-term use of donepezil in AD has been found to delay nursing-home placement and to result in caregiver respite. Donepezil also slows deterioration of cognition and global function in patients with moderate-to-severe AD, with improvement of abnormal behaviours. In addition to AD, donepezil demonstrates significant improvement in cognition, global function and activities of daily living in comparison with placebo-treated patients with vascular dementia and has potential therapeutic benefit for other neurological conditions.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Dementia, Vascular; Donepezil; Dose-Response Relationship, Drug; Humans; Indans; Piperidines; Psychiatric Status Rating Scales; Receptors, Cholinergic; Schizophrenia

The first part of the present review describes the exciting journey of dopamine stabilizers, starting in the early eighties with the development of the partial dopamine agonist (-)-3-PPP of phenylpiperidine structure, via various compounds with aminotetraline structure with preferential autoreceptor antagonist properties, and then back again to phenylpiperidine compounds carrying substituents on the aromatic ring that transformed them from partial dopamine agonists to partial dopamine receptor antagonists, such as OSU6162. OSU6162 was brought to the clinic and has in preliminary trials showed antidyskinetic and antipsychotic efficacy. The second part of this review describes results from a hypoglutamatergia mouse model for cognitive symptoms of schizophrenia, where we have tested traditional neuroleptics, new generation antipsychotics with marked 5-HT2 vs dopamine D2 receptor blockade as well as a dopamine stabilizer belonging to the partial dopamine receptor antagonist category.

Topics: Animals; Antipsychotic Agents; Aripiprazole; Disease Models, Animal; Dopamine; Dopamine Agonists; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Glutamic Acid; Mice; Piperazines; Piperidines; Quinolones; Schizophrenia

Schizophrenia is a serious and disabling psychiatric disorder affecting approximately 1% of the world's population. A new generation of atypical antipsychotics has been introduced over the past decade. These atypical antipsychotics have comparable or greater efficacy than traditional antipsychotics in the treatment of the psychotic symptoms of schizophrenia and a much improved neurologic side effect profile. This paper reviews the pharmacological efficacy and safety of a potential atypical antipsychotic, NRA0562. NRA0562 has a high affinity for dopamine D1, D2L, D4.2, 5-HT2A receptors as well as alpha1-adrenoceptors, and has a moderate affinity for H1 receptors. NRA0562 strongly binds to 5-HT2A receptors and alpha1-adrenoceptors in the frontal cortex, its binding to striatal D2 receptors is weaker, similar to that of clozapine. NRA562 displayed potent antipsychotic activities in animal models of schizophrenia, such as methamphetamine (MAP)-induced hyperactivity, apomorphine-induced disruption of pre-pulse inhibition and conditioned avoidance test. NRA0562 is more potent in reversing the inhibitory effects of MAP at A10 than at A9 dopamine neurons. It increased Fos-like immunoreactivity in the nucleus accumbens more effectively than in the dorsolateral striatum, indicating that NRA0562 has the profile of an atypical antipsychotic. In vivo assays for extrapyramidal side effect liability showed that NRA0562 has a low rate of neurological side effects. Thus, NRA0562 may have unique antipsychotic activity with a lower propensity for extrapyramidal side effects.

Topics: Animals; Antipsychotic Agents; Brain; Dopamine Antagonists; Humans; Methamphetamine; Motor Activity; Neuropharmacology; Piperidines; Receptors, Dopamine; Schizophrenia; Serotonin Antagonists; Thiazoles

There is a consensus that current treatments of schizophrenia do not offer satisfactory efficacy for negative and cognitive symptoms. Recently, the dopaminergic hyperfunction hypothesis of schizophrenia has been enriched by the addition of the glutamatergic hypofunction concept. Accordingly, agents enhancing glutamatergic transmission should provide benefit in psychosis. In fact, some preclinical studies suggest that positive modulators of alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) receptors, previously developed mainly for dementia, may fulfill such expectations. These agents attenuate various biochemical or behavioral effects produced by amphetamine or methamphetamine and enhance the action of antipsychotics. More importantly, preliminary clinical studies with the most advanced member of this class, CX-516(Cortex Pharmaceuticals Inc), indicate beneficial action on negative and cognitive symptoms as an add-on treatment t o clozapine. If these observations are confirmed in a larger scale clinical trial, this approach could be a major improvement in the treatment of schizophrenia.

Topics: Animals; Clinical Trials as Topic; Dioxoles; Drug Industry; Excitatory Amino Acid Agonists; Humans; Piperidines; Receptors, AMPA; Schizophrenia

The early demonstration of chlorpromazine efficacy in schizophrenia and its subsequent identification as a dopamine receptor antagonist, established the only known mechanism for antipsychotic development to date. By extension, it is easy to hypothesize that any mechanism shown to reduce dopamine-mediated transmission in brain will have antipsychotic properties. The evaluation of partial dopamine agonists for antipsychotic efficacy and their application in the treatment of psychosis has derived from this background. Partial dopamine agonists at the D2 dopamine receptor, have high affinity for that receptor, but reduced intrinsic activity. These agonists have higher affinity for the presynaptic autoreceptor than for the postsynaptic receptor. Hence, these compounds reduce dopamine synthesis and release through an agonist action at the dopamine autoreceptor. Moreover, the agonists have lower intrinsic activity at the postsynaptic receptor than its natural ligand dopamine. Therefore, they diminish the dopaminergic signal at postsynaptic sites as well through delivering a reduced message; this component of drug action becomes more prominent the lower the intrinsic activity of the drug. Several partial dopamine agonists have been evaluated in schizophrenia. One of them, aripiprazole, is nearing approval for marketing. With partial dopamine agonist treatment, advantages should accrue to schizophrenia treatment in the areas of affect control and cognitive performance.

Topics: Animals; Dopamine Agonists; Humans; Piperidines; Psychotic Disorders; Receptors, Dopamine; Schizophrenia

Innovation in atypical antipsychotic agents continues with new preparations of available drugs as well as novel agents. In this article, we provide an update on these novel products by reviewing information from a computerised literature search, recent abstracts and discussions with industry representatives. A generic formulation of clozapine is now available. It may be less well absorbed and/or less effective than Clozaril, although evidence is conflicting. A fatty acid amide derivative of clozapine is in early development. A liquid formulation of risperidone is currently available, which may be a useful treatment for psychotic agitation as well as a preferable alternative to tablets for some patients. A depot formulation is in development for the long-term management of psychosis. An orally disintegrating tablet formulation of olanzepine is a useful alternative to standard tablets. A short-acting injectable formulation of the drug is in development for psychotic agitation. Sachets and slow-release formulations of quetiapine are in development. Ziprasidone, a recently launched agent, is available in tablet form for schizophrenia/schizoaffective disorder, psychotic depression and mania. A short-acting injectable formulation is in development for psychotic agitation. Aripiprazole (tablets) and iloperidone (tablets and depot injection) are two antipsychotics in development for schizophrenia/schizoaffective disorder (available information regarding iloperidone is very limited). These new formulations and agents should broaden options for the treatment of psychosis.

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clinical Trials as Topic; Clozapine; Dosage Forms; Humans; Isoxazoles; Olanzapine; Piperazines; Piperidines; Pirenzepine; Quinolones; Risperidone; Schizophrenia; Thiazoles

Osanetant is a neurokinin (NK3) receptor antagonist under development by Sanofi-Synthélabo (formerly Sanofi) as a potential treatment for schizophrenia [328910]. Sanofi was originally investigating its potential use as a treatment for psychosis and anxiety [169511]. Following phase IIa clinical trials [307656], [328910], [359231], osanetant entered phase IIb development in February 2001 [409432]. Osanetant was the first potent and selective non-peptide antagonist described for the NK3 tachykinin receptor [176305]. It has a higher affinity for human and guinea pig NK3 receptors than for rat NK3 receptors [176305]. In October 1999, Lehman Brothers predicted that the probability of the product reaching the market was 10%, with a possible launch in 2003 and potential peak sales of US $200 million in 2011 [346267].

Topics: Acetylcholine; Animals; Antipsychotic Agents; Brain; Cardiovascular System; Dopamine; Humans; Piperidines; Receptors, Neurokinin-3; Schizophrenia; Stereoisomerism; Structure-Activity Relationship; Tachykinins

Iloperidone (Novartis' Zomariltrade mark) is an atypical antipsychotic agent for the treatment of schizophrenia. Current trends in the treatment of schizophrenia indicate that some atypical antipsychotics are being recommended as first-line therapy. Atypical antipsychotics, in addition to being dopamine (D) receptor antagonists, are all relatively potent serotonin (5-HT) receptor antagonists and are less likely than conventional dopamine antagonists to induce movement disorders. However, all of these agents differ in their receptor profiles and clinical profiles. Iloperidone, a benzisoxazole, is a mixed 5-HT(2A)/D(2)antagonist. Iloperidone was found to be more potent than its analogues when compared with haloperidol in antagonising climbing behaviour in mice. Iloperidone is extensively metabolised and the main circulating metabolite is reduced iloperidone. In patients treated with iloperidone, a low incidence of extrapyramidal symptoms and weight gain has been shown. Data from Phase II trials demonstrated efficacy in patients at doses of 8 mg/day and tolerability was good up to 32 mg/day. Phase III prospective, double-blind, randomised trials with iloperidone are in progress under the ZEUS (Zomariltrade mark Efficacy Utility and Safety) programme involving 3300 patients. Iloperidone, with a balance of activity at the dopaminergic and serotonergic receptors, has obvious advantages over clozapine and olanzapine, both of which have a similar receptor profile as they favour serotonergic over dopamine receptors. Iloperidone is likely to reach the market in 2001 and has favourable prospects in the atypical antipsychotic market for schizophrenia, which is expanding from US$ 1.5 billion in 2000 to US$ 3 billion in 2005.

Topics: Animals; Antipsychotic Agents; Clinical Trials as Topic; Humans; Isoxazoles; Piperidines; Schizophrenia

Antipsychotic drug development has been a slow process since the discovery of chlorpromazine more than 45 years ago. Researchers identify a large number of potential compounds; screen them for antipsychotic activity in in vitro and animal test models; devise appropriate formulations; perform preclinical pharmacology, pharmacokinetic, and toxicology studies; perform healthy volunteer and then patient clinical studies; and finally negotiate with regulatory agencies for drug approval. In the United States, this process takes an average of 10 to 12 years and costs more than $500 million per approved drug. More recently, the pharmaceutical industry is benefiting from a new wave of technologic innovations that have advanced our understanding of the biology of disease processes and increased the efficiency of the research and development process. However, while these new technologies may appear to be expensive, by providing the basis for early go/no-go decisions, technologies such as PET can actually be cost-effective. To ensure that innovative drug research continues, a practical strategy (rational drug design) to evaluate drugs more efficiently in terms of both time and cost (fewer studies with fewer patients) must be developed for each new drug candidate. One of the most important and difficult steps in the drug development process is defining the dose-response relationship. Using M100907 as an example, we demonstrated that mechanism-based research promotes cost-effective drug development. The therapeutic index of M100907 was defined in phase I single- and multiple-dose tolerability studies. Nuclear imaging using PET technology was then used to confirm the mechanism of action of M100907 in the target organ (living human brain) and to target an appropriate dose range and regimen. With these data, clear go/no-go decision points could be established early within the clinical drug development process, and the selection of M100907 doses to carry forward into large-scale clinical trials in patients with schizophrenia could be narrowed.

Topics: Antipsychotic Agents; Brain Chemistry; Clinical Trials as Topic; Dopamine; Fluorobenzenes; Humans; Piperidines; Schizophrenia; Serotonin Antagonists; Technology, Pharmaceutical; Tomography, Emission-Computed

Serotonin-dopamine antagonists (SDAs) offer the possibility of improved treatment of schizophrenia compared with conventional neuroleptics and have superior safety profiles. Clinical trial data have so far been published for only three SDAs to date, namely, risperidone, sertindole, and olanzapine. Of these, extensive data are available only for risperidone, showing that at doses of 4 to 16 mg/day, it is superior to haloperidol at 10 to 20 mg/day. Furthermore, risperidone, 6 and 16 mg/day, significantly improved negative/symptoms, whereas 20 mg/day of haloperidol was ineffective. Risperidone also appears to cause fewer extrapyrimidal symptoms (EPS) than haloperidol, 10 or 20 mg/day. Similar advantages of risperidone over perphenazine have also been found. A clinical trial of sertindole showed that, at 20 mg/day, it was equivalent to haloperidol, 16 mg/day, and caused fewer EPS. Olanzapine, a chemical derivative of clozapine, has also been shown to be superior to haloperidol (10 to 20 mg/day) at doses of 7.5 to 17.5 mg/day. In addition, at doses of 12.5 to 17.5 mg/day, olanzapine was found to have a significantly superior effect on negative symptoms over haloperidol, 10 to 20 mg/day. Doses of up to 17.5 mg/day of olanzapine also caused fewer EPS than haloperidol, 10 to 20 mg/day. There was no evidence of any leukopenia in patients treated with olanzapine in this small study (N = 335). The low EPS liability of these SDAs, combined with their efficacy, suggests that SDAs should become the mainstay of treatment for schizophrenia.

Topics: Antipsychotic Agents; Benzodiazepines; Clinical Trials as Topic; Dopamine Antagonists; Humans; Imidazoles; Indoles; Isoxazoles; Olanzapine; Piperidines; Pirenzepine; Risperidone; Schizophrenia; Serotonin Antagonists

The clinical use of clozapine and risperidone is reviewed. Traditional antipsychotic drugs are effective for treating the positive symptoms of schizophrenia but have little or no effect on the negative symptoms of this disease. Newer antipsychotic agents, such as clozapine and risperidone, are effective for treating both positive and negative symptoms in acutely ill and treatment-resistant patients. Clozapine and risperidone also have a lower incidence of extrapyramidal symptoms (EPS) than traditional antipsychotic drugs. Three hypotheses have been proposed to account for the newer agents' ability to relieve negative symptoms: (1) Improvement in negative symptoms may be linked to improvement in positive symptoms. (2) Negative symptoms may improve in the absence of the EPS often caused by traditional agents. (3) The newer antipsychotic agents may directly affect the neural circuits that trigger negative symptoms.

Topics: Adult; Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Female; Formularies as Topic; Haloperidol; Humans; Isoxazoles; Male; Middle Aged; Piperidines; Risperidone; Schizophrenia

The atypical antipsychotic risperidone combines dopaminergic and serotonergic antagonism. This results in a drug that is both clinically effective, reducing positive and negative symptoms of schizophrenia, and has a low incidence of adverse effects. At a dosage of 4 to 8 mg/day, risperidone is comparable to 10 mg/day of haloperidol. This dosage has a low incidence of extrapyramidal adverse effects and is nonsedative, although it may cause orthostatic hypotension. There is no current evidence for specific biochemical and haematological abnormalities associated with risperidone. Although the clinical benefits appear to outweigh the risks, this drug continues to be a relatively expensive treatment option in the UK. There is therefore a need for a formal cost-utility assessment of risperidone and for comparisons between this drug and other atypical neuroleptics.

Topics: Antipsychotic Agents; Humans; Isoxazoles; Piperidines; Risk; Risperidone; Schizophrenia

A rapidly growing body of data suggests that dysfunction in serotonergic (5-HT) function may be involved in the pathophysiology of schizophrenia, and that pharmacologic agents for this illness have their therapeutic effects mediated through serotonergic mechanisms. The purpose of this paper is to critically review data relevant to 5-HT's role in the pathophysiology and drug treatment of schizophrenia. Pathophysiologic evidence includes the psychotomimetic effects of lysergic acid (LSD), postmortem studies, single-dose 'challenge' studies and investigations of CSF and peripheral levels of 5-HT and its metabolites. The current nomenclature, potential therapeutic effects and importance of 5-HT receptor subtype antagonism will be examined. In addition, relatively novel strategies of 5-HT uptake blockade and direct acting 5-HT agonists will be assessed. A hypothesis of cortical-subcortical imbalance with an increase in subcortical 5-HT function responsible for positive symptoms and a decrease in prefrontal 5-HT function responsible for negative symptoms is proposed. Future implications of these data are discussed.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Humans; Isoxazoles; Piperazines; Piperidines; Risperidone; Schizophrenia; Serotonin; Tryptophan

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Humans; Isoxazoles; Piperidines; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Serotonin; Risperidone; Schizophrenia

Many conflicts in the literature about negative symptoms arise because different authors use different definitions of negative symptoms. If narrow definitions are used, it appears that drugs have little effect against negative symptoms, although those who use broader definitions tend to conclude that negative symptoms do respond to drugs. Another complication is that negative symptoms may be secondary to other causes, such as psychotic symptoms, the side effects of drugs, depression and understimulation as a result of hospitalisation. Attempting to measure drug effects on negative symptoms can be complicated by such factors as different co-medication in the test and control groups and different pharmacological profiles of test and standard drugs, in particular in terms of extrapyramidal side effects or antidepressant effects. Several approaches to dissecting the direct effect of drugs from their indirect effects on negative symptoms have included analyses of covariance, regression analyses and path analyses. Applying path analysis to the data from the North American clinical trial of risperidone suggests that a significant component of the advantageous effect of risperidone on negative symptoms, compared with haloperidol, is due to a direct effect that cannot be accounted for by the effect of risperidone on positive symptoms and its superior side-effect profile. Although it is possible to analyse studies retrospectively in this way, the best approach is probably to design future clinical trials so that the effects of drugs on negative symptoms are more easily determined than has been the case in the past.

Topics: Affective Symptoms; Antipsychotic Agents; Haloperidol; Humans; Isoxazoles; Piperidines; Psychiatric Status Rating Scales; Psychometrics; Risperidone; Schizophrenia; Schizophrenic Psychology

Negative symptoms in schizophrenia comprise a psychopathologic and pathophysiologic syndrome which is absent from normal mental function. Renewed interest in negative symptoms has led to the development of better measuring instruments, among which is the Positive And Negative Syndrome Scale (PANSS), which provides a way of measuring and reporting positive and negative symptoms in a balanced and convenient form. A number of strategies are being investigated for treating negative symptoms. Dopamine agonists such as levodopa, amphetamines and bromocriptine have been shown to produce improvements in negative symptoms, although good, well-controlled clinical trials are lacking. Partial dopamine agonists, such as MAR 327, are also currently under investigation and results are expected soon. Tricyclic, selective serotonin reuptake inhibitors and monoamine oxidase antidepressants appear to be able to modify negative symptoms in schizophrenia, although, once again, carefully designed trials are needed. Modification of GABAergic transmission has shown little promise, but the use of glycine to augment transmission at N-methyl-D-aspartate (NMDA) synapses suggests that the strategy may be beneficial. These results also imply that altered glutamate receptor function may be partly responsible for negative symptoms. One strategy that has been shown to have a beneficial effect against negative symptoms is combined serotonin/dopamine antagonism. Clozapine was found to have this profile after its introduction, and the recently introduced antipsychotic, risperidone was developed intentionally to be a combined 5-HT2/D2 antagonist. Both risperidone and clozapine have been shown to be effective against negative symptoms. One problem associated with the assessment of drug effects on negative symptoms, however, is that drugs can act on both primary and secondary negative symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Affective Symptoms; Antipsychotic Agents; Clozapine; Humans; Isoxazoles; Piperidines; Psychiatric Status Rating Scales; Psychometrics; Risperidone; Schizophrenia; Schizophrenic Psychology; Syndrome

Mood disorders in schizophrenia are common and are associated with a poor outcome, an increased risk of relapse and a high rate of suicide. Consequently, treatment strategies need to take mood disorders into account. In depressed and actively psychotic schizophrenic and schizoaffective patients, treatment with neuroleptic plus antidepressant may be less effective than neuroleptic alone. However, patients with post-psychotic depression on maintenance neuroleptics respond well to tricyclic antidepressants. Mood disorders can be caused by neuroleptics and if so will often improve if the dose is reduced or if the drug is changed. Anticholinergics may also help. In schizoaffective disorder, lithium is usually beneficial, especially for patients with classical affective disorder. Carbamazepine may be more effective in patients with schizoaffective and schizophreniform disorders. At doses comparable with those effective in schizophrenia, clozapine may be as good or better than conventional neuroleptics in schizophrenic patients with psychotic mood disorder or schizoaffective disorder. In patients with high BPRS anxiety/depression scores, risperidone (8 mg/day) was more effective than haloperidol (10 mg/day). Risperidone at a mean dose of 8.6 mg/day was also more effective than haloperidol (mean dose 9.2 mg/day) or levomepromazine (methotrimeprazine -- mean dose 125 mg/day) on the Psychotic Anxiety Scale. Mood-related symptoms are therefore amenable to treatment. Risperidone and clozapine appear to be good candidates for the long-term treatment of mood disorders in schizophrenia, although long-term, double-blind, controlled studies are needed to confirm this.

Topics: Affective Symptoms; Antidepressive Agents; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Humans; Isoxazoles; Lithium; Long-Term Care; Piperidines; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology

At the end of the last century, Hughlings-Jackson suggested that positive and negative syndromes should be kept apart in psychotic disorders. When the concepts of dementia praecox and schizophrenia were introduced by Kraepelin and Bleuler, emphasis was laid on the negative symptoms, regarded as fundamental. After the introduction of the "first rank symptoms" by Schneider emphasis switched to the positive symptoms in schizophrenia and these symptoms were included in most diagnostic criteria. In the 1980s Andreasen and Crow suggested a dichotomy into positive and negative syndromes in schizophrenia. Kay and co-workers introduced a Positive And Negative Syndrome Scale (PANSS) for schizophrenia. In the original studies satisfactory construct validity and inter-rater reliability were demonstrated. However, in studies outside the USA a high construct validity was found for the negative scales but not for the positive and general psychopathology scales. Furthermore, the inter-rater reliability of the negative scale was a problem. After introduction of the Structured Clinical Interview for the PANSS (SCI-PANSS) the inter-rater reliability increased for all three scales. In an early study Kay and Sevy found seven factors in a principal component analysis of the PANSS and suggested a four factor pyramidical model. Later principal component analyses by Lepine, Peralta et al. and Kawasaki et al. suggested that the four factor model was an oversimplification and Lindström and von Knorring suggested a five factor pyramidical model. A similar model was later suggested by Bell et al. after a reanalysis of the original series of Kay and Sevy.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Affective Symptoms; Antipsychotic Agents; Humans; Isoxazoles; Piperidines; Psychiatric Status Rating Scales; Psychometrics; Reproducibility of Results; Risperidone; Schizophrenia; Schizophrenic Psychology; Syndrome

Antipsychotic medication remains the mainstay of both acute and long-term treatment for schizophrenia. Recent research has underscored the need for optimum dosing strategies. Relatively few patients benefit from high doses (e.g. greater than 15-20 mg per day of haloperidol or 500-800 mg/day of chlorpromazine). In poor or partial responders clozapine continues to be the treatment of choice. Risperidone is an effective antipsychotic with a good safety profile. Its potential advantages in terms of efficacy need to be further studied. An expanded data base from maintenance trials supports the use of continuing maintenance medication and provides guidelines for dosage requirements.

Topics: Antipsychotic Agents; Clozapine; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Isoxazoles; Piperidines; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology

To review pharmacologic, pharmacokinetic, therapeutic, and safety information for the antipsychotic agent risperidone and to evaluate its place in the treatment of schizophrenia.. MEDLINE and Exerpta Medica databases; Janssen Pharmaceuticals; Food and Drug Administration Psychopharmacology Advisory Committee; PJB Publications; published articles and abstracts; unpublished research reports and abstracts.. In vivo animal studies (pharmacology); volunteer studies (pharmacokinetics); clinical case reports, open clinical studies, and controlled clinical studies (clinical efficacy and adverse effects; long-term studies; studies in special populations.. Relevant data were extracted from published and unpublished source documents, evaluated, and summarized in tables for comparative review. Abstracts were used in 6 of 8 pharmacokinetic studies, 4 of 8 open clinical studies, and 2 of 9 controlled clinical studies. Use of abstracts limits the extent of data extracted.. Risperidone is an effective treatment for positive symptoms of schizophrenia and may be effective for negative symptoms. Efficacy in treatment-resistant patients is inconclusive. In patients in whom low-to-moderate dosage is effective, there should be fewer and less severe adverse effects with risperidone than with haloperidol. Optimal dosage for schizophrenia appears to be 6 mg/d. Although data are limited, risperidone may be toxic on overdose.. Risperidone is a useful addition to the antipsychotic drug armamentarium, but it should be viewed as an atypical antipsychotic agent. It is reasonable to consider a trial of risperidone in treatment-resistant schizophrenic patients prior to the use of clozapine and as a first-line treatment for newly diagnosed patients with schizophrenia.

Topics: Antipsychotic Agents; Clinical Trials as Topic; Controlled Clinical Trials as Topic; Humans; Isoxazoles; Piperidines; Risperidone; Schizophrenia

Topics: Antipsychotic Agents; Behavior Therapy; Clozapine; Cognitive Behavioral Therapy; Family Therapy; Humans; Isoxazoles; Piperidines; Psychotherapy; Rehabilitation, Vocational; Risperidone; Schizophrenia

Topics: Antipsychotic Agents; Drug Interactions; Humans; Isoxazoles; Piperidines; Risperidone; Schizophrenia

Topics: Antipsychotic Agents; Brain; Clozapine; Dyskinesia, Drug-Induced; Extrapyramidal Tracts; Humans; Isoxazoles; Piperidines; Psychiatric Status Rating Scales; Receptors, Dopamine; Receptors, Serotonin; Remoxipride; Risperidone; Schizophrenia; Schizophrenic Psychology

Topics: Antipsychotic Agents; Drug Approval; Humans; Isoxazoles; Piperidines; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

The effectiveness of conventional neuroleptics in schizophrenia is often limited by extrapyramidal side effects (EPS), which are known to contribute to poor compliance and relapse. However, there is now evidence that drugs that block 5-HT2 receptors as well as D2 receptors have better EPS profiles. Risperidone has these pharmacologic properties. In two large clinical trials, risperidone (2, 6, 10, 16 mg/day or 4, 8, 12, 16 mg/day) was compared with either placebo and haloperidol (20 mg/day) or risperidone (1 mg/day) and haloperidol (10 mg/day). Extrapyramidal side effects were assessed using the Extrapyramidal Symptom Rating Scale and by recording the use of anticholinergic medication. Other adverse effects were assessed using the UKU Side Effects Scale. In both studies, the severity of EPS in the risperidone groups was significantly less than in the haloperidol group. In the placebo-controlled study, doses of 2 and 6 mg/day of risperidone produced no worse EPS than placebo. Other side effects were minor, and included brief hypotension (mediated via alpha-blockade) and weight gain. Overall, risperidone at antipsychotic doses was better tolerated than haloperidol.

Topics: Akathisia, Drug-Induced; Antipsychotic Agents; Clinical Trials as Topic; Dyskinesia, Drug-Induced; Dystonia; Haloperidol; Humans; Isoxazoles; Piperidines; Risperidone; Schizophrenia

Clozapine has proved effective in alleviating a wide range of psychiatric symptoms in schizophrenia. Its effects on cognitive function in schizophrenia are more variable. Clozapine appears to have a salutary effect on some aspects of attention, response speed, and fluency, whereas it appears to have a mild but adverse effect on visual memory and some executive functions. This profile may be related to the affinity of clozapine for dopaminergic type I and muscarinic receptors and relative lack of affinity for dopaminergic type II receptors.

Topics: Clozapine; Cognition; Cognition Disorders; Dopamine; Humans; Isoxazoles; Neuropsychological Tests; Piperidines; Receptors, Dopamine; Receptors, Muscarinic; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Risperidone, a benzisoxazol derivative, is a novel antipsychotic agent which combines potent serotonin (5-hydroxytryptamine) 5-HT2 and dopamine D2 receptor antagonism. Development of the drug was stimulated by reports that the selective serotonin 5-HT2 antagonist ritanserin improved the negative symptoms of schizophrenia and decreased extrapyramidal symptoms when combined with haloperidol. The relatively low incidence of extrapyramidal symptoms with risperidone may reflect a preferential action on mesolimbic rather than nigrostriatal dopaminergic pathways. Recent clinical investigation suggests that risperidone is of at least comparable efficacy to haloperidol and perphenazine in improving the symptoms of acute and chronic schizophrenia on short term administration. Advantages offered by risperidone over haloperidol include a faster onset of antipsychotic action, a lower incidence of extrapyramidal effects and possibly greater efficacy against the negative symptoms of schizophrenia. If these benefits prove to be maintained during long term therapy, risperidone is likely to make a significant contribution to the treatment of schizophrenia.

Topics: Absorption; Adult; Aged; Aging; Animals; Antipsychotic Agents; Central Nervous System; Cross-Over Studies; Disease Models, Animal; Drug Interactions; Hemodynamics; Humans; Isoxazoles; Neurosecretory Systems; Piperidines; Risperidone; Schizophrenia; Synaptic Transmission; Tissue Distribution

Risperidone, a novel antipsychotic with high binding affinity for serotonin 5-HT2 and a lesser affinity for dopamine D2 receptors, is described and clinical studies are reviewed. In two large-scale trials in North America and Europe, risperidone 6 mg and 4 mg to 8 mg/day compared favourably with haloperidol 20 mg or 10 mg/day in controlling the positive symptoms of schizophrenia. In the North American trial, risperidone produced a significant improvement in negative symptoms; no comparable improvement was reported among haloperidol-treated patients. Risperidone would, thus, appear to offer a potential advantage over other neuroleptics, although the place of this new compound in the pharmacological armamentarium of schizophrenia must be clarified in clinical practice.

Topics: Antipsychotic Agents; Brain; Clinical Trials as Topic; Humans; Isoxazoles; Piperidines; Psychiatric Status Rating Scales; Receptors, Dopamine D2; Receptors, Serotonin; Risperidone; Schizophrenia; Schizophrenic Psychology

The assessment and clinical characterization of the negative symptoms of schizophrenia are reviewed. While negative symptoms may be secondary to positive symptoms, extrapyramidal side-effects, depressive illness, chronic institutionalization or other factors, they may also be primary, i.e., integral to the disease process itself. Recent literature has suggested that negative symptoms may represent a distinct pathophysiological process mediated in part by serotonergic mechanisms. Atypical neuroleptics, which have dual effects on D2/5-HT2 receptors, have demonstrated clinical efficacy on both negative and positive symptoms of schizophrenia, and might help to clarify the pathogenesis of these symptom clusters.

Topics: Antipsychotic Agents; Brain; Depression; Dose-Response Relationship, Drug; Humans; Isoxazoles; Piperidines; Psychiatric Status Rating Scales; Receptors, Dopamine D2; Receptors, Serotonin; Risperidone; Schizophrenia; Schizophrenic Psychology

Traditional antipsychotic medications have targeted the dopamine system. Yet, the isolation and cloning of multiple dopamine receptor subtypes and the recognition of non-dopaminergic pathways (for example, serotonin) in schizophrenia have led to the development of new pharmacological strategies in pharmacotherapy. The author summarizes recent biochemical and pharmacological data and the clinical experience with novel antischizophrenic compounds.

Topics: Antipsychotic Agents; Brain; Clozapine; Humans; Isoxazoles; Piperidines; Psychiatric Status Rating Scales; Receptors, Dopamine; Receptors, Serotonin; Risperidone; Schizophrenia; Schizophrenic Psychology

The major advance in the psychopharmacology of schizophrenia has been the rediscovery of clozapine and the development of other novel antipsychotic drugs, all of which are superior to typical neuroleptic drugs with regard to extrapyramidal symptoms. Clozapine, the best studied of these agents, is also superior in efficacy with regard to psychopathology and cognitive function and has been shown not to cause tardive dyskinesia. A variety of other novel agents, e.g., risperidone, olanazpine, amperozide, seroquel, sertindole, zaprisidone and melperone, must be further studied to establish their efficacy relative to clozapine or the typical neuroleptics, or both. It is likely that these novel agents will displace the typical neuroleptic drugs as the primary treatment of schizophrenia.

Topics: Adult; Antipsychotic Agents; Brain; Clozapine; Dopamine; Humans; Isoxazoles; Piperidines; Risperidone; Schizophrenia

The discovery of antipsychotic medications has revolutionized the treatment of schizophrenia and other psychotic disorders. However, side effects such as extrapyramidal symptoms (EPS) and tardive dyskinesia have been limiting factors in treatment. The introduction of atypical drugs such as clozapine and risperidone has ushered in a new era. This article provides an overview of the pharmacology, efficacy, and techniques for the clinical use of risperidone, which has recently become available.

Topics: Antipsychotic Agents; Clinical Trials as Topic; Humans; Isoxazoles; Piperidines; Placebos; Risperidone; Schizophrenia; Treatment Outcome

Clozapine, risperidone and remoxipride are three neuroleptics that represent an interesting alternative in the psychopharmacological treatment of schizophrenia. Pharmacodynamic and pharmacokinetic properties, efficacy, dosages as well as the indication of these three substances are studied. In certain particular situations, a complementary treatment is of important therapeutic use, the addition of benzodiazepines, lithium, carbamazepine or beta-blockers are discussed.

Topics: Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Humans; Isoxazoles; Piperidines; Psychotropic Drugs; Remoxipride; Risperidone; Schizophrenia; Schizophrenic Psychology

The introduction of neuroleptics over 40 years ago was a landmark in medical history. Although effective, antipsychotics have many side-effects, some severe. Because of the great needs in this therapeutic area, there has been a risk of viewing the introduction of new agents such as clozapine as panaceas. The true advantages of the new atypical neuroleptics need to be assessed realistically, by critically evaluating their effects on positive and negative symptomatology, potential adverse effects and cost benefit. Due in part to the toxic effects of neuroleptics, obtaining consent to treatment is fraught with complexities of a legal and ethical nature. However, despite the many burdensome aspects of this disease, including the high risk of suicide among patients, clinicians should foster patients insight and a collaborative approach to coping with schizophrenia.

Topics: Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Ethics, Medical; Humans; Informed Consent; Isoxazoles; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology

A number of new agents to treat schizophrenia have been, or will soon be, introduced that address the limitations of traditional neuroleptics. The new class of atypical neuroleptics promises better efficacy and/or side-effects profiles, leading to improved overall clinical outcomes. However, in order to assess the potential clinical value of these new therapies, it is important not only to study the results of various clinical trials, but also to analyze the methodology and design of the trials themselves. An understanding of the relevant patient-related issues, outcome measures, pharmacological and non-pharmacological factors is necessary to apply the findings of clinical trials to daily clinical practice.

Topics: Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Dyskinesia, Drug-Induced; Humans; Isoxazoles; Neurologic Examination; Piperidines; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

The pharmacodynamics and pharmacokinetics of risperidone, an important atypical antipsychotic drug with potent serotonin-5-HT2 and dopamine-D2 receptor blocking effects, are presented. The pharmacology of atypical versus typical antipsychotic drugs is discussed in the contest of a pathophysiological conceptualization for schizophrenia which incorporates a parkinsonian model with an important role for serotonin and excitatory amino acid neurotransmission. In the normal therapeutic dose range, risperidone displays dose-linear pharmacokinetics in humans and reaches steady-state within 24 hours. Risperidone metabolism yields a active metabolite, 9-OH-risperidone, that has a similar pharmacological profile to the patient compound and therefore contributes to the clinical efficacy of the drug.

Topics: Antipsychotic Agents; Brain; Dose-Response Relationship, Drug; Haloperidol; Humans; Isoxazoles; Metabolic Clearance Rate; Piperidines; Receptors, Dopamine D2; Receptors, Serotonin; Risperidone; Schizophrenia; Schizophrenic Psychology

Phase II clinical trials with risperidone have proven it to have a potent antipsychotic effect, improving both positive and negative symptoms of schizophrenia. It was found to have a low potential for inducing extrapyramidal symptoms and has been shown to have a possible antidyskinetic effect without increasing parkinsonism. Risperidone has a rapid onset of action and a favourable side-effect profile. One-year data on risperidone suggest that its therapeutic action in patients with chronic schizophrenia can be maintained without the significant neurological side-effects associated with the use of standard neuroleptics.

Topics: Antipsychotic Agents; Clinical Trials, Phase III as Topic; Humans; Isoxazoles; Multicenter Studies as Topic; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology

Clinical studies to date have shown that risperidone is an effective antipsychotic agent in the treatment of both positive and negative symptomatologies, with a side-effect profile that is superior to standard neuroleptics. It may represent a potentially useful first-line agent in the treatment of schizophrenia, and clinicians may consider switching to risperidone if current neuroleptic therapy yields poor control of symptoms or problematic side-effects, such as extrapyramidal symptoms or tardive dyskinesia. This article discusses the relevant clinical considerations in switching neuroleptics and proposes practical guidelines on issues such as dosing and course of therapy with risperidone.

Topics: Clinical Trials as Topic; Dose-Response Relationship, Drug; Humans; Isoxazoles; Piperidines; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology

Despite the enormous benefits provided by antipsychotic medication in the management of schizophrenia, available compounds have serious limitations. Firstly, they are not always effective. Secondly, positive psychopathological symptoms may benefit more than negative or deficit symptoms. Thirdly, antipsychotics are generally associated with a variety of neurological adverse effects. Three drugs have recently been or are close to being introduced into widespread clinical use: clozapine, risperidone and remoxipride. Each of these compounds appears to have some advantages over traditional antipsychotic agents, particularly in terms of reduced propensity to induce adverse neurological effects. All three drugs have been shown to be clinically effective in large scale trials. Future clinical trials are required to establish their relative merits in comparison with one another.

Topics: Antipsychotic Agents; Clozapine; Humans; Isoxazoles; Piperidines; Remoxipride; Risperidone; Schizophrenia; Treatment Outcome

Sigma ligands have been identified as psychotomimetic agents unrelated to opioids. A number of neuroleptics possess moderate to high affinity for sigma binding sites, raising the possibility that sigma receptors mediate some of the antipsychotic effects of neuroleptics. In addition, sigma binding sites have been reported to be reduced in the temporal cortex and in the hippocampus of schizophrenic patients. This hypothesis is further supported by the use of the sigma ligands rimcazole, BMY-14802 and remoxipride as effective antipsychotic agents. The present report, reviewing briefly the physiological effects of sigma ligands, suggests that their antipsychotic properties are related to modulation of NMDA receptors. Thus, the use of sigma ligands may provide further understanding of the pathophysiology of psychoses and open new avenues for their treatment.

Topics: Antipsychotic Agents; Carbazoles; Hippocampus; Humans; Piperidines; Psychotropic Drugs; Pyrimidines; Receptors, sigma; Remoxipride; Schizophrenia; Thalamus

Compared to traditional neuroleptics, most of the new antipsychotics are characterized by a low extrapyramidal side effect (EPS) liability and varying antipsychotic efficacy. This topic is reviewed for four principal classes of new, established, and potential antipsychotics: (1) Antipsychotics such as sulpiride and remoxipride that block a subgroup of dopamine (DA) D2/D3 receptors produce a relatively low level of side effects, including EPS, and have an antipsychotic effect equal to or slightly weaker than traditional neuroleptics. D1 antagonists demonstrate a low level of EPS in primates and may prove to be a valuable new type of antipsychotic drug. (2) Theoretically, partial D2 agonists have the advantage of producing few or no EPS and a specific beneficial effect in negative symptoms, but as yet the expectations have not been fulfilled. (3) Nondopamine drugs such as serotonin (5HT1) agonists, 5HT2 antagonists, 5HT3 antagonists, and gamma-amino-butyric-acid-A (GABA-A) benzodiazepine agonists have anxiolytic, antidepressant, antiaggressive, and maybe antiparkinsonian effects and may play an adjunctive role in the treatment of schizophrenia. 5HT3 antagonists (e.g., ondansetron), partial benzodiazepine agonists, and partial glutamate agonists may prove to be effective antipsychotics. (4) Antipsychotics such as clozapine and risperidone, which affect D2/D3 receptors as well as 5HT, alpha 1, and/or D1 receptors appear to have the most pronounced antipsychotic effect.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Benzamides; Humans; Isoxazoles; Piperidines; Receptors, Dopamine; Receptors, Glutamate; Receptors, Neurotransmitter; Receptors, Serotonin; Remoxipride; Risperidone; Schizophrenia; Serotonin Antagonists; Sulpiride

Topics: Animals; Basal Ganglia Diseases; Brain; Butyrophenones; Cognition; Dogs; Dopamine; Haplorhini; Homovanillic Acid; Humans; Limbic System; Mice; Oxidative Phosphorylation; Phenothiazines; Piperidines; Psychopharmacology; Receptors, Drug; Schizophrenia; Synaptic Transmission; Tranquilizing Agents

Topics: Adolescent; Adult; Aged; Alcoholism; Antisocial Personality Disorder; Child; Dementia; Epilepsy; Female; Humans; Intellectual Disability; Male; Mental Disorders; Middle Aged; Neurotic Disorders; Nitriles; Paranoid Disorders; Personality Disorders; Phenothiazines; Piperidines; Psychotic Disorders; Schizophrenia; Tranquilizing Agents

In the first part of this paper, a classification was proposed which divided dysleptic drugs into two categories. Further evidence in support of this classification is drawn from the variability of the clinical picture in schizophrenics elicited by mescaline or allied substances, whereas dysleptics with potent anticholinergic properties always induce the same symptomatology. If the therapeutic usefulness of LSD-25 for instance still may be argued, dysleptics belonging to the second group seem to have no therapeutic usefulness. The dysleptics of the first group include in their chemical formula an aromatic or an indole nucleus; the second group is characterized by a phenylglycolate group. The classification proposed here may be compared with Henri Ey's ideas: in this Jacksonian perspective, dysleptics like LSD would impair the superior strata of the psycho-organic structure whereas Ditran (in the second group) would act at a lower level.

Topics: Cerebral Cortex; Chemical Phenomena; Chemistry; Classification; Dosage Forms; Drug Combinations; Electroencephalography; Glycolates; Hallucinogens; Humans; Indoles; Lysergic Acid Diethylamide; Mescaline; Phencyclidine; Piperidines; Psychopharmacology; Pyrrolidines; Schizophrenia; Toxicology

Globally, evidence from short-term studies is insufficient for the guidelines to uniformly recommend a particular antipsychotic(s) for the maintenance treatment of schizophrenia. Therefore, long-term comprehensive evaluation of antipsychotics is required from a social rehabilitation perspective, especially for drugs that have not yet been studied. The Japan Useful Medication Program for Schizophrenia (JUMPs) is a large-scale, long-term naturalistic study to present pivotal 52-week data on the continuity of second-generation antipsychotics (SGA: aripiprazole, blonanserin, and paliperidone).. JUMPs was an open-label, three-arm, randomized, parallel-group, 52-week study. Enrolled patients had schizophrenia, were ≥20 years old, and required antipsychotic treatment or switched from previous therapy. The primary endpoint was treatment discontinuation rate over 52 weeks. Secondary outcomes included remission rate, social functioning, and quality-of-life scores [Personal and Social Performance Scale (PSP) and EuroQol-5 dimensions], and safety.. In total, 251 patients received aripiprazole (n = 82), blonanserin (n = 85), or paliperidone (n = 84). The discontinuation rate (P = 0.9771) and remission rates (P > 0.05) over 52 weeks did not differ significantly between the three treatment groups. The discontinuation rates were 68.3%, 68.2%, and 65.5% in the aripiprazole, blonanserin, and paliperidone groups, respectively. Significant improvements (all P < 0.05) from baseline in PSP scores were observed at start of monotherapy, week 26, and week 52 in the overall cohort and blonanserin group and at week 26 in the aripiprazole group. The adverse event profile favored blonanserin.. All three SGAs evaluated in this study showed similar treatment discontinuation rates in patients with chronic schizophrenia in Japan.

Topics: Antipsychotic Agents; Aripiprazole; Female; Humans; Japan; Male; Medication Adherence; Middle Aged; Paliperidone Palmitate; Piperazines; Piperidines; Remission Induction; Schizophrenia; Social Interaction; Treatment Outcome

Blonanserin is a second-generation antipsychotic for the treatment of schizophrenia. Blonanserin has two different routes of administration: oral tablets/powder and transdermal patches. The aim of this study was to investigate as a post-hoc analysis of an original study whether switching from blonanserin tablets/powders to transdermal patches would reduce extrapyramidal symptoms (EPS) and/or the dose of antiparkinsonian drugs for the stabilization of blood pharmacokinetics in patients with schizophrenia. Patients with schizophrenia (n = 155) were enrolled in either cohort 1 or 2. In cohort 1 (n = 97), patients received 40-80 mg/day blonanserin transdermal patches for one year after taking 8-16 mg/day blonanserin tablets for 6 weeks, and the dose of patches was determined based on the dose of the tablets. In cohort 2 (n = 58), all patients started with 40 mg/day blonanserin patches and then received 40-80 mg/day for a year after taking blonanserin tablets/powders. Changes from the start of transdermal patch treatment in EPS and the dose of antiparkinsonian drugs at 3, 6, and 12 months were assessed using the Drug-Induced EPS Scale (DIEPSS) and biperiden equivalents of total antiparkinsonian drugs (BPD-eq), respectively. Among 155 patients, only four patients in cohort 1 discontinued owing to EPS during a patch period. Significant improvements from the start of patch treatment in the DIEPSS total score at any point were observed (mean change±SD): -0.44 ± 1.50 (p = 0.013), -0.07 ± 1.78 (p = 0.73), and - 0.14 ± 1.37 (p = 0.44) in cohort 1 and - 0.16 ± 1.32 (p = 0.40), -0.74 ± 1.92 (p = 0.020), and - 0.81 ± 2.22 (p = 0.047) in cohort 2 at 3, 6, and 12 months, respectively. In contrast, there were no significant changes from the start of patch treatment in BPD-eq at any month (p > 0.05). Transdermal patches of blonanserin are a more effective route of administration to diminish EPS than oral tablets/powder.

Topics: Administration, Oral; Adult; Antiparkinson Agents; Antipsychotic Agents; Dose-Response Relationship, Drug; Dyskinesias; Female; Humans; Male; Piperazines; Piperidines; Powders; Schizophrenia; Tablets; Transdermal Patch

Negative symptoms of schizophrenia are associated with adverse clinical outcomes, but there are few effective treatments. We aimed to assess the effects of pimavanserin, a selective 5-HT. The ADVANCE study was a phase 2, 26-week, randomised, double-blind, placebo-controlled study of pimavanserin in stable outpatients with schizophrenia aged 18-55 years with predominant negative symptoms. Patients were randomly assigned (1:1) across 83 sites (18 in North America and 65 in Europe) to receive pimavanserin or placebo daily, added to an ongoing antipsychotic medication, per a computer-generated schedule (stratification by geographical region). Eligible patients had a score of at least 20 on the sum of seven Positive and Negative Syndrome Scale (PANSS) Marder negative factor items (and scores of ≥4 on at least three or ≥5 on at least two of negative symptom items). The starting dosage of 20 mg of pimavanserin or placebo could be adjusted to 34 mg or 10 mg within the first 8 weeks of the study, after which dosage remained stable until the end of the study. Both pimavanserin and placebo were administered orally once daily as two individual tablets (pimavanserin tablets were either 10 mg or 17 mg). The primary endpoint was change in total score using the 16-item Negative Symptom Assessment (NSA-16) from baseline to week 26. Primary outcomes were analysed in patients who received at least one dose of the study drug and had NSA-16 assessments at baseline and at least once post-baseline (full analysis set). Safety outcomes were analysed in patients who had received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, NCT02970305, and is complete.. Between Nov 4, 2016, and April 16, 2019, we randomly assigned 403 patients to pimavanserin (n=201; 131 [65%] male; 187 [93%] White) or placebo (n=202; 137 [68%] male, 186 (92%) White), of whom 400 were included in the efficacy analysis (199 in the pimavanserin group, 201 in the placebo group). Mean age was 37·7 years (SD 9·4) in the pimavanserin group and 36·7 (9·2) years in the placebo group. The change in total NSA-16 score from baseline to week 26 was significantly improved with pimavanserin (least squares mean -10·4 [SE 0·67]) versus placebo (least squares mean -8·5 [0·67]; p=0·043; effect size: 0·211). The number of patients with treatment-emergent adverse events (TEAEs) was similar between groups: 80 (40%) patients experienced TEAEs in the pimavanserin group and 71 (35%) in the placebo group. Most TEAEs were headache (6% [n=13] vs 5% [n=10]) and somnolence (5% [n=11] vs 5% [n=10]). One patient from the placebo group reported severe headache (0·5%), rhinorrhoea (0·5%), cough (0·5%), and influenza (0·5%). In the pimavanserin group, one patient reported severe toothache (0·5%), and two patients had worsening of schizophrenia (1%). Mean change in QTcF interval was higher with pimavanerin (4·5 ms [SD 18·0]) than with placebo (0·0 ms [16·0]).. Stable patients with predominant negative symptoms of schizophrenia showed a reduction in negative symptoms after treatment with pimavanserin. However, given the small effect size, further investigation with optimised dosing is warranted to determine the clinical significance of this effect.. Acadia Pharmaceuticals.

Topics: Adolescent; Adult; Double-Blind Method; Europe; Female; Humans; Male; Middle Aged; North America; Outcome Assessment, Health Care; Piperidines; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Urea; Young Adult

Both the pharmacological characteristics of blonanserin and its related small sample size studies suggest that blonanserin could alleviate social and cognitive dysfunctions in patients with schizophrenia. However, no large sample size studies have been performed so far. This study aimed to investigate the effectiveness and safety of blonanserin in improving social and cognitive functions in patients with first-episode schizophrenia.. This is a prospective, multicentre, single-arm clinical trial. A total of 188 patients with first-episode schizophrenia will be enrolled and will undergo a 0-7 day washout period before blonanserin administration. Doses of blonanserin will first be set to 4 mg P.O. twice per day after meals and gradually increased to 8-16 mg/d P.O., depending on patient's age and symptoms, for 26 weeks. Maximum dose of blonanserin will not be exceeding 24 mg/day. The primary endpoint of the study is the changes of Personal and Social Performance (PSP) score in patients from baseline to week 26. Secondary endpoints include changes in MATRICS consensus cognitive battery (MCCB), Paced Auditory Serial Addition Test (PASAT), grooved pegboard test (GPT), Positive and Negative Syndrome Scale (PANSS) total score and PANSS 5-factor subscale scores. Other endpoints include changes of serum brain-derived neurotrophic factor (BDNF) at corresponding visits and MRI results. Moreover, incidence of adverse events, changes in endocrine and metabolic profiles, renal, hepatic and sexual functions and extrapyramidal symptoms will be strictly monitored and recorded.. The study was approved by the ethics committee of the leading site Peking University Sixth Hospital (No. 2018-18), and all included patients are requested to provide written informed consent before enrolment. The study will be conducted according to the principles of the Declaration of Helsinki and follow the principles for clinical research.. NCT03784222.

Topics: Antipsychotic Agents; Cognition; Humans; Multicenter Studies as Topic; Piperazines; Piperidines; Prospective Studies; Schizophrenia; Schizophrenic Psychology; Social Interaction; Treatment Outcome

Transdermal antipsychotic patch formulations offer potential benefits, including improved adherence. This study investigated the striatal dopamine D2 receptor occupancy with daily blonanserin transdermal patch application.. This open-label, phase II study enrolled 18 Japanese outpatients (20 to <65 years) with schizophrenia (DSM-IV-TR criteria; total Positive and Negative Syndrome Scale score <120 at screening) treated with blonanserin 8-mg or 16-mg tablets. Patients continued tablets for 2-4 weeks at their current dose and were then assigned to once-daily blonanserin patches (10/20/40/60/80 mg daily) for 2-4 weeks based on the oral dose. [11C]raclopride positron emission tomography scanning determined blonanserin striatal dopamine D2 receptor occupancy (primary endpoint). Secondary endpoints included assessment of receptor occupancy by dose, changes in Positive and Negative Syndrome Scale and Clinical Global Impressions-Severity of Illness-Severity scores, patient attitudes towards adherence, and patch adhesiveness.. Of 18 patients who started the blonanserin tablet treatment period, 14 patients completed treatment. Mean D2 receptor occupancy for blonanserin tablets 8 mg/d (59.2%, n = 5) and 16 mg/d (66.3%, n = 9) was within the values for blonanserin patches: 10 mg/d (33.3%, n = 3), 20 mg/d (29.9%, n = 2), 40 mg/d (61.2%, n = 3), 60 mg/d (59.0%, n = 3), and 80 mg/d (69.9%, n = 3). Occupancy generally increased with increasing blonanserin dose for both formulations with the half maximal receptor occupancy for tablets and patches associated with doses of 6.9 mg/d and 31.9 mg/d, respectively. Diurnal variability in occupancy was lower during transdermal patch treatment than during tablet treatment. Blonanserin transdermal patches were well tolerated with no major safety concerns.. Blonanserin patches (40/80 mg/d) have lower diurnal variability in occupancy than blonanserin tablets (8/16 mg/d), and patches at doses of 40 mg/d and 80 mg/d appear to be a suitable alternative for blonanserin tablets at doses of 8 mg/d and 16 mg/d, respectively. Blonanserin patches represent a potential new treatment option for patients with schizophrenia.. JAPIC Clinical Trials Information registry (www.clinicaltrials.jp; JapicCTI-No: JapicCTI-121914).

Topics: Adult; Antipsychotic Agents; Corpus Striatum; Female; Humans; Japan; Male; Middle Aged; Piperazines; Piperidines; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2; Schizophrenia; Transdermal Patch; Young Adult

Blonanserin is a second-generation antipsychotic used for the treatment of schizophrenia. This study determined the efficacy, safety and pharmacokinetics of a blonanserin transdermal patch in patients with acutely exacerbated schizophrenia.. This double-blind, multicenter, phase 3 study consisted of a 1-week observation period during which patients were treated with two patches of placebo, followed by a 6-week double-blind period where patients were randomized (1:1:1) to receive once-daily blonanserin 40 mg, blonanserin 80 mg, or placebo patches. The primary endpoint was the change from baseline in the total Positive and Negative Symptom Scale (PANSS) score. Safety assessments included treatment-emergent adverse events (TEAEs).. Between December 2014 and October 2018, patients were recruited and randomly assigned to blonanserin 40 mg (n = 196), blonanserin 80 mg (n = 194), or placebo (n = 190); of these, 77.2% completed the study. Compared with placebo, blonanserin significantly improved PANSS total scores at 6 weeks (least square mean [LSM] difference vs placebo: -5.6 with blonanserin 40 mg; 95% confidence interval [CI] -9.6, -1.6; adjusted p = 0.007, and - 10.4 with blonanserin 80 mg; 95% CI -14.4, -6.4; adjusted p < 0.001). Blonanserin was well tolerated; the most common TEAEs reported were application-site erythema and pruritus, akathisia, tremor, and insomnia.. Blonanserin transdermal patch improved the symptoms of acute schizophrenia with acceptable tolerability.

Topics: Acute Disease; Adult; Antipsychotic Agents; Double-Blind Method; Female; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Piperazines; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Transdermal Patch

To report the efficacy and safety of blonanserin in patients with schizophrenia compared with risperidone in a Japanese multicenter, randomized, double-blind study based on post hoc sensitivity analysis in addition to the previous results reported by Miura and discuss the current approaches for schizophrenia treatment.. Of 302 patients randomized, 156 received blonanserin (8-24 mg/d) and 145 received risperidone (2-6 mg/d) for 8 weeks. Efficacy variables included the Positive and Negative Syndrome Scale (PANSS) total score for the primary outcome, PANSS subscale, Brief Psychiatric Rating Scale (BPRS), and Clinical Global Impression-Improvement (CGI-I) for secondary outcomes. Safety variables included treatment-emergent adverse events, Drug Induced Extrapyramidal Symptoms Scale scores, laboratory data, vital signs, electrocardiogram, etc RESULTS: Blonanserin was not inferior to risperidone in the change in PANSS total score at a non-inferior margin of -7 (intergroup difference, -0.46; 95% CI, -4.40 to 3.48). Post hoc analyses wholly supported the primary result. No major difference was found in the changes in BPRS scores and the improvement rate on CGI-I between the drugs. The incidence of adverse events was similar in the two drugs. Blonanserin was associated with a lower risk of prolactin increase, weight gain, and orthostatic hypotension compared with risperidone. However, blonanserin was associated with a higher incidence of akathisia and excitability compared with risperidone. Most of the adverse events were mild to moderate in severity with no specific events of predominant high severity in the both drugs.. Blonanserin exerted the similar efficacy to risperidone in both positive and negative symptoms in schizophrenia with a lower risk of prolactin increase, weight gain, and orthostatic hypotension compared with risperidone. Blonanserin will serve as a favorable treatment option for schizophrenia in daily clinical practice.

Topics: Adult; Antipsychotic Agents; Double-Blind Method; Female; Humans; Japan; Male; Middle Aged; Outcome Assessment, Health Care; Piperazines; Piperidines; Risperidone; Schizophrenia

This study examined randomized controlled trial data for blonanserin and risperidone in Chinese schizophrenia patients (N = 264). Data related to historical changes in the Positive and Negative Syndrome Scale (PANSS) were used to successfully construct a longitudinal E

Topics: Adolescent; Adult; Antipsychotic Agents; Double-Blind Method; Female; Humans; Male; Middle Aged; Models, Statistical; Piperazines; Piperidines; Prolactin; Risperidone; Schizophrenia; Sex Factors; Young Adult

Blonanserin transdermal patch therapy is now available in Japan for the treatment of schizophrenia and may provide several advantages over the tablet formulation.. The aim was to evaluate the long-term safety and efficacy of blonanserin transdermal patches in Japanese patients with schizophrenia.. An open-label study was conducted in adults with schizophrenia at 37 sites in Japan. Patients were enrolled in either cohort 1 or 2. Patients in cohort 1 received 8-16 mg/day blonanserin tablets for 6 weeks and then 40-80 mg/day blonanserin patches for 52 weeks. The dose of blonanserin patches was determined according to the dose of the tablets. In cohort 2, every patient started from 40 mg/day and then 40-80 mg/day blonanserin transdermal patches for 52 weeks. Both cohorts had 1-2 weeks of follow-up. Safety endpoints included the incidence of adverse events (AEs), treatment-related AEs, extrapyramidal AEs [also assessed using the change in Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) score], the use of any concomitant antiparkinsonian drugs, and skin-related AEs, including skin irritation. Patients also underwent assessment of laboratory values including for serum prolactin concentration, vital signs, body weight, electrocardiographic (ECG) changes, and the corrected QT (QTc) interval. Suicidal ideation was assessed via the Columbia-Suicide Severity Rating Scale (C-SSRS) score. Efficacy was assessed via duration of blonanserin transdermal patch treatment, Positive and Negative Syndrome Scale (PANSS) total and subscale scores, and Clinical Global Impression-Severity (CGI-S) scores. Other endpoints included total Drug Attitude Inventory 10 (DAI-10) scores, EuroQol-5 Dimension (EQ-5D) effect values, and a patient questionnaire about the dosage form.. A total of 223 patients with consents, 117 in cohort 1 and 106 in cohort 2 were included in the study. Of the 117 patients in cohort 1, 108 were treated with blonanserin tablets, and 97 received blonanserin patches and were included in the safety analysis set. In cohort 2, 103 of the 106 patients were treated with blonanserin transdermal patches and were included in the safety analysis set. In total, 91 patients were male (45.5%). The mean age was 43.8 years. Discontinuation occurred in 40 patients (41.2%) in cohort 1 and 44 patients (42.7%) in cohort 2. Discontinuation resulted from AEs in 18.6% (cohort 1) and 11.7% (cohort 2) and from withdrawal of consent in 13.4% (cohort 1) and 20.4% (cohort 2), and seven patients overall discontinued due to skin reactions. AEs were reported in 174 patients (87.0%), and 13 serious AEs occurred in 12 patients (6.0%), of which six patients were in cohort 1 and six patients were in cohort 2. Serious AEs were six schizophrenia (n = 6) and seven other AEs (n = 6), which included impulse-control disorder, fracture, epistaxis, asthma, pneumonia aspiration, pneumonia hemophilus, and pneumonia. The most common AEs were nasopharyngitis (n = 62, 31.0%), application site erythema (n = 45, 22.5%), application site pruritus (n = 23, 11.5%), and akathisia (n = 20, 10.0%). AE incidence was similar in cohort 1 (84.5%) and cohort 2 (89.3%). Extrapyramidal and skin-related AEs were reported in 51 patients (25.5%) and 83 patients (41.5%), respectively. None of these AEs were serious. The mean change from baseline in total DIEPSS score at Week 52 {last observation carried forward [LOCF] (standard deviation [SD])} was -0.1 (1.55), indicating no marked effect. In terms of concomitant medications used in cohort 1 and cohort 2, 33.0% (32/97) and 22.3% (23/103) used antiparkinsonian drugs, respectively. The majority of skin-related AEs occurred early in treatment and were appropriately managed with topical therapies. Of the patients who answered "No" to all C-SSRS categories at baseline (n = 129), 13 patients (10.1%) were evaluated as having emergence of suicidal ideation. Among patients who answered "No" to all C-SSRS suicidal behavior categories at baseline (n = 172), one (0.6%) was evaluated as having suicidal behavior during blonanserin transdermal patch treatment. There were no clinically significant changes in laboratory tests or examinations, including prolactin level, vital signs, body weight, ECG, metabolism-related parameters, and QT. Blonanserin transdermal patches are safe and effective in the long-term treatment of schizophrenia. CLINICALTRIALS.. NCT02335658.

Topics: Administration, Cutaneous; Adult; Aged, 80 and over; Asian People; Female; Humans; Male; Middle Aged; Piperazines; Piperidines; Schizophrenia; Transdermal Patch; Treatment Outcome

Dopamine supersensitivity psychosis (DSP) is a key factor contributing to the development of antipsychotic treatment-resistant schizophrenia. We examined the efficacy and safety of blonanserin (BNS) and olanzapine (OLZ) as adjuncts to prior antipsychotic treatment in patients with schizophrenia and DSP in a 24-week, multicenter (17 sites), randomized, rater-blinded study with two parallel groups (BNS and OLZ add-on treatments) in patients with schizophrenia and DSP: the ROADS Study. The primary outcome was the change in the Positive and Negative Syndrome Scale (PANSS) total score from baseline to week 24. Secondary outcomes were changes in the PANSS subscale scores, Clinical Global Impressions, and Extrapyramidal Symptom Rating Scale (ESRS), and changes in antipsychotic doses. The 61 assessed patients were allocated into a BNS group (n = 26) and an OLZ group (n = 29). The PANSS total scores were reduced in both groups (mean ± SD: -14.8 ± 24.0, p = 0.0042; -10.5 ± 12.9, p = 0.0003; respectively) with no significant between-group difference (mean, -4.3, 95 %CI 15.1-6.4, p = 0.42). The BNS group showed significant reductions from week 4; the OLZ group showed significant reductions from week 8. The ESRS scores were reduced in the BNS group and the others were reduced in both groups. The antipsychotic monotherapy rates at the endpoint were 26.3 % (n = 6) for BNS and 23.8 % (n = 5) for OLZ. The concomitant antipsychotic doses were reduced in both groups with good tolerability. Our results suggest that augmentations with BNS and OLZ are antipsychotic treatment options for DSP patients, and BNS may be favorable for DSP based on the relatively quick responses to BNS observed herein.

Topics: Antipsychotic Agents; Benzodiazepines; Dopamine; Humans; Olanzapine; Piperazines; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Treatment Outcome

This Japanese, multicenter, randomized, double-blind trial, evaluating the efficacy and safety of blonanserin compared with haloperidol in patients with schizophrenia, was previously published by Murasaki in the Japanese language. In this article, we present the results of the trial based on full analysis dataset instead of per protocol dataset formerly reported and discuss the findings in light of the latest knowledge of pharmacological treatment for schizophrenia.. A total of 265 patients were randomized to receive blonanserin (8 to 24 mg/d) or haloperidol (4 to 12 mg/d) twice daily for 8 weeks. Efficacy assessments included the Clinical Global Impressions-Improvement (CGI-I) and the Positive and Negative Syndrome Scale (PANSS).. Blonanserin was not inferior to haloperidol with a margin of 10% with respect to the improvement rate on CGI-I at end of study (60.5% vs 50.0%, P < 0.001). The decrease in the PANSS total score did not differ between the drugs (-10.3 vs -7.1). For the PANSS negative symptom score, the decrease was significantly greater with blonanserin than with haloperidol (P = 0.006). Blonanserin was well tolerated. The incidence of adverse events was similar for the two drugs. Extrapyramidal adverse events, sedation, hypotension, and prolactin increase were rarer with blonanserin than with haloperidol. No clinically important weight gain was observed.. Blonanserin is as effective as haloperidol for the treatment of schizophrenia. Blonanserin is more effective for negative symptoms with a lower risk of extrapyramidal symptoms compared with haloperidol.

Topics: Adult; Antipsychotic Agents; Double-Blind Method; Drug Tolerance; Female; Haloperidol; Humans; Male; Middle Aged; Piperazines; Piperidines; Schizophrenia; Weight Gain

The purpose of this study was to evaluate the safety and effectiveness of iloperidone for the prevention of relapse in schizophrenia.. Study subjects were adults with schizophrenia who started on oral open-label iloperidone titrated to an initial target dose of 12 mg/day (6 mg twice daily) and then stabilized on a flexible-dose iloperidone regimen (range 8-24 mg/day) for up to 24 weeks. Subjects meeting stabilization criteria then entered the relapse-prevention phase and were randomized 1:1 in a double-blind fashion to continue with iloperidone or placebo withdrawal for up to 26 weeks or until meeting relapse or other withdrawal criteria.. A total of 303 subjects were randomized to the relapse-prevention phase; 153 continued to receive iloperidone, and 150 were withdrawn to placebo. The modal total daily dose for iloperidone in all phases of the study was 12 mg/day. The pre-defined unblinded interim analysis upon reaching 68 relapse events confirmed the hypothesis that iloperidone (n = 97) was more effective than placebo (n = 96) in preventing relapse events, and the trial was stopped early. The estimated relapse rates were 63.4 % (Kaplan-Meier [KM] estimate) for placebo compared with 20.4 % (KM estimate) for those continuing to receive iloperidone (log rank test: p < 0.0001). The mean time to relapse was 71 days for placebo and 139 days for iloperidone (hazard ratio 4.7; 95 % confidence interval 2.7-8.3; p < 0.0001). The safety profile observed in previous short-term studies was also reaffirmed in this maintenance treatment setting. The most common treatment-emergent adverse events (TEAEs) in the stabilization phase were dizziness (11.6 %), somnolence (8.3 %), and dry mouth (6.8 %). Rates of reported extrapyramidal disorder or akathisia during stabilization were 2.5 and 3.7 %, respectively.. Flexible dosing of iloperidone for maintenance-phase therapy, with a modal dose of 12 mg/day was effective in preventing relapse in subjects previously stabilized on iloperidone. The adverse event profile for iloperidone was consistent with other studies, and the low extrapyramidal symptom and akathisia burden during stabilization was sustained during the course of the study. ClinicalTrials.gov identifier: NCT01291511.

Topics: Adult; Antipsychotic Agents; Double-Blind Method; Female; Humans; Isoxazoles; Male; Piperidines; Recurrence; Schizophrenia; Secondary Prevention; Treatment Outcome

To describe secondary analyses from a 12-week, randomized, open-label trial where adult schizophrenia outpatients receiving risperidone, olanzapine, or aripiprazole were switched to iloperidone.. Patients were randomized into two groups: one where the antecedent antipsychotic dose was titrated downwards to zero over 2 weeks (n=240), and the other group where the antecedent antipsychotic was abruptly stopped (n=260). Adaptations of the Clinical Global Impression scale were used to evaluate clinical changes. Other assessments included the reporting of adverse events (AEs), study discontinuation, body weight, and metabolic variables.. Improvement was steady throughout the study for both gradual- and immediate-switch groups starting at Week 1 and continuing through Week 12. Discontinuations due to AEs in the first 2 weeks of treatment were higher for the immediate-switch group compared with the gradual-switch group (10.8% vs. 5.4%, NNT 19, 95% CI 10-151). Fewer patients in the gradual-switch group experienced dizziness as an AE, whereas a higher percentage of patients in the immediate-switch group exhibited earlier onset of a therapeutic response within the first 2 weeks; both groups were comparable thereafter with low rates of dizziness and similar efficacy outcomes.. Switching to iloperidone can be accomplished either with a gradual crossover or immediate discontinuation of the prior antipsychotic; however, the immediate-switch method is associated with greater proportion of initial dizziness. The observed outcomes are consistent with what has been previously reported regarding iloperidone's favorable akathisia/EPS profile and modest impact on somnolence/sedation, body weight, and metabolic variables.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Dizziness; Female; Humans; Isoxazoles; Male; Olanzapine; Piperazines; Piperidines; Quinolones; Risperidone; Schizophrenia; Treatment Outcome

This randomized, double-blind study compared the efficacy and safety of blonanserin and risperidone to treat Chinese schizophrenia patients aged ≥18 and < 65 years. Patients with Positive and Negative Syndrome Scale (PANSS) total scores ≥70 and ≤ 120 were randomized to receive blonanserin or risperidone using a gradual dose-titration method (blonanserin tablets: 8-24 mg/day; risperidone tablets: 2-6 mg/day), twice daily. Treatment populations consisted of 128 blonanserin-treated patients and 133 risperidone-treated patients. Intention-to-treat analysis was performed using the last observation carried forward method. Reductions of PANSS total scores by blonanserin and risperidone treatment were -30.59 and -33.56, respectively. Risperidone treatment was associated with elevated levels of serum prolactin (67.16% risperidone versus 52.31% blonanserin) and cardiac-related abnormalities (22.39% risperidone versus 12.31% blonanserin), and blonanserin patients were more prone to extrapyramidal side effects (48.46% blonanserin versus 29.10% risperidone). In conclusion, blonanserin was as effective as risperidone for the treatment of Chinese patients with schizophrenia. The overall safety profiles of these drugs are comparable, although blonanserin was associated with a higher incidence of EPS and risperidone was associated with a higher incidence of prolactin elevation and weight gain. Thus, blonanserin is useful for the treatment of Chinese schizophrenia patients.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Asian People; China; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Piperazines; Piperidines; Prolactin; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Weight Gain; Young Adult

The serotoninergic system as a target for add-on treatment seems to be a promising approach in patients with schizophrenia.. To clarify if selective 5HT-6 antagonist AVN-211 (CD-008-0173) adds clinical and cognitive effects to stable antipsychotic treatment.. A randomized, double-blind, placebo-controlled, add-on, 4r-week trial in 47 schizophrenia patients (21 patients receiving study drug and 26 receiving placebo) who were stabilized on antipsychotic medication was performed. Seventeen patients from the study drug group and 25 patients from the placebo group completed the trial. Treatment effects were measured using clinical rating scales and attention tests.. With no differences at baseline, there was a significant difference between the groups in Positive and Negative Syndrome Scale (PANSS) positive subscale score (p = 0.058) in favor of patients in the treatment group at the endpoint. The PANSS positive subscore (p = 0.0068) and Clinical Global Impression-Severity (CGI-S) (p = 0.048) score significantly changed only in the treatment group. Only in the placebo group were significant changes in Calgary Depression Rating Scale (CDRS) total score registered. The indices of attention tests at endpoint did not show differences between the groups, with the exception of the scope of change in the results of the subtest VIII of the Wechsler Adult Intelligence Scale (WAIS), which showed difference between the groups (p = 0.02) and was significantly larger in the treatment group. Only inside the study drug group, significant changes in selectivity and continuous attention were observed regarding total correct responses (p = 0.0038) and reaction time (p = 0.058) in the Continuous Attention Task (CAT) test.. Selective 5HT6 antagonist AVN-211 (CD-008-0173) added antipsychotic and some procognitive (attention) effects to antipsychotic medication.

Topics: Adult; Animals; Antipsychotic Agents; Attention; Behavior, Animal; Cholinergic Antagonists; Cholinesterase Inhibitors; Cognition; Donepezil; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Indans; Male; Maze Learning; Mice; Mice, Inbred BALB C; Middle Aged; Pilot Projects; Piperidines; Prepulse Inhibition; Pyrazoles; Pyrimidines; Reaction Time; Receptors, Serotonin; Reflex, Startle; Schizophrenia; Schizophrenic Psychology; Scopolamine; Serotonin Antagonists; Tacrine; Treatment Outcome; Young Adult

In a 12-week randomized open-label trial, adults diagnosed with schizophrenia experiencing inadequate efficacy and/or poor tolerability on risperidone, olanzapine, or aripiprazole were randomized to switch to iloperidone either gradually (ie, down-titration of current therapy over the first 2weeks [to 50% on Day 1, 25% by Week 1, 0% by Week 2]) or immediately. All patients were titrated on iloperidone to 6mg BID by Day 4, then flexibly dosing between 6 and 12mg BID, as needed. The primary variable was the Integrated Clinical Global Impression of Change (I-CGI-C) and the primary analysis time point was Week 12. A total of 500 patients were randomized and received iloperidone (gradual switch, 240; immediate switch, 260), with 175, 155, and 170 patients switched from risperidone, olanzapine, and aripiprazole, respectively. I-CGI-C Results confirmed improved outcomes at Week 12, with scores that were similar between the gradual- and immediate-switch groups, respectively, for risperidone, 2.82 and 2.67 (95% CI: -0.229, 0.511); olanzapine, 2.87 and 3.03 (95% CI: -0.548, 0.235); and aripiprazole, 2.79 and 2.81 (95% CI: -0.405, 0.368). Incidence of adverse events (AEs) was similar in both switch groups, with the most frequently reported (≥10%) being dizziness, dry mouth, somnolence, and weight increase. In conclusion, switching to iloperidone by either a gradual or an immediate method did not reveal any clinically significant differences in ratings of overall efficacy and safety/tolerability outcomes, based on the I-CGI-C at 12weeks. Similar overall safety/AE profiles were observed regardless of the specific agent from which patients were switched.

Topics: Adolescent; Adult; Analysis of Variance; Antipsychotic Agents; Aortic Bodies; Aripiprazole; Benzodiazepines; Cohort Studies; Drug Administration Schedule; Drug Substitution; Female; Humans; Isoxazoles; Male; Middle Aged; Olanzapine; Piperazines; Piperidines; Psychiatric Status Rating Scales; Quinolones; Risperidone; Schizophrenia; Surveys and Questionnaires; Treatment Outcome; Young Adult

Blonanserin is a novel atypical antipsychotic drug that has efficacy equal to risperidone. We investigated the effects of aripiprazole and blonanserin on clinical symptoms and plasma levels of homovanillic acid (pHVA) and 3-methoxy-4hydroxyphenylglycol in the switching strategy of schizophrenia.. Twenty two Japanese patients with schizophrenia were enrolled into this open study. The antipsychotics of all patients were switched to aripiprazole or blonanserin for the improvement of clinical symptoms or side effects. Plasma monoamine metabolites levels were analyzed with high-performance liquid chromatography.. There were no significant effects for time (p = 0.346) or time × group interaction (p = 0.27) on the changes of positive and negative syndrome scale (PANSS) total score, although blonanserin decreased PANSS scores. We observed negative correlation between pHVA at baseline and the change in PANSS total score (rs = -0.450, p = 0.046). We also found positive correlation between the changes in pHVA and the changes in PANSS total (rs = 0.536, p = 0.015) and positive (rs = 0.572, p = 0.008) scores.. There were no differences between blonanserin and aripiprazole in the improvement of clinical symptoms. Our results suggest that pHVA may be useful indicator for the switching strategy to aripiprazole or blonanserin in schizophrenia.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Chromatography, High Pressure Liquid; Female; Homovanillic Acid; Humans; Japan; Male; Methoxyhydroxyphenylglycol; Middle Aged; Piperazines; Piperidines; Psychiatric Status Rating Scales; Quinolones; Schizophrenia; Time Factors; Treatment Outcome

JNJ-37822681 is a selective, fast-dissociating dopamine D2-receptor antagonist currently in development as a candidate antipsychotic. The aim of the analyses was to develop a population pharmacokinetic model to describe the pharmacokinetics of JNJ-37822681 in healthy subjects and patients with schizophrenia and to identify covariates of interest. The model was then used to simulate D2-receptor occupancy in support of dose selection for subsequent studies.. Data were obtained from 378 subjects enrolled in three phase I and two phase II studies. Nonlinear mixed effects modeling of pooled data was conducted using NONMEM(®) to estimate population pharmacokinetic parameters and the effect of covariates on these parameters. The model was evaluated on a subset of data that was not used for model building and was subsequently used to simulate steady-state exposure for each subject in the phase IIb study. Striatal D2-receptor occupancy was predicted using simulated exposure combined with pharmacodynamic parameters from a sigmoid maximum effect model established from previous [(11)C]raclopride positron emission tomography studies.. A two-compartment disposition model with zero-order input in a depot compartment followed by first-order absorption into and first-order elimination from the central compartment combined with a transit compartment provided the best fit to the data. Significant covariates were sex and bioavailability on apparent clearance and food intake on the absorption rate constant. Clearance was 11 % higher in females compared with males. The model passed external evaluation. The estimated pharmacokinetic parameters for the phase IIb study were similar to those observed in the phase IIa study. D2-receptor occupancy was predicted to be in the 65-80 % range at 10 mg twice daily and partially or fully reaching the 80 % threshold at doses of 20 and 30 mg twice daily.. The population pharmacokinetic model of JNJ-37822681 successfully described the pharmacokinetics of JNJ-37822681 and allowed the reliable determination of individual exposure parameters in a phase IIb study. It was concluded that 5 or 7.5 mg twice daily would likely be minimal- or no-effect doses, whereas 10 mg twice daily was expected to provide an optimal balance of efficacy and tolerability.

Topics: Adult; Aged; Antipsychotic Agents; Dopamine D2 Receptor Antagonists; Female; Healthy Volunteers; Humans; Male; Middle Aged; Models, Biological; Piperidines; Pyridazines; Receptors, Dopamine D2; Schizophrenia; Young Adult

Blonanserin is a relatively new atypical antipsychotic drug, and has been used in Korea and Japan for 1 and 3 years, respectively. Therefore, the clinical characteristics of blonanserin remain unclear. In this study, to clarify the features of blonanserin, we performed prospective and long-term comparative investigations of patients treated with blonanserin.. We followed 10 psychiatric patients who were switched to blonanserin from other antipsychotics for 1 year (schizophrenia: 8; mental retardation: 2). In the light of quality of life, we focused on adverse effects of patients during the follow-up.. In the long-term follow-up, (i) hyperprolactinemia is more frequently in risperidone than in blonanserin; however, it is more often in blonanserin than in olanzapine; and (ii) weight gain is more common in olanzapine than in blonanserin.. We switched to blonanserin from other antipsychotic drugs within the same case, and then followed the case for 1 year. We consider that long-term observations within the same case lead to obvious comparisons among drugs. On the basis of our findings, we conclude that blonanserin may be useful for the maintenance treatment of schizophrenia without inducing hyperprolactinemia and weight gain.

Topics: Adult; Antipsychotic Agents; Female; Follow-Up Studies; Humans; Piperazines; Piperidines; Prolactin; Psychotic Disorders; Quality of Life; Schizophrenia

The highly selective and fast dissociating D2 receptor antagonist JNJ-37822681 may be associated with lower risk for weight gain and undesirable metabolic effects compared with available antipsychotics.. In this double-blind, randomized study, patients were randomly assigned (1:1:1:1:1) to 12 weeks of JNJ-37822681 (10 mg, 20 mg, or 30 mg, twice daily) or olanzapine (10 mg/d during week 1; 15 mg/d after week 1), or 6 weeks of placebo (followed by 6 weeks of olanzapine, 15 mg/d). Metabolic and body mass parameters were assessed at weeks 6 and 12.. For metabolic parameters, at week 6 none of the JNJ-37822681 groups demonstrated significant change vs placebo; however, significant changes (P < .05) were observed in the olanzapine vs placebo group in triglycerides, low-density lipoprotein (LDL) and very-LDL cholesterol, and free fatty acids. For all JNJ-37822681 groups, mean weight changes at week 12 (-0.3 [10 mg], + 0.3 [20 mg], + 0.8 kg [30 mg]) were significantly less (P < .001) than for the olanzapine group (+ 2.7 kg). A higher percentage of overweight or obese patients (baseline body mass index: ≥25 kg/m2) receiving olanzapine had ≥7% increase in weight than those receiving JNJ-37822681 (9.8% vs 2.3%, respectively).. JNJ-37822681 treatment was associated with a more favorable outcome on weight and metabolic adverse effects vs olanzapine for treating schizophrenia; the 10 mg twice-daily dose demonstrated minimal to no weight gain.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Biomarkers; Blood Glucose; Body Mass Index; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Insulin; Male; Middle Aged; Olanzapine; Piperidines; Pyridazines; Schizophrenia; Triglycerides; Waist Circumference

Early predictability of sustained response to atypical antipsychotics in patients with schizophrenia has important implications for clinical decision making. In order to investigate whether early onset of efficacy correlates with week-6 response for the selective fast-dissociating D2 receptor antagonist JNJ-37822681, we analysed data from a 12-week placebo- and active-controlled (olanzapine) study designed to evaluate efficacy and safety of JNJ-37822681. Factors, including baseline Positive and Negative Syndrome Scale (PANSS) total score, waist circumference, weight, body mass index group, number of previous hospitalisations, age at diagnosis, race, sex and age at study entry, and relative (%) change from baseline on day 3 (early improvement) in PANSS total score, were analysed using logistic regression models and receiver operator characteristic (ROC) curve analysis, to predict the week-6 efficacy response (≥ 30% improvement in PANSS total score). Results showed that week-6 response with JNJ-37822681 30 mg bid treatment could be reliably predicted by improvement in PANSS total score on day 3, the number of previous hospitalisations, and race (80% accuracy [ROC area under curve]). Early improvement (day 3) in PANSS score had the highest predictive value as a single factor across all JNJ-37822681 doses. At a specificity of 70%, sensitivity for predicting week-6 response was: 0.60, 0.64, and 0.74 in the 10-, 20-, and 30 mg bid JNJ-37822681 groups, respectively; 0.40 in olanzapine group. Early improvement in PANSS may be a simple and reliable way to predict sustained response with JNJ-37822681 in patients with acute schizophrenia.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Olanzapine; Piperidines; Predictive Value of Tests; Pyridazines; Receptors, Dopamine D2; Schizophrenia; Schizophrenic Psychology; Time Factors; Treatment Outcome

Topics: Adult; Antipsychotic Agents; Appetite Depressants; Body Mass Index; Body Weight; Brain; Cannabinoid Receptor Antagonists; Double-Blind Method; Drug Inverse Agonism; Eating; Energy Intake; Female; Humans; Male; Middle Aged; Overweight; Pilot Projects; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Satiety Response; Schizophrenia; Schizophrenic Psychology; Signal Transduction; Treatment Outcome

Long-term use of the atypical antipsychotic iloperidone has not been investigated at doses above 16 mg/d. This article describes safety and tolerability results from the 25-week open-label extension of a 4-week placebo- and ziprasidone-controlled clinical trial of iloperidone.. Patients received a dose of 24 mg/d (given as 12 mg twice daily; mean dose = 21.6 mg) that could be reduced to 12 mg/d (given once daily at bedtime) any time after day 35 at the investigator's discretion.. A total of 72/173 patients (41.6%) completed the open-label extension. Treatment-emergent adverse events (TEAEs), most mild to moderate in severity, included headache (13.9%), weight increase (9.2%), dizziness (6.9%), nausea (6.4%), sedation (6.4%), and insomnia (5.2%). The only notable dose-related TEAEs were increased weight and headache. Levels of serum glucose, lipids, and prolactin were essentially unchanged or decreased during treatment. In general, akathisia and extrapyramidal symptoms (EPS) improved or were unchanged during treatment. There was no signal of worsening of efficacy based on changes from baseline in the Positive and Negative Syndrome Scale-Total.. This study further supports the long-term safety and tolerability of iloperidone for the treatment of schizophrenia, including iloperidone's favorable effect on metabolic laboratory parameters and low propensity to cause akathisia or EPS.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Substitution; Female; Humans; India; Isoxazoles; Longitudinal Studies; Male; Middle Aged; Piperazines; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Thiazoles; Time Factors; Treatment Outcome; United States; Young Adult

We examined 6 single nucleotide polymorphisms (SNPs) previously reported to be associated with response to iloperidone therapy for association with response to risperidone therapy.. Patients with schizophrenia (DSM-IV) were assessed during 2006 and 2007 for response/nonresponse (defined as ≥ 20%/<20% improvement in Positive and Negative Syndrome Scale [PANSS] total score) after 2 weeks of risperidone treatment (2 to 6 mg/d). Responders continued risperidone treatment; nonresponders were randomly assigned to either risperidone or olanzapine treatment (10 to 20 mg/d) for an additional 10 weeks. Associations between change in PANSS total (primary outcome measure), positive, and negative scores and the 6 SNPs were examined in risperidone-treated patients (N = 145). Genotype frequencies and improvement in PANSS total scores were analyzed for those SNPs significantly associated with change in PANSS total score.. The SNPs XKR4 rs9643483 and GRIA4 rs2513265 were significantly associated with change in PANSS total response (adjusted P < .05 for both), with the same direction of effect as reported for iloperidone. For patients with nonresponsive genotypes for these SNPs, mean improvement in PANSS total score for African Americans was two-thirds that seen for whites (XKR4: -13.9 versus -21.4; GRIA4: -12.5 versus -20.9).. In this retrospective pharmacogenomic analysis, we found that 2 SNPs previously linked to iloperidone response were also associated with response to risperidone.. clinicaltrials.gov Identifier: NCT00337662.

Topics: Adult; Antipsychotic Agents; Apoptosis Regulatory Proteins; Benzodiazepines; Biomarkers, Pharmacological; Black or African American; Drug Resistance; Genotype; Humans; Isoxazoles; Membrane Proteins; Membrane Transport Proteins; Olanzapine; Piperidines; Polymorphism, Single Nucleotide; Psychiatric Status Rating Scales; Receptors, AMPA; Risperidone; Schizophrenia; White People

To examine the effect of rimonabant on neurocognitive impairments in people with schizophrenia.. Participants entered a 16-week double-blind, placebo-controlled, randomized clinical trial. A neurocognitive battery was administered at baseline and end of study.. In comparison to rimonabant (20mg/day), placebo-treated participants exhibited a significant improvement on the Repeatable Battery for the Assessment of Neuropsychological Status total score. In contrast, rimonabant was associated with significant improvement on a probabilistic learning task. There were no other significant treatment effects.. Rimonabant did not improve global cognitive functioning, but did improve a specific learning deficit based on response to positive feedback.

Topics: Adolescent; Adult; Analysis of Variance; Cannabinoid Receptor Antagonists; Cognition Disorders; Depression; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neuropsychological Tests; Piperidines; Psychiatric Status Rating Scales; Pyrazoles; Rimonabant; Schizophrenia; Treatment Outcome; Young Adult

The efficacy and tolerability characteristics of an antipsychotic are difficult to determine from a single registration study. We thus conducted an analysis that assessed key efficacy and tolerability outcomes post hoc from four pooled short-term (4-6 weeks) phase III studies that evaluated iloperidone versus placebo in patients with schizophrenia or schizoaffective disorder.. Patient-level data were pooled from four prospective, randomized, double-blind, placebo-controlled and active-controlled, multicenter trials of iloperidone in patients with schizophrenia or schizoaffective disorder aged 18-65 years. Iloperidone 4-8, 10-16, and 20-24 mg/day (all dosed twice daily) were compared with placebo. Active controls used for assay sensitivity included risperidone 4-8 mg/day, haloperidol 15 mg/day, and ziprasidone 160 mg/day. Outcomes of interest were change from baseline to endpoint in the Brief Psychiatric Rating Scale (derived) (BPRSd), Positive and Negative Syndrome Scale (PANSS)-total (PANSS-T) score, and PANSS-positive (PANSS-P) and PANSS-negative (PANSS-N) subscale scores. An analysis of covariance (with treatment and study as factors, baseline as a covariate) was performed to compare changes between the iloperidone treatment groups versus placebo, on the basis of a last-observation-carried-forward approach for the intent-to-treat (ITT) populations. Tolerability outcomes were obtained from spontaneously reported adverse events (AEs), and number needed to harm was calculated for each antipsychotic versus placebo for the total population.. The ITT population included both schizoaffective and schizophrenia patients (N = 2401): n = 370, n = 494, and n = 424 for iloperidone 4-8, 10-16, and 20-24 mg/day, respectively; n = 294 for risperidone; n = 114 for haloperidol; n = 144 for ziprasidone; and n = 561 for placebo. Treatment with iloperidone 10-16 mg/day or 20-24 mg/day was associated with significantly improved BPRSd, PANSS-T, PANSS-P, and PANSS-N scores versus treatment with placebo. When only patients with schizophrenia were included (n = 1941), the pattern of results was essentially unchanged. The active controls confirmed assay sensitivity. Across all iloperidone dose groups, the incidences of extrapyramidal disorders and akathisia were similar to those observed with placebo. AEs for which the frequency was greater for iloperidone than placebo and for which the 95% confidence interval for number needed to harm did not contain infinity were dizziness, dry mouth, somnolence, nasal congestion, fatigue, sedation, and tachycardia; in general, for these AEs, frequency was higher with higher doses, resulting in a lower number needed to harm.. Consistent with product labeling, iloperidone 10-16 mg/day or 20-24 mg/day demonstrated significant improvement over placebo on BPRSd and PANSS-T scores, as well as on PANSS-P and PANSS-N subscale scores over 6 weeks of treatment in patients with schizophrenia and in the ITT population, which includes patients with schizoaffective disorder. Iloperidone did not differ from placebo in terms of extrapyramidal disorders and akathisia.

Topics: Adolescent; Adult; Aged; Analysis of Variance; Antipsychotic Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Labeling; Female; Haloperidol; Humans; Isoxazoles; Male; Middle Aged; Piperazines; Piperidines; Prospective Studies; Psychiatric Status Rating Scales; Psychotic Disorders; Risperidone; Schizophrenia; Thiazoles; Treatment Outcome; Young Adult

The purpose of this study was to evaluate the effects of blonanserin, a novel antipsychotic, on cognitive function in first-episode schizophrenia.. Twenty-four antipsychotic-naïve patients with first-episode schizophrenia participated in the study. Blonanserin was given in an open-label design for 8 weeks. The Brief Assessment of Cognition in Schizophrenia-Japanese language version (BACS-J) was administered as the primary outcome measure at baseline and 8 weeks. Clinical evaluation included the Positive and Negative Syndrome Scale (PANSS), the Schizophrenia Quality of Life Scale-Japanese language version (SQLS-J), and the Clinical Global Impression-Severity of Illness Scale (CGI-S). To exclude the possibility of retest effects on the BACS-J, 10 age-matched patients with chronic schizophrenia treated with blonanserin were tested at baseline and after an 8-week interval.. Twenty first-episode patients completed the study. Repeated measures analysis of covariance revealed a significant group-by-time interaction effect on the letter fluency task due to better performance in the first-episode group, but not in the control group. Main effect of time or group-by-time interaction effect on the Tower of London task was not significant; however, the first-episode group, but not the control group, showed substantial improvement with a moderate effect size. All items on the PANSS, SQLS-J, and CGI-S significantly improved after 8 weeks of treatment.. These results suggest that blonanserin improves some types of cognitive function associated with prefrontal cortical function.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Chronic Disease; Cognition Disorders; Female; Humans; Male; Piperazines; Piperidines; Prospective Studies; Psychiatric Status Rating Scales; Quality of Life; Schizophrenia; Severity of Illness Index; Single-Blind Method; Treatment Outcome; Young Adult

JNJ-37822681 is a novel, highly selective dopamine D₂ receptor antagonist characterized by a rapid dissociation rate from the dopamine D₂ receptor. This profile was hypothesized to confer antipsychotic efficacy and improved tolerability. In this 12-week study, the efficacy and safety of JNJ-37822681 were evaluated in patients with an acute exacerbation of schizophrenia, randomly assigned (1:1:1:1:1) to JNJ-37822681 (10-, 20- or 30-mg bid), olanzapine (15 mg once-daily), or placebo (for 6 weeks followed by olanzapine for 6 weeks). Of 498 randomized patients, 298 (60%) completed the study. All JNJ-37822681 dose groups and the olanzapine group showed significantly greater reduction in PANSS total score from baseline to week 6 versus placebo (all p-values < 0.001). Least-squares adjusted mean changes from baseline to week 6 in PANSS total score were: -6.4 (placebo); -18.4 (10 mg JNJ-37822681), -17.7 (20 mg JNJ-37822681), -20.0 (30 mg JNJ-37822681) and -22.9 (olanzapine). All JNJ-37822681 groups showed significant improvement versus placebo from baseline to week 6 in the PANSS subscales, Marder factors, Clinical Global Impression of Severity, and in the Subjective Well-Being on Neuroleptics scale (all p-values < 0.05). The most common treatment-emergent adverse events with JNJ-37822681 were insomnia (17%) and akathisia (13%). Incidences of extrapyramidal symptoms were dose-related and were comparable for JNJ-37822681 10 mg bid and olanzapine groups. All JNJ-37822681 dose groups showed lesser weight gain compared with olanzapine. The efficacy and tolerability profile of the JNJ-37822681 10 mg bid was consistent with the study hypothesis.

Topics: Acute Disease; Adult; Akathisia, Drug-Induced; Antipsychotic Agents; Benzodiazepines; Diagnostic and Statistical Manual of Mental Disorders; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Incidence; Intention to Treat Analysis; Male; Middle Aged; Olanzapine; Patient Dropouts; Piperidines; Psychiatric Status Rating Scales; Pyridazines; Receptors, Dopamine D2; Schizophrenia; Schizophrenic Psychology; Sleep Initiation and Maintenance Disorders

Most atypical antipsychotic drugs (APDs), e.g. risperidone (RIS), produce more extensive blockade of brain serotonin (5-HT)(2A) than dopamine (DA) D(2) receptors. This distinguishes them from typical APDs, e.g. haloperidol (HAL). Our objective was to test the hypothesis that augmentation of low doses of RIS or HAL (2mg/day) with pimavanserin (PIM), a selective 5-HT(2A) inverse agonist, to enhance 5-HT(2A) receptor blockade, can achieve efficacy comparable to RIS, 6mg/day, but with lesser side effects. In a multi-center, randomized, double-blind, 6week trial, 423 patients with chronic schizophrenia experiencing a recent exacerbation of psychotic symptoms were randomized to RIS2mg+placebo (RIS2PBO), RIS2mg+PIM20mg (RIS2PIM), RIS6mg+PBO (RIS6PBO), HAL2mg+PBO (HAL2PBO), or HAL2mg+PIM20mg (HAL2PIM). Improvement in psychopathology was measured by the PANSS and CGI-S. The reduction in PANSS Total Score with RIS2PIM at endpoint was significantly greater than RIS2PBO: -23.0 vs. -16.3 (p=0.007), and not significantly different from the RIS6PBO group: -23.2 points. The percentage of patients with ≥20% improvement at day 15 in the RIS2PIM group was 62.3%, significantly greater than the RIS6PBO (42.1%; p=0.01) and the RIS2PBO groups (37.7%; p=0.002). Weight gain and hyperprolactinemia were greater in the RIS6PBO group than the RIS2PIM group but there was no difference in extrapyramidal side effects (EPS). HAL2PBO and HAL2PIM were not significantly different from each other in efficacy but HAL2PIM had less EPS at end point. Both HAL groups and RIS6PBO showed equal improvement in psychopathology at endpoint, indicating HAL 2mg/day is effective to treat an acute exacerbation in chronic schizophrenia patients. In conclusion, a sub-effective RIS dose combined with PIM to enhance 5-HT(2A) receptor blockade provided faster onset of action, and at endpoint, equal efficacy and better safety, compared to standard dose RIS. These results support the conclusion that 5-HT(2A) receptor blockade is a key component of the action of some atypical APDs and can reduce EPS due to a typical APD.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Interactions; Female; Follow-Up Studies; Haloperidol; Humans; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Time Factors; Urea; Young Adult

Weight gain is a major adverse effect of several second-generation antipsychotic medications. Rimonabant is a cannabinoid-1 receptor antagonist that promotes weight loss in the general population. We conducted a 16-week, double-blind, placebo-controlled study of rimonabant (20 mg/d) in people with schizophrenia or schizoaffective disorder, based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria, who were clinically stable on second-generation antipsychotics. Participants had a body mass index of 27 kg/m or higher with hyperlipidemia or body mass index of 30 kg/m or higher, and no current substance abuse/dependence (except nicotine), more than weekly cannabis use, or recent depressive symptoms/suicidality. An exercise and dietary counseling group was offered weekly. Target enrollment was 60; the trial was terminated early because of withdrawal of rimonabant from the European market. Fifteen participants were randomized (7 rimonabant, 8 placebo); 5 completed in each group. Rimonabant was associated with a greater reduction in Brief Psychiatric Rating Scale total score versus placebo (mean ± SE difference, -1.9 ± 0.8, P = 0.02), driven by differences in the Brief Psychiatric Rating Scale anxiety/depression (-1.4 ± 0.35, P = 0.0004) and hostility (-0.7 ± 0.3, P = 0.02) factors. Group differences were not significant for the Calgary Depression Scale total score (P = 0.24), Scale for the Assessment of Negative Symptoms total score (P = 0.13), weight, blood pressure, or fasting lipids or glucose. Rimonabant was well tolerated with no significant adverse events. No significant weight loss, metabolic effects, or adverse psychiatric effects were associated with the cannabinoid-1 receptor antagonist rimonabant in this small sample of people with schizophrenia. The endocannabinoid system remains a promising target for pharmacotherapy of schizophrenia and obesity.

Topics: Adult; Antipsychotic Agents; Double-Blind Method; Female; Humans; Male; Middle Aged; Overweight; Pilot Projects; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Schizophrenia; Schizophrenic Psychology

The aim of this study was to assess human striatal dopamine receptor 2 (D(2)) and cortical 5-hydroxytryptamine receptor 2A (5-HT(2A)) occupancy of SB-773812 to demonstrate brain penetration and binding to the target receptors and assess the pharmacokinetics-receptor occupancy relationship over time to aid dose selection and dosage regimen, in preparation for the phase II trials.. D(2) and 5-HT(2A) occupancy were measured over time (both at the time of maximum [T(max); 6 ± 2 h] and at the time of minimum [T(trough); 24 ± 4 h] plasma concentration after dosing) by means of (123)I-iodobenzamide and (123)I-4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]5-iodo-2-methoxybenzamide ((123)I-R91150) SPECT in 3 studies. Study A consisted of SB-773812 single doses in healthy volunteers-D(2) occupancy measured at 48 (n = 9) and 56 mg (n = 9) and 5-HT(2A) occupancy at 56 mg (n = 9); study B consisted of D(2) and 5-HT(2A) occupancy measured in 12 stabilized-schizophrenia patients on stable doses (16-18 d of 56 mg/d) after washout of previous medication; and study C included D(2) occupancy measured in a double-blind study of patients with acutely exacerbated schizophrenia (n = 10) on stable doses (18-21 d) of SB-773812 (100 mg/d; n = 7) or risperidone (6 mg/d; n = 3).. Study A showed less than 30% D(2) occupancy at T(max), maintained at T(trough). 5-HT(2A) occupancy was 74%-97% and also maintained over time. Study B revealed that 8 of the 12 schizophrenia patients showed more than 40% D(2) occupancy. 5-HT(2A) occupancy ranged from 91% to 100%. In study C, SB-773812-induced D(2) occupancy was 60.3% ± 13.3% at T(max) and 55.1% ± 4.9% at T(trough). The pharmacokinetics-receptor occupancy relationship was assessed in each study and strengthened, combining all data to yield a concentration associated with 50% occupancy (EC(50)) of 92.7 ± 13.5 ng/mL for D(2) and 2.11 ± 0.50 ng/mL for 5-HT(2A).. In all subjects, SB-773812 showed penetration into the brain, reaching its target receptors. In patients with schizophrenia, D(2) occupancy levels induced by a single dose were maintained over time, indicating that once-daily dosing regimens are appropriate. Pharmacokinetics-receptor occupancy analysis provided guidance for the selection of a clinically effective dose, supporting progression in phase II.

Topics: Adult; Algorithms; Antipsychotic Agents; Brain; Cohort Studies; Diagnostic and Statistical Manual of Mental Disorders; Dose-Response Relationship, Drug; Humans; Image Processing, Computer-Assisted; Iodobenzenes; Male; Piperidines; Radiopharmaceuticals; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Risperidone; Schizophrenia; Tomography, Emission-Computed, Single-Photon; Young Adult

Preclinical and clinical research suggests that the endogenous cannabinoid system is involved in cognitive impairments related to schizophrenia. In particular, the deficient generation of mismatch negativity (MMN) indicating auditory sensory memory is a characteristic finding in schizophrenic patients. Experimental studies implicate deficient N-methyl-D: -aspartate (NMDA) receptor functioning in such abnormalities.. The primary aim of this study was to investigate the effects of the cannabinoid CB(1) receptor antagonist rimonabant on MMN deficits in the NMDA receptor antagonist model of schizophrenia by using ketamine.. Twenty-four healthy male subjects participated in a randomized, double-blind, placebo-controlled cross-over study with subanesthetic doses of intravenous ketamine. The MMNs to frequency and duration deviants were elicited within an auditory oddball paradigm and recorded by a 32-channel EEG. Psychopathology was assessed using the Psychotomimetic States Inventory.. Twenty subjects completed both experimental sessions. Ketamine infusion had no significant effect on MMN amplitudes in both deviance conditions. In contrast to placebo, co-administration of rimonabant produced significant deficits in MMN amplitudes to duration deviants at electrode position Fz.. The results point to the involvement of the endogenous cannabinoid system in auditory sensory memory as a cognitive key feature in schizophrenia. They particularly suggest that CB(1) receptor antagonism may impair cognitive performance by a disturbed interaction between endocannabinergic activity and glutamatergic neurotransmission implied in schizophrenia.

Topics: Adult; Cross-Over Studies; Double-Blind Method; Evoked Potentials, Auditory; Excitatory Amino Acid Antagonists; Humans; Ketamine; Male; Piperidines; Prospective Studies; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, N-Methyl-D-Aspartate; Rimonabant; Schizophrenia; Young Adult

The Positive and Negative Syndrome Scale (PANSS) total score is widely used to assess antipsychotic efficacy, however schizophrenia is a multi-dimensional disorder. We conducted a 5-factor analysis for evaluating the efficacy of iloperidone vs. placebo across these different domains in the treatment of schizophrenia.. The 5-factor model was determined from pooled data from 7 clinical trials (4 placebo- and active-controlled and 3 non-inferiority active-comparator trials of iloperidone) in schizophrenia (N=3580).Five factors were derived (excitement/hostility [P4,P7,G8,G14], depression/anxiety [G1,G2,G3,G4,G6], cognition [P2,N5,N7,G5,G10,G11,G12,G13,G15], positive [P1,P3,P5,P6,G9], and negative [N1,N2,N3,N4,N6,G7,G16]) from a factor analysis on the covariance matrix of 30 baseline PANSS items using a varimax rotation; factors retained had eigenvalues of ≥ 0.5. These newly derived 5 factors differ only slightly from other 5-factor analyses published by others using different datasets. The analysis of covariance model was then applied to assess these efficacy outcomes from the 4-6 week double-blind placebo and active controlled clinical trials of iloperidone.. Based on the placebo-controlled trials, iloperidone improvements from baseline (least squared mean change ± standard error) were as follows: excitement/hostility, 0.4 ± 0.21 for 10-16 mg, 0.6 ± 0.43 for 20-24 mg vs. -1.0 ± 0.23 for placebo; P<0.001 for both iloperidone doses vs. placebo; depression/anxiety, 1.9 ± 0.21 for 10-16 mg, 1.9 ± 0.41 for 20-24 mg vs. 1.1 ± 0.22 for placebo; P<0.05 for 10-16 mg dose vs. placebo; cognition, 2.8 ± 0.35 for 10-16 mg, 3.9 ± 0.69 for 20-24 mg vs. 1.6 ± 0.38 for placebo; P<0.05 for both iloperidone doses vs. placebo; positive, 3.7 ± 0.26 for 10-16 mg, 4.1 ± 0.53 for 20-24 mg vs. 2.7 ± 0.29 for placebo; P<0.05 for both iloperidone doses vs. placebo; and negative, 2.2 ± 0.29 for 10-16 mg, 2.5 ± 0.58 for 20-24 mg vs. 1.3 ± 0.32 for placebo; P<0.05 for 10-16 mg vs. placebo. Active controls validated iloperidone efficacy.. Iloperidone demonstrated positive treatment effects on these newly derived PANSS factors. The 10-16 mg and 20-24 mg dose groups had similar efficacy on the PANSS factors, with the exception of the depression/anxiety and negative factors, on which the 10-16 mg dose group showed statistical separation from placebo and the 20-24 mg dose group did not. At 6 weeks, the lack of separation from placebo for the higher dose group may have been due to the much smaller sample size in that group.

Topics: Adolescent; Adult; Age Factors; Aged; Antipsychotic Agents; Cognition Disorders; Dose-Response Relationship, Drug; Double-Blind Method; Factor Analysis, Statistical; Female; Follow-Up Studies; Humans; Isoxazoles; Male; Middle Aged; Mood Disorders; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Treatment Outcome; Young Adult

Weight gain is a common side effect of antipsychotics, contributing to poor treatment adherence, and previously linked to the -759C/T polymorphism near the serotonin receptor 2C gene. The effect of this polymorphism was analyzed in schizophrenia patients treated with iloperidone for up to 7 months. No association was detected with the modest weight changes observed in these patients.

Topics: Analysis of Variance; Antipsychotic Agents; Female; Follow-Up Studies; Gene Frequency; Genotype; Humans; Isoxazoles; Male; Piperazines; Piperidines; Polymorphism, Genetic; Receptor, Serotonin, 5-HT2C; Schizophrenia; Thiazoles; Weight Gain

The objective of this study was to evaluate the efficacy and tolerability of blonanserin for the treatment of Korean patients with schizophrenia using a double-blind risperidone-compared design.. Patients aged 18 to 65 years with schizophrenia were randomly assigned to blonanserin or risperidone treatment for 8 weeks. The efficacy was assessed using the mean change in Positive and Negative Syndrome Scale score total scores from baseline to week 8. Safety assessments included monitoring of vital signs, a physical examination, laboratory tests, and adverse events.. Of 206 randomly enrolled patients, 103 receiving blonanserin and 103 receiving risperidone were included in the analysis. In this study, noninferiority between blonanserin and risperidone was demonstrated. The mean change in the Positive and Negative Syndrome Scale total score at the final evaluation time point was -23.48 +/- 19.73 for the blonanserin group and -25.40 +/- 18.38 for the risperidone group. Adverse events, which occurred less frequently in the blonanserin than in the risperidone group, included dysarthria (P = 0.0288), dizziness (P = 0.0139), increased alanine aminotransferase and aspartate aminotransferase (P = 0.0095 and P = 0.0032, respectively), and increased level blood prolactin (P = 0.0012). On the other hand, the adverse events that occurred more frequently in the blonanserin than in the risperidone group was hand tremor (P = 0.0006).. Blonanserin was effective in the treatment of Korean patients with schizophrenia compared with risperidone and was more tolerable with a better safety profile, particularly with respect to prolactin elevation. These findings suggest that blonanserin is useful in the treatment of schizophrenia.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Hyperprolactinemia; Male; Middle Aged; Piperazines; Piperidines; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Weight Gain; Young Adult

A whole genome association study was performed in a phase 3 clinical trial conducted to evaluate a novel antipsychotic, iloperidone, administered to treat patients with schizophrenia. Genotypes of 407 patients were analyzed for 334,563 single nucleotide polymorphisms (SNPs). SNPs associated with iloperidone efficacy were identified within the neuronal PAS domain protein 3 gene (NPAS3), close to a translocation breakpoint site previously observed in a family with schizophrenia. Five other loci were identified that include the XK, Kell blood group complex subunit-related family, member 4 gene (XKR4), the tenascin-R gene (TNR), the glutamate receptor, inotropic, AMPA 4 gene (GRIA4), the glial cell line-derived neurotrophic factor receptor-alpha2 gene (GFRA2), and the NUDT9P1 pseudogene located in the chromosomal region of the serotonin receptor 7 gene (HTR7). The study of these polymorphisms and genes may lead to a better understanding of the etiology of schizophrenia and of its treatment. These results provide new insight into response to iloperidone, developed with the ultimate goal of directing therapy to patients with the highest benefit-to-risk ratio.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Basic Helix-Loop-Helix Transcription Factors; Double-Blind Method; Female; Genome-Wide Association Study; Glial Cell Line-Derived Neurotrophic Factor Receptors; Humans; Isoxazoles; Male; Middle Aged; Nerve Tissue Proteins; Pharmacogenetics; Piperazines; Piperidines; Polymorphism, Single Nucleotide; Pseudogenes; Receptors, AMPA; Schizophrenia; Tenascin; Thiazoles; Transcription Factors; Young Adult

Administration of certain drugs (for example, antiarrhythmics, antihistamines, antibiotics, antipsychotics) may occasionally affect myocardial repolarization and cause prolongation of the QT interval. We performed a whole genome association study of drug-induced QT prolongation after 14 days of treatment in a phase 3 clinical trial evaluating the efficacy, safety and tolerability of a novel atypical antipsychotic, iloperidone, in patients with schizophrenia. We identified DNA polymorphisms associated with QT prolongation in six loci, including the CERKL and SLCO3A1 genes. Each single nucleotide polymorphism (SNP) defined two genotype groups associated with a low mean QT change (ranging from -0.69 to 5.67 ms depending on the SNP) or a higher mean QT prolongation (ranging from 14.16 to 17.81 ms). The CERKL protein is thought to be part of the ceramide pathway, which regulates currents conducted by various potassium channels, including the hERG channel. It is well established that inhibition of the hERG channel can prolong the QT interval. SLCO3A1 is thought to play a role in the translocation of prostaglandins, which have known cardioprotective properties, including the prevention of torsades de pointes. Our findings also point to genes involved in myocardial infarction (PALLD), cardiac structure and function (BRUNOL4) and cardiac development (NRG3). Results of this pharmacogenomic study provide new insight into the clinical response to iloperidone, developed with the goal of directing therapy to those patients with the optimal benefit/risk ratio.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Carrier Proteins; CELF Proteins; Cytoskeletal Proteins; Double-Blind Method; Electrocardiography; Female; Follow-Up Studies; Gene Frequency; Genome-Wide Association Study; Genotype; Humans; Intracellular Signaling Peptides and Proteins; Isoxazoles; Linear Models; Linkage Disequilibrium; Long QT Syndrome; Male; Middle Aged; Neuregulins; Organic Anion Transporters; Pharmacogenetics; Phosphoproteins; Phosphotransferases (Alcohol Group Acceptor); Piperazines; Piperidines; Polymorphism, Single Nucleotide; RNA-Binding Proteins; Schizophrenia; Thiazoles; Young Adult

Despite the beneficial effects of atypical antipsychotics on cognition, many schizophrenic patients continue to suffer from cognitive impairment. Postmortem findings suggest that altered cholinergic activity is involved in cognitive impairment in schizophrenia.. This study investigated whether adjunctive donepezil added to atypical antipsychotics can improve cognition in schizophrenic patients.. We conducted an open-label trial of donepezil, at doses of up to 10 mg/day for 12 weeks, added to ongoing atypical antipsychotics in 28 stable schizophrenic patients. At baseline and 12 weeks, the patients were evaluated using the Positive and Negative Syndrome Scale (PANSS), Schizophrenia Cognition Rating Scale (SCoRS), and Computerized Neurocognitive Function Test (CNT).. Donepezil treatment resulted in significant improvements in attention, memory, psychomotor speed, and mental set-shifting ability.. Adjunctive treatment with donepezil improves cognition in patients with schizophrenia who are stabilized on atypical antipsychotics. Further studies controlling for smoking, age, and severity of cognitive impairment of the participants are needed.

Topics: Adult; Antipsychotic Agents; Cognition Disorders; Donepezil; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Blonanserin is a novel atypical antipsychotic agent with potent dopamine D(2) and serotonin 5-HT(2) antagonist properties. It may potentially have a lower incidence of adverse events than other antipsychotic agents.. To determine the efficacy and safety of three doses of blonanserin compared with placebo and haloperidol in patients with acute-phase schizophrenia.. This was a 6-week, randomized, double-blind, placebo- and haloperidol-controlled, international, multicentre study. Patients with an acute exacerbation of their schizophrenia, with a Positive and Negative Syndrome Scale (PANSS) score >/=70 and a Clinical Global Impression - Severity of Illness (CGI-S) score >/=4 ('moderately ill') [with no decrease >/=20% or >/=1 point, respectively, during the wash-out period] were randomized into one of five treatment groups (blonanserin 2.5, 5 or 10 mg, haloperidol 10 mg or placebo once daily). Patients were assessed weekly for clinical efficacy, adverse events, extrapyramidal symptoms (EPS) and drug compliance, and were assessed biweekly for other safety variables.. All 307 randomized patients received at least one dose of study medication and 228 (74.3%) completed the study. The mean reduction in PANSS total score at week 6 was significantly greater with all active treatments compared with placebo (-12.58; p < 0.001); blonanserin 10 mg was significantly superior to blonanserin 2.5 mg (-30.18 vs -20.6; p < 0.001), but blonanserin 5 mg (-27.19) and haloperidol 10 mg (-28.16) were not. All active treatments showed greater efficacy against the positive symptoms of schizophrenia, and blonanserin (5 and 10 mg) was more effective against the negative symptoms than haloperidol. Blonanserin was well tolerated at all doses and there was no evidence of clinically important weight gain, orthostatic hypotension, corrected QT interval prolongation or clinically relevant changes in laboratory test results. Haloperidol caused persistent elevation in prolactin levels, but this was not seen with any dose of blonanserin throughout the study period. There was a lower incidence of EPS with blonanserin 10 mg (26.6%) than with haloperidol 10 mg (53.3%).. Blonanserin was effective in the treatment of acute schizophrenia and showed greater efficacy in negative symptoms compared with placebo and haloperidol. Blonanserin was well tolerated and its safety profile compared favourably with haloperidol, particularly with respect to prolactin elevation and EPS frequency.

Topics: Adolescent; Adult; Aged; Analysis of Variance; Antipsychotic Agents; Dose-Response Relationship, Drug; Double-Blind Method; Female; Haloperidol; Humans; International Cooperation; Male; Middle Aged; Piperazines; Piperidines; Prospective Studies; Psychiatric Status Rating Scales; Schizophrenia; Severity of Illness Index; Young Adult

To demonstrate how several polymorphisms previously associated with the efficacy of the novel antipsychotic iloperidone could be used together to predict clinical response and provide practical information for individualized treatment.. This inpatient randomized, double-blind, placebo- and ziprasidone-controlled, 28-day study of the efficacy of iloperidone was conducted from November 2005 to September 2006. Likelihood ratios, predicted probabilities of response, and number needed to treat were calculated for patients with schizophrenia (DSM-IV criteria) using 6 genetic markers of iloperidone response as measured by change in the Positive and Negative Syndrome Scale-Total (PANSS-T) score. Data analysis was performed on 409 patients of various ethnic origins.. The 6-marker genotype combinations defined 4 groups of patients with distinct probabilities of response. More than 75% of iloperidone-treated patients in the group with the optimal genotype combinations showed a 20% or greater improvement, compared with 37% for patients with other genotypes. These patients had a significant response by the first week of treatment, which was earlier than for patients with other genotype combinations. The odds of responding to iloperidone treatment with at least 20% improvement ranged from 2.4 to 3.6 for patients with 1 of the 6 favorable single-marker genotypes. The odds increased to 9.5 or greater for patients with the most favorable 6-marker combinations. The difference in PANSS-T score improvement observed between the genotype groups was also seen for the positive, negative, and general psychopathology PANSS subscales. The relationship between treatment efficacy and genotype combinations was not observed for patients treated with ziprasidone.. These results illustrate the combined use of genetic markers to predict enhanced response to iloperidone and support the application of pharmacogenetics to differentiate medication options and improve individualized treatments for schizophrenia.. (ClinicalTrials.gov) Identifier: NCT00254202.

Topics: Adult; Alleles; Antipsychotic Agents; Double-Blind Method; Female; Genetic Markers; Genotype; Humans; Isoxazoles; Likelihood Functions; Male; Middle Aged; Odds Ratio; Pharmacogenetics; Piperazines; Piperidines; Polymorphism, Single Nucleotide; Probability; Psychiatric Status Rating Scales; Psychometrics; Schizophrenia; Thiazoles; Treatment Outcome

There is considerable incentive to develop new treatment strategies that effectively target cognitive deficits in schizophrenia. One of the theoretically promising novel treatment candidates is acetylcholinesterase inhibitors that increase the synaptic levels of cholinergic, nicotinic, and muscarinic receptor activity. The purpose of this study was to assess the efficacy of donepezil as an adjuvant agent in the treatment of chronic schizophrenia in particular for cognitive impairments. This investigation was a 12-week, double-blind study of parallel groups of patients with stable chronic schizophrenia. Thirty patients were recruited from inpatient and outpatient departments, age ranging from 22 to 44 years. All participants met DSM-IV-TR. diagnostic criteria for schizophrenia. To be eligible, patients were required to have been treated with a stable dose of risperidone as their primary antipsychotic treatment for a minimum period of 8 weeks. The subjects were randomized to receive donepezil (10 mg/day) or placebo, in addition to risperidone (4-6 mg/day). Clinical psychopathology was assessed with Positive and Negative Syndrome Scale (PANSS). Cognition was measured by a cognitive battery. Patients were assessed by a psychiatrist at baseline and after 8, and 12 weeks after the medication started. The PANSS scores and cognitive performance were used as the outcome measures. The donepezil group had significantly greater improvement in the negative symptoms over the 12-week trial. There were no differences between the donepezil and placebo groups on any neurocognitive assessments at endpoint (week 12). The present study indicates donepezil as a potential adjunctive treatment strategy for negative symptoms of chronic schizophrenia.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Mental Status Schedule; Neuropsychological Tests; Nootropic Agents; Piperidines; Prospective Studies; Risperidone; Schizophrenia; Treatment Outcome; Young Adult

AMPA-receptor-positive modulators (Ampakines) facilitate learning and memory in animal models and in preliminary trials in human subjects. CX516 is the first Ampakine to be studied for cognitive enhancement in schizophrenia. Stable schizophrenia patients treated with clozapine (n=52), olanzapine (n=40), or risperidone (n=13) were randomly assigned to add-on treatment with CX516 900 mg three times daily or placebo for 4 weeks. Subjects were assessed with a cognitive battery at baseline, week 4, and at 4-week follow-up. Clinical scales and safety monitoring were also performed. The primary endpoint was the change from baseline in a composite cognitive score at week 4 for the intent-to-treat sample. Additional analyses examined change in symptom rating scores and examined drug effects on patients treated with clozapine separately from patients treated with either olanzapine or risperidone. A total of 105 patients were randomized and 95 (90%) completed the 4-week trial. Patients treated with CX516 did not differ from placebo in change from baseline on the composite cognitive score, or on any cognitive test at weeks 4 or 8. The between groups effect size at week 4 for the cognitive composite score was -0.19 for clozapine-treated patients and 0.24 for patients treated with olanzapine or risperidone. The placebo group improved more on the PANSS total score than the CX516 group; no other clinical rating differed between treatment groups. CX516 was associated with fatigue, insomnia and epigastric discomfort compared to placebo, but was generally well tolerated. CX516 was not effective for cognition or for symptoms of schizophrenia when added to clozapine, olanzapine, or risperidone.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Cognition Disorders; Dioxoles; Double-Blind Method; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Olanzapine; Pilot Projects; Piperidines; Psychiatric Status Rating Scales; Psychomotor Performance; Risperidone; Sample Size; Schizophrenia; Schizophrenic Psychology

Altered expression of central muscarinic and nicotinic acetylcholine receptors in hippocampal and cortical regions may contribute to the cognitive impairment exhibited in patients with schizophrenia. Increasing cholinergic activity through the use of a cholinesterase inhibitor (ChEI) therefore represents a possible strategy for cognitive augmentation in schizophrenia. We examined the efficacy and safety of the ChEI donepezil as cotreatment for mild to moderate cognitive impairment in schizophrenia or schizoaffective disorder in a prospective, 12-week, placebo-controlled, double-blind, parallel-group study. In total, 250 patients (18-55 years) with schizophrenia or schizoaffective disorder who were clinically stabilized on risperidone, olanzapine, quetiapine, ziprasidone, or aripiprazole, alone or in combination, were enrolled at 38 outpatient psychiatric clinics in the United States. Patients were randomized to donepezil 5 mg q.d. for 6 weeks then 10 mg q.d. for 6 weeks, or placebo administered as oral tablets. The primary outcome measure was the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) neurocognitive battery composite score. In the intent-to-treat sample (donepezil, n=121; placebo, n=124), both treatments showed improvement in the composite score from baseline to week 12. At week 12, cognitive improvement with donepezil was similar to that with placebo (last-observation-carried-forward effect size, 0.277 vs 0.411; p=0.1182) and statistically significantly inferior for the observed-cases analysis (0.257 vs 0.450; p=0.044). There was statistically significant improvement in the Positive and Negative Syndrome Assessment Scale negative symptoms score for placebo compared with donepezil, while total and positive symptom scores were similar between both treatments. Statistically significant improvements in positive symptoms score and Clinical Global Impression-Improvement for donepezil compared with placebo were noted at Week 6. Treatment-emergent adverse events (AEs) were observed for 54.5% of donepezil- and 61.3% of placebo-treated patients; most AEs were rated as mild to moderate in severity. Donepezil was safe and well-tolerated but was not effective compared with placebo as a cotreatment for the improvement of cognitive impairment in this patient population. A significant and surprisingly large placebo/practice effect was observed among placebo-treated patients, and is a serious consideration in future clinical trial study desig

Topics: Adult; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Piperidines; Placebo Effect; Practice, Psychological; Prospective Studies; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Time Factors

Presence of the null FS63TER allele of the rs1800169 polymorphism in the gene encoding the ciliary neurotrophic factor (CNTF) may increase the risk of schizophrenia. This study prospectively evaluated the CNTF rs1800169 genotype (G/G vs non-G/G) effects on response to iloperidone.. Iloperidone 24 mg/day was evaluated in a study of patients with schizophrenia. Efficacy measurements included Positive and Negative Syndrome Scale total (PANSS-T), Brief Psychiatric Rating Scale (BPRS) and Clinical, Global, Impression (CGI) scores. The step-down primary end point was the difference in PANSS-T scores based on CNTF rs1800169 G/G genotype.. This study genotyped 417 patients (279 iloperidone and 138 placebo) for the rs1800169 polymorphism. Iloperidone significantly improved PANSS-T, PANSS positive subscale (PANSS-P), PANSS negative subscale (PANSS-N), BPRS, Clinical Global Impression of Change (CGI-C) and Clinical Global Impression of Severity (CGI-S) scores versus placebo. G/G versus non-G/G patients had greater improvement with iloperidone versus placebo in PANSS, BPRS and CGI scores.. The relative treatment benefit of iloperidone compared with placebo in patients with schizophrenia is enhanced in patients homozygous G/G for the rs1800169 polymorphism.

Topics: Adult; Antipsychotic Agents; Ciliary Neurotrophic Factor; Double-Blind Method; Female; Humans; Isoxazoles; Male; Piperidines; Placebos; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Racial Groups; Schizophrenia; Schizophrenic Psychology

Iloperidone is a mixed D2/5-HT2 antagonist in development for treatment of schizophrenia. This trial aimed to evaluate the efficacy and safety of a fixed dose of iloperidone in patients with acute exacerbations of schizophrenia. This randomized, placebo-controlled, multicenter study comprised a 1-week titration period and a 3-week double-blind maintenance period. Eligible patients (n = 593) were randomized to iloperidone 24 mg/d, ziprasidone 160 mg/d as an active control, or placebo. Primary efficacy variable was change from baseline in the Positive and Negative Syndrome Scale Total (PANSS-T) score, using a mixed-effects model repeated measures analysis. Iloperidone demonstrated significant reduction versus placebo on the PANSS-T score (P< 0.01). Significant improvement versus placebo was also demonstrated with ziprasidone (P < 0.05). Compared with ziprasidone, iloperidone was associated with lower rates of many adverse events (AEs) that are particularly troublesome with antipsychotics, including sedation, somnolence, extrapyramidal symptoms, akathisia, agitation, and restlessness; iloperidone was associated with higher rates of weight gain, tachycardia, orthostatic hypotension, dizziness, and nasal congestion as reported as an AE. Most AEs were mild to moderate. A similar amount of QT prolongation was observed with both active treatments, although no patient had a treatment-emergent postbaseline corrected QT interval of 500 msec or greater. The incidence of clinically relevant changes in laboratory parameters was comparable between iloperidone and ziprasidone. Iloperidone was associated with a low incidence of extrapyramidal symptoms. Overall, there was improvement in akathisia with iloperidone treatment. Iloperidone treatment was effective, safe, and well tolerated in patients with acute exacerbation of schizophrenia.

Topics: Acute Disease; Adolescent; Adult; Aged; Antipsychotic Agents; Double-Blind Method; Drug Administration Schedule; Female; Humans; Isoxazoles; Male; Middle Aged; Piperazines; Piperidines; Prospective Studies; Schizophrenia; Thiazoles; Treatment Outcome

To study the effects of acetylcholinesterase inhibitors (AChEIs) in the management of cognitive impairments in patients with schizophrenia, we investigated the effects of 12 weeks of adjunctive therapy with donepezil on their cognitive impairments. Twenty-four subjects stabilized on haloperidol treatment (5-30 mg/day) for a minimum of 3 months were entered into a double-blind, placebo-controlled trial of donepezil as an adjunctive treatment. Subjects were randomly assigned under double-blind conditions to receive either 5 mg/day donepezil (N = 12) or pLacebo (N = 12) for 12 weeks. The subjects were evaluated at baseline, and after 4, 8, and 12 weeks using the Korean version of Mini Mental State Examination (K-MMSE), Brief Psychiatric Rating Scale (BPRS), and standard neuropsychological assessment. The K-MMSE scores improved significantly (p < 0.05) but the BPRS scores did not improve significantly in patients given donepezil; subjects showed slight improvement in several cognitive measures. At the end of the study, the difference in the mean K-MMSE scores between the donepezil and placebo groups approached statistical significance (p = 0.056). Of the several domains of cognitive functions assessed, verbal recognition and visual recall memory improved significantly (p < 0.05). But donepezil did not affect scores in the executive function tests. Our findings support a potential positive effect of AChEIs in the management of cognitive impairments in patients with chronic schizophrenia. Further studies with large subjects are needed to confirm our findings.

Topics: Adult; Antipsychotic Agents; Cholinesterase Inhibitors; Chronic Disease; Cognition Disorders; Donepezil; Double-Blind Method; Drug Therapy, Combination; Haloperidol; Humans; Indans; Piperidines; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Thirteen outpatients with chronic but stable schizophrenia received donepezil and placebo augmentation of their maintenance antipsychotic medication regimen. Each subject received in a randomized, counterbalanced order 1) donepezil 5 mg for 6 weeks then donepezil 10 mg for six weeks and 2) placebo donepezil for 12 weeks. Serial ratings of the Positive and Negative Symptom Scale (PANSS) [Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13(2): 261-276] were performed by a trained rater blind to the donepezil order and condition: at baseline, 12 weeks and 24 weeks. On donepezil as compared to baseline or placebo, there was a significant improvement in PANSS negative scores (p=.018, n=13). These results are discussed with respect to other studies using cholinesterase inhibitors as an augmentation strategy in schizophrenia.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Cholinesterase Inhibitors; Clozapine; Cross-Over Studies; Donepezil; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Indans; Male; Middle Aged; Nootropic Agents; Olanzapine; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Cognitive dysfunction is common in schizophrenia and linked with psychosocial dysfunction. We examined the possible effect of a 16-week trial of donepezil on cognition in young persons with stable schizophrenia.. Twenty-six outpatients who met criteria for age, duration of illness, clinical stability, and medications were randomly assigned to 16-week treatment with donepezil or placebo using a double blind design. At beginning and conclusion of the trial, participants completed standardised computerised assessment of neurocognition and social cognition. Symptomatology and functioning were assessed using standard rating scales for negative and positive symptoms, depression and mania, and quality of life.. No treatment effects were found on any cognitive functions or clinical symptoms in placebo or donepezil groups.. Similar to other studies using acetylcholinesterase inhibitors in more heterogeneous and symptomatic groups of patients with schizophrenia, donepezil does not appear to enhance cognitive abilities. Persistent cognitive impairment in schizophrenia with pervasive effects on psychosocial functioning and outcome, urge the search for agents that may offer improvement.

Topics: Adult; Brain; Brief Psychiatric Rating Scale; Cholinesterase Inhibitors; Cognition Disorders; Diagnostic and Statistical Manual of Mental Disorders; Donepezil; Female; Humans; Indans; Male; Neuropsychological Tests; Piperidines; Schizophrenia; Severity of Illness Index; Social Perception

Donepezil, 5 mg/d for 6 wk then 10 mg/d for 6 wk, and placebo daily for 12 wk in a double-blind cross-over paradigm, was added to the therapeutic regimen of 13 patients with schizophrenia or schizoaffective disorders, clinically stable on atypical antipsychotic medications. Patients had varying degrees of depressive symptoms, ranging from no depression to clinically significant depression. There was no worsening or induction of depression in individual patients or the group as a whole. In addition there was a statistically significant antidepressant effect in the group as a whole during the donepezil condition and a clinically significant antidepressant effect in the patients with clinically significant depressive symptoms, although there were not enough depressed patients in the group to conclude that donepezil may have antidepressant effects. Thus, in this study, donepezil did not induce or worsen depressive symptoms in schizophrenic and schizoaffective disorder patients.

Topics: Adult; Affect; Analysis of Variance; Cross-Over Studies; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology

Cognitive impairment and negative signs are common in patients with schizophrenia. Up to 35% of elderly patients with schizophrenia fulfill the diagnostic criteria of dementia. Donepezil inhibits cholinesterase, thus enhancing cholinergic neurotransmission. We tested the efficacy of donepezil in elderly patients with chronic schizophrenia and severe cognitive impairment.. Following baseline assessment, patients were randomly assigned to receive either donepezil or placebo. The dose was 5 mg daily for the first week and 10 mg for an additional 11 weeks. The procedure was repeated using the crossover compound. The Positive and Negative Symptom Scale (PANSS), Clinical Global Impression Scale (CGI) and Alzheimer Disease Assessment Scale - Cognitive subscale (ADAS-Cog) were used to assess the severity of symptoms, cognitive status and intervention effects.. Twenty subjects were enrolled (15 females, five males), mean age 70.2 years (SD 6.5) and mean duration of disease 38.5 years (SD 9.3). A modest treatment effect was found for both placebo and donepezil treatment periods. No crossover effect was found. No statistical differences were demonstrated between the two treatment groups (CGI p = 0.37, PANSS p = 0.71, ADAS-Cog p = 0.86). Two patients died during the study period due to unrelated causes and one patient discontinued participation due to increased agitation.. Donepezil does not seem to improve negative signs and cognitive impairment in elderly patients with chronic schizophrenia.

Topics: Aged; Alzheimer Disease; Antipsychotic Agents; Chronic Disease; Cognition Disorders; Comorbidity; Cross-Over Studies; Dementia; Depressive Disorder; Donepezil; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

The article mentions the conclusions of most evidential works investigating donepezil in the treatment of cognitive deficit in schizophrenia. It focuses on an analysis of a sub-group of 20 patients receiving treatment of the donepezil in an extended Czech double-blind placebo controlled study.

Topics: Adolescent; Adult; Cholinesterase Inhibitors; Cognition Disorders; Czech Republic; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Memory; Middle Aged; Neuropsychological Tests; Piperidines; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Schizophrenia is a disorder with cognitive deficits that could stem from cholinergic dysfunction.. Our aim was to examine if donepezil administered to stable, medicated outpatients with schizophrenia improves cognition and psychopathology.. We conducted a double-blind placebo-controlled trial of donepezil up to 10 mg/day added for 8 weeks to ongoing antipsychotic treatment in 36 typical community-treated schizophrenia patients not selected for cognitive impairment.. Donepezil did not improve measures of cognition or psychopathology. It was well tolerated.. Consistent with other studies, addition of donepezil to stable patients with schizophrenia did not improve cognition or measures of psychopathology. This result does not support the hypothesis that residual symptoms and cognitive problems result from a cholinergic deficit that can be remedied by an acetylcholinesterase inhibitor. A donepezil add-on strategy might make sense in selected schizophrenia cases where a pathological process is known to affect cholinergic neurons (e.g., history of head injury or comorbid dementia).

Topics: Capsules; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Dyskinesias; Female; Humans; Indans; Male; Middle Aged; Piperidines; Placebos; Schizophrenia; Sialorrhea; Time Factors; Treatment Outcome

Although there have been several case reports suggesting the beneficial effect of acetylcholinesterase inhibitors in the cognitive deficits seen in schizophrenia, controlled studies have revealed contradictory results. The aim of this study was to investigate if donepezil could improve cognitive functions in schizophrenia. Twelve schizophrenic patients, who were diagnosed according to DSM-IV criteria and who had been on a stable dose of a high-potency typical antipsychotic for a minimum period of 3 months, participated in this 12-wk double-blind, placebo controlled, cross-over study of donepezil adjunctive treatment. Patients were randomly assigned under double-blind conditions to receive 5 mg/d donepezil or placebo for 6 wk, and then were crossed over to the alternate condition for 6 additional weeks. At baseline, 6 and 12 wk, patients were evaluated with the Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale, the Wechsler Memory Scale Revised (WMS-R), a test for Verbal Fluency, Trail Making Test, Parts A and B, and Wisconsin Card Sorting Test (WCST). Treatment effect was not significant in any of the cognitive measures. There were also no significant changes in the PANSS and depression scores. Nicotinic receptor desensitization may cause non-responsiveness to acetylcholine as previously suggested, but the most likely explanation appears to be that defects in other neurotransmitter systems account for the cognitive deficits seen in schizophrenic patients.

Topics: Adult; Cognition Disorders; Cross-Over Studies; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Memory; Neuropsychological Tests; Nootropic Agents; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Four studies using identical protocols evaluated the safety and efficacy of four novel, evidence-based targets for antipsychotic agents: a neurokinin (NK(3)) antagonist (SR142801), a serotonin 2A/2C (5-HT(2A/2C)) antagonist (SR46349B), a central cannabinoid (CB(1)) antagonist (SR141716), and a neurotensin (NTS(1)) antagonist (SR48692).. Adults with schizophrenia or schizoaffective disorder (N=481) were randomly assigned in a 3:1:1 ratio to receive fixed doses of investigational drug, placebo, or haloperidol for 6 weeks. Primary efficacy variables included changes from baseline in total score on the Positive and Negative Syndrome Scale, severity of illness score on the Clinical Global Impression (CGI), and total score and psychosis cluster score on the Brief Psychiatric Rating Scale (BPRS).. Significantly greater improvement in all primary efficacy variables was seen in the group receiving haloperidol than in the group receiving placebo at 6 weeks (endpoint analyses), indicating the validity of the study. The group receiving the NK(3) antagonist showed significantly greater improvement over baseline than the group receiving placebo as measured by Positive and Negative Syndrome Scale total score, CGI severity of illness score, and BPRS psychosis cluster score. Reductions in the Positive and Negative Syndrome Scale total and negative scores in the group receiving the 5-HT(2A/2C) antagonist were significantly larger than those in the group receiving placebo. The improvements in psychopathology produced by the NK(3) and 5-HT(2A/2C) antagonists were smaller than those produced by haloperidol, although the response to the NK(3) antagonist was positively correlated with plasma levels. The groups receiving the CB(1) and NTS(1) antagonists did not differ from the group receiving placebo on any outcome measure. All investigational drugs were well tolerated.. The novel design used in this study permitted the use of a smaller number of patients receiving placebo to test the efficacy of the four novel compounds. The NK(3) and 5-HT(2A/2C) antagonists showed evidence of efficacy in the treatment of schizophrenia and schizoaffective disorder. Study limitations preclude a definitive conclusion on the efficacy of CB(1) and NTS(1) antagonists in the treatment of schizophrenia. Further study of these two promising nondopaminergic mechanisms to treat schizophrenia and schizoaffective disorder appears indicated.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Cannabinoids; Double-Blind Method; Drugs, Investigational; Female; Haloperidol; Humans; Male; Middle Aged; Neurotensin; Peptide Fragments; Piperidines; Placebos; Psychotic Disorders; Pyrazoles; Pyrrolidonecarboxylic Acid; Receptors, Neurokinin-3; Research Design; Rimonabant; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Treatment Outcome

Increasing evidence suggests that the cholinergic system is involved in the pathogenesis of schizophrenia. Donepezil, a central cholinesterase inhibitor, improves psychotic symptomatology in demented patients, however, evidence for its role in the management of active psychosis in schizophrenia remains limited. An 18-week double blind cross-over study was conducted in which eight patients were randomly assigned to either donepezil (5 mg/day for the first 4 weeks and 10 mg/day for the following 4 weeks) or placebo as augmentation treatment to clozapine. After this initial phase, there was a 2-week washout period of the study medication after which the same regimen was crossed over at the same dose and for the same period (8 weeks). No significant difference was noted in the total positive and negative symptom scale scores when donepezil was compared with placebo (16.7%+12.97% vs 3.20%+13.94% respectively, p = 0.18). However, three patients improved (>15%) in the total PANSS scores (37.03%, 16.6% and 25.33%) during the donepezil treatment phase, while only one patient improved (20.87%) during the placebo phase. No differences were noted in the Calgary depression scale (p = 0.305), Simpson Angus scale (p = 0.374), clinical global impression-improvement scale (p = 0.23) and clinical global impression-severity of illness scores (p = 0.116). Although this preliminary study failed to demonstrate a clear effect of donepezil augmentation in clozapine treated chronic schizophrenia patients, it seems that the subtle positive effect of donepezil observed in some of our patients should encourage further investigation in a larger sample of this patient subpopulation.

Topics: Adult; Antipsychotic Agents; Cholinesterase Inhibitors; Clozapine; Cross-Over Studies; Donepezil; Double-Blind Method; Drug Synergism; Drug Therapy, Combination; Female; Humans; Indans; Male; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Treatment Outcome

This open-label, multiple-dose trial investigated the effect of concurrent administration of donepezil HCl with risperidone on the pharmacokinetics (PK) and safety profiles of both drugs.. Sixteen male patients with schizophrenia, who were receiving stable, physician-optimized risperidone (1-4 mg twice daily), and 15 healthy age- and weight-matched male controls, received donepezil HCl 5 mg daily for 7 days. Patients with schizophrenia remained on their physician-optimized dose of risperidone throughout the study. Pharmacokinetic parameters (C(max), t(max) and AUC) were assessed from plasma drug concentrations measured in blood collected before, during and after administration (for 12 h after risperidone on days 0 and 7, and for 24 h after donepezil HCl on day 7).. The mean age of all the subjects was 38.5 years. Donepezil PK parameters were similar between patients taking donepezil HCl + risperidone (AUC(0-24 h) = 329.0 +/- 17.2 ng x h ml(-1)) and controls taking donepezil HCl alone (AUC(0-24 h) = 354.7 +/- 28.2 ng x h ml(-1)). Pharmacokinetic parameters for risperidone and 9-OH risperidone were not altered in patients with schizophrenia after 7 days of donepezil HCl administration (AUC(0-12 h) standardized by dose: risperidone = 59.6 +/- 16.3 ng.h ml(-1) at day 0, 56.0 +/- 15.8 ng x h ml(-1) at day 7; 9-OH risperidone = 162.1 +/- 19.2 ng x h ml(-1) at day 0, 163.3 +/- 15.0 ng x h ml(-1) at day 7). The most common adverse event in both treatment groups was diarrhoea (6/16 risperidone + donepezil HCl patients and 9/16 donepezil HCl only subjects). There were no significant changes in physical examination, ECG, vital signs or treatment-emergent abnormal laboratory values associated with either of the treatment regimens. No subject developed extrapyramidal side-effects following donepezil administration.. These results suggest that once-daily dosing of 5 mg donepezil HCl does not alter the PK of risperidone in patients with schizophrenia. The combination of risperidone and donepezil HCl was well tolerated.

Topics: Administration, Oral; Adult; Aged; Antipsychotic Agents; Area Under Curve; Cholinesterase Inhibitors; Donepezil; Drug Combinations; Drug Interactions; Humans; Indans; Male; Middle Aged; Piperidines; Risperidone; Schizophrenia

A pilot study was conducted to examine if donepezil could enhance cognitive function in patients with schizophrenia. Fifteen subjects who were on stable olanzapine treatment were entered into a 6-week open-labeled trial of donepezil. Subjects received baseline and end-of-study P50 and neuropsychological assessments. Donepezil treatment resulted in significant improvement in manual dexterity. There were moderate improvements in verbal recall memory and visual memory and processing speed, with smaller changes in P50 and verbal recognition memory. There was no effect on an attention measure. There were no changes in either positive or negative symptoms. These results suggest that cholinergic tone modulation may enhance selective behavioral functions in patients with schizophrenia, but further study is required to delineate the full extent of the potential benefit of this approach.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Cognition Disorders; Donepezil; Drug Therapy, Combination; Evoked Potentials; Female; Humans; Indans; Male; Memory; Nootropic Agents; Olanzapine; Pilot Projects; Piperidines; Pirenzepine; Schizophrenia

Cognitive impairments are cardinal features of schizophrenia and predictors of poor vocational and social outcome. Imaging studies with verbal fluency tasks (VFT) lead some to suggest that in schizophrenia, the combination of a failure to deactivate the left temporal lobe and a hypoactive frontal lobe reflects a functional disconnectivity between the left prefrontal cortex and temporal lobe. Others have theorized that an abnormal cingulate gyrus modulates such fronto-temporal connectivity. Thus addition of a cognitive enhancing medication to current antipsychotic therapy might improve functionality of networks necessary in working memory and internal concept generation. To test this hypothesis, we serially measured brain activity in 6 subjects on stable atypical antipsychotics performing a VFT, using BOLD fMRI. Measurements were made at baseline and again after groups were randomized to receive 12 weeks of donepezil (an acetylcholinesterase inhibitor) and placebo in a blind cross-over design. Donepezil addition provided a functional normalization with an increase in left frontal lobe and cingulate activity when compared to placebo and from baseline scans. This pilot study supports the cingulate's role in modulating cognition and neuronal connectivity in schizophrenia.

Topics: Adult; Antipsychotic Agents; Cholinesterase Inhibitors; Cognition Disorders; Cross-Over Studies; Donepezil; Double-Blind Method; Drug Therapy, Combination; Humans; Indans; Magnetic Resonance Imaging; Male; Memory; Middle Aged; Outpatients; Piperidines; Placebos; Schizophrenia; Treatment Outcome

We used L-(quinoxalin-6-ylcarbonyl)piperidine (CX516) (a modulator of the alpha-amino-3-hydroxy-5-methyl-4-isoxasole propionic acid (AMPA) receptor) as a sole agent in a double blind placebo-controlled design in a small series of patients with schizophrenia who were partially refractory to treatment with traditional neuroleptics. The study entailed weekly increments in doses of CX516, from 300 mg tid for week 1 up to 900 mg tid on week 4. Patients were followed with clinical ratings, neuropsychological testing, and were monitored for adverse events. Four patients received 2 to 4 weeks of CX516, two received placebo and two withdrew during the placebo phase. Adverse events associated with drug administration were transient and included leukopenia in one patient and elevation in liver enzymes in another. No clear improvement in psychosis or in cognition was observed over the course of the study. CX516 at the doses tested did not appear to yield dramatic effects as a sole agent, but inference from this study is limited.

Topics: Adult; Antipsychotic Agents; Dioxoles; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperidines; Psychotic Disorders; Schizophrenia

Despite the beneficial effects of atypical antipsychotics on cognition, these improvements will not return most schizophrenic patients to normative standards of cognitive functioning. Therefore, other treatments need to be considered. Subtle changes in cholinergic function in schizophrenic patients provide the rationale to test the effectiveness of cholinesterase inhibitors in treating cognitive impairment in schizophrenia.. Given this, a 12-week, double-blind, placebo-controlled trial of donepezil (5 mg and 10 mg) as adjunctive treatment to risperidone was conducted in a total of 36 schizophrenic patients.. Neither the 5-mg nor 10-mg dose of donepezil produced significant improvements in any cognitive measure compared with placebo.. It is possible that nicotinic receptor desensitization produced by chronic tobacco use in these patients rendered their nicotinic receptors refractory to the effects of increased agonist activity produced by donepezil. An alternative treatment is the allosterically potentiating ligands, which enhance the activity of (sensitize) nicotinic receptors in the presence of acetylcholine.

Topics: Adult; Aged; Antipsychotic Agents; Cognition Disorders; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology

CX516, a positive modulator of the glutamatergic alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor, improves performance in tasks requiring learning and memory in animals. CX516 was added to clozapine in 4-week, placebo-controlled, dose-finding (N = 6) and fixed-dose (N = 13) trials. CX516 was tolerated well and was associated with moderate to large, between-group effect sizes compared with placebo, representing improvement in measures of attention and memory. These preliminary results suggest that CX516 and other "ampakines" hold promise for the treatment of schizophrenia.

Topics: Adult; Antipsychotic Agents; Attention; Clozapine; Cognition; Dioxoles; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Memory; Middle Aged; Pilot Projects; Piperidines; Psychological Tests; Schizophrenia

Selective drugs are required to test the hypothesis whether antipsychotic effects may be induced or modulated by 5HT(2A) receptor antagonism. M100907 (previously known as MDL 100,907) is a highly selective 5HT(2A) antagonist in clinical development.. To test if the suggested clinical dose of 20 mg M100907 daily induces high 5HT(2A) receptor occupancy in patients with schizophrenia.. The 5HT(2A) receptor occupancy was determined in two patients with schizophrenia treated with M100907, 20 mg once a day. Positron emission tomography (PET) with (11)C-labeled M100907, was performed prestudy and under steady state conditions. Clinical ratings were performed weekly.. Clinical treatment with M100907, 20 mg daily induced a very high 5HT(2A) receptor occupancy in the frontal cortex of both patients (>90%). M100907 was well tolerated. One patient improved minimally and one patient became minimally worse during treatment.. The results confirm that an oral dose of 20 mg per day ensures adequate 5HT(2A) receptor occupancy for clinical proof of concept. The sample is too small to allow conclusions about the clinical effect.

Topics: Adult; Antipsychotic Agents; Female; Fluorobenzenes; Humans; Male; Piperidines; Prefrontal Cortex; Psychiatric Status Rating Scales; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Schizophrenia; Serotonin Antagonists; Tomography, Emission-Computed

Panamesine (PAN) is a nearly specific sigma ligand. Recently, we showed that PAN in doses up to 90 mg/day improved psychometric variables in patients with an acute episode of schizophrenia. No side effects connected to the extrapyramidal motoric system occurred; there was even an absence of daytime sedation. We investigated the effects of PAN on plasma cytokine and soluble cytokine receptor levels and blood cell counts during 4 weeks in ten patients out of the previous study sample. Under PAN treatment, tumor necrosis factor (TNF)-alpha, soluble TNF receptors p55 and p75, and soluble interleukin-2 receptor levels were not increased and neither were monocyte and lymphocyte counts affected. This absence of immunomodulation is in contrast to clozapine, but similar to haloperidol treatment. In a second study, a single dose of PAN (30 mg) or placebo was administered at 2200 hours to ten young male controls in order to investigate changes in the sleep EEG under the substance. Sleep efficiency index increased, whereas time spent awake decreased. No significant changes in rapid eye movement (REM) sleep or non-REM parameters occurred. The sleep-EEG investigation showed sleep-consolidating effects of the drug, comparable to those of classical neuroleptics. Our results support the hypothesis that the sigma ligand PAN, which has antipsychotic properties, shares biological aspects with haloperidol.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Antipsychotic Agents; Blood Cell Count; Double-Blind Method; Electroencephalography; Female; Humans; Locus Coeruleus; Male; Oxazoles; Piperidines; Receptors, sigma; Schizophrenia; Sleep; Tumor Necrosis Factor-alpha

EMD 57455 (panamesine) is a new sigma receptor ligand alleged to have antipsychotic effects. Animal studies have demonstrated that EMD 57445 has a functional antidopaminergic activity without extrapyramidal side effects and a c-fos expression pattern similar to that obtained with atypical neuroleptics. Therefore, the substance might be of interest for the treatment of schizophrenia. The present article describes the results of an exploratory open clinical trial that was aimed at determining the appropriate dose range for clinical efficacy and safety of EMD 57455 in patients with an acute episode of schizophrenia. In a treatment period of 4 weeks, 12 patients received EMD 57445 up to 60 mg/day for 4 weeks. Seven patients completed the study: four were classified as responders (as defined by at least a 50% decrease in the BPRS total score), two improved slightly and one patient remained unimproved. The intent-to-treat analysis showed significant improvement in the psychometric variables assessed by the Brief Psychiatric Rating Scale, Clinical Global Impression and Positive and Negative Symptoms Scale. Major side effects were extrapyramidal symptoms in two patients and restlessness in one patient. With respect to efficacy and safety, our data agree with a previous study, except that in our study EMD 57455 was not totally free of extrapyramidal side effects.

Topics: Adult; Antipsychotic Agents; Female; Humans; Ligands; Male; Middle Aged; Oxazoles; Piperidines; Psychiatric Status Rating Scales; Receptors, sigma; Schizophrenia; Schizophrenic Psychology

Antipsychotic efficacy and side effects of the selective sigma ligand EMD 57445 (panamesine) were investigated in 12 patients (6 males, 6 females) who met DSM-III-R criteria for schizophrenia. A 4-week open clinical study revealed only modest effects of EMD 57445 and its metabolites on positive and negative symptoms of schizophrenia. Extrapyramidal and other side effects were moderate, although a significant increase in mild dyskinetic movements was found. Five patients, four of whom were females, completed the trial. Dropouts were mainly due to treatment failure. Antipsychotic effects were significantly greater in female than male patients.

Topics: Acute Disease; Adult; Aged; Antipsychotic Agents; Basal Ganglia Diseases; Biotransformation; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Oxazoles; Piperidines; Psychiatric Status Rating Scales; Receptors, sigma; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

In an ongoing effort to characterize the clinical pharmacologic profile of the partial dopamine agonist (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [(-)-3PPP], we administered it to drug-free schizophrenic patients in two consecutive studies.. In a preliminary dose-finding study, 9 patients were treated using a 6-week placebo-controlled crossover design. Then, to properly demonstrate the antipsychotic effect, we carried out an early efficacy study; here 10 patients received (-)-3PPP, 300 mg B.I.D., in a 1-week placebo-controlled crossover study.. Dose-Finding Study: (-)-3PPP showed apparent antipsychotic effect in repeated dosing, with 300 mg B.I.D. being the most effective dose for antipsychotic action; however, the apparent antipsychotic action was not sustained for longer than 1 week, presumably because of desensitization of the receptor by the agonist. Early Efficacy Study: Positive symptoms as measured by the Psychosis Change Scale decreased in 1 week by 30% with (-)-3PPP compared to placebo, and negative symptoms measured with the Brief Psychiatric Rating Scale Withdrawal subscale decreased by 28% with the drug. In both studies, (-)-3PPP lacked any evidence of motor side effects.. These data show that psychotic symptoms decrease with (-)-3PPP and suggest that the treatment of schizophrenia with partial dopamine agonist is a promising strategy. Future attention will be directed toward testing techniques to diminish the tachyphylaxis to allow an ongoing therapeutic effect.

Topics: Adult; Antiparkinson Agents; Antipsychotic Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

The sigma (sigma) receptor has been proposed as a target of neuroleptic drugs. Preclinical data suggest that panamesine (EMD 57445), a novel sigma ligand, has antipsychotic effects and is free of side effects related to the extrapyramidal motoric system (EPMS). Here we report the results of an exploratory study aimed at determining the appropriate dose range and the safety of panamesine in patients with an acute episode of schizophrenia. The first trial with four patients revealed insufficient clinical efficacy of a protocol where the daily dosage was increased stepwise from 7.5 mg during week 1, up to 30 mg during weeks 3 and 4. In a second set of trials, 12 patients received 15 mg at the beginning, this being increased up to 60 mg/day within 3 days and then maintained at this level for 4 weeks. As assessed by a decrease in the Brief Psychiatric Rating Scale score by at least 50%, five patients were judged as responders, whereas six patients showed only a slight improvement, and one deteriorated. Moreover, intent-to-treat analysis showed significant improvement in psychometric variables. In all patients prolactin levels increased during treatment, probably due to an active metabolite with weak dopamine-2-receptor antagonistic effects. No major side effects occurred, and in particular, no EPMS symptoms were seen.

Topics: Acute Disease; Adolescent; Adult; Antipsychotic Agents; Brief Psychiatric Rating Scale; Female; Humans; Male; Oxazoles; Piperidines; Prolactin; Receptors, sigma; Schizophrenia; Sleep

The psychotomimetic effects of opiate agonists/antagonists led to the hypothesis that opiate sigma receptors could be involved in the etiology of schizophrenia. This assumption is supported by animal trials with selective sigma-receptor antagonists. SL 82.0715 is a substance with a highly selective affinity for sigma receptors. To clarify the question whether it improves negative symptoms of schizophrenia, ten chronic schizophrenic patients with a predominant negative symptomatology were examined and treated with increasing doses (2.5 - 10.0 mg/d). Psychopathology was evaluated weekly using the PANSS, BPRS, and CGI, side-effects were assessed by the HAS and the S/A scale. Four patients showed improvement of negative symptoms (two slight, two marked improvement), two patients deteriorated as regards the positive symptomatology, psychopathology in the other patients did not change. The tolerability of SL 82.0715 was very good, no extrapyramidal side-effects occurred. To further evaluate the therapeutic efficacy, open studies with a larger number of patients and/or double-blind studies are necessary.

Topics: Adult; Excitatory Amino Acid Antagonists; Female; Humans; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Receptors, sigma; Schizophrenia; Schizophrenic Psychology

Risperidone and remoxipride are recently introduced atypical antipsychotics, with clinical efficacy comparable to that of classical antipsychotics but lower propensity to induce extrapyramidal side effects (EPS). It is unclear whether these properties relate to weak dopamine D2 receptor blockade in vivo, as has been suggested for the archetypal atypical antipsychotic clozapine. We have used 123I-IBZM single photon emission tomography (SPET) to characterize the patterns of striatal D2 receptor binding in vivo in DSMIII-R-diagnosed schizophrenic and schizo-affective patients treated with either risperidone (n = 6) or remoxipride (n = 4) but predominantly EPS free. These groups were compared to age- and BPRS- matched subjects from a previously reported D2 receptor binding database of patients treated with clozapine (n = 10) and classical antipsychotics (n = 10). Patients on risperidone and remoxipride had high levels of D2 receptor blockade, comparable to those of patients on classical antipsychotics, and significantly greater than those obtained with clozapine-treated patients (risperidone versus clozapine, P < 0.005; remoxipride versus clozapine, P < 0.025). These results suggest high levels of striatal D2 receptor occupancy in association with remoxipride and risperidone treatment and argue against modest D2 antagonism as the explanation for the low incidence of EPS associated with these drugs.

Topics: Adult; Antipsychotic Agents; Basal Ganglia; Benzamides; Cerebral Cortex; Dopamine D2 Receptor Antagonists; Female; Humans; Image Processing, Computer-Assisted; Iodine Radioisotopes; Isoxazoles; Male; Middle Aged; Neostriatum; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Pyrrolidines; Remoxipride; Risperidone; Schizophrenia; Tomography, Emission-Computed, Single-Photon

In the Canadian multicenter, double-blind clinical trial of risperidone, 135 hospitalized chronic schizophrenic patients were randomly assigned to one of six parallel treatment groups for 8 weeks: risperidone, 2, 6, 10, or 16 mg/day; haloperidol, 20 mg/day; or placebo. Risperidone (6 to 16 mg)-treated patients showed significantly (p < 0.05) lower dyskinetic scores than those receiving placebo, whereas in haloperidol- and placebo-treated patients, no significant differences for dyskinetic symptoms were noted. To explore the antidyskinetic effect of risperidone, a post hoc analysis was performed on two selected patient samples: (1) patients meeting Research Diagnosis Criteria (RDC) for tardive dyskinesia (TD) at baseline or during double-blind treatment (N = 49) and (2) patients with RDC TD and with a Clinical Global Impression (CGI) Severity of dyskinesia score > or = 5 (at least moderately severe) (N = 48). The composition of the two subsamples was found to be almost identical because all but one of the patients with RDC TD (N = 49) were members of the group with at least moderately severe TD (N = 48). Analysis of four parameters (Extrapyramidal Symptom Rating Scale-dyskinesia total score, CGI severity of dyskinesia, buccolinguomasticatory [BLM] factor score, and extremities [choreoathetoid factor] score confirmed the antidyskinetic effect that was noted in the intent-to-treat analysis, which included all patients, whether they had RDC TD or not. Results indicated that risperidone at 6 mg/day had the most beneficial effect on TD, especially on the BLM syndrome, without inducing significant parkinsonism while treating psychotic symptoms. This antidyskinetic effect was greater than with either placebo or haloperidol.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Double-Blind Method; Dyskinesia, Drug-Induced; Female; Haloperidol; Humans; Isoxazoles; Male; Middle Aged; Piperidines; Risperidone; Schizophrenia

This study compares the antipsychotic efficacy and the tolerability of risperidone and clozapine in patients with schizophrenia. Patients were randomized to double-blind treatment with risperidone, 4 mg (N = 20), risperidone, 8 mg (N = 19), or clozapine, 400 mg (N = 20), daily for 28 days. Efficacy was assessed by improvement of psychotic symptoms, measured on the Brief Psychiatric Rating Scale, and Clinical Global Impression. The tolerability was assessed by the Simpson and Angus scale for extrapyramidal side effects (EPS), the Association for Methodology and Documentation in Psychiatry (AMDP) scale for somatic side effects, spontaneous reports of adverse events, clinical laboratory assessments, and vital signs. All treatments reduced psychotic symptoms. The global tolerability was significantly better in the risperidone than in the clozapine-treated patients (p < 0.01). There were no differences between treatments on the AMDP scale. The most frequent spontaneously reported adverse effects were dizziness, fatigue, accommodation disturbance, and EPS in all treatment groups and increased salivation, mainly in the clozapine-treated patients. Although there were no changes in vital signs during risperidone treatment, clozapine was associated with a mean reduction in heart rate of 10 beats/minute. Risperidone tolerability at endpoint was classified as "very good" by 60 and 47% of patients treated with risperidone, 4 and 8 mg daily, respectively; the corresponding figure in clozapine-treated patients was 30%. The results suggest that risperidone is at least as effective as an antipsychotic as clozapine, providing a valuable new approach for the treatment of schizophrenia.

Topics: Adult; Antipsychotic Agents; Clozapine; Double-Blind Method; Female; Humans; Isoxazoles; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology

The hypothesis that differences in drug effects of risperidone and haloperidol on negative symptoms in schizophrenia are secondary to effects on positive, extrapyramidal, and depressive symptoms was investigated by means of an analysis of the data from the USA-Canada risperidone double-blind randomized clinical trial of 523 chronic schizophrenic patients. Regression analyses in the total sample and within treatment groups confirmed a strong relationship between changes in negative symptoms and the other variables studied (R2 = 0.50-0.51, p < 0.001). Only depressive symptoms did not contribute significantly to these results (p > 0.10). Path analysis showed that the greater mean change (p < 0.05) of negative symptoms with risperidone compared to haloperidol could not be fully explained by correlations with favourable effects on positive and extrapyramidal symptoms. The relationship between shift in extrapyramidal symptoms and shift in negative symptoms failed to reach statistical significance; however, there was a clear tendency in the expected direction in both treatment groups.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Chronic Disease; Double-Blind Method; Haloperidol; Humans; Isoxazoles; Piperidines; Risperidone; Schizophrenia

Many conflicts in the literature about negative symptoms arise because different authors use different definitions of negative symptoms. If narrow definitions are used, it appears that drugs have little effect against negative symptoms, although those who use broader definitions tend to conclude that negative symptoms do respond to drugs. Another complication is that negative symptoms may be secondary to other causes, such as psychotic symptoms, the side effects of drugs, depression and understimulation as a result of hospitalisation. Attempting to measure drug effects on negative symptoms can be complicated by such factors as different co-medication in the test and control groups and different pharmacological profiles of test and standard drugs, in particular in terms of extrapyramidal side effects or antidepressant effects. Several approaches to dissecting the direct effect of drugs from their indirect effects on negative symptoms have included analyses of covariance, regression analyses and path analyses. Applying path analysis to the data from the North American clinical trial of risperidone suggests that a significant component of the advantageous effect of risperidone on negative symptoms, compared with haloperidol, is due to a direct effect that cannot be accounted for by the effect of risperidone on positive symptoms and its superior side-effect profile. Although it is possible to analyse studies retrospectively in this way, the best approach is probably to design future clinical trials so that the effects of drugs on negative symptoms are more easily determined than has been the case in the past.

Topics: Affective Symptoms; Antipsychotic Agents; Haloperidol; Humans; Isoxazoles; Piperidines; Psychiatric Status Rating Scales; Psychometrics; Risperidone; Schizophrenia; Schizophrenic Psychology

Negative symptoms in schizophrenia comprise a psychopathologic and pathophysiologic syndrome which is absent from normal mental function. Renewed interest in negative symptoms has led to the development of better measuring instruments, among which is the Positive And Negative Syndrome Scale (PANSS), which provides a way of measuring and reporting positive and negative symptoms in a balanced and convenient form. A number of strategies are being investigated for treating negative symptoms. Dopamine agonists such as levodopa, amphetamines and bromocriptine have been shown to produce improvements in negative symptoms, although good, well-controlled clinical trials are lacking. Partial dopamine agonists, such as MAR 327, are also currently under investigation and results are expected soon. Tricyclic, selective serotonin reuptake inhibitors and monoamine oxidase antidepressants appear to be able to modify negative symptoms in schizophrenia, although, once again, carefully designed trials are needed. Modification of GABAergic transmission has shown little promise, but the use of glycine to augment transmission at N-methyl-D-aspartate (NMDA) synapses suggests that the strategy may be beneficial. These results also imply that altered glutamate receptor function may be partly responsible for negative symptoms. One strategy that has been shown to have a beneficial effect against negative symptoms is combined serotonin/dopamine antagonism. Clozapine was found to have this profile after its introduction, and the recently introduced antipsychotic, risperidone was developed intentionally to be a combined 5-HT2/D2 antagonist. Both risperidone and clozapine have been shown to be effective against negative symptoms. One problem associated with the assessment of drug effects on negative symptoms, however, is that drugs can act on both primary and secondary negative symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Affective Symptoms; Antipsychotic Agents; Clozapine; Humans; Isoxazoles; Piperidines; Psychiatric Status Rating Scales; Psychometrics; Risperidone; Schizophrenia; Schizophrenic Psychology; Syndrome

A double-blind, randomized, multi-center, parallel-group study was conducted in Finland to compare the efficacy and safety of risperidone with zuclopenthixol in patients with acute exacerbations of schizophrenia or schizophreniform disorder. Ninety-eight patients were randomly assigned to treatment with risperidone (n = 48) or zuclopenthixol (n = 50), in variable doses, for 6 weeks. The mean daily doses of risperidone and zuclopenthixol at the end of the trial were 8 mg and 38 mg respectively. Efficacy was assessed throughout by the Positive and Negative Syndrome Scale for schizophrenia and Clinical Global Impression. Safety assessments included the Extrapyramidal Symptom Rating Scale, UKU Side-Effect Rating Scale, vital signs, body weight and laboratory screening. The results indicate that risperidone is at least as effective as zuclopenthixol for the treatment of acute schizophrenic episodes, with a trend towards greater improvement in the overall severity of symptoms. The onset of action was significantly shorter with risperidone than with zuclopenthixol. Although the general tolerability of the two drugs was comparable, fewer patients experienced extrapyramidal symptoms with risperidone, so that significantly fewer risperidone-treated patients required antiparkinsonian medication.

Topics: Acute Disease; Adolescent; Adult; Aged; Antipsychotic Agents; Clopenthixol; Double-Blind Method; Female; Humans; Isoxazoles; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology

Topics: Canada; Double-Blind Method; Haloperidol; Humans; Isoxazoles; Piperidines; Research Design; Risperidone; Schizophrenia

This study was performed in order to evaluate the short-term efficacy and safety of fixed risperidone doses compared to haloperidol.. In a multi-national, parallel-group, double-blind study, patients with chronic schizophrenia (DSM-III-R) were randomly assigned to risperidone 1, 4, 8, 12 or 16 mg or haloperidol 10 mg daily for 8 weeks. Efficacy was assessed by the Positive and Negative Syndrome Scale for schizophrenia (PANSS) and clinical global impression (CGI), and safety primarily by the Extrapyramidal Symptom Rating Scale (ESRS).. One thousand three hundred and sixty-two patients were evaluated. The optimum risperidone doses were 4 mg and 8 mg, with response rates of 63.4% (56.8%; 69.7%) and 65.8% (59.2%; 71.9%) respectively. Response rate in haloperidol-treated patients was 58.7% (52.0%; 65.3%); the 95% confidence intervals (CI) of the differences between risperidone 4 mg or 8 mg and haloperidol were (- 4.3%; 13.7%) and (- 1.9%; 16.0%) respectively. There were no significant differences in CGI scores at endpoint between risperidone 4 mg, 8 mg, 12 mg and 16 mg and haloperidol (3.0, 3.0, 3.2, 3.1 and 3.1 respectively); the 95% CI of the differences between risperidone 4 mg or 8 mg and haloperidol were ( - 0.4; 0.1) and ( - 0.3; 0.2) respectively. Mean shifts to the maximum total ESRS scores versus baseline (mean (confidence interval)) were significantly greater in haloperidol-treated patients (5.1 (4.0; 6.2)) than in the risperidone 1, 4, 8 and 12 mg groups (1.1 (0.3; 1.9); 1.8 (0.9; 2.7); 2.7 (1.8; 3.6) and 3.2 (2.3; 4.1) respectively (P < 0.05)).. Risperidone is an effective antipsychotic for the treatment of chronic schizophrenia; doses of 4 and 8 mg seem to be optimal and have a lower incidence of side-effects than haloperidol.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Haloperidol; Humans; Isoxazoles; Male; Piperidines; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology

The purpose of this study was to investigate the safety and efficacy of risperidone in the treatment of schizophrenic patients and determine its optimal dose.. This double-blind study included 388 schizophrenic patients drawn from 20 sites in the United States. Patients were randomly assigned to 8 weeks' treatment with placebo, one of four doses of risperidone (2, 6, 10, or 16 mg), or 20 mg of haloperidol daily.. Clinical improvement (20% reduction in total scores on the Positive and Negative Syndrome Scale for Schizophrenia) at the study end point was shown by 35% of the patients receiving 2 mg of risperidone, 57% receiving 6 mg, 40% receiving 10 mg, and 51% receiving 16 mg; and by 30% receiving haloperidol and 22% receiving placebo. Statistically significant differences in clinical improvement were found between 6 and 16 mg of risperidone versus placebo and versus haloperidol. Positive symptom scores were significantly lower after 6, 10, and 16 mg of risperidone and 20 mg of haloperidol than placebo; negative symptom scores, however, were reduced significantly, compared with placebo, only after 6 and 16 mg of risperidone. The incidence of extra-pyramidal side effects (measured by the Extrapyramidal Symptom Rating Scale) was significantly higher in patients treated with 16 mg of risperidone or 20 mg of haloperidol than placebo. The results indicate that the optimal daily dose of risperidone for most schizophrenic patients in this study was 6 mg; this dose was as effective as 16 mg, and the incidence of extrapyramidal symptoms in patients receiving 6 mg of risperidone was no higher than that in patients receiving placebo.. Risperidone is a safe antipsychotic that is effective against both the positive and negative symptoms of schizophrenia.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Double-Blind Method; Drug Administration Schedule; Female; Haloperidol; Humans; Isoxazoles; Male; Middle Aged; Piperidines; Placebos; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

In studies by means of the Swedish version of the Positive and Negative Syndrome Scale, we have demonstrated a 5-factor model of schizophrenia, including positive, negative, excited, anxious/depressive and cognitive factors. In this study, the 5 factors were correlated with background factors in a series comprising 140 patients with schizophrenic syndromes. None of the 5 factors revealed any significant age or sex differences. The positive factor correlated positively with the number of previous hospitalizations and the negative factor correlated negatively. The excited factor correlated negatively with age at onset, age at first hospitalization and positively with the duration of the illness and the number of previous hospitalizations. The cognitive factor correlated negatively with age at onset and age at first hospitalization and positively with the duration of the illness. Age at onset was positively correlated with delusions, excitement, unusual thought content and poor impulse control and negatively with lack of spontaneity. The duration of illness correlated positively with excitement, difficulty in abstract thinking and mannerisms. The number of previous hospitalizations correlated positively with delusions, excitement, unusual thought content and poor impulse control and significant negative correlations were demonstrated as concerns blunted affect and lack of spontaneity.

Topics: Adult; Age Factors; Age of Onset; Aged; Antipsychotic Agents; Female; Haloperidol; Hospitalization; Hospitals, Psychiatric; Humans; Isoxazoles; Male; Middle Aged; Patient Admission; Piperidines; Risperidone; Ritanserin; Schizophrenia; Schizophrenic Psychology; Sex Factors

This article reviews the definitions of negative symptoms and the deficit syndrome of schizophrenia, rating scale criteria (the Scale for Assessment of Negative Symptoms and the Positive and Negative Syndrome Scale), Crow's Type II syndrome, and Carpenter's deficit syndrome in relation to the DSM-IV. The effectiveness of conventional neuroleptics against negative symptoms is still in question. Improvement in negative symptoms may occur in tandem with improvement in the florid symptoms of schizophrenia, but negative symptoms may be difficult to discriminate from the extrapyramidal side effects that are caused by conventional neuroleptics. In a multicenter trial comparing the novel antipsychotic risperidone with haloperidol and placebo in symptomatic schizophrenia, negative symptoms (assessed using the Positive and Negative Syndrome Scale) were reduced more by risperidone at a dose of 6, 10, and 16 mg/day than by placebo. Haloperidol at a dose of 20 mg/day was not significantly better than placebo. Risperidone 6 mg was the lowest dose that produced substantial change in negative symptoms and no increase in extrapyramidal symptoms and antiparkinsonian medication use.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Female; Haloperidol; Humans; Isoxazoles; Male; Middle Aged; Piperidines; Risperidone; Schizophrenia; Single-Blind Method

Dopaminergic hyperactivity mediated via D2 receptors is implicated in the etiology of positive symptoms of schizophrenia, but selective D2 antagonists provide imperfect therapy. This article describes a subanalysis of a trial of risperidone, a combined 5-HT2A/D2 antagonist, in 513 patients with DSM-III-R chronic schizophrenia. Risperidone at 2, 6, 10, and 16 mg/day was compared with placebo and haloperidol 20 mg/day. All doses of risperidone and the 20-mg dose of haloperidol were superior to placebo (mean change from baseline on the PANSS positive and general psychopathology subscales). The 6-mg dose of risperidone also produced significantly more improvement than haloperidol 20 mg. We conclude that risperidone is an effective drug for patients with positive features of schizophrenia.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Double-Blind Method; Haloperidol; Humans; Isoxazoles; Piperidines; Receptors, Dopamine D2; Receptors, Serotonin; Risperidone; Schizophrenia; Treatment Outcome

Risperidone, a rather selective blocker of D-2 and 5-HT-2 receptors, was, in the doses 1 mg, 4 mg, 8 mg, 12 mg and 16 mg a day, compared to the rather selective D-2 blocker haloperidol in the dose of 10 mg a day, in 88 chronic schizophrenic patients. After one week placebo wash-out, the patients were randomly assigned to one of the six treatment groups and the study was performed as a double blind parallel-group study for 8 weeks. In the present analysis, a special emphasis has been laid on the effects on single symptoms and separate factors in the schizophrenic syndrome. Overall, risperidone in a dose of 4 mg a day was comparable to haloperidol in a dose of 10 mg a day. Risperidone was found to have a curvilinear dose-response curve with an optimum effect of 4 mg day on the negative, anxious/depressive and cognitive factors and with an optimum effect of 8 mg day on the positive and excited factors. While haloperidol had significant effects on the negative and anxious/depressive factors, risperidone had significant effects on all five factors - the positive, the negative, the excited, the anxious/depressive and the cognitive. The fact that the novel drug had significant effects on the cognitive factor might be of great importance as concerns the possibilities for rehabilitation of chronic schizophrenic patients.

Topics: Double-Blind Method; Haloperidol; Humans; Isoxazoles; Piperidines; Risperidone; Schizophrenia

Risperidone, a benzisoxazol derivative, is a novel antipsychotic agent which combines potent serotonin (5-hydroxytryptamine) 5-HT2 and dopamine D2 receptor antagonism. Development of the drug was stimulated by reports that the selective serotonin 5-HT2 antagonist ritanserin improved the negative symptoms of schizophrenia and decreased extrapyramidal symptoms when combined with haloperidol. The relatively low incidence of extrapyramidal symptoms with risperidone may reflect a preferential action on mesolimbic rather than nigrostriatal dopaminergic pathways. Recent clinical investigation suggests that risperidone is of at least comparable efficacy to haloperidol and perphenazine in improving the symptoms of acute and chronic schizophrenia on short term administration. Advantages offered by risperidone over haloperidol include a faster onset of antipsychotic action, a lower incidence of extrapyramidal effects and possibly greater efficacy against the negative symptoms of schizophrenia. If these benefits prove to be maintained during long term therapy, risperidone is likely to make a significant contribution to the treatment of schizophrenia.

Topics: Absorption; Adult; Aged; Aging; Animals; Antipsychotic Agents; Central Nervous System; Cross-Over Studies; Disease Models, Animal; Drug Interactions; Hemodynamics; Humans; Isoxazoles; Neurosecretory Systems; Piperidines; Risperidone; Schizophrenia; Synaptic Transmission; Tissue Distribution

Topics: Administration, Intranasal; Adult; Antipsychotic Agents; Deamino Arginine Vasopressin; Double-Blind Method; Enuresis; Female; Haloperidol; Humans; Isoxazoles; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology

In a randomized, crossover study, 24 schizophrenic patients received a single 4-mg dose of risperidone in caplet or tablet form. Each of the two study periods lasted 5 days. Blood samples to determine (by radioimmunoassay) plasma levels of risperidone and its major metabolite, 9-hydroxy-risperidone (9-OH-risperidone), were obtained each day. The two formulations of risperidone were bioequivalent. Following are the mean pharmacokinetics of risperidone and risperidone + 9-OH-risperidone: area under the plasma concentration curve (AUC) from 0 to 96 hours; 278.0 and 716.9 ng.hr/mL; AUC from 0 to infinity, 291.9 and 762.4 ng.hr/mL; peak plasma concentration, 33.0 and 44.5 ng/mL; time to peak concentration, 1.39 and 1.78 hours; and elimination half-life, 14.93 and 23.04 hours. These results demonstrate that the active moiety (risperidone plus 9-OH-risperidone) has a half-life of 23 hours and reveal a pool of risperidone (terminal half-life, 14.9 hours) that may allow twice-daily or even once-daily dosing.

Topics: Adolescent; Adult; Antipsychotic Agents; Chronic Disease; Cross-Over Studies; Humans; Isoxazoles; Male; Middle Aged; Piperidines; Risperidone; Schizophrenia; Therapeutic Equivalency

1. Supersensitivity psychosis (SSP) has emerged as a potential side effect of long-term neuroleptic therapy similar to tardive dyskinesia (TD). 2. Six schizophrenic patients with SSP, considered to be drug-resistant, were treated with risperidone, while another 5 were treated with clozapine. 3. The 6 risperidone-treated patients (all women) were rated on the Clinical Global Impression Improvement Scale as at least very much improved. Among the 5 clozapine-treated patients, all 4 men were found to have a marked response to clozapine, while the female patient was judged to be minimally improved. 4. It is hypothesized that not only TD but also SSP arise from destruction of cholinergic interneurons in the striatum as a consequence of prolonged neuroleptic administration. Thus, the drug-induced parkinsonism, which was proposed as mediating the antipsychotic effect of dopamine D2 blocking drugs, depends on the integrity of these cholinergic neurons. If these neurons are destroyed, drugs such as haloperidol lose their therapeutic effect. 5. In contrast, atypical neuroleptics like clozapine and risperidone reduce dopamine release in the striatum independently of prior production of extrapyramidal symptoms and, in this way, may be effective in psychotic illnesses unresponsive to classical anti-D2 neuroleptics. 6. In the present sample of patients, it is worth noting that schizophrenic men were good responders to clozapine. In comparison, risperidone was found to be efficacious in schizophrenic women.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Resistance; Dyskinesia, Drug-Induced; Female; Haloperidol; Humans; Isoxazoles; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Psychoses, Substance-Induced; Risperidone; Schizophrenia; Schizophrenic Psychology; Sex Characteristics

Risperidone (RIS), a new neuroleptic with 5-HT2- and dopamine D2 receptor-blocking properties, was compared with perphenazine (PER) in a double-blind, multicentre, parallel-group study in 107 chronic schizophrenics with acute exacerbation. RIS 5-15 mg or PER 16-48 mg daily was given for 8 weeks. Psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression. Seventy-eight patients completed the trial; there was an equal number of dropouts on both drugs. The mean daily dose at endpoint was 8.5 mg RIS and 28 mg PER. The reduction in total PANSS score to endpoint did not differ significantly, although there was a tendency in favour of RIS. The number of patients with predominantly negative symptoms who showed at least 20% reduction in total PANSS score was significantly larger in the RIS group. Furthermore, the number of patients showing at least 20% reduction in Brief Psychiatric Rating Scale (BPRS) score (BPRS being a subscale of PANSS) was significantly larger in the RIS group. The hostility cluster of BPRS improved more on RIS than on PER in the endpoint analysis. The overall prevalence of side effects was fairly similar in the two groups.

Topics: Acute Disease; Adult; Aged; Antipsychotic Agents; Denmark; Double-Blind Method; Female; Humans; Isoxazoles; Male; Middle Aged; Norway; Parkinson Disease, Secondary; Perphenazine; Piperidines; Prevalence; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index

In a double-blind study, 135 inpatients with a diagnosis of chronic schizophrenia were randomly assigned to 8 weeks of treatment with one of six parallel treatments: risperidone (a new central 5-hydroxytryptamine2 and dopamine D2 antagonist), 2, 6, 10, 16 mg/day; haloperidol, 20 mg/day; or placebo, after a single-blind placebo washout period. Doses were increased in fixed increments up to a fixed maintenance dose reached after 1 week. On the Clinical Global Impression-Severity of Illness and Improvement, all active medications were superior to placebo except for risperidone (2 mg) on the Clinical Global Impression-Improvement. On the total Positive and Negative Syndrome Scale (PANSS) score and positive subscale, superiority to placebo was observed for all treatment groups except for haloperidol and risperidone (2 mg), which tended to be superior to placebo on total PANSS and the positive subscale, respectively. On the PANSS negative subscale, only risperidone (6 mg/day) was significantly better than placebo. Risperidone (6 mg) was superior to haloperidol on the total PANSS, General Psychopathology, and Brief Psychiatric Rating Scale subscales. Although there was a linear increase in parkinsonism with increasing risperidone dosage, there were no statistically significant differences between risperidone (2, 6, and 16 mg/day) and placebo. At doses of 6 to 16 mg, risperidone displayed a marked antidyskinetic effect compared with placebo. This effect was more pronounced in patients with severe dyskinesia. By contrast, haloperidol produced significantly more parkinsonism than placebo and risperidone (2, 6 and 16 mg), with no effect on tardive dyskinesia. These data suggest that risperidone, at the optimal therapeutic dose of 6 mg/day, produced significant improvement in both positive and negative symptoms without an increase in drug-induced parkinsonian symptoms and with a significant beneficial effect on tardive dyskinesia.

Topics: Adult; Aged; Antipsychotic Agents; Chronic Disease; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Dyskinesia, Drug-Induced; Female; Haloperidol; Humans; Isoxazoles; Male; Middle Aged; Neurologic Examination; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology

A parallel group double-blind comparative trial was conducted to study the efficacy and safety of risperidone compared with haloperidol. After a one-week wash-out, 35 chronic schizophrenic patients (17 males, 18 females) were randomly assigned to one of two groups for eight weeks of double-blind treatment. The patients' psychopathology was assessed by means of the Positive and Negative Syndrome Scale for Schizophrenia (PANSS) and the Clinical Global Impression (CGI). Safety assessments included the Extrapyramidal Symptom Rating Scale (ESRS), the UKU Side Effect Rating Scale, vital signs, body weight, ECG and laboratory screening. Thirty-two patients completed the trial: there were 3 dropouts in the risperidone group. The results on the PANSS and CGI indicate that the mean changes from baseline on the total PANSS score and on the total BPRS score were comparable in both treatment groups. The number of patients where a clinical improvement at least 20% reduction in baseline score was also similar in both treatment groups. Risperidone caused less extrapyramidal symptoms and less side effects in UKU scale than haloperidol. No significant ECG changes were induced, no relevant changes in blood pressure or clinical laboratory parameters were observed. This study has demonstrated that the combined serotonin 5-HT2 and dopamine-D2 antagonist risperidone is an antipsychotic as potent as haloperidol. Risperidone causes less extrapyramidal symptoms, and is better tolerated than haloperidol.

Topics: Adolescent; Adult; Chronic Disease; Double-Blind Method; Female; Haloperidol; Humans; Isoxazoles; Male; Middle Aged; Piperidines; Risperidone; Schizophrenia

The objective of this study was twofold: (1) to describe the effects of risperidone on the quantitative electroencephalogram (EEG) in schizophrenic patients and (2) to explore the relationships between EEG changes and clinical improvement. The subjects were nine male schizophrenic patients participating in a placebo-controlled, double-blind clinical trial (duration, 9 weeks) aimed to assess the effects of risperidone. The EEG effects of risperidone were compared with those of haloperidol. Nine haloperidol patients were selected from a separate treatment study that had a similar design and selection criteria and used identical EEG methods. We found that risperidone treatment induced widespread changes in interhemispheric power asymmetry. Furthermore, overall clinical improvement was related to two EEG measures: (1) absolute power changes in the beta frequency band and (2) power asymmetry in the theta and delta bands. Both relationships were most expressed in the anterior areas. The first relationship could not be linked to any specific cluster of behavioral symptoms. The second relationship was linked to improvements of affective symptoms and hostility-suspiciousness. The relationships observed in the risperidone group could not be detected in the haloperidol-treated patients. We hypothesized that the first relationship is attributable to an interaction between the serotonergic and dopaminergic system; the second relationship was associated with serotonergic mechanisms.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Dominance, Cerebral; Dose-Response Relationship, Drug; Double-Blind Method; Electroencephalography; Evoked Potentials; Haloperidol; Humans; Isoxazoles; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Receptors, Dopamine; Receptors, Serotonin; Risperidone; Schizophrenia; Schizophrenic Psychology; Social Behavior

A double-blind eight-week study was carried out to compare the efficacy and safety of risperidone in relation to haloperidol. Sixty-two inpatients suffering from acute schizophrenic or schizoaffective psychoses diagnosed according to ICD-9 were treated with risperidone 2-20 mg daily or haloperidol 2-20 mg daily. The mean total BPRS scores were reduced from 45.5 to 32.4 in the risperidone group and from 43.1 to 28.5 in haloperidol group. There were no significant differences between the two treated groups with regard to the total BPRS score and the percentage of remissions achieved. No statistically significant difference was found between the groups in any of the factors or items except guilt feeling (p < 0.02), anxiety (p < 0.005), and factor I--anxiety/depression--(p < 0.02) in favour of haloperidol. Risperidone had the benefit of a lower incidence of extrapyramidal side-effects.

Topics: Adult; Antiparkinson Agents; Antipsychotic Agents; Basal Ganglia Diseases; Double-Blind Method; Female; Haloperidol; Humans; Isoxazoles; Male; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Risperidone; Schizophrenia; Schizophrenic Psychology

The Positive and Negative Syndrome Scale (PANSS) has been translated into Swedish and tested in 88 chronic schizophrenic patients. All 4 subscales exhibited a roughly normal distribution. The overall alpha for the positive, negative and general psychopathology subscales were 0.81, 0.58 and 0.63, respectively. The correlation between the positive and negative subscales was -0.17 (NS). The interrater reliability was 0.73-0.75 for the positive, 0.65-0.74 for the negative and 0.75-0.77 for the general psychopathology subscales. The intraclass coefficients were 0.75-0.77 for the positive, 0.27-0.46 for the negative, 0.56-0.72 for the general psychopathology subscales and 0.66-0.71 for the total scale. Thus, the validity and reliability of the PANSS (Swedish version) are quite satisfactory.

Topics: Antipsychotic Agents; Chronic Disease; Cross-Cultural Comparison; Double-Blind Method; Haloperidol; Humans; Isoxazoles; Observer Variation; Piperidines; Psychiatric Status Rating Scales; Psychometrics; Reproducibility of Results; Risperidone; Schizophrenia; Schizophrenic Psychology; Sweden

The dopamine (DA) autoreceptor agonist (-)-3PPP (preclamol) was tested in male schizophrenic volunteers for safety. The drug was administered intramuscularly in a single rising dose design, crossed with a similar "rising dose" placebo period; all evaluations and raters were blind to drug or placebo administration. Pharmacokinetic, endocrine, safety, and mental status outcome measures were completed before and after each single dose of drug or placebo. Pharmacokinetic analysis showed blood levels between 200-500 pmoles/ml after the intramuscular drug doses of 30-40 mg. Drug half life is 2-2.5 hrs. Growth hormone (GH) levels were elevated in a linear fashion to the 30 mg dose; whereafter, the drug failed to affect GH at all. All safety evaluations were negative, including any untoward effects on the major organ systems. After single dose drug administration, evidence of antipsychotic action occurred in two of the four subjects. This study suggests that (-)-3PPP/preclamol is a safe drug for study in the treatment of schizophrenia and may have antipsychotic efficacy.

Topics: Administration, Oral; Adult; Chromatography, Gas; Dopamine Agents; Double-Blind Method; Half-Life; Humans; Injections, Intramuscular; Male; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Forty-four chronic schizophrenic inpatients participated in this multicentre 12-week parallel-group double-blind trial. After a run-in period of 2 weeks and a single-blind placebo wash-out of 1 week, they were randomly assigned to treatment with either the serotonin2 and dopamine-D2 antagonist risperidone or haloperidol. Two patients were excluded from the efficacy analysis. Five patients dropped out in the haloperidol group and 1 in the risperidone group. At the end of the trial, the mean daily dose was 12 mg for risperidone and 10 mg for haloperidol. The risperidone group showed greater improvement on the Positive and Negative Syndrome Scale for Schizophrenia, the Schedule for Affective Disorders and Schizophrenia-change version, and the Nurses' Observation Scale for Inpatient Evaluation. The improvement of negative symptoms was more pronounced in the risperidone group until week 8 of double-blind treatment. The consumption of antiparkinsonian medication was 10 times lower with risperidone. Both drugs were well tolerated and the laboratory, endocrinological and cardiovascular safety parameters were comparable. This study suggests that risperidone is comparable to haloperidol as an antipsychotic, but that it has a safer EPS profile.

Topics: Adult; Aged; Antipsychotic Agents; Chronic Disease; Double-Blind Method; Female; Haloperidol; Hospitalization; Humans; Isoxazoles; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology

The ventricle-brain ratio (VBR) of 42 chronic schizophrenic patients was compared with that of 42 age-matched medical controls. For the schizophrenics, the relationship of various clinical parameters to the VBR was assessed, and the outcome of 12 weeks of double-blind treatment with either risperidone or haloperidol. The results confirm that schizophrenic patients have slightly enlarged lateral ventricles compared with medical controls. Only for schizophrenics, an effect of age, but not of duration of illness, was noticed. This study does not support the validity of a clinical subdivision of chronic schizophrenic patients on the basis of the VBR. Neither negative, positive nor general psychopathological symptoms, as measured by the Positive and Negative Syndrome Scale for Schizophrenia (PANSS), were related to the VBR, nor were abnormal involuntary movements or extrapyramidal symptoms. No association between season of birth or a family history of major mental disorder and VBR could be demonstrated. Treatment response was predicted by the total PANSS score and the PANSS general psychopathology subscale score at baseline. There was a trend for patients with higher VBR to have a more or haloperidol). or haloperidol).

Topics: Adult; Aged; Antipsychotic Agents; Brain; Cerebral Ventricles; Chronic Disease; Dilatation, Pathologic; Double-Blind Method; Female; Haloperidol; Humans; Isoxazoles; Male; Middle Aged; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology; Tomography, X-Ray Computed

Topics: Antipsychotic Agents; Dopamine Antagonists; Double-Blind Method; Electrocardiography; Humans; Isoxazoles; Piperidines; Psychiatric Status Rating Scales; Receptors, Dopamine D2; Risperidone; Schizophrenia; Serotonin Antagonists

Topics: Antipsychotic Agents; Double-Blind Method; Haloperidol; Humans; Isoxazoles; Piperidines; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology

This multicenter trial indicates that risperidone is an effective treatment for the positive and negative symptoms of schizophrenia. The most effective dose appears to be about 6 mg of risperidone daily. This dose was more effective than 20 mg of haloperidol. In addition, this dose was associated with very low rates of extrapyramidal side effects.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Chronic Disease; Double-Blind Method; Humans; Isoxazoles; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Risperidone; Schizophrenia

Risperidone represents a unique pharmacology of potent antagonism of both serotonin and dopamine receptors. In a randomized, parallel-group, double-blind trial of risperidone vs. haloperidol and placebo in 36 schizophrenic patients in acute exacerbation, risperidone showed a quicker onset of antipsychotic activity than did haloperidol. Risperidone treatment was statistically superior to placebo, with a trend toward superiority to haloperidol. Risperidone did not differ from placebo on assessment scales of extrapyramidal side effects, but produced significantly less than did haloperidol. There were no major adverse reactions associated with risperidone use, but it was noted to reduce the signs of tardive dyskinesia. This study suggests that risperidone may offer a superior side-effect profile, and possibly greater efficacy, than a standard neuroleptic such as haloperidol.

Topics: Adult; Antipsychotic Agents; Double-Blind Method; Female; Humans; Isoxazoles; Male; Middle Aged; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology

Compared to traditional neuroleptics, most of the new antipsychotics are characterized by a low extrapyramidal side effect (EPS) liability and varying antipsychotic efficacy. This topic is reviewed for four principal classes of new, established, and potential antipsychotics: (1) Antipsychotics such as sulpiride and remoxipride that block a subgroup of dopamine (DA) D2/D3 receptors produce a relatively low level of side effects, including EPS, and have an antipsychotic effect equal to or slightly weaker than traditional neuroleptics. D1 antagonists demonstrate a low level of EPS in primates and may prove to be a valuable new type of antipsychotic drug. (2) Theoretically, partial D2 agonists have the advantage of producing few or no EPS and a specific beneficial effect in negative symptoms, but as yet the expectations have not been fulfilled. (3) Nondopamine drugs such as serotonin (5HT1) agonists, 5HT2 antagonists, 5HT3 antagonists, and gamma-amino-butyric-acid-A (GABA-A) benzodiazepine agonists have anxiolytic, antidepressant, antiaggressive, and maybe antiparkinsonian effects and may play an adjunctive role in the treatment of schizophrenia. 5HT3 antagonists (e.g., ondansetron), partial benzodiazepine agonists, and partial glutamate agonists may prove to be effective antipsychotics. (4) Antipsychotics such as clozapine and risperidone, which affect D2/D3 receptors as well as 5HT, alpha 1, and/or D1 receptors appear to have the most pronounced antipsychotic effect.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Benzamides; Humans; Isoxazoles; Piperidines; Receptors, Dopamine; Receptors, Glutamate; Receptors, Neurotransmitter; Receptors, Serotonin; Remoxipride; Risperidone; Schizophrenia; Serotonin Antagonists; Sulpiride

Topics: Brain; Butyrophenones; Humans; Isoxazoles; Piperidines; Pyrimidinones; Randomized Controlled Trials as Topic; Receptors, Serotonin; Risperidone; Ritanserin; Schizophrenia; Schizophrenic Psychology; Serotonin Antagonists

Topics: Adolescent; Adult; Chlorpromazine; Clinical Trials as Topic; Clozapine; Dibenzazepines; Double-Blind Method; Humans; Male; Middle Aged; Penfluridol; Piperidines; Schizophrenia

In a double-blind, 4 week study, 42 chronic schizophrenic inpatients receiving antipsychotic and antiparkinsonian (AP) drugs for greater than 3 months were either switched to placebo or maintained on biperiden. In the majority of the patients no clinically apparent discomfort was observed, and only two of 21 placebo patients developed extrapyramidal side effects (EPS) severe enough to require resumption of AP therapy. No significant increase was shown in most items on EPS. Our data suggest that for the majority of patients on long-term AP medication AP drugs should be prescribed only when EPS develop.

Topics: Adult; Aged; Antipsychotic Agents; Biperiden; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperidines; Placebos; Schizophrenia; Substance Withdrawal Syndrome

Topics: Clinical Trials as Topic; Depressive Disorder; Humans; Piperidines; Ritanserin; Schizophrenia; Serotonin Antagonists; Sleep

Topics: Adolescent; Adult; Chlorpromazine; Clinical Trials as Topic; Clozapine; Dibenzazepines; Double-Blind Method; Humans; Male; Penfluridol; Piperidines; Psychiatric Status Rating Scales; Schizophrenia

Topics: Adult; Clinical Trials as Topic; Dexetimide; Drug Interactions; Drug Therapy, Combination; Female; Fluspirilene; Humans; Male; Middle Aged; Piperidines; Schizophrenia; Spiro Compounds

In a double-blind, placebo-controlled study, ten chronic schizophrenic patients with pronounced symptoms of tardive dyskinesia (TD) were withdrawn from anticholinergic medication. All patients had previously been under long-term treatment with neuroleptics and anticholinergics for at least two years. The rating-scales used were the AIMS, our own TD Scale, and the Simpson-Angus scale for extra-pyramidal side-effects. The severity of TD decreased significantly in nine patients with in two weeks; this improvement, most pronounced in the oral region (P less than .001), persisted during a six-week placebo period. There was a slight increase in parkinsonian symptoms (P less than .05), which was not a prerequisite for improvement in TD. Hence, discontinuation of anticholinergic medication is a possible therapeutic approach in patients with TD.

Topics: Adult; Aged; Antipsychotic Agents; Biperiden; Clinical Trials as Topic; Double-Blind Method; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Piperidines; Schizophrenia

Topics: Brief Psychiatric Rating Scale; Chronic Disease; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Male; Piperidines; Placebos; Schizophrenia

Penfluridol is a diphenylbutylpiperdine derivative with a half-life of sixty-six (66) hours. The present study was designed to determine its efficacy for the maintenance of schizophrenia. In a 52 week double-blind study, once weekly doses of penfluridol were compared with once daily doses of chlorpromazine in 56 schizophrenic patients receiving maintenance treatment on an outpatient basis. Both drugs were similar in their clinical effectiveness; no major side effects occurred with either drug.

Topics: Adult; Chlorpromazine; Clinical Trials as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Drug Evaluation; Female; Humans; Male; Penfluridol; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia

A pilot study with the new oral long-acting neuroleptic agent clopimozide, a diphenylbutylpiperidine derivative, has been reported. 30 female patients, only 20 of whom completed the trial, were treated with dosages of between 5 and 35 mg. The treatment comprised four periods in which the maximum tolerated daily dosage, the optimal weekly dosage (mean: 20.25 mg), the maximum tolerated weekly dosage and the optimal daily dosage were to be determined. In 10 patients plasma levels were determined with the radio-immunological method. The product exhibited a marked effect on schizophrenic target symptoms (significant at the 0.001 and 0.01 levels), of at least one week's duration, with an absence of sedation and a low degree of extrapyramidal side-effects. Clopimozide appears to be particularly suitable for the neuroleptic long-term treatment of compensated schizophrenic patients with insight into their disease.

Topics: Adult; Aged; Antipsychotic Agents; Benzimidazoles; Clinical Trials as Topic; Female; Humans; Middle Aged; Piperidines; Schizophrenia; Time Factors

Sixty patients meeting the criteria established for schizophrenia who attained a clinical plateau following hospital discharge were randomized to receive for one year either penfluridol, 20 to 160 mg orally once each week, or fluphenazine decanoate, 0.5 to 4 ml every two weeks. The relapse rate for both treatments was low and equal. The rate of recurrence of psychosis for patients receiving penfluridol was 7% and for those receiving fluphenazine decanoate 10%. A retrospective comparison of the penfluridol group was made to a similar group of patients assigned to placebo in an earlier study. Placebo-treated patients had a relapse rate of 68%. Penfluridol patients had statistically fewer psychotic relapses. Questions about the possible carcinogenicity of penfluridol in animals will have to be resolved before it can be widely used. This study demonstrates the feasibility of using an oral, long-acting antipsychotic agent. It would be a useful psychopharmacologic addition in the treatment of outpatient schizophrenics.

Topics: Administration, Oral; Adult; Clinical Trials as Topic; Double-Blind Method; Female; Fluphenazine; Humans; Injections, Intravenous; Long-Term Care; Male; Penfluridol; Piperidines; Recurrence; Schizophrenia

During an open clinical trial, 51 schizophrenic patients were treated with Penfluirdol, 34 for 1 year and 17 for a shorter time. The mean dosage of Penfluirdol was 22 up to 28 mg per week. Assessments were made on days 0, 14, 28, 56, 90, 180, 270, and 365 using the AMP system and the EPRS scale of Simpson and Angus. The symptomatology was mainly reduced during the first 3 months of treatment and remained afterwards relative unchanged. Penfluridol showed a good antipsychotic effect on productive schizophrenic symptoms (thought disorders and paranoid symptoms, autism and schizophrenic affective disorders). The dosage used showed only a slight sedative effect and was well tolerated concerning autonomic and extrapyramidal side-effects.

Topics: Adult; Clinical Trials as Topic; Female; Humans; Male; Penfluridol; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Time Factors

This investigation is a 52-week double-blind study comparing the efficacy and safety of penfluridol and trifluoperazine in 25 chronic schizophrenic outpatients. Penfluridol was administered once weekly and trifluoperazine daily. Measurements were made at baseline, various fixed intervals during the study period and termination. The data reveals that both agents were similarly effective in maintaining control of the symptoms of chronic schizophrenic patients at a level commensurate with or better than that provided by their previous medication. Besides being effective, medications were also well tolerated. The side effects were characteristic of marketed neuroleptics. Akathisia was more common with penfluridol but readily controlled with anti-parkinsonian medication. Other side effects were similar in severity and occurrence between study-drug groups. Both agents had low autonomic liability, and neither agent was depressogenic.

Topics: Adult; Chronic Disease; Clinical Trials as Topic; Double-Blind Method; Drug Evaluation; Female; Humans; Interpersonal Relations; Male; Penfluridol; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Trifluoperazine

Penfluridol, a diphenylbutylpiperidene derivative, is a new long acting neuroleptic, administered orally, once weekly. It is marketed in several European countries and has been used successfully in the treatment of various acute psychoses, for severely ill chronic schizophrenic patients, and as maintenance therapy for chronic schizophrenic patients. The present study was designed to compare, in a double-blind fashion, the efficacy of penfluridol and fluphenazine decanoate in the maintenance therapy of schizophrenic outpatients.

Topics: Adult; Ambulatory Care; Chronic Disease; Double-Blind Method; Drug Evaluation; Female; Fluphenazine; Humans; Male; Middle Aged; Penfluridol; Piperidines; Psychiatric Status Rating Scales; Schizophrenia

Psychotic women with schizophrenic symptoms were treated with melperone 100 mg X 3 (n = 29) or thiothixene 10 mg X 3 (N = 34) USING A DOUBLE-BLIND PROCEDURE. Before and during treatment, levels of HVA, MOPEG, and 5-HIAA, the major metabolites of DA, NE, and 5-HT, were determined in lumbar cerebrospinal fluid by a mass fragmentographic technique. Both treatments resulted in an elevation of the HVA levels after 2 weeks, thiothixene having a more marked effect. The effect of thiothixene but not of melperone persisted after 4 weeks. Thiothixene did not influence the MOPEG level, but melperone reduced it after 4 weeks of treatment. The 5-HIAA levels were not significantly altered by the drugs. The HVA/MOPEG and the HVA/5-HIAA ratios were highly significantly elevated by both drugs after 2 as well as 4 weeks. Thiothixene induced a significantly greater change of these ratios than melperone. The results supply evidence that thiothixene accelerates central dopamine metabolism in man, presumably by blocking DA receptors. Melperone appears to act similarly, but has an effect which is weaker and/or of shorter duration. During long-term treatment with melperone the receptors develop tolerance to it. The acceleration in DA metabolism declines and the effect of melperone switches instead to central NA metabolism. The results indicate that both drugs cause long-term changes in the activity ratios of central monoamine systems. It is suggested that such changes in several systems rather than single biochemical events may be related to the antipsychotic effects of neuroleptic drugs. This study also demonstrated the versatility of using monoamine metabolite analysis of the CSF as a tool for the quantification of biochemical effects of neuroleptic drugs on the human CNS.

Topics: Antipsychotic Agents; Butyrophenones; Clinical Trials as Topic; Double-Blind Method; Female; Glycols; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Methoxyhydroxyphenylglycol; Phenylacetates; Piperidines; Schizophrenia; Thiothixene

Topics: Administration, Oral; Adult; Chronic Disease; Clinical Trials as Topic; Drug Administration Schedule; Female; Fluphenazine; Humans; Male; Middle Aged; Penfluridol; Piperidines; Psychiatric Status Rating Scales; Schizophrenia

Topics: Adult; Clinical Trials as Topic; Double-Blind Method; Drug Administration Schedule; Drug Evaluation; Female; Humans; Male; Middle Aged; Penfluridol; Piperidines; Schizophrenia; Trifluoperazine

Topics: Administration, Oral; Clinical Trials as Topic; Double-Blind Method; Drug Evaluation; Fluphenazine; Humans; Injections; Penfluridol; Piperidines; Recurrence; Schizophrenia

Topics: Adult; Butyrophenones; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Middle Aged; Piperidines; Prolactin; Receptors, Dopamine; Schizophrenia; Substance Withdrawal Syndrome; Thiothixene; Tranquilizing Agents

Topics: Adult; Aged; Clinical Trials as Topic; Depressive Disorder, Major; Female; Humans; Long-Term Care; Male; Middle Aged; Obsessive-Compulsive Disorder; Penfluridol; Piperidines; Schizophrenia

Plasma levels of penfluridol and thiothixene were studied after 4 weeks treatment in a double-blind controlled trial of 47 patients suffering from chronic schizophrenic syndromes. There was found a tenfold variation in plasma levels for penfluridol, and about a twentyfold variation for thiothixene. For penfluridol, a significant correlation between dosage and plasma level and also between dosage and changes in psychopathology as regards factor 5 in the Märtens & Jonsson S scale which comprises the items most characteristic of a schizophrenic syndrome, was found. For thiothixene, a significant correlation between plasma levels and changes in factor 5 was found. A gas-chromatographic method for penfluridol is also described.

Topics: Adult; Chromatography, Gas; Chronic Disease; Clinical Trials as Topic; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Penfluridol; Piperidines; Schizophrenia; Thiothixene

Topics: Adolescent; Adult; Clinical Trials as Topic; Drug Evaluation; Female; Humans; Intellectual Disability; Male; Middle Aged; Penfluridol; Piperidines; Psychotic Disorders; Schizophrenia; Tablets; Time Factors

Topics: Adult; Clinical Trials as Topic; Female; Humans; Male; Middle Aged; Penfluridol; Piperidines; Psychiatric Status Rating Scales; Schizophrenia

Topics: Adult; Chronic Disease; Clinical Trials as Topic; Drug Evaluation; Electroencephalography; Female; Humans; Male; Middle Aged; Penfluridol; Piperidines; Schizophrenia; Sleep; Sleep Stages; Sleep, REM; Time Factors

Topics: Antipsychotic Agents; Clinical Trials as Topic; Humans; Injections, Intramuscular; Penfluridol; Phenothiazines; Piperidines; Placebos; Psychiatric Status Rating Scales; Schizophrenia

Topics: Adult; Chronic Disease; Clinical Trials as Topic; Female; Humans; Male; Middle Aged; Penfluridol; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Time Factors

The authors discuss the historical aspects, as well as the various etiological and clinical factors which contribute to the so-called pharmacogenically induced depressions during treatment by means of neuroleptics generally, and long-term neuroleptics especially. An open study on 161 schizophrenic patients treated by means of fluspirilene and 123 patients treated by means of penfluridol is described. A single blind trial on 48 patients, by means of fluphenazine-decanoate and flupenthixol-decanoate, which compares the possible depression-inducing or antidepressant activity of the above drugs, is presented. The criteria for evaluating drug-induced depressions and their two clinical types are discussed.

Topics: Adult; Antidepressive Agents; Clinical Trials as Topic; Depression; Female; Flupenthixol; Fluphenazine; Fluspirilene; Humans; Long-Term Care; Male; Penfluridol; Personality Inventory; Piperidines; Schizophrenia; Spiro Compounds; Thioxanthenes

Findings in this study support earlier investigations in attesting to the antipsychotic efficacy and relatively low toxicity of pipotiazine palmitate. Results with all efficacy measures utilized were consistent in indicating a high level of efficacy for this investigational compound. Pipotiazine palmitate apparently has an average duration of action that extends beyond 4 weeks in severely ill schizophrenic patients. This particular long acting IM antipsychotic preparation appears to have an even longer duration of activity than some of the other available standard long acting agents. The optimal dosage range for severely ill schizophrenic patients appears to be between 100 and 600 mg once monthly. While this type of drug (as is the case with many antipsychotic drugs) does reduce the psychotic symptomatology and improves the thought associations sufficient to enable the patient to leave the hospital, it should be re-emphasized that socioeconomic and guidance counseling services are necessary to maintain the patient in the community. The availability of this type of long acting preparation is not only economical in terms of nursing care and hospital cost but it should also increase the efficacy of psychopharmacologic treatment of schizophrenics by reducing both patient errors and staff errors in administration of medication. In addition, this IM preparation should prove to be of invaluable help in maintaining the schizophrenic patient in his community by reducing the relapse and the rehospitalization rates. It should be noted that there are schizophrenic patients who either absorb compounds from the gastrointestinal tract in a very poor manner or too rapidly metabolize the antipsychotic agents with resultant suboptimal blood levels and these subjects may be called "drug refractory." This type of long acting medication is an ideal preparation for the schizophrenic patient who has these types of absorption or metabolic problems since the "circulatory pass" through the liver is minimal after IM medication as compared to that encountered by an orally administered agent. The clinical disadvantage of pipotiazine palmitate is the delay in onset of therapeutic activity after injection. Significant improvement is first noted after 3 to 4 days after the highest IM dosage administration. Therefore, it may be necessary to use an oral or IM preparation of a neuroleptic with a more rapid onset of activity or utilize an oral dosage of the pipotiazine salt during the first

Topics: Administration, Oral; Adult; Blood Pressure Determination; Chemical Phenomena; Chemistry; Clinical Trials as Topic; Dose-Response Relationship, Drug; Extrapyramidal Tracts; Female; Humans; Intestinal Absorption; Male; Middle Aged; Palmitic Acids; Phenothiazines; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Sulfonamides; Time Factors

Five depot neuroleptics (fluphenazinedeconoate, fluspirilene, pipothiazinepalmitate, penfluridol and perphenazine-enanthate) were compared based on clinical trials in subacute and chronic schizophrenic patients. The psychopathological symptoms were documented by means of the AMP-system. Statistical analyses showed several differences between the effects of the five substances. The AMP-system proved a useful instrument to differentiate similar drugs.

Topics: Administration, Oral; Bipolar Disorder; Catatonia; Clinical Trials as Topic; Delayed-Action Preparations; Drug Evaluation; Female; Fluorobenzenes; Fluphenazine; Hallucinations; Hostility; Humans; Hydrocarbons, Halogenated; Hypochondriasis; Injections, Intramuscular; Methods; Paranoid Disorders; Perphenazine; Piperidines; Schizophrenia; Spiro Compounds; Sulfonamides; Time Factors; Tranquilizing Agents

Topics: Administration, Oral; Chronic Disease; Clinical Trials as Topic; Humans; Penfluridol; Piperidines; Placebos; Psychiatric Status Rating Scales; Schizophrenia

Fifty-six out of 60 schizophrenic patients completed a double-blind study of two long-acting neuroleptics, penfluridol (peroral) and flupenthixol decanoate (parenteral). Half of the patients were on maintenance therapy of flupenthixol prior to the study, the other half on penfluridol. The actual double-blind study (12 weeks) was commenced after a preliminary period of 4 weeks, the patients in the two main groups being randomly divided into two further groups, one continuing the medication unchanged, the other changing to the alternative drug. It was found possible to make a sudden switch from penfluridol to flupenthixol decanoate and vice versa without any significant change in the condition of the patient. The same dosage (in 70% of the patients from 40 to 80 mg) of penfluridol was used per week as was employed for flupenthixol decanoate per fortnight. Changes in the intensity of the symptoms (total Brief Psychiatric Rating Scale (BPRS) score) were moe pronounced in the preliminary period (during unchanged treatment) than on changed medication in the blind period. Both drugs induced approximately the same degree of akathisia, Parkinsonism and autonomic side effects. The practical consequences of equipotent therapeutical effect of a peroral and parenteral long-acting neuroleptic are briefly discussed.

Topics: Administration, Oral; Adolescent; Adult; Aged; Clinical Trials as Topic; Delayed-Action Preparations; Drug Evaluation; Flupenthixol; Humans; Injections; Male; Middle Aged; Penfluridol; Piperidines; Placebos; Schizophrenia; Thioxanthenes

Twenty-two hospitalized schizophrenic patients, participating in a large-scale phase II double-blind dose-effect study (30, 60, and 120 mg weekly) of penfluridol, a new diphenylbutylpiperidine neuroleptic, were maintained on a regular dosage regimen for 13 wk. Several blood samples were taken during the last dosage interval. Results show that the peak concentration develops within 12 hr after the last dose. A rapid decline, probably due to tissue re-equilibration, then occurs and is followed by a much slower falloff. Detectable concentrations 168 hr after administration are consistent with the long duration of action of penfluridol. Statistically significant differences between doses were found in the analysis of variance of plasma concentrations at all sampling times and in mean steady-state plasm concentrations. Wide differences in plasma concentrations were noted in patients receiving the same absolute dose, but a good relationship was defined between mean steady-state concentration and the dose expressed as mg per either kg of body weight or square meter of body surface area.

Topics: Administration, Oral; Adult; Clinical Trials as Topic; Dose-Response Relationship, Drug; Female; Humans; Kinetics; Male; Middle Aged; Penfluridol; Piperidines; Schizophrenia

Topics: Antipsychotic Agents; Chlorpromazine; Clinical Trials as Topic; Evaluation Studies as Topic; Female; Humans; Male; Piperidines; Psychiatric Status Rating Scales; Schizophrenia

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clinical Trials as Topic; Female; Hospitalization; Hospitals, Psychiatric; Humans; Male; Mental Disorders; Phenothiazines; Piperidines; Schizophrenia

Topics: Antipsychotic Agents; Clinical Trials as Topic; Cooperative Behavior; Delayed-Action Preparations; Drug Evaluation; Female; Humans; Phenothiazines; Piperazines; Piperidines; Schizophrenia; Sulfonamides; Thioxanthenes; Tranquilizing Agents

Topics: Antipsychotic Agents; Clinical Trials as Topic; Female; Humans; Phenothiazines; Piperazines; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Sulfonamides; Thioxanthenes; Tranquilizing Agents

Topics: Aggression; Analysis of Variance; Arrhythmias, Cardiac; Basal Ganglia Diseases; Benzoates; Butyrophenones; Chronic Disease; Clinical Trials as Topic; Dose-Response Relationship, Drug; Handwriting; Humans; Male; Piperidines; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Statistics as Topic; Tranquilizing Agents; Tremor

Topics: Adult; Analysis of Variance; Basal Ganglia Diseases; Body Weight; Chlorpromazine; Chronic Disease; Clinical Trials as Topic; Electrocardiography; Electroencephalography; Female; Humans; Hydrocarbons, Halogenated; Male; Middle Aged; Piperidines; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Social Behavior; Substance Withdrawal Syndrome; Thioridazine; Toluene; Tranquilizing Agents; Vision Tests

Topics: Benzoates; Butyrophenones; Clinical Trials as Topic; Haloperidol; Humans; Piperidines; Placebos; Psychiatric Status Rating Scales; Schizophrenia

Topics: Administration, Oral; Adult; Behavior; Benztropine; Clinical Trials as Topic; Drug Evaluation; Drug Tolerance; Electrocardiography; Eye; Humans; Hydrocarbons, Halogenated; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Time Factors; Toluene; Tranquilizing Agents

Topics: Acute Disease; Administration, Oral; Chromatography, Gas; Clinical Trials as Topic; Cooperative Behavior; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Evaluation; Female; Haloperidol; Humans; Hydrocarbons, Halogenated; Male; Motivation; Patients; Piperidines; Placebos; Psychiatric Nursing; Psychiatric Status Rating Scales; Recurrence; Schizophrenia; Tranquilizing Agents

Topics: Adult; Behavior; Chronic Disease; Clinical Trials as Topic; Drug Evaluation; Female; Humans; Male; Middle Aged; Paranoid Disorders; Piperidines; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenia, Paranoid

Topics: Adult; Clinical Trials as Topic; Haloperidol; Humans; Hydrocarbons, Halogenated; Learning; Male; Middle Aged; Motor Skills; Piperidines; Placebos; Schizophrenia; Toluene; Tranquilizing Agents

Topics: Adolescent; Adult; Clinical Trials as Topic; Delayed-Action Preparations; Drug Evaluation; Fatigue; Female; Fluorobenzenes; Fluphenazine; Humans; Male; Middle Aged; Movement Disorders; Piperidines; Schizophrenia; Spiro Compounds; Tranquilizing Agents; Xerostomia

Topics: Adult; Chronic Disease; Clinical Trials as Topic; Dibenzazepines; Drug Evaluation; Enuresis; Female; Humans; Intellectual Disability; Middle Aged; Neurasthenia; Piperidines; Psychotropic Drugs; Schizophrenia

Topics: Adult; Caproates; Chronic Disease; Clinical Trials as Topic; Delayed-Action Preparations; Drug Evaluation; Female; Fluorobenzenes; Fluphenazine; Humans; Hypnotics and Sedatives; Male; Middle Aged; Paranoid Disorders; Piperidines; Psychiatric Status Rating Scales; Psychological Tests; Schizophrenia; Spiro Compounds; Time Factors

Topics: Adult; Aged; Antiparkinson Agents; Chronic Disease; Clinical Trials as Topic; Drug Evaluation; Drug Therapy, Combination; Female; Haloperidol; Hospitalization; Humans; Hydrocarbons, Halogenated; Interview, Psychological; Middle Aged; Piperidines; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Surveys and Questionnaires; Time Factors; Toluene; Tranquilizing Agents

Topics: Acute Disease; Adolescent; Adult; Antipsychotic Agents; Chlorpromazine; Clinical Trials as Topic; Evaluation Studies as Topic; Female; Humans; Injections, Intramuscular; Ketones; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Schizophrenia

Topics: Adolescent; Adult; Antipsychotic Agents; Catatonia; Chlorpromazine; Clinical Trials as Topic; Drug Evaluation; Female; Humans; Injections; Male; Methotrimeprazine; Middle Aged; Palmitic Acids; Pilot Projects; Piperidines; Schizophrenia; Schizophrenia, Disorganized; Schizophrenia, Paranoid; Sulfonamides; Time Factors; Tremor

Topics: Adult; Aged; Antiparkinson Agents; Antipsychotic Agents; Basal Ganglia Diseases; Clinical Trials as Topic; Diazepam; Drug Evaluation; Female; Fluphenazine; Humans; Imipramine; Injections; Male; Middle Aged; Palmitic Acids; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Sulfonamides; Time Factors

Topics: Adult; Aged; Antipsychotic Agents; Basal Ganglia Diseases; Chronic Disease; Clinical Trials as Topic; Esters; Female; Humans; Male; Methotrimeprazine; Middle Aged; Piperidines; Schizophrenia; Sulfonamides; Time Factors; Undecylenic Acids

Topics: Adolescent; Adult; Age Factors; Aged; Antiparkinson Agents; Antipsychotic Agents; Clinical Trials as Topic; Drug Evaluation; Female; Humans; Male; Middle Aged; Palmitic Acids; Paranoid Disorders; Phenothiazines; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Sulfonamides

Topics: Adult; Aged; Antipsychotic Agents; Basal Ganglia Diseases; Clinical Trials as Topic; Drug Evaluation; Female; Humans; Length of Stay; Male; Methotrimeprazine; Middle Aged; Palmitic Acids; Piperidines; Schizophrenia; Sulfonamides; Time Factors

Topics: Acute Disease; Adult; Aged; Antidepressive Agents; Antipsychotic Agents; Chlorpromazine; Clinical Trials as Topic; Drug Hypersensitivity; Female; Humans; Male; Methotrimeprazine; Middle Aged; Palmitic Acids; Paranoid Disorders; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Sulfonamides; Time Factors

Topics: Adult; Age Factors; Aged; Antidepressive Agents; Antiparkinson Agents; Antipsychotic Agents; Chronic Disease; Clinical Trials as Topic; Female; Humans; Hypnotics and Sedatives; Injections; Male; Middle Aged; Palmitic Acids; Phenothiazines; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Sulfonamides; Time Factors

Topics: Antipsychotic Agents; Chronic Disease; Clinical Trials as Topic; Fluphenazine; Humans; Piperidines; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Sulfonamides; Undecylenic Acids

Topics: Adult; Aged; Clinical Trials as Topic; Drug Evaluation; Female; Humans; Hydrocarbons, Halogenated; Long-Term Care; Male; Middle Aged; Piperidines; Schizophrenia; Tranquilizing Agents

Topics: Adult; Clinical Trials as Topic; Female; Humans; Hydrocarbons, Halogenated; Leukocyte Count; Liver Function Tests; Male; Piperidines; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenia, Disorganized; Schizophrenia, Paranoid; Spiro Compounds; Trifluoperazine

Topics: Adult; Attention; Chronic Disease; Clinical Trials as Topic; Delayed-Action Preparations; Fluorobenzenes; Galvanic Skin Response; Humans; Memory; Motor Skills; Occupational Therapy; Perception; Piperidines; Placebos; Schizophrenia; Spiro Compounds; Tranquilizing Agents; Word Association Tests

Topics: Basal Ganglia Diseases; Blood Pressure; Chronic Disease; Clinical Trials as Topic; Female; Fluorobenzenes; Fluphenazine; Heart Rate; Humans; Injections, Intramuscular; Male; Parkinson Disease, Secondary; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Spiro Compounds; Time Factors; Tranquilizing Agents

Topics: Administration, Oral; Adolescent; Adult; Benzimidazoles; Child; Clinical Trials as Topic; Evaluation Studies as Topic; Factor Analysis, Statistical; Female; Humans; Ketones; Male; Middle Aged; Piperidines; Schizophrenia; Time Factors; Tranquilizing Agents

Topics: 1-Propanol; Adult; Antiparkinson Agents; Basal Ganglia Diseases; Benztropine; Biperiden; Chronic Disease; Clinical Trials as Topic; Drug Combinations; Evaluation Studies as Topic; Humans; Male; Middle Aged; Movement Disorders; Parasympatholytics; Piperidines; Procyclidine; Pyrrolidines; Schizophrenia; Tranquilizing Agents; Trihexyphenidyl; Tropanes

Topics: Adult; Aged; Clinical Trials as Topic; Evaluation Studies as Topic; Female; Humans; Imipramine; Ketones; Male; Middle Aged; Phenothiazines; Piperidines; Schizophrenia; Thioridazine

Topics: Acute Disease; Adolescent; Adult; Aged; Benzimidazoles; Butyrophenones; Clinical Trials as Topic; Evaluation Studies as Topic; Female; Humans; Ketones; Middle Aged; Perphenazine; Piperidines; Placebos; Schizophrenia; Tranquilizing Agents

Topics: Adult; Benzimidazoles; Chronic Disease; Clinical Trials as Topic; Female; Humans; Male; Middle Aged; Movement Disorders; Piperidines; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Tranquilizing Agents; Trifluoperazine

Topics: Administration, Oral; Adult; Aged; Chronic Disease; Clinical Trials as Topic; Delayed-Action Preparations; Evaluation Studies as Topic; Female; Humans; Injections, Intramuscular; Interview, Psychological; Length of Stay; Middle Aged; Occupational Therapy; Piperidines; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Surveys and Questionnaires; Tranquilizing Agents

Topics: Administration, Oral; Adolescent; Adult; Chemical Phenomena; Chemistry; Child; Clinical Trials as Topic; Dibenzazepines; Female; Humans; Male; Middle Aged; Pimozide; Piperidines; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Time Factors

Topics: Acute Disease; Adult; Aged; Chlorpromazine; Clinical Trials as Topic; Evaluation Studies as Topic; Humans; Injections, Intramuscular; Ketones; Middle Aged; Phenothiazines; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Tranquilizing Agents

Topics: Clinical Trials as Topic; Dopamine; Humans; London; Piperidines; Schizophrenia

Topics: Benzimidazoles; Clinical Trials as Topic; Humans; Piperidines; Psychotic Disorders; Schizophrenia; Tranquilizing Agents

Topics: Adolescent; Adult; Aged; Clinical Trials as Topic; Evaluation Studies as Topic; Female; Humans; Hydrocarbons, Halogenated; Injections, Intramuscular; Intellectual Disability; Middle Aged; Piperidines; Schizophrenia; Spiro Compounds; Tranquilizing Agents

Topics: Adult; Butyrophenones; Carbamates; Clinical Trials as Topic; Female; Humans; Male; Piperidines; Placebos; Psychiatric Status Rating Scales; Schizophrenia

Topics: Adult; Benzimidazoles; Chronic Disease; Clinical Trials as Topic; Electroencephalography; Evaluation Studies as Topic; Humans; Male; Piperidines; Placebos; Schizophrenia; Tranquilizing Agents

Topics: Adult; Body Weight; Clinical Trials as Topic; Dioxoles; Electroencephalography; Humans; Indoles; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Sleep

Topics: Adult; Benzimidazoles; Female; Humans; Male; Middle Aged; Piperidines; Schizophrenia; Tranquilizing Agents

Topics: Adolescent; Adult; Antidepressive Agents; Butyrophenones; Clinical Trials as Topic; Depressive Disorder, Major; Female; Fluorine; Humans; Light; Male; Middle Aged; Myoclonus; Perphenazine; Piperidines; Placebos; Reflex; Schizophrenia; Trifluperidol

Topics: Adolescent; Adult; Aged; Antidepressive Agents; Butyrophenones; Clinical Trials as Topic; Female; Fluorine; Humans; Middle Aged; Perphenazine; Piperidines; Placebos; Schizophrenia

Topics: Adolescent; Adult; Antidepressive Agents; Butyrophenones; Clinical Trials as Topic; Humans; Middle Aged; MMPI; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Trifluoperazine; Trifluperidol

Topics: Adult; Aggression; Anticonvulsants; Anxiety; Carbamazepine; Clinical Trials as Topic; Diazepam; Dibenzazepines; Epilepsy; Frustration; Hallucinations; Humans; Intellectual Disability; Middle Aged; Nitriles; Object Attachment; Perceptual Disorders; Phenothiazines; Piperidines; Psychiatric Status Rating Scales; Psychopathology; Schizophrenia; Thiazines; Tranquilizing Agents

Topics: Acute Disease; Adolescent; Adult; Aged; Antidepressive Agents; Butyrophenones; Chronic Disease; Clinical Trials as Topic; Community Mental Health Services; Female; Fluorine; Humans; Male; Middle Aged; Piperidines; Schizophrenia; Trifluperidol

Topics: Adult; Age Factors; Antidepressive Agents; Butyrophenones; Chronic Disease; Clinical Trials as Topic; Female; Fluorine; Hospitalization; Humans; Middle Aged; Piperidines; Placebos; Schizophrenia; Trifluperidol

Topics: Adult; Antidepressive Agents; Butyrophenones; Chlorpromazine; Chronic Disease; Clinical Trials as Topic; Female; Fluorine; Humans; Middle Aged; Piperidines; Placebos; Schizophrenia; Trifluperidol

There have been concerns that antipsychotics increase the incidence of hyperglycemic progression. Many factors have been suggested to contribute to the risk of antipsychotic-induced hyperglycemic progression, including the type, daily dose, and number of antipsychotics; however, few studies have examined these relationships. This study aimed to examine the affect of antipsychotic treatment-associated factors on hyperglycemic progression, after adjustment for the affect of background factors suggested to be associated with hyperglycemic progression. This was a nationwide, multicenter, prospective cohort study examining the incidence of hyperglycemic progression during a 12 mo period following the initiation of newly prescribed antipsychotic medication. Demographic data, medication history, and blood test values were collected from 631 study participants with normal blood glucose levels at baseline for 12 mo. The primary endpoint (incidence of hyperglycemic progression) was defined as progression from normal to prediabetic or probable diabetic status, and was evaluated based on the Japanese monitoring guidance in patients with schizophrenia. To further examine the affect of antipsychotics on glucose metabolism over time, we examined changes in HbA1c levels 3, 6, and 12 mo after the initiation of treatment with each antipsychotic. We found that treatment with zotepine and clozapine was associated with a significantly high incidence of hyperglycemic progression. Furthermore, changes in HbA1c levels 6 mo after the initiation of zotepine treatment were significantly higher than those following blonanserin and haloperidol treatments. In contrast, there was no significant difference in the change in total cholesterol, triglycerides, HDL cholesterol, and BMI during the same period. Moreover, the "daily dose" and "number" of antipsychotics did not show an association with the incidence of hyperglycemic progression. However, in a post hoc analysis in which the antipsychotics were divided into two groups according to the strength of blockade of H

Topics: Adult; Antipsychotic Agents; Clozapine; Dibenzothiepins; Female; Haloperidol; Humans; Hyperglycemia; Incidence; Japan; Male; Middle Aged; Piperazines; Piperidines; Prospective Studies; Schizophrenia

Topics: Antipsychotic Agents; Electroconvulsive Therapy; Haloperidol; Humans; Piperazines; Piperidines; Schizophrenia; Schizophrenia, Treatment-Resistant

Topics: Antipsychotic Agents; Bradycardia; Humans; Piperazines; Piperidines; Schizophrenia

Topics: Antipsychotic Agents; Humans; Piperazines; Piperidines; Schizophrenia; Transdermal Patch

The large number of people infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has plunged the world into fear in recent times. In Japan, 18,769 novel coronavirus disease 2019 (COVID-19) cases have been reported as of June 30, 2020. This study aimed to assess whether cluster infection prevention is possible by evaluating the association between viral transmission and meteorological factors.. This study included 1263 people who were successively diagnosed with COVID-19 in Hokkaido, Japan between January 24, 2020 and June 30, 2020. After obtaining the values from the Japanese Meteorological Agency, the average scores of air temperature and humidity were calculated and compared with COVID-19 reproduction numbers, and the association between COVID-19 incidence or reproduction number and meteorological factors was assessed.. The COVID-19 reproduction number in Hokkaido had three peaks that came several days before the surge in COVID-19 cases. The peaks are indicative of cluster infections. There was a strong negative correlation between the kinematic viscosity of atmospheric air and the reproduction number.. Analysis of the reproduction number is important for predicting or suppressing COVID-19 infection clusters. The authors found a strong association between meteorological factors, such as kinematic viscosity of atmospheric air and the incidence of COVID-19 infection. Meteorological forecasts could provide foreknowledge about COVID-19 infection clusters in the future.

Topics: COVID-19; Double-Blind Method; Humans; Japan; Piperazines; Piperidines; SARS-CoV-2; Schizophrenia; Transdermal Patch; Viscosity

Methoxphenidine is a dissociative-based novel psychoactive designer drug. Although fatal accidents from methoxphenidine abuse have been reported, recreational use of the drug continues. We aim to provide scientific supportfor legal regulation of recreational abuse of methoxphenidine by demonstrating its the pharmacological action.. Addictive potential of methoxphenidine was examined using intravenous self-administration test with rats and conditioned place preference test with mice. Further, a series of behavioural tests (open field test, elevated plus maze test, novel object recognition test, social interaction test and tail suspension test) performed to assess whether methoxphenidine caused schizophrenia-related symptoms in mice. Additionally, neurotransmitter enzyme-linked immunosorbent assay and western blot were used to confirm methoxphenidine-induced neurochemical changes in specific brain regions related to abnormal behaviours.. Methoxphenidine caused addictive behaviours via reinforcing and rewarding effects. Consistently, methoxphenidine induced over-activation of dopamine pathways in the nuclear accumbens, indicating activation of the brain reward circuit. Also, methoxphenidine caused all categories of schizophrenia-related symptoms, including positive symptoms (hyperactivity, impulsivity), negative symptoms (anxiety, social withdrawal, depression) and cognitive impairment. Consistently, methoxphenidine led to the disruption of the hippocampal-prefrontal cortex pathway that is considered to be pathological involved in schizophrenia.. We demonastrate that methoxphenidine causes addictive and schizophrenia-like behaviours and induces neurochemical changes in brain regions associated with these behaviours. We propose that methoxphenidine could be used in developing useful animal disease models and that it also requires legal restrictions on its recreational use.

Topics: Animals; Behavior, Addictive; Brain; Mice; Piperidines; Rats; Schizophrenia

Cortical circuit dysfunction is thought to be an underlying mechanism of schizophrenia (SZ) pathophysiology with normalization of aberrant circuit activity proposed as a biomarker for antipsychotic efficacy. Cannabidiol (CBD) shows potential as an adjunctive antipsychotic therapy; however, potential sex effects in these drug interactions remain unknown. In the present study, we sought to elucidate sex effects of CBD coadministration with the atypical antipsychotic iloperidone (ILO) on the activity of primary cortical neuron cultures derived from the rat methylazoxymethanol acetate (MAM) model used for the study of SZ. Spontaneous network activity measurements were obtained using a multielectrode array at baseline and following administration of CBD or ILO alone, or combined. At baseline, MAM male neurons displayed increased bursting activity whereas MAM female neurons exhibited no difference in bursting activity compared to sex-matched controls. CBD administered alone showed a rapid but transient increase in neuronal activity in the MAM networks, an effect more pronounced in females. Furthermore, ILO had an additive effect on CBD-induced elevations in activity in the MAM male neurons. In the MAM female neurons, CBD or ILO administration resulted in time-dependent elevations in neuronal activity, but the short-term CBD-induced increases in activity were lost when CBD and ILO were combined. Our findings indicate that CBD induces rapid increases in cortical neuronal activity, with sex-specific drug interactions upon ILO coadministration. This suggests that sex should be a consideration when implementing adjunct therapy for treatment of SZ.

Topics: Animals; Animals, Newborn; Antipsychotic Agents; Cannabidiol; Cell Culture Techniques; Cerebral Cortex; Disease Models, Animal; Female; Isoxazoles; Male; Neurons; Piperidines; Rats; Rats, Sprague-Dawley; Schizophrenia; Sex Characteristics

Topics: Animals; Antipsychotic Agents; Cytochrome P-450 Enzyme System; Gene Expression; Isoxazoles; Liver; Male; Microsomes, Liver; Piperidines; Rats; Rats, Wistar; Schizophrenia

Topics: Humans; Piperazines; Piperidines; Schizophrenia

Prepulse inhibition of the startle reflex (PPI) is disrupted in several psychiatric disorders including schizophrenia. Understanding PPI pharmacology may help elucidate the pathophysiology of these disorders and lead to better treatments. Given the advantages of multi-target approaches for complex mental illnesses treatment, we have investigated the interaction between receptors known to modulate PPI (5-HT. To investigate serotonin and cannabinoid receptor (CBR) co-modulation in a model of PPI disruption relevant to schizophrenia METHODS: Male Swiss mice were pretreated with WIN 55,212-2 (CBR agonist), rimonabant (CB1R inverse agonist), 8-OH-DPAT (5-HT. WIN 55,212-2 and rimonabant did not change PPI nor block MK-801-induced deficits. 8-OH-DPAT increased PPI in control mice and, in a higher dose, inhibited MK-801-induced impairments. Volinanserin also increased PPI in control and MK-801-treated mice, presenting an inverted U-shaped dose-response curve. Co-administration of either cannabinoid ligand with 8-OH-DPAT did not change PPI; however, the combination of volinanserin with rimonabant increased PPI in both control and MK-801-exposed mice.. WIN 55,212-2 and rimonabant had similar effects in PPI. Moreover, serotonin and cannabinoid receptors interact to modulate PPI. While co-modulation of CBR and 5-HT

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Benzoxazines; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Cannabinoids; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fluorobenzenes; Male; Mice; Morpholines; Naphthalenes; Piperidines; Prepulse Inhibition; Receptor, Serotonin, 5-HT2A; Receptors, Cannabinoid; Reflex, Startle; Schizophrenia; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Treatment Outcome

Topics: Animals; Antipsychotic Agents; Drug Design; Humans; Ligands; Models, Molecular; Piperidines; Receptors, G-Protein-Coupled; Schizophrenia; Structure-Activity Relationship

Topics: Administration, Oral; Animals; Antipsychotic Agents; Biological Availability; Chemistry, Pharmaceutical; Dizocilpine Maleate; Drug Carriers; Emulsions; Excipients; Humans; Isoxazoles; Locomotion; Male; Models, Animal; Particle Size; Piperidines; Rats; Schizophrenia; Solubility; Surface-Active Agents; Suspensions; Tablets

Iloperidone, a second-generation atypical antipsychotic drug, is widely used in the treatment of schizophrenia. However, the side-effects of iloperidone on vascular K

Topics: Antipsychotic Agents; Coronary Vessels; Isoxazoles; Membrane Potentials; Myocytes, Smooth Muscle; Piperidines; Potassium Channel Blockers; Schizophrenia; Voltage-Dependent Anion Channels

Patients diagnosed with schizophrenia typically receive life-long treatments with antipsychotic drugs (APDs). However, the impact of chronic APDs treatment on neuroplastic mechanisms in the brain remains largely elusive.. Here, we focused on blonanserin, a second-generation antipsychotic (SGA) that acts as an antagonist at dopamine D2, D3, and serotonin 5-HT2A receptors, and represents an important tool for the treatment of schizophrenia.. We used rats to investigate the ability of chronic treatment blonanserin to modulate the activity of brain structures relevant for schizophrenia, under baseline conditions or in response to an acute forced swim session (FSS). We measured the expression of different immediate early genes (IEGs), including c-Fos, Arc/Arg 3.1, Zif268 and Npas4.. Blonanserin per se produced limited changes in the expression of these genes under basal conditions, while, as expected, FSS produced a significant elevation of IEGs transcription in different brain regions. The response of blonanserin-treated rats to FSS show anatomical and gene-selective differences. Indeed, the upregulation of IEGs was greatly reduced in the striatum, a brain structure enriched in dopamine receptors, whereas the upregulation of some genes (Zif268, Npas4) was largely preserved in other regions, such as the prefrontal cortex and the ventral hippocampus.. Taken together, our findings show that chronic exposure to blonanserin modulates selective IEGs with a specific anatomical profile. Moreover, the differential activation of specific brain regions under challenging conditions may contribute to specific clinical features of the drug.

Topics: Animals; Antipsychotic Agents; Brain; Drug Administration Schedule; Genes, Immediate-Early; Male; Piperazines; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Schizophrenia; Stress, Psychological

We report the optimisation of a series of novel amide-piperidine (piperazine) derivatives using the multiple ligand approach with dopamine and serotonin receptors. Of the derivatives, compound 11 exhibited high affinity for the D

Topics: Amides; Animals; Antipsychotic Agents; Dose-Response Relationship, Drug; Ether-A-Go-Go Potassium Channels; Humans; Ligands; Molecular Structure; Piperazine; Piperidines; Rats; Receptors, Dopamine D2; Receptors, Serotonin; Schizophrenia; Structure-Activity Relationship

In agreement with the neurodevelopmental hypothesis of schizophrenia, prenatal exposure of rats to the antimitotic agent methylazoxymethanol acetate (MAM) at gestational day 17 produced long-lasting behavioral alterations such as social withdrawal and cognitive impairment in the social interaction test and in the novel object recognition test, respectively. At the molecular level, an increased cannabinoid receptor type-1 (CB1) mRNA and protein expression, which might be due to reduction in DNA methylation at the gene promoter in the prefrontal cortex (PFC), coincided with deficits in the social interaction test and in the novel object recognition test in MAM rats. Both the schizophrenia-like phenotype and altered transcriptional regulation of CB1 receptors were reversed by peripubertal treatment (from PND 19 to PND 39) with the non-psychotropic phytocannabinoid cannabidiol (30 mg/kg/day), or, in part, by treatment with the cannabinoid CB1 receptor antagonist/inverse agonist AM251 (0.5 mg/kg/day), but not with haloperidol (0.6 mg/kg/day). These results suggest that early treatment with cannabidiol may prevent both the appearance of schizophrenia-like deficits as well as CB1 alterations in the PFC at adulthood, supporting that peripubertal cannabidiol treatment might be protective against MAM insult.

Topics: Amides; Animals; Arachidonic Acids; Cannabidiol; Disease Models, Animal; Endocannabinoids; Ethanolamines; Female; Glycerides; Hippocampus; Interpersonal Relations; Male; Methylazoxymethanol Acetate; Motor Activity; Oleic Acids; Palmitic Acids; Piperidines; Polyunsaturated Alkamides; Prefrontal Cortex; Pregnancy; Prenatal Exposure Delayed Effects; Puberty; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Recognition, Psychology; RNA, Messenger; Schizophrenia

We previously reported that centrally acting non-narcotic antitussives, including tipepidine, inhibit G-protein-coupled inwardly rectifying potassium (GIRK) channel-activated currents of neurons. In addition, when administered at a cough suppressant dose, the drugs ameliorated the symptoms of various models of intractable brain disease in rodents. In the current study, we investigated whether tipepidine causes recovery from schizophrenia-like cognitive dysfunction, which was induced by MK-801 (0.2 mg/kg, i.p.) in mice. We also examined the effect of tipepidine and clozapine co-administration on the dysfunction. Moreover, we studied whether clozapine inhibits GIRK channel activated currents in single brain neurons using the patch-clamp technique. Tipepidine elicited recovery from MK-801-induced cognitive impairment in the novel objective recognition test and Y-maze test. Further, co-administration of tipepidine and clozapine, at subthreshold doses of each drug, improved MK-801-induced cognitive impairment in the novel objective recognition test. Clozapine (3 × 10

Topics: Animals; Antidepressive Agents; Antitussive Agents; Clozapine; Cognitive Dysfunction; Disease Models, Animal; Dizocilpine Maleate; Dopaminergic Neurons; G Protein-Coupled Inwardly-Rectifying Potassium Channels; Male; Mice; Patch-Clamp Techniques; Piperidines; Rats; Rats, Wistar; Schizophrenia; Ventral Tegmental Area

Clozapine was the widely accepted gold standard treatment for treatment resistant psychotic symptoms. Clozapine has efficacy of about 50% and some responding patients have to discontinue it due to serious adverse effects. The search for novel agents to use for clozapine-non-responders continues. One such possible agent is the non-dopaminergic antipsychotic pimavanserin, an inverse agonist of serotonin 5-HT2A receptors which was recently approved for the hallucinations and delusions of Parkinson's Disease Psychosis. We report here the successful results of using pimavanserin in patients with refractory hallucinations and delusions who failed to respond to clozapine. We also report similar results in refractory psychosis patients who did not receive clozapine.. We present ten cases of patients with schizophrenia and schizoaffective disorder with refractory hallucinations and delusions who received a trial of pimavanserin when clozapine or multiple antipsychotics failed. Six of ten patients had not responded to a clozapine trial. The subjects' ages ranged between 21 and 77 years and were followed up for several months.. All 10 patients with refractory hallucinations and delusions showed marked response to pimavanserin 34 mg/day within 4-8 weeks, with continuation of the response for several months of follow-up. Improvements in negative symptoms and social functioning were also observed in several patients.. This series of 10 cases of patients with refractory psychosis who responded to pimavanserin is an important new finding that has never been reported before. Controlled studies comparing clozapine and pimavanserin in refractory schizophrenia are warranted to confirm these clinical observations.

Topics: Adult; Aged; Antipsychotic Agents; Clozapine; Delusions; Drug Resistance; Female; Hallucinations; Humans; Male; Middle Aged; Piperidines; Psychotic Disorders; Retrospective Studies; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Urea; Young Adult

Maternal infection during pregnancy increases risk of neurodevelopmental disorders such as schizophrenia and autism spectrum disorder (ASD) in offspring. In rodents, maternal immune activation (MIA) yields offspring with schizophrenia- and ASD-like behavioral abnormalities. Soluble epoxide hydrolase (sEH) plays a key role in inflammation associated with neurodevelopmental disorders. Here we found higher levels of sEH in the prefrontal cortex (PFC) of juvenile offspring after MIA. Oxylipin analysis showed decreased levels of epoxy fatty acids in the PFC of juvenile offspring after MIA, supporting increased activity of sEH in the PFC of juvenile offspring. Furthermore, expression of sEH (or

Topics: Animals; Epoxide Hydrolases; Female; Gene Expression Regulation, Enzymologic; Maternal Exposure; Mice; Neurodevelopmental Disorders; Phenylurea Compounds; Piperidines; Prefrontal Cortex; Pregnancy; Prenatal Exposure Delayed Effects; Schizophrenia

The connection between the endocannabinoid system (ECS) and schizophrenia is supported by a large body of research. The ECS is composed of two types cannabinoid (CB: CB1 and CB2) receptors and their endogenous ligands, endocannabinoids. The best-known endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are intracellularly degraded by fatty acid hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. Thus, the function of ECS might be modulated in a direct way, through CB receptor ligands or indirectly by FAAH and MAGL inhibitors. We evaluated that the direct influence of ECS, using FAAH (URB 597) and MAGL (JZL 184) inhibitors, on the schizophrenia-like effects in mice. The behavioral schizophrenia-like symptoms were obtained in animals by using N-methyl D-aspartate (NMDA) receptor antagonists, MK-801. An acute administration of MK-801 (0.3 and 0.6 mg/kg) induced psychotic symptoms in rodents, manifested as the increase in locomotor activity, measured in actimeters, as well as the memory impairment, assessed in the passive avoidance (PA) task. We revealed that an acute administration of URB 597, at the dose of 0.3 mg/kg, attenuated MK-801 (0.6 mg/kg)-induced memory impairment. In turn, an acute administration of URB 597 at a higher dose (1 mg/kg) potentiated MK-801 (0.3 mg/kg)-induced memory impairment. Similarly, an acute administration of JZL 184 (20 and 40 mg/kg) intensified an amnestic effect of MK-801 (0.3 mg/kg). Moreover, an acute injection of JZL 184 (1 mg/kg) potentiated hyperlocomotion is provoked by MK-801 (0.3 and 0.6 mg/kg) administration. The present findings clearly indicate that ECS, through an indirect manner, modulates a variety of schizophrenia-like responses in mice.

Topics: Amidohydrolases; Animals; Avoidance Learning; Benzamides; Benzodioxoles; Carbamates; Cognition; Dizocilpine Maleate; Enzyme Inhibitors; Injections; Male; Memory; Mice; Motor Activity; Piperidines; Schizophrenia

Topics: Adult; Anticipation, Psychological; Antipsychotic Agents; Aripiprazole; Female; Humans; Magnetic Resonance Imaging; Male; Olanzapine; Piperazines; Piperidines; Prefrontal Cortex; Reward; Schizophrenia; Ventral Striatum

The monoamine stabilizer (3S)-3-[3-(methenesulfonyl)phenyl]-1-propylpiperidine hidrochloride [(-)-OSU6162] is a promising compound for the treatment of neurological and psychiatric disorders, such as schizophrenia. Here, we tested the hypothesis that (-)-OSU6162 prevents hyperlocomotion and sensorimotor deficits in prepulse inhibition of the startle response (PPI) induced by psychomimetic drugs. Male Swiss mice received injections of (-)-OSU6162 (1, 3, 10, or 30 mg/kg), and their motor responses were investigated in the open field and in the catalepsy tests, which predicts liability to induce sedation and extrapyramidal side effects, respectively. Next, in independent experiments, this compound was evaluated for its efficacy to prevent hyperlocomotion induced by cocaine (10 mg/kg; dopamine transporter inhibitor) or ketamine (60 mg/kg; glutamate NMDA channel blocker) in the open field. Finally, we tested if (-)-OSU6162 prevents PPI disruption induced by MK-801 (0.5 mg/kg; glutamate NMDA channel blocker). (-)-OSU6162 induced neither locomotion impairment nor catalepsy. This compound prevented cocaine-induced hyperlocomotion at the doses of 10 and 30 mg/kg and ketamine-induced hyperlocomotion at the doses of 1 and 3 mg/kg. In the sensorimotor test, (-)-OSU6162 failed to reverse MK-801-induced PPI deficits. The dopamine stabilizer (-)-OSU6162 prevents the hyperactivity induced by dopaminergic and anti-glutamatergic drugs at doses that preserve motor functions, although it failed in the PPI test. Its therapeutic potential for specific symptoms of schizophrenia warrants further investigation in both preclinical and clinical studies.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Cocaine; Dopamine Uptake Inhibitors; Excitatory Amino Acid Antagonists; Ketamine; Locomotion; Male; Mice; Piperidines; Receptors, N-Methyl-D-Aspartate; Reflex, Startle; Schizophrenia

Currently available antipsychotics are unsatisfactory given their side effects and limited efficacy for the cognitive symptoms of schizophrenia. Many currently available drugs, such as haloperidol, are T-type calcium channel antagonists in addition to their well-established antagonism of dopamine D2 receptors. Thus, preclinical research into the effects of T-type calcium channel antagonists/blockers in behavioral assays related to schizophrenia may inform novel therapeutic strategies.. We explored the effects of a recently developed highly selective T-type calcium channel antagonist, Z944 (2.5, 5.0, 10.0 mg/kg), on the MK-801 (0.15 mg/kg) model of acute psychosis.. To examine the effects of Z944 on behaviors relevant to schizophrenia, we tested touchscreen-based paired associates learning given its relevance to the cognitive symptoms of the disorder and locomotor activity given its relevance to the positive symptoms.. Acute treatment with Z944 failed to reverse the visuospatial associative memory impairments caused by MK-801 in paired associates learning. The highest dose of drug (10.0 mg/kg) given alone produced subtle impairments on paired associates learning. In contrast, Z944 (5.0 mg/kg) blocked the expected increase in locomotion following MK-801 treatment in a locomotor assay.. These experiments provide support that Z944 may reduce behaviors relevant to positive symptoms of schizophrenia, although additional study of its effects on cognition is required. These findings and other research suggest T-type calcium channel antagonists may be an alternative to currently available antipsychotics with less serious side effects.

Topics: Acetamides; Animals; Association Learning; Benzamides; Calcium Channel Blockers; Calcium Channels, T-Type; Conditioning, Operant; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Locomotion; Male; Memory Disorders; Piperidines; Rats; Rats, Long-Evans; Receptors, N-Methyl-D-Aspartate; Schizophrenia

Social withdrawal should not be considered a direct measure of the negative symptoms of schizophrenia as it may result not only from asociality (primary negative symptom) but also from other altered processes such as anxiety. To understand the contribution of these two factors to social deficit, we investigated whether the social withdrawal observed in the subchronic phencyclidine (PCP) rat model of schizophrenia could be attributed to increased anxiety. Compared to saline controls, PCP-treated rats (5 mg/kg, twice daily for 7 days, followed by a washout period) spent significantly less time in social interaction, but did not show anxiety-like behaviors in different relevant behavioral paradigms. In addition, their social deficit was not affected by a behavioral procedure known to reduce anxiety-like behavior (repeated exposure to the same partner) nor by systemic administration of the classical anxiolytic diazepam. In contrast, PCP-induced social withdrawal was reversed by the cannabinoid agonist CP55,940, a drug with known anxiogenic properties. Furthermore, when using the social approach task, PCP-treated animals performed similarly to control animals treated with diazepam, but not to those treated with the anxiogenic compound pentylenetetrazole. Taken together, our results indicate that PCP-induced social withdrawal cannot be attributed to increased anxiety. These data are discussed in the context of primary versus secondary negative symptoms and the deficit syndrome of schizophrenia.

Topics: Animals; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Behavior, Animal; Cannabinoids; Carbamates; Disease Models, Animal; Exploratory Behavior; Interpersonal Relations; Male; Phencyclidine; Piperidines; Rats; Rats, Wistar; Schizophrenia; Schizophrenic Psychology; Social Behavior

The dopamine hypothesis states that decreased dopaminergic neurotransmission reduces schizophrenia symptoms. Neurokinin-3 receptor (NK3) antagonists reduce dopamine release and have shown positive effects in pre-clinical and clinical trials. We employed 2D and 3D-QSAR analysis on a series of 40 non-peptide NK3 antagonists. Multivariate statistical analysis, PCA and HCA, were performed to rational training/test set splitting and PLS regression was employed to construct all QSAR models. We constructed one highly predictive CoMFA model (q(2)= 0.810 and r(2)= 0.929) and acceptable HQSAR and CoMSIA models (HQSAR q(2)= 0.644 and r(2)= 0.910; CoMSIA q(2)= 0.691, r(2)= 0.911). The three different techniques provided convergent physicochemical results. All models indicate cyclopropane, piperidine and di-chloro-phenyl ring attached to cyclopropane ring and also the amide group attached to the piperidine ring could play an important role in ligand-receptor interactions. These findings may contribute to develop potential NK3 receptor antagonists for schizophrenia.

Topics: Cyclopropanes; Humans; Piperidines; Quantitative Structure-Activity Relationship; Receptors, Neurokinin-3; Schizophrenia

Chronic exposure to cannabinoids during adolescence results in long-lasting behavioral deficits that match some symptomatologic aspects of schizophrenia. The aim of this study was to investigate the reversibility of the emotional and the cognitive effects of chronic exposure to cannabinoids during adolescence, via subsequent modulation of the serotoninergic 5-HT4 and dopaminergic D3 receptors. RS67333 as a 5-HT4 agonist and U-99194A as a D3 antagonist were administered separately at 1 mg/kg and 20 mg/kg, and in combination at 0.5 mg/kg and 10 mg/kg to adult animals undergoing chronic treatment with the synthetic cannabinoid receptor agonist WIN55,212-2 (1 mg/kg) during adolescence. Animals were tested for anxiety-like behavior and episodic-like memory in the open field and novel object recognition tests respectively 30 minutes after the last drug administration. Chronic WIN55,212-2 treated animals exhibited a lasting disruption of episodic memory and increased anxiety levels. The effect on episodic-like memory were partially restored by acute administration of RS67333 and U-99194A and completely by administration of both drugs in combination at lower doses. However, only RS67333 (20 mg/kg) improved the anxiogenic-like effect of WIN55,212-2. These findings give further support that chronic exposure to cannabinoids during adolescence may be used as an animal model for schizophrenia, and highlight D3 and 5-HT4 receptors as potential targets for an enhanced treatment of the cognitive aspect of this disease.

Topics: Aging; Aniline Compounds; Animals; Anxiety; Behavior, Animal; Cannabinoids; Disease Models, Animal; Dopaminergic Neurons; Indans; Male; Memory; Morpholines; Piperidines; Rats, Wistar; Receptors, Dopamine D3; Receptors, Serotonin, 5-HT4; Schizophrenia; Serotonin 5-HT4 Receptor Antagonists

Previous studies have shown that social withdrawal in the phencyclidine (PCP) rat model of schizophrenia results from deficient endocannabinoid-induced activation of CB1 receptors. To understand the underlying cognitive mechanisms of the social deficit in PCP-treated rats, we examined the impact of pharmacological manipulation of the endocannabinoid system on sociability (i.e. social approach) and social novelty preference (which relies on social recognition). Control rats showed a clear preference for a "social" cage (i.e. unfamiliar stimulus rat placed under a wire mesh cage) versus an "empty" cage, and spent more time exploring a "novel" cage (i.e. new stimulus rat) versus a "familiar" cage. In contrast, rats receiving PCP (5 mg/kg, b.i.d. for 7 days, followed by a 7 day-washout period) showed intact sociability, but lacked social novelty preference. This PCP-induced deficit was due to increased activity at CB1 receptors as it was reversed by systemic administration of the CB1 antagonist AM251 (1 mg/kg). In agreement with this hypothesis, the cannabinoid agonist CP55,940 (0.003-0.03 mg/kg) dose-dependently suppressed social novelty preference in control animals without affecting sociability. Taken together, these data suggest that PCP-treated rats have a deficit in social cognition, possibly induced by increased stimulation of CB1 receptors. This deficit, however, is distinct from the social withdrawal previously observed in these animals, as the latter is due to deficient, rather than increased, CB1 stimulation.

Topics: Analysis of Variance; Animals; Cannabinoid Receptor Modulators; Cyclohexanols; Discrimination, Psychological; Disease Models, Animal; Endocannabinoids; Excitatory Amino Acid Antagonists; Exploratory Behavior; Male; Odorants; Phencyclidine; Piperidines; Pyrazoles; Rats; Rats, Wistar; Schizophrenia; Schizophrenic Psychology; Social Behavior Disorders; Social Perception

A growing body of psychiatric research has emerged, focusing on the role of endocannabinoid system in psychiatric disorders. For example, the endocannabinoid system, via cannabinoid CB (CB1 and CB2) receptors, is able to control the function of many receptors, such as N-methyl-D-aspartate (NMDA) receptors connected strictly with psychosis or other schizophrenia-associated symptoms. The aim of the present research was to investigate the impact of the CB1 receptor ligands on the symptoms typical for schizophrenia. We provoked psychosis-like effects in mice by an acute administration of NMDA receptor antagonist, MK-801 (0.1-0.6 mg/kg). An acute administration of MK-801 induced psychotic symptoms, manifested in the increase in locomotor activity (hyperactivity), measured in actimeters, as well as the memory impairment, assessed in the passive avoidance task. We revealed that an acute injection of CB1 receptor agonist, oleamide (5-20 mg/kg), had no influence on the short- and long-term memory-related disturbances, as well as on the hyperlocomotion in mice, provoking by an acute MK-801. In turn, an amnestic effects or hyperactivity induced by an acute MK-801 was attenuated by an acute administration of AM 251 (0.25-3 mg/kg), a CB1 receptor antagonist. The present findings confirm that endocannabinoid system is able to modify a variety of schizophrenia-like responses, including the cognitive disturbances and hyperlocomotion in mice. Antipsychotic-like effects induced by CB1 receptor antagonist, obtained in our research, confirm the potential effect of CB1 receptor blockade and could have important therapeutic implications on clinical settings, in the future.

Topics: Animals; Antipsychotic Agents; Cannabinoid Receptor Modulators; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Endocannabinoids; Excitatory Amino Acid Antagonists; Male; Memory Disorders; Memory, Long-Term; Memory, Short-Term; Mice; Motor Activity; Oleic Acids; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Schizophrenia; Schizophrenic Psychology

Dopamine supersensitivity psychosis (DSP) is one of the key factors contributing to the development of antipsychotic treatment-resistant schizophrenia (TRS). We investigated the efficacy of blonanserin, an atypical antipsychotic, for patients with TRS and DSP.. In this 12-month retrospective follow-up study, we investigated the cases of eight consecutive patients with unstable TRS and DSP treated with blonanserin as an add-on therapy. We examined changes in scores for the Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression-Severity of Illness (CGI-S) scale and the Global Assessment of Functioning scale (GAF) during the 12 months after the administration of blonanserin.. The patients' total scores on the BPRS and GAF scores were significantly improved by 3 months at the latest. Positive BPRS and CGI-S scores were also improved by 6 months at the latest. The total chlorpromazine-equivalent doses of antipsychotics were significantly reduced from 1462.3±499.6mg to 794.1±642.8mg (p=0.001) after 12 months of blonanserin treatment, with a favorable safety and tolerability profile.. Blonanserin may be a promising antipsychotic for the treatment of TRS and DSP.

Topics: Adult; Antipsychotic Agents; Brief Psychiatric Rating Scale; Dopamine; Drug Resistance; Female; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Piperazines; Piperidines; Psychiatric Status Rating Scales; Retrospective Studies; Schizophrenia

Subchronic administration of an N-methyl-D-aspartate receptor (NMDAR) antagonist, e.g. phencyclidine (PCP), produces prolonged impairment of novel object recognition (NOR), suggesting they constitute a hypoglutamate-based model of cognitive impairment in schizophrenia (CIS). Acute administration of atypical, e.g. lurasidone, but not typical antipsychotic drugs (APDs), e.g. haloperidol, are able to restore NOR following PCP (acute reversal model). Furthermore, atypical APDs, when co-administered with PCP, have been shown to prevent development of NOR deficits (prevention model). Most atypical, but not typical APDs, are more potent 5-HT(2A) receptor inverse agonists than dopamine (DA) D2 antagonists, and have been shown to enhance cortical and hippocampal efflux and to be direct or indirect 5-HT(1A) agonists in vivo. To further clarify the importance of these actions to the restoration of NOR by atypical APDs, sub-effective or non-effective doses of combinations of the 5-HT(1A) partial agonist (tandospirone), the 5-HT(2A) inverse agonist (pimavanserin), or the D2 antagonist (haloperidol), as well as the combination of all three agents, were studied in the acute reversal and prevention PCP models of CIS. Only the combination of all three agents restored NOR and prevented the development of PCP-induced deficit. Thus, this triple combination of 5-HT(1A) agonism, 5-HT(2A) antagonism/inverse agonism, and D2 antagonism is able to mimic the ability of atypical APDs to prevent or ameliorate the PCP-induced NOR deficit, possibly by stimulating signaling cascades from D1 and 5-HT(1A) receptor stimulation, modulated by D2 and 5-HT(2A) receptor antagonism.

Topics: Animals; Antipsychotic Agents; Disease Models, Animal; Dopamine D2 Receptor Antagonists; Haloperidol; Isoindoles; Memory Disorders; Phencyclidine; Piperazines; Piperidines; Pyrimidines; Random Allocation; Rats, Long-Evans; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Recognition, Psychology; Schizophrenia; Schizophrenic Psychology; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Agonists; Urea

Topics: Adult; Antipsychotic Agents; Female; Humans; Long QT Syndrome; Piperazines; Piperidines; Risperidone; Schizophrenia

The concept of targeted therapies remains a holy grail for the pharmaceutical drug industry for identifying responder populations or new drug targets. Here we provide quantitative systems pharmacology as an alternative to the more traditional approach of retrospective responder pharmacogenomics analysis and applied this to the case of iloperidone in schizophrenia. This approach implements the actual neurophysiological effect of genotypes in a computer-based biophysically realistic model of human neuronal circuits, is parameterized with human imaging and pathology, and is calibrated by clinical data. We keep the drug pharmacology constant, but allowed the biological model coupling values to fluctuate in a restricted range around their calibrated values, thereby simulating random genetic mutations and representing variability in patient response. Using hypothesis-free Design of Experiments methods the dopamine D4 R-AMPA (receptor-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor coupling in cortical neurons was found to drive the beneficial effect of iloperidone, likely corresponding to the rs2513265 upstream of the GRIA4 gene identified in a traditional pharmacogenomics analysis. The serotonin 5-HT3 receptor-mediated effect on interneuron gamma-aminobutyric acid conductance was identified as the process that moderately drove the differentiation of iloperidone versus ziprasidone. This paper suggests that reverse-engineered quantitative systems pharmacology is a powerful alternative tool to characterize the underlying neurobiology of a responder population and possibly identifying new targets.

Topics: Antipsychotic Agents; Computer Simulation; Genotype; Humans; Isoxazoles; Models, Biological; Molecular Targeted Therapy; Neurobiology; Pharmacogenetics; Piperazines; Piperidines; Schizophrenia; Thiazoles

Previously we designed a series of pyridinic anticholinesterasic compounds based on molecular hybridization between tacrine and the natural piperidine alkaloid (-)-3-O-acetylspectaline isolated from Senna spectabilis. Based on the information that the cholinergic system has an important role in the treatment of schizophrenia and depression, we herein report the evaluation of a series of pyridinic compounds in animal models for antipsychotic and antidepressant-like activities. Compound 2 decreased the immobility time of mice in the forced swimming test (5 and 10mg/kg p.o.) and prevented the climbing behavior induced by apomorphine (10mg/kg, p.o.), without impairing animals locomotor activity.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Central Nervous System Diseases; Disease Models, Animal; Mice; Piperidines; Pyridines; Schizophrenia

The present study describes the optimization of a series of novel benzoxazole-piperidine (piperazine) derivatives combining high dopamine D2 and serotonin 5-HT1A, 5-HT2A receptor affinities. Of these derivatives, the pharmacological features of compound 29 exhibited high affinities for the DA D2, 5-HT1A and 5-HT2A receptors, but low affinities for the 5-HT2C and histamine H1 receptors and human ether-a-go-go-related gene (hERG) channels. Furthermore, compound 29 reduced apomorphine-induced climbing and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head twitching without observable catalepsy, even at the highest dose tested. Thus, compound 29 is a promising candidate as a multi-target antipsychotic treatment.

Topics: Animals; Antipsychotic Agents; Ether-A-Go-Go Potassium Channels; Humans; Mice; Oxazoles; Patch-Clamp Techniques; Piperazines; Piperidines; Potassium Channel Blockers; Rats; Receptors, Dopamine D2; Schizophrenia; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Agonists; Structure-Activity Relationship; Swine

Having separated a sub-group of people with schizophrenia based on a marked loss of cortical [(3)H]pirenzepine binding (MRDS); we wished to determine if MRDS had lower levels of [(3)H]pirenzepine and other muscarinic receptor antagonist binding to the striatum and if this was due to loss of pre- or post-synaptic neurons or glia measured using surrogate markers (25 kilodalton synaptosomal-associated protein (SNAP 25), postsynaptic density protein 95 (PSD 95), glial fibrillary acidic protein (GFAP) 41/43) of cell number.. [(3)H]pirenzepine, [(3)H]AF-DX 384 and [(3)H]4-DAMP binding to the striatum from 37 subjects with schizophrenia (19 MRDS) and 20 controls as well as SNAP 25, PSD 95 and GFAP 41/43 in crude particulate membrane were measured.. [(3)H]pirenzepine and [(3)H]AF-DX 384 binding to the striatum were significantly lower in schizophrenia due to lower binding of both radioligands in the striatum from MRDS. Levels of PSD 95 were higher in schizophrenia, predominantly due to higher levels in MRDS.. Our data suggest muscarinic M1 ([(3)H]pirenzepine) and M2 and/or M4 receptors ([(3)H]AF-DX 384) are lower in the striatum from MRDS which could mediate inappropriate adaption to internal and external cues which, in turn, would affect motivation, cognition and motor control. Increased levels of PSD 95 could indicate increased post-synaptic boutons or changes in NMDA receptor-mediated signalling in MRDS.

Topics: Autoradiography; Blotting, Western; Corpus Striatum; Disks Large Homolog 4 Protein; Female; Glial Fibrillary Acidic Protein; Humans; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Middle Aged; Muscarinic Antagonists; Neuroglia; Neurons; Piperidines; Pirenzepine; Radioligand Assay; Radiopharmaceuticals; Receptors, Muscarinic; Schizophrenia; Synaptosomal-Associated Protein 25; Tritium

JNJ-37822681 is a potent, specific and fast dissociating dopamine D2 receptor antagonist intended for the treatment of schizophrenia. Its nonclinical toxicological profile was investigated in a series of general repeat dose toxicity studies in cynomolgus monkeys and Sprague-Dawley rats. The maximum duration of treatment was 9 and 6 months, respectively. Interspecies differences were noted in the response to JNJ-37822681 in terms of extrapyramidal (EPS)-like clinical signs and prolactin-mediated tissue changes in the mammary gland. Monkeys showed severe EPS-like clinical signs such as abnormal posture, abnormal eye movements and hallucination-like behavior at relatively low exposures compared to those associated with EPS in patients with schizophrenia. The high sensitivity of the monkey to JNJ-37822681-induced EPS-like signs was unexpected based on the fast dissociating properties of the compound. Rats, however, were not prone to EPS. Elevated serum prolactin levels were found in rats and monkeys. While rats showed slight to moderate prolactin-related tissue changes upon histopathological examination in all studies, which among others affected the mammary gland, only minor mammary gland tissue changes were noted in monkeys. Prolactin levels were only slightly increased in patients with schizophrenia receiving relatively high dose levels of JNJ-37822681. The monkey toxicology studies did not provide an exposure-based safety margin, while in rats adverse effects were only noted at exposures considerably higher than those achieved at efficacious plasma concentrations in the clinic. Overall, the available data suggest that the cynomolgus monkey showed better predictivity towards the nature of JNJ-37822681-associated adverse events in humans than the Sprague-Dawley rat.

Topics: Animals; Antipsychotic Agents; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Female; Humans; Macaca fascicularis; Male; Mammary Glands, Animal; Piperidines; Prolactin; Pyridazines; Rats; Rats, Sprague-Dawley; Schizophrenia; Toxicity Tests

Studies have suggested that the endocannabinoid system is implicated in the pathophysiology of schizophrenia. We have recently reported that Spontaneously Hypertensive Rats (SHRs) present a deficit in social interaction that is ameliorated by atypical antipsychotics. In addition, SHRs display hyperlocomotion - reverted by atypical and typical antipsychotics. These results suggest that this strain could be useful to study negative symptoms (modeled by a decrease in social interaction) and positive symptoms (modeled by hyperlocomotion) of schizophrenia and the effects of potential drugs with an antipsychotic profile. The aim of this study was to investigate the effects of WIN55-212,2 (CB1/CB2 agonist), ACEA (CB1 agonist), rimonabant (CB1 inverse agonist), AM404 (anandamide uptake/metabolism inhibitor), capsaicin (agonist TRPV1) and capsazepine (antagonist TRPV1) on the social interaction and locomotion of control animals (Wistar rats) and SHRs. The treatment with rimonabant was not able to alter either the social interaction or the locomotion presented by Wistar rats (WR) and SHR at any dose tested. The treatment with WIN55-212,2 decreased locomotion (1mg/kg) and social interaction (0.1 and 0.3mg/kg) of WR, while the dose of 1mg/kg increased social interaction of SHR. The treatment with ACEA increased (0.3mg/kg) and decreased (1mg/kg) locomotion of both strain. The administration of AM404 increased social interaction and decreased locomotion of SHR (5mg/kg), and decreased social interaction and increased locomotion in WR (1mg/kg). The treatment with capsaicin (2.5mg/kg) increased social interaction of both strain and decreased locomotion of SHR (2.5mg/kg) and WR (0.5mg/kg and 2.5mg/kg). In addition, capsazepine (5mg/kg) decreased locomotion of both strains and increased (5mg/kg) and decreased (10mg/kg) social interaction of WR. Our results indicate that the schizophrenia-like behaviors displayed by SHR are differently altered by cannabinoid and vanilloid drugs when compared to control animals and suggest the endocannabinoid and the vanilloid systems as a potential target for the treatment of schizophrenia.

Topics: Analysis of Variance; Animals; Arachidonic Acids; Benzoxazines; Cannabinoid Receptor Modulators; Capsaicin; Disease Models, Animal; Dose-Response Relationship, Drug; Interpersonal Relations; Male; Morpholines; Motor Activity; Naphthalenes; Piperidines; Pyrazoles; Rats; Rats, Inbred SHR; Rats, Wistar; Rimonabant; Schizophrenia; Schizophrenic Psychology; TRPV Cation Channels

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Dystonia; Female; Humans; Olanzapine; Piperazines; Piperidines; Risperidone; Schizophrenia; Young Adult

The purpose of this study was to evaluate the long-term effectiveness and safety of blonanserin, a second-generation antipsychotic drug developed in Japan, in patients with first-episode schizophrenia.. Twenty-three antipsychotic-naïve patients with first-episode schizophrenia were treated within an open-label, 1-year, prospective trial of blonanserin (2-24 mg/day). Clinical evaluations were conducted at baseline and 2, 6, and 12 months after the start of treatment. The main outcome measures were changes in subjective well-being and subjective quality of life, as assessed by the Subjective Well-being under Neuroleptic treatment scale Short form-Japanese version and the Schizophrenia Quality of Life Scale-Japanese version, respectively. Secondary outcome measures included the Positive and Negative Syndrome Scale, the Brief Assessment of Cognition in Schizophrenia-Japanese version, laboratory tests, bodyweight, and extrapyramidal symptoms.. Fourteen patients (60.9%) remained on the study at 1 year. In the intention-to-treat analysis, significant improvements were observed in several subscales on the Subjective Well-being under Neuroleptic treatment scale Short form-Japanese version, the Schizophrenia Quality of Life Scale-Japanese version, and the Brief Assessment of Cognition in Schizophrenia-Japanese version, and in all factor scores on the Positive and Negative Syndrome Scale. Improvement in depressive symptoms with blonanserin treatment was positively correlated with improvements in subjective well-being and subjective quality of life, as well as verbal memory. No significant changes were noted for any safety measure during the 1-year study period.. Blonanserin was well tolerated and effective for the treatment of first-episode schizophrenia in terms of subjective wellness, cognition, and a wide range of pathological symptoms. Further large-scale studies are warranted to confirm our findings.

Topics: Adult; Antipsychotic Agents; Female; Follow-Up Studies; Humans; Male; Piperazines; Piperidines; Quality of Life; Schizophrenia; Time Factors; Treatment Outcome

Paradoxically, N-methyl-D-aspartate (NMDA) receptor antagonists are used to model certain aspects of schizophrenia as well as to treat refractory depression. However, the role of different subunits of the NMDA receptor in both conditions is poorly understood. Here we used biochemical and behavioral readouts to examine the in vivo prefrontal efflux of serotonin and glutamate as well as the stereotypical behavior and the antidepressant-like activity in the forced swim test elicited by antagonists selective for the GluN2A (NVP-AAM077) and GluN2B (Ro 25-6981) subunits. The effects of the non-subunit selective antagonist, MK-801; were also studied for comparison. The administration of MK-801 dose dependently increased the prefrontal efflux of serotonin and glutamate and markedly increased the stereotypy scores. NVP-AAM077 also increased the efflux of serotonin and glutamate, but without the induction of stereotypies. In contrast, Ro 25-6981 did not change any of the biochemical and behavioral parameters tested. Interestingly, the administration of NVP-AAM077 and Ro 25-6981 alone elicited antidepressant-like activity in the forced swim test, in contrast to the combination of both compounds that evoked marked stereotypies. Our interpretation of the results is that both GluN2A and GluN2B subunits are needed to induce stereotypies, which might be suggestive of potential psychotomimetic effects in humans, but the antagonism of only one of these subunits is sufficient to evoke an antidepressant response. We also propose that GluN2A receptor antagonists could have potential antidepressant activity in the absence of potential psychotomimetic effects.

Topics: Animals; Antidepressive Agents; Depressive Disorder, Treatment-Resistant; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Glutamic Acid; Male; Phenols; Piperidines; Prefrontal Cortex; Quinoxalines; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Serotonin; Stereotyped Behavior

Cognitive impairment associated with schizophrenia (CIAS) is an important etiological feature of this disorder with implications for symptom severity and quality of life. Acute N-methyl-d-aspartate receptor (NMDAR) blockade using MK-801, a non-competitive antagonist to NMDARs, is assumed to produce temporary cognitive impairments in mice similar to those seen in schizophrenia patients. Less is known, however, about the effects of subchronic MK-801 administration on cognition. In the current study, twenty-eight male C57/BL6 mice received a daily dose of MK-801 (0.1mg/kg, i.p.) for seven days. Spatial memory was assessed using an object location task prior to MK-801 administration as well as at multiple time points after the treatment. Subchronic treatment with MK-801 caused lasting memory deficits, which were ameliorated by acute doses of an acetylcholinesterase inhibitor (donepezil) and an alpha-7 nicotinic agonist (PHA 568487), but were unaffected by acute administration of the atypical antipsychotic risperidone. Subchronic administration of MK-801 may lend this pharmaceutical model increased face validity, while its resemblance to prodromal schizophrenia makes it suitable for screening new CIAS treatments.

Topics: Acetylcholinesterase; alpha7 Nicotinic Acetylcholine Receptor; Animals; Antipsychotic Agents; Aza Compounds; Cholinesterase Inhibitors; Cognition Disorders; Dioxins; Disease Models, Animal; Dizocilpine Maleate; Donepezil; Indans; Male; Mice, Inbred C57BL; Nicotinic Agonists; Nootropic Agents; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology; Spatial Memory

We previously identified a group of subjects with schizophrenia who, on average, have a 75% decrease in cholinergic receptor, muscarinic 1 (CHRM1) in Brodmann's area (BA) 9. To extend this finding, we determined i) if the decrease in CHRM1 was present in another functionally related CNS region (BA6), ii) whether the marked decrease in CHRM1 was accompanied by changes in levels of other CHRMs and iii) potential factors responsible for the decreased CHRM1 expression. We measured CHRM1 and CHRM3 using in situ radioligand binding with [(3)H]pirenzepine and [(3)H]4-DAMP respectively in BA6 from 20 subjects with schizophrenia who had low levels of CHRM1 in BA9 (SzLow[(3)H]PZP), 18 subjects with schizophrenia whose levels of CHRM1 were similar to controls (SzNormal[(3)H]PZP) and 20 control subjects. Levels of CHRM1, 3 and 4 mRNA were measured using qPCR and levels of the transcription factors, SP1 and SP3, were determined using Western blots. In BA6, the density of [(3)H]pirenzepine binding was decreased in subjects with SzLow[(3)H]PZP (p<0.001) compared to controls. The density of [(3)H]4-DAMP binding, levels of CHRM1, 3 and 4 mRNA and levels of SP1 and SP3 was not significantly different between the three groups. This study shows that the previously identified decrease in CHRM1 expression is not confined to the dorsolateral prefrontal cortex but is present in other cortical areas. The effect shows some specificity to CHRM1, with no change in levels of binding to CHRM3. Furthermore, this decrease in CHRM1 does not appear to be associated with low levels of CHRM1 mRNA or to simply be regulated by the transcription factors, SP1 and SP3, suggesting that other mechanisms are responsible for the decreased CHRM1 in these subjects.

Topics: Adult; Blotting, Western; Brain; Cohort Studies; Humans; Middle Aged; Piperidines; Pirenzepine; Polymerase Chain Reaction; Radioligand Assay; Receptor, Muscarinic M1; Receptor, Muscarinic M3; Receptor, Muscarinic M4; Receptors, Muscarinic; RNA, Messenger; Schizophrenia; Sp1 Transcription Factor; Sp3 Transcription Factor; Tritium

The comorbidity schizophrenia and cannabis has a high prevalence. The consumption of cannabis is ten times higher among schizophrenia patients, suggesting that these patients could be differentially sensitive to its motivational effects. To study this question, we investigated the motivational effects of cannabinoid agonists using the brain stimulation reward paradigm and a neurodevelopmental model of schizophrenia: neonatal ventral hippocampus lesions (NVHL). Using the curve-shift paradigm, we first compared the effect single dose (0.75mg/kg) of amphetamine in sham and NVHL rats on reward and operant responding. Then, in different groups of NVHL and sham rats, we studied the effect of delta-9-tetrahydrocannabinnol (THC, 0.5mg/kg, i.p.) and WIN55,212-2 (WIN, 1 and 3mg/kg, i.p.) Rats were initially trained to self-administer an electrical stimulation to the posterio-medial mesencephalon. Once responding was stable, reward threshold defined as the frequency required to induce a half maximum response rate was measured before and after injection of the drug or the vehicle. Results show that amphetamine enhanced reward in sham and NVHL rats, an effect that was shorter in duration in NVHL rats. THC produced a weak attenuation of reward in sham rats while WIN produced a dose-dependent attenuation in NVHL; the attenuation effect of WIN was blocked by the cannabinoid antagonist, AM251. WIN also produced an attenuation of performance in sham and NVHL rats, and this effect was partially prevented by AM251. These results provide the additional evidence that the motivational effect of cannabinoids is altered in animals with a schizophrenia-like phenotype.

Topics: Amphetamine; Analysis of Variance; Animals; Animals, Newborn; Benzoxazines; Brain; Brain Injuries; Central Nervous System Stimulants; Conditioning, Operant; Disease Models, Animal; Dronabinol; Female; Hippocampus; Male; Morpholines; Motivation; Naphthalenes; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Reward; Schizophrenia; Self Administration; Time Factors

The deleterious effects of cannabis use in schizophrenia have been linked, in part, to underlying disturbances in endogenous cannabinoid signaling in the prefrontal cortex. However, while receptor autoradiography studies of the primary cannabinoid receptor (CB1R) have consistently found higher CB1R binding in the prefrontal cortex in schizophrenia, deficits in CB1R mRNA levels and protein immunoreactivity have also been reported in the illness. To investigate this apparent discrepancy, we quantified CB1R binding using receptor autoradiography with the selective CB1R ligand [(3)H]-OMAR in the prefrontal cortex of 21 subjects with schizophrenia who were previously found to have lower levels of both CB1R mRNA using in situ hybridization and CB1R protein using radioimmunocytochemistry relative to matched healthy comparison subjects. We observed higher levels of [(3)H]-OMAR binding in the prefrontal cortex of schizophrenia subjects that did not appear to be attributable to psychotropic medications or substance abuse. The combination of lower levels of CB1R mRNA and immunoreactivity with higher CB1R receptor binding may reflect 1) altered trafficking of the receptor resulting in higher levels of membrane-bound CB1R or 2) higher CB1R affinity. In either case, greater CB1R receptor availability may contribute to the increased susceptibility of schizophrenia subjects to the deleterious effects of cannabis use.

Topics: Adult; Analysis of Variance; Autoradiography; Female; Humans; Male; Middle Aged; Piperidines; Positron-Emission Tomography; Prefrontal Cortex; Protein Binding; Pyrazoles; Receptor, Cannabinoid, CB1; RNA, Messenger; Schizophrenia; Tritium

Topics: Antipsychotic Agents; Double-Blind Method; Humans; Multicenter Studies as Topic; Piperazines; Piperidines; Randomized Controlled Trials as Topic; Schizophrenia

Blonanserin is a novel antipsychotic with high affinities for dopamine D(2) and 5-HT(2A) receptors, and it was recently approved for the treatment of schizophrenia in Japan and Korea. Although double-blind clinical trials have demonstrated that blonanserin has equal efficacy to risperidone, and with a better profile especially with respect to prolactin elevation, its profile of in vivo receptor binding has not been investigated in patients with schizophrenia. Using positron emission tomography (PET), we measured striatal and extrastriatal dopamine D(2) receptor occupancy by blonanserin in 15 patients with schizophrenia treated with fixed doses of blonanserin (ie, 8, 16, and 24 mg/d) for at least 4 weeks before PET scans, and in 15 healthy volunteers. Two PET scans, 1 with [(11)C]raclopride for the striatum and 1 with [(11)C]FLB 457 for the temporal cortex and pituitary, were performed on the same day. Striatal dopamine D(2) receptor occupancy by blonanserin was 60.8% (3.0%) [mean (SD)] at 8 mg, 73.4% (4.9%) at 16 mg, and 79.7% (2.3%) at 24 mg. The brain/plasma concentration ratio calculated from D(2) receptor occupancy in the temporal cortex and pituitary was 3.38, indicating good blood-brain barrier permeability. This was the first study to show clinical daily dose amounts of blonanserin occupying dopamine D(2) receptors in patients with schizophrenia. The clinical implications obtained in this study were the optimal therapeutic dose range of 12.9 to 22.1 mg/d of blonanserin required for 70% to 80% dopamine D(2) receptor occupancy in the striatum, and the good blood-brain barrier permeability that suggested a relatively lower risk of hyperprolactinemia.

Topics: Adult; Antipsychotic Agents; Blood-Brain Barrier; Brain; Case-Control Studies; Corpus Striatum; Dopamine Antagonists; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Piperazines; Piperidines; Positron-Emission Tomography; Pyrrolidines; Raclopride; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Tissue Distribution; Young Adult

The neuronal mechanisms underlying social withdrawal, one of the core negative symptoms of schizophrenia, are not well understood. Recent studies suggest an involvement of the endocannabinoid system in the pathophysiology of schizophrenia and, in particular, of negative symptoms. We used biochemical, pharmacological, and behavioral approaches to investigate the role played by the endocannabinoid system in social withdrawal induced by sub-chronic administration of phencyclidine (PCP). Pharmacological enhancement of endocannabinoid levels via systemic administration of URB597, an inhibitor of endocannabinoid degradation, reversed social withdrawal in PCP-treated rats via stimulation of CB1 receptors, but reduced social interaction in control animals through activation of a cannabinoid/vanilloid-sensitive receptor. In addition, the potent CB agonist CP55,940 reversed PCP-induced social withdrawal in a CB₁-dependent manner, whereas pharmacological blockade of CB₁ receptors by either AM251 or SR141716 reduced the time spent in social interaction in control animals. PCP-induced social withdrawal was accompanied by a decrease of anandamide (AEA) levels in the amygdala and prefrontal cortex, and these deficits were reversed by URB597. As CB₁ receptors are predominantly expressed on GABAergic interneurons containing the anxiogenic peptide cholecystokinin (CCK), we also examined whether the PCP-induced social withdrawal resulted from deficient CB₁-mediated modulation of CCK transmission. The selective CCK2 antagonist LY225910 blocked both PCP- and AM251-induced social withdrawal, but not URB597 effect in control rats. Taken together, these findings indicate that AEA-mediated activation of CB₁ receptors is crucial for social interaction, and that PCP-induced social withdrawal results from deficient endocannabinoid transmission.

Topics: Amidohydrolases; Amygdala; Animals; Arachidonic Acids; Benzamides; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Carbamates; Cyclohexanols; Dose-Response Relationship, Drug; Endocannabinoids; Male; Phencyclidine; Piperidines; Polyunsaturated Alkamides; Prefrontal Cortex; Pyrazoles; Quinazolinones; Rats; Receptor, Cannabinoid, CB1; Receptor, Cholecystokinin B; Rimonabant; Schizophrenia; Social Behavior

Topics: Adult; Antipsychotic Agents; Chronic Disease; Female; Follow-Up Studies; Humans; Hyperprolactinemia; Male; Middle Aged; Piperazines; Piperidines; Prolactin; Schizophrenia

The cognitive deficits associated with schizophrenia are recognized as a core component of the disorder, yet there remain no available therapeutics to treat these symptoms of the disease. As a result, there is a need for establishing predictive preclinical models to identify the therapeutic potential of novel compounds. In the present study, rhesus monkeys were trained in the object retrieval-detour task, which is dependent on the prefrontal cortex, a brain region implicated in the cognitive deficits associated with schizophrenia. The NMDA receptor antagonist ketamine significantly impaired performance without affecting measures of motor or visuospatial abilities. Pre-treatment with the nicotinic α7 agonist GTS-21 (0.03 mg/kg) significantly attenuated the ketamine-induced impairment, consistent with reports from clinical trials suggesting that nicotinic α7 receptor agonism has pro-cognitive potential in clinical populations. In contrast, pretreatment with the acetylcholinesterase inhibitor donepezil failed to reverse the ketamine-induced impairment, consistent with studies showing a lack of pro-cognitive effects in patients with schizophrenia. These data suggest that the ketamine-impaired object retrieval-detour task could provide a model with improved predictive validity for drug development, and confirm the need for additional efforts in back-translation. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Animals; Behavior, Animal; Benzylidene Compounds; Cholinesterase Inhibitors; Cognition; Cognition Disorders; Disease Models, Animal; Donepezil; Drug Evaluation, Preclinical; Excitatory Amino Acid Antagonists; Indans; Ketamine; Macaca mulatta; Male; Molecular Targeted Therapy; Nicotinic Agonists; Nootropic Agents; Piperidines; Psychomotor Performance; Pyridines; Receptors, N-Methyl-D-Aspartate; Receptors, Nicotinic; Schizophrenia

Classical antipsychotics, e.g. haloperidol, chlorpromazine, are potent at controlling the positive symptoms of schizophrenia but frequently elicit extrapyramidal motor side-effects. The introduction of atypical antipsychotics such as risperidone, olanzapine and clozapine has obviated this problem, but none of the current drugs seem to improve the cognitive deficits accompanying schizophrenia. Thus there is an unmet need for agents that not only suppress the psychotic symptoms but also ameliorate the impairment of cognition. Here, we report the preclinical properties of a candidate antipsychotic, Egis-11150, that shows marked pro-cognitive efficacy. Egis-11150 displayed high affinity for adrenergic α(1), α(2c), 5-HT(2A) 5-HT₇, moderate affinity for adrenergic α(2a) and D₂ receptors. It was a functional antagonist on all of the above receptors, with the exception of 5-HT₇ receptors, where it was an inverse agonist. Phencyclidine-induced hypermotility in mice and inhibition of conditioned avoidance response in rats were assessed to estimate efficacy against the positive and social withdrawal test in rats was used to predict efficacy against the negative symptoms of schizophrenia. Passive-avoidance learning, novel object recognition and radial maze tests in rats were used to assess pro-cognitive activity, while phencyclidine-induced disruption of prepulse inhibition in mice was examined to test for effects on attention. Egis-11150 (0.01-0.3 mg/kg, ip.) was effective in all of the preclinical models of schizophrenia examined. Moreover, a robust pro-cognitive profile was apparent. In summary, work in preclinical models indicates that Egis-11150 is a potential treatment for controlling the psychosis as well as the cognitive dysfunction in schizophrenia. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Antipsychotic Agents; Behavior, Animal; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs, Investigational; Male; Memory, Short-Term; Mice; Mice, Inbred Strains; Nootropic Agents; Piperidines; Pyridazines; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists

As perturbations in auditory filtering appear to be a candidate trait marker of schizophrenia, there has been considerable interest in the development of translational rat models to elucidate the underlying neural and neurochemical mechanisms involved in sensory gating. This is the first study to investigate the effects of the non-selective muscarinic antagonist scopolamine, the muscarinic M1 antagonist biperiden and the cholinesterase inhibitor donepezil (also in combination with scopolamine and biperiden) on auditory evoked potentials (AEPs) and sensory gating. In the saline condition, only the N50 peak displayed sensory gating. Scopolamine and biperiden both disrupted sensory gating by increasing N50 amplitude for the S2 click. Donepezil was able to fully reverse the effects of biperiden on N50 sensory gating, but had residual effects when combined with scopolamine; i.e., it enhanced sensory gating by increasing N50 amplitude of the S1 stimulus. Donepezil by itself improved sensory gating by enhancing N50 amplitude of S1, and reducing N50 amplitude of the S2 click. In conclusion, due to its relatively more selective effects biperiden is to be preferred over scopolamine as a means for pharmacologically inducing cholinergic impairments in auditory processing in healthy rats. Changes in auditory processing and sensory gating induced by cholinergic drugs may serve as a translational model for aging instead of schizophrenia.

Topics: Alzheimer Disease; Animals; Behavior, Animal; Biperiden; Cholinergic Neurons; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Electroencephalography; Evoked Potentials, Auditory; Hippocampus; Indans; Male; Muscarinic Antagonists; Nerve Tissue Proteins; Piperidines; Rats; Rats, Wistar; Receptor, Muscarinic M1; Schizophrenia; Scopolamine; Sensory Gating

Metabotropic glutamate-5 receptors (mGluR5), which physically and functionally interact with N-methyl-D-Aspartate (NMDA) receptors, likewise control cognitive processes and have been proposed as targets for novel classes of antipsychotic agent. Since social cognition is impaired in schizophrenia and disrupted by NMDA receptor antagonists like dizocilpine, we evaluated its potential modulation by mGluR5. Acute administration (0.63-40 mg/kg) of the mGluR5 positive allosteric modulators (PAMs), 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) and ADX47273, reversed a delay-induced impairment in social novelty discrimination (SND) in adult rats. The action of CDPPB was blocked by the mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (2.5-10 mg/kg), and was also expressed upon microinjection into frontal cortex (0.63-10 μg/side), but not striatum. Supporting an interrelationship between mGluR5 and NMDA receptors, enhancement of SND by CDPPB was blocked by dizocilpine (0.08 mg/kg) while, reciprocally, dizocilpine-induced impairment in SND was attenuated by CDPPB (10 mg/kg). The SND deficit elicited by post-natal administration of phencyclidine (10 mg/kg, days 7-11) was reversed by CDPPB or ADX47273 in adults at week 8. This phencyclidine-induced impairment in cognition emerged in adult rats from week 7 on, and chronic, pre-symptomatic treatment of adolescent rats with CDPPB over weeks 5-6 (10 mg/kg per day) prevented the appearance of SND deficits in adults until at least week 13. In conclusion, as evaluated by a SND procedure, mGluR5 PAMs promote social cognition via actions expressed in interaction with NMDA receptors and exerted in frontal cortex. MGluR5 PAMs not only reverse but also (when given during adolescence) prevent the emergence of cognitive impairment associated with a developmental model of schizophrenia.

Topics: Aging; Allosteric Regulation; Animals; Animals, Newborn; Behavior, Animal; Benzamides; Brain; Discrimination, Psychological; Dizocilpine Maleate; Dose-Response Relationship, Drug; Male; Microinjections; Oxadiazoles; Phencyclidine; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Social Behavior

This case series describes the development of retrograde ejaculation with the antipsychotic iloperidone. Iloperidone is a relatively new antipsychotic and has a strong α-1 receptor antagonism, which may explain this rare adverse effect.

Topics: Antipsychotic Agents; Capgras Syndrome; Ejaculation; Humans; Isoxazoles; Male; Piperidines; Schizophrenia; Sexual Dysfunctions, Psychological; Young Adult

7-Arylsulfonyl substituted benzofuropiperidine was discovered as a novel scaffold for 5HT(6) receptor antagonists. Optimization by substitution at C-1 position led to identification of selective, orally bioavailable, brain penetrant antagonists with reduced hERG liability. An advanced analog tested in rat social recognition model showed significant activity suggesting potential utility in the enhancement of short-term memory.

Topics: Animals; Benzofurans; Brain; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Humans; Inhibitory Concentration 50; Kinetics; Memory, Short-Term; Models, Chemical; Piperidines; Rats; Receptors, Serotonin; Schizophrenia; Serotonin Antagonists; Structure-Activity Relationship

 Blonanserin is a second-generation antipsychotic that was developed in Japan. We investigated the relationships between plasma concentration, the plasma anti-5-HT(2A) activity/anti-D₂ activity (S/D) ratio and extrapyramidal symptoms (EPS) in blonanserin dosing..  The subjects were 29 outpatients with schizophrenia. We assessed EPS using the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). The plasma concentrations were measured by high performance liquid chromatography, and the plasma anti-D₂ and anti-5-HT(2A) activities were measured by [³H]-spiperone and [³H]-ketanserin radioreceptor assays.. The results revealed that there were significant correlations between both the plasma concentration and the DIEPSS total score (P<0.05). A negative correlative tendency was found between the S/D ratio and the DIEPSS total score. Furthermore, the plasma concentrations were divided into a low plasma concentration group and a high plasma concentration group, and the S/D ratios were divided into a low S/D ratio group and a high S/D ratio group. We then compared each group based on the DIEPSS total scores. The score in the high plasma concentration-low S/D ratio group was significantly higher than in the high plasma concentration-high S/D ratio, low plasma concentration-high S/D ratio and low plasma concentration-low S/D ratio groups (P<0.05 for all)..  These findings indicate that the incidence of EPS during treatment with blonanserin is mainly determined by plasma concentration, but the incidence of EPS may be inhibited when anti-5HT(2A) activity is predominant over anti-D₂ activity.

Topics: Adult; Antipsychotic Agents; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Piperazines; Piperidines; Receptors, Dopamine D2; Receptors, Serotonin, 5-HT2; Schizophrenia

All marketed antipsychotics act by blocking dopamine D(2) receptors. Fast dissociation from D(2) receptors may be one of the elements contributing to the lower incidence of extrapyramidal symptoms (EPS) exhibited by newer antipsychotics. Therefore, we screened for specific D(2) receptor blockers with a fast rate of dissociation. Radioligand binding experiments identified N-[1-(3,4-difluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine (JNJ-37822681) as a fast-dissociating D(2) ligand. Its D(2) receptor specificity was high compared with atypical antipsychotics, with little activity at receptors associated with unwanted effects [α(1), α(2), H(1), muscarinic, and 5-hydroxytryptamine (5-HT) type 2C] and for receptors that may interfere with the effects of D(2) antagonism (D(1), D(3), and 5-HT(2A)). JNJ-37822681 occupied D(2) receptors in rat brain at relatively low doses (ED(50) 0.39 mg/kg) and was effective in animal models of psychosis (e.g., inhibition of apomorphine-induced stereotypy or D-amphetamine/phencyclidine-induced hyperlocomotion). Prolactin levels increased from an ED(50) (0.17 mg/kg, peripheral D(2) receptors) close to the ED(50) required for apomorphine antagonism (0.19 mg/kg, central D(2) receptors), suggesting excellent brain disposition and minimal prolactin release at therapeutic doses. JNJ-37822681 induced catalepsy and inhibited avoidance behavior, but with a specificity margin relative to apomorphine antagonism that was larger than that obtained for haloperidol and similar to that obtained for olanzapine. This larger specificity margin (compared with haloperidol) may reflect lower EPS liability and less behavioral suppression after JNJ-37822681. JNJ-37822681 is a novel, potent, specific, centrally active, fast-dissociating D(2) antagonist with optimal brain disposition, and it is the first compound that allows the evaluation of the potential value of fast D(2) antagonism for the treatment of schizophrenia and bipolar disorder.

Topics: Animals; Antipsychotic Agents; Apomorphine; Behavior, Animal; Benzodiazepines; Brain; Catalepsy; Cells, Cultured; CHO Cells; Cricetinae; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Female; Haloperidol; Humans; Ligands; Locomotion; Male; Olanzapine; Piperidines; Prolactin; Pyridazines; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Dopamine D2; Schizophrenia; Serotonin

It is important to develop novel antipsychotics that can effectively treat schizophrenia with minor side-effects. The aim of our work is to develop novel antipsychotics that act on dopamine D(2) and D(3), serotonin 5-HT(1A) and 5-HT(2A) receptors with low affinity for the serotonin 5-HT(2C) and H(1) receptors, which can effectively cure positive symptoms, negative symptoms and cognitive impairment without the weight gain side-effect.. A series of 2-substituted-5-thiopropylpiperazine (piperidine) -1,3,4-oxadiazoles derivatives have been synthesized and the target compounds were evaluated for binding affinities to D(2), 5-HT(1A) and 5-HT(2A) receptors. Preliminary results indicated that compounds 14, 16 and 22 exhibited high affinities to D(2), 5-HT(1A) and 5-HT(2A) receptors among these compounds. Further binding tests showed that compound 22 had high affinity for D(3) receptor, and low affinity for serotonin 5-HT(2C) and H(1) receptors. In addition, compound 22 inhibited apomorphine-induced climbing behavior and MK-801-induced hyperactivity with no extrapyramidal symptoms liability in mice. Moreover, compound 22 exhibited acceptable pharmacokinetic properties.. Compound 22 showed an atypical antipsychotic activity without liability for extrapyramidal symptoms. We anticipate compound 22 to be useful for developing a novel class of drug for the treatment of schizophrenia.

Topics: Animals; Antipsychotic Agents; Drug Discovery; Humans; Hyperkinesis; Mice; Molecular Structure; Oxadiazoles; Piperidines; Protein Binding; Receptors, Dopamine D2; Receptors, Dopamine D3; Receptors, Serotonin, 5-HT1; Schizophrenia

The immediate-early gene early growth response 3 (Egr3) is associated with schizophrenia and expressed at reduced levels in postmortem patients' brains. We have previously reported that Egr3-deficient (Egr3(-/-)) mice display reduced sensitivity to the sedating effects of clozapine compared with wild-type (WT) littermates, paralleling the heightened tolerance of schizophrenia patients to antipsychotic side effects. In this study, we have used a pharmacological dissection approach to identify a neurotransmitter receptor defect in Egr3(-/-) mice that may mediate their resistance to the locomotor suppressive effects of clozapine. We report that this response is specific to second-generation antipsychotic agents (SGAs), as first-generation medications suppress the locomotor activity of Egr3(-/-) and WT mice to a similar degree. Further, in contrast to the leading theory that sedation by clozapine results from anti-histaminergic effects, we show that H1 histamine receptors are not responsible for this effect in C57BL/6 mice. Instead, selective serotonin 2A receptor (5HT(2A)R) antagonists ketanserin and MDL-11939 replicate the effect of SGAs, repressing the activity in WT mice at a dosage that fails to suppress the activity of Egr3(-/-) mice. Radioligand binding revealed nearly 70% reduction in 5HT(2A)R expression in the prefrontal cortex of Egr3(-/-) mice compared with controls. Egr3(-/-) mice also exhibit a decreased head-twitch response to 5HT(2A)R agonist 1-(2,5-dimethoxy 4-iodophenyl)-2-amino propane (DOI). These findings provide a mechanism to explain the reduced sensitivity of Egr3(-/-) mice to the locomotor suppressive effects of SGAs, and suggest that 5HT(2A)Rs may also contribute to the sedating properties of these medications in humans. Moreover, as the deficit in cortical 5HT(2A)R in Egr3(-/-) mice aligns with numerous studies reporting decreased 5HT(2A)R levels in the brains of schizophrenia patients, and the gene encoding the 5HT(2A)R is itself a leading schizophrenia candidate gene, these findings suggest a potential mechanism by which putative dysfunction in EGR3 in humans may influence risk for schizophrenia.

Topics: Animals; Clozapine; Disease Models, Animal; Early Growth Response Protein 3; Humans; Hypnotics and Sedatives; Ketanserin; Male; Mice; Mice, Transgenic; Motor Activity; Piperidines; Receptor, Serotonin, 5-HT2A; Schizophrenia; Serotonin 5-HT2 Receptor Agonists; Serotonin Antagonists

Clinical and neurobiological findings suggest that cannabinoids and their receptors are implicated in schizophrenia. Cannabidiol (CBD), a non-psychotomimetic compound of the Cannabis sativa plant, has been reported to have central therapeutic actions, such as antipsychotic and anxiolytic effects. We have recently reported that spontaneously hypertensive rats (SHR) present a deficit in contextual fear conditioning (CFC) that is specifically ameliorated by antipsychotics and aggravated by proschizophrenia manipulations. These results led us to suggest that the CFC deficit presented by SHR could be used as a model to study emotional processing impairment in schizophrenia. The aim of this study is to evaluate the effects of CBD and rimonabant (CB1 receptor antagonist) on the contextual fear conditioning in SHR and Wistar rats (WR).. Rats were submitted to CFC task after treatment with different doses of CBD (experiment 1) and rimonabant (experiment 2).. In experiment 1, SHR showed a decreased freezing response when compared to WR that was attenuated by 1 mg/kg CBD. Moreover, all CBD-treated WR presented a decreased freezing response when compared to control rats. In experiment 2, SHR showed a decreased freezing response when compared to WR that was attenuated by 3 mg/kg rimonabant.. Our results suggest a potential therapeutical effect of CBD and rimonabant to treat the emotional processing impairment presented in schizophrenia. In addition, our results reinforce the anxiolytic profile of CBD.

Topics: Animals; Cannabidiol; Cannabinoid Receptor Antagonists; Disease Models, Animal; Emotions; Male; Piperidines; Pyrazoles; Rats, Wistar; Rimonabant; Schizophrenia; Schizophrenic Psychology

Hypoglutamatergic function may contribute to cognitive impairment in schizophrenia (CIS). Subchronic treatment with the N-methyl-D-aspartate receptor antagonist, phencyclidine (PCP), induces enduring deficits in novel object recognition (NOR) in rodents. Acute treatment with atypical antipsychotic drugs (APDs), which are serotonin (5-HT)(2A)/dopamine D(2) antagonists, but not typical APDs, eg, haloperidol, reverses the PCP-induced NOR deficit in rats. We have tested the ability of lurasidone, an atypical APD with potent 5-HT(1A) partial agonist properties, tandospirone, a selective 5-HT(1A) partial agonist, haloperidol, a D(2) antagonist, and pimavanserin, a 5-HT(2A) inverse agonist, to prevent the development of the PCP-induced NOR deficit. Rats were administered lurasidone (0.1 or 1 mg/kg), tandospirone (5 mg/kg), pimavanserin (3 mg/kg), or haloperidol (1 mg/kg) b.i.d. 30 min before PCP (2 mg/kg, b.i.d.) for 7 days (day1-7), followed by a 7-day washout (day 8-14). Subchronic treatment with PCP induced an enduring NOR deficit. Lurasidone (1 mg/kg) but not 0.1 mg/kg, which is effective to acutely reverse the deficit due to subchronic PCP, or tandospirone, but not pimavanserin or haloperidol, significantly prevented the PCP-induced NOR deficit on day 15. The ability of lurasidone co-treatment to prevent the PCP-induced NOR deficit was enduring and still present at day 22. The preventive effect of lurasidone was blocked by WAY100635, a selective 5-HT(1A) antagonists, further evidence for the importance of 5-HT(1A) receptor stimulation in the NOR deficit produced by subchronic PCP. Further study is needed to determine whether these results concerning mechanism and dosage can be the basis for prevention of the development of CIS in at risk populations.

Topics: Animals; Cognition Disorders; Disease Models, Animal; Dopamine D2 Receptor Antagonists; Female; Haloperidol; Isoindoles; Lurasidone Hydrochloride; Phencyclidine; Piperazines; Piperidines; Pyridines; Pyrimidines; Rats; Rats, Long-Evans; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists; Serotonin 5-HT2 Receptor Agonists; Thiazoles; Urea

Translational control depends on phosphorylation of eIF2α by PKR-like ER kinase (PERK). To examine the role of PERK in cognitive function, we selectively disrupted PERK expression in the adult mouse forebrain. In the prefrontal cortex (PFC) of PERK-deficient mice, eIF2α phosphorylation and ATF4 expression were diminished and were associated with enhanced behavioral perseveration, decreased prepulse inhibition, reduced fear extinction, and impaired behavioral flexibility. Treatment with the glycine transporter inhibitor SSR504734 normalized eIF2α phosphorylation, ATF4 expression, and behavioral flexibility in PERK-deficient mice. Moreover, the expression levels of PERK and ATF4 were reduced in the frontal cortex of human patients with schizophrenia. Together, our findings reveal that PERK plays a critical role in information processing and cognitive function and that modulation of eIF2α phosphorylation and ATF4 expression may represent an effective strategy for treating behavioral inflexibility associated with several neurological disorders such as schizophrenia.

Topics: Activating Transcription Factor 4; Animals; Behavior, Animal; Benzamides; Brain; Cognition; eIF-2 Kinase; Eukaryotic Initiation Factor-2; Exploratory Behavior; Gene Deletion; Grooming; Humans; Mice; Mice, Knockout; Motor Activity; Organ Specificity; Phosphorylation; Piperidines; Prefrontal Cortex; Protein Biosynthesis; Protein Serine-Threonine Kinases; Receptors, N-Methyl-D-Aspartate; Reflex, Startle; Reversal Learning; Rotarod Performance Test; Schizophrenia

Topics: Antipsychotic Agents; Dibenzothiazepines; Female; Homeostasis; Humans; Insulin Resistance; Piperazines; Piperidines; Quetiapine Fumarate; Schizophrenia; Waist Circumference; Weight Loss; Young Adult

The tremendous advances in understanding the neurobiological circuits involved in schizophrenia have not translated into more effective treatments. An alternative strategy is to use a recently published 'Quantitative Systems Pharmacology' computer-based mechanistic disease model of cortical/subcortical and striatal circuits based upon preclinical physiology, human pathology and pharmacology. The physiology of 27 relevant dopamine, serotonin, acetylcholine, norepinephrine, gamma-aminobutyric acid (GABA) and glutamate-mediated targets is calibrated using retrospective clinical data on 24 different antipsychotics. The model was challenged to predict quantitatively the clinical outcome in a blinded fashion of two experimental antipsychotic drugs; JNJ37822681, a highly selective low-affinity dopamine D(2) antagonist and ocaperidone, a very high affinity dopamine D(2) antagonist, using only pharmacology and human positron emission tomography (PET) imaging data. The model correctly predicted the lower performance of JNJ37822681 on the positive and negative syndrome scale (PANSS) total score and the higher extra-pyramidal symptom (EPS) liability compared to olanzapine and the relative performance of ocaperidone against olanzapine, but did not predict the absolute PANSS total score outcome and EPS liability for ocaperidone, possibly due to placebo responses and EPS assessment methods. Because of its virtual nature, this modeling approach can support central nervous system research and development by accounting for unique human drug properties, such as human metabolites, exposure, genotypes and off-target effects and can be a helpful tool for drug discovery and development.

Topics: Antipsychotic Agents; Computer Simulation; Humans; Models, Neurological; Neostriatum; Piperidines; Prospective Studies; Pyridazines; Pyrimidinones; Schizophrenia; Treatment Outcome

Clinical and laboratory studies suggest that the endocannabinoid system is involved in schizophrenia disorders. Recent evidence indicates that cannabinoid receptor (CB1) antagonists have a pharmacological profile similar to antipsychotic drugs. We investigated the behavioural and biochemical effects of the CB1 antagonist AM251 in a phencyclidine (PCP) animal paradigm modelling the cognitive deficit and some negative symptoms of schizophrenia. Chronic AM251 (0.5 mg/kg for 3 wk) improved the PCP-altered recognition memory, as indicated by a significant amelioration of the discrimination index compared to chronic PCP alone (2.58 mg/kg for 1 month). AM251 also reversed the PCP-induced increase in immobility in the forced swim test resembling avolition, a negative sign of schizophrenia. In order to analyse the mechanisms underlying these behaviours, we studied the effects of AM251 on the endocannabinoid system (in terms of CB1 receptor density and functional activity and endocannabinoid levels) and c-Fos protein expression. The antagonist counteracted the alterations in CB1 receptor function induced by PCP in selected cerebral regions involved in schizophrenia. In addition, in the prefrontal cortex, the key region in the integration of cognitive and negative functions, AM251 markedly raised anandamide levels and reversed the PCP-induced increase of 2-arachidonoylglycerol concentrations. Finally, chronic AM251 fully reversed the PCP-elicited expression of c-Fos protein in the prefrontal cortical region. These findings suggest an antipsychotic-like profile of the CB1 cannabinoid receptor antagonist which, by restoring the function of the endocannabinoid system, might directly or indirectly normalize some of the neurochemical maladaptations present in this schizophrenia-like animal model.

Topics: Animals; Behavior, Animal; Cannabinoid Receptor Modulators; Disease Models, Animal; Excitatory Amino Acid Antagonists; Hippocampus; Male; Motor Activity; Phencyclidine; Piperidines; Prefrontal Cortex; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Schizophrenia; Time Factors

Although a reduced dose of propofol combined with remifentanil is often used in anesthesia for electroconvulsive therapy (ECT), there have been few studies in which the optimal technique for injection of remifentanil was examined in detail. The aim of this study was to evaluate the effects of single and divided injection of remifentanil combined with propofol on seizure duration and hemodynamic responses during ECT.. Twenty-six ASA I-II patients were enrolled in this study and received a total of 78 ECTs. Each patient received propofol 1.2 mg/kg (group P), remifentanil 1 μg/kg followed by propofol 0.5 mg/kg (group R1), and remifentanil 1 μg/kg followed by propofol 0.5 mg/kg and thereafter remifentanil 2 μg/kg (group R2). Succinylcholine 1 mg/kg was used for muscle paralysis after loss of consciousness.. Although mean motor seizure durations were significantly longer in groups R1 and R2 than in group P (P < 0.05), they were similar in groups R1 and R2. Although the percentage increases in mean arterial pressure after ECT were significantly smaller in groups P (P < 0.01) and R2 (P < 0.05) than in group R1, they did not significantly differ between groups P and R2.. Divided use of remifentanil at 1 and 2 μg/kg combined with propofol 0.5 mg/kg produces an acceptable outcome in both seizure duration and hemodynamic stability during ECT compared with the standard hypnotic doses of propofol alone or remifentanil 1 μg/kg followed by propofol 0.5 mg/kg.

Topics: Adult; Aged; Anesthesia, Intravenous; Anesthetics, Intravenous; Depressive Disorder, Major; Dose-Response Relationship, Drug; Electroencephalography; Electroshock; Female; Hemodynamics; Humans; Male; Middle Aged; Piperidines; Preanesthetic Medication; Propofol; Remifentanil; Schizophrenia; Seizures

Topics: Antipsychotic Agents; Bipolar Disorder; Dibenzocycloheptenes; Drug Approval; Heterocyclic Compounds, 4 or More Rings; Humans; Isoxazoles; Piperidines; Safety; Schizophrenia; Treatment Outcome; United States; United States Food and Drug Administration

Topics: Antipsychotic Agents; Drug Administration Schedule; Drug Costs; Humans; Isoxazoles; Piperidines; Schizophrenia

This article briefly reviews the novel atypical second-generation antipsychotic drugs iloperidone (Fanapt®), asenapine (Saphris®), and lurasidone (Latuda®), all of which have been approved by the U.S. Food and Drug Administration since 2009. Each is indicated for the treatment of schizophrenia, and asenapine has an additional indication for bipolar disorder. Very little information is available on their use in other disorders, pediatric and geriatric patients, and during pregnancy and breastfeeding. Their overall efficacy is no different than other antipsychotic drugs, but they do have different side effect profiles. Because of their unique pharmacologies and different tolerability profiles, they may be a more effective alternative for patients who do not respond to or cannot tolerate other antipsychotic drugs.

Topics: Adult; Aged; Antipsychotic Agents; Bipolar Disorder; Child; Clinical Trials as Topic; Dibenzocycloheptenes; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Isoindoles; Isoxazoles; Lurasidone Hydrochloride; Male; Piperidines; Pregnancy; Schizophrenia; Thiazoles; Treatment Outcome

Topics: Adult; Antipsychotic Agents; Delusions; Dopamine Antagonists; Hallucinations; Humans; Male; Piperazines; Piperidines; Schizophrenia; Serotonin Antagonists; Treatment Outcome

This study examined the efficacy of sertindole in comparison with a selective 5-HT(6) and a 5-HT(2A) receptor antagonist to reverse sub-chronic phencyclidine (PCP)-induced cognitive deficits in female rats.. In the first test, adult female hooded Lister rats were trained to perform an operant reversal learning task to 90% criterion. After training, rats were treated with PCP at 2 mg/kg (i.p.) or vehicle twice daily for 7 days, followed by 7 days washout. For the second test, novel object recognition (NOR), a separate batch of rats, had the same sub-chronic PCP dosing regime and washout period. In reversal learning, rats were treated acutely with sertindole, the selective 5-HT(2A) receptor antagonist M100.907 or the selective 5-HT(6) receptor antagonist SB-742457.. The PCP-induced selective reversal learning deficit was significantly improved by sertindole, M100.907 and SB-742457. Sertindole also significantly improved the sub-chronic PCP-induced deficit in NOR, a test of episodic memory following a 1 min and 1 h inter-trial interval. In vivo binding studies showed that the dose-response relationship for sertindole in this study most closely correlates with affinity for 5-HT(6) receptor in vivo binding in striatum, although contribution from binding to 5-HT(2A) receptors in vivo in cortex may also provide an important mechanism.. The efficacies of selective 5-HT(2A) and 5-HT(6) receptor antagonists suggest potential mechanisms mediating the effects of sertindole, which has high affinity for these 5-HT receptor subtypes. The sertindole-induced improvement in cognitive function in this animal model suggests relevance for the management of cognitive deficit symptoms in schizophrenia.

Topics: Animals; Antipsychotic Agents; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Fluorobenzenes; Imidazoles; Indoles; Memory Disorders; Phencyclidine; Piperidines; Quinolines; Rats; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Reversal Learning; Schizophrenia; Sulfones

Metabotropic glutamate receptors of the subtype 5 (mGluR(5)) are located in brain regions implicated in schizophrenia such as the cerebral cortex or the nucleus accumbens. They may therefore provide an interesting target for the treatment of psychoses. Currently available agonists of mGluR(5) are not selective, do not penetrate the brain and induce a tonic activation resulting in a rapid desensitization. Therefore, the research focus was shifted to positive allosteric modulators (PAMs). Subsequently several mGluR(5) PAMs have been discovered, e.g. ADX47273 (S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone). In the present study, effects of ADX47273 (1-100mg/kg) were evaluated in rat models used for detecting antipsychotic-like activity: the conditioned avoidance response (CAR) and the phencyclidine (PCP)-induced hyperlocomotion models. Furthermore, the cataleptogenic potential of ADX47273 was compared to that of haloperidol. ADX47273 (100mg/kg) and various clinically used neuroleptics (haloperidol, olanzapine, and aripiprazole) attenuated CAR behaviour in rats. However, ADX47273 and aripiprazole failed to reduce the PCP-induced hyperlocomotion, whereas olanzapine and haloperidol diminished it. In contrast to haloperidol, ADX47273 (100mg/kg) failed to induce consistent catalepsy in rats. In conclusion, ADX47273 shows promising antipsychotic activity in some tests which require future investigation.

Topics: Allosteric Regulation; Animals; Avoidance Learning; Disease Models, Animal; Locomotion; Oxadiazoles; Phencyclidine; Piperidines; Rats; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Schizophrenia

Enlarged ventricles and reduced hippocampal volume are consistently found in patients with first-episode schizophrenia. Studies investigating brain structure in antipsychotic-naive patients have generally focused on the striatum. In this study, we examined whether ventricular enlargement and hippocampal and caudate volume reductions are morphological traits of antipsychotic-naive first-episode schizophrenia.. We obtained high-resolution 3-dimensional T1-weighted magnetic resonance imaging scans for 38 antipsychotic-naive first-episode schizophrenia patients and 43 matched healthy controls by use of a 3-T scanner. We warped the brain images to each other by use of a high-dimensional intersubject registration algorithm. We performed voxel-wise group comparisons with permutation tests. We performed small volume correction for the hippocampus, caudate and ventricles by use of a false discovery rate correction (p < 0.05) to control for multiple comparisons. We derived and analyzed estimates of brain structure volumes. We grouped patients as those with (n = 9) or without (n = 29) any lifetime substance abuse to examine the possible effects of substance abuse.. We found that hippocampal and caudate volumes were decreased in patients with first-episode schizophrenia. We found no ventricular enlargement, differences in global volume or significant associations between tissue volume and duration of untreated illness or psychopathology. The hippocampal volume reductions appeared to be influenced by a history of substance abuse. Exploratory analyses indicated reduced volume of the nucleus accumbens in patients with first-episode schizophrenia.. This study was not a priori designed to test for differences between schizophrenia patients with or without lifetime substance abuse, and this subgroup was small.. Reductions in hippocampal and caudate volume may constitute morphological traits in antipsychotic-naive first-episode schizophrenia patients. However, the clinical implications of these findings are unclear. Moreover, past substance abuse may accentuate hippocampal volume reduction. Magnetic resonance imaging studies addressing the potential effects of substance abuse in antipsychotic-naive first-episode schizophrenia patients are warranted.

Topics: Adolescent; Adult; Benzydamine; Brain; Caudate Nucleus; Cerebral Ventricles; Dibucaine; Drug Combinations; Female; Hippocampus; Humans; Hyaluronoglucosaminidase; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Nucleus Accumbens; Organ Size; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Substance-Related Disorders; Time Factors; Young Adult

To describe the contents of a Drug Approval Package and to describe the efficacy and safety of iloperidone for the treatment of schizophrenia.. Drug Approval Package from the US Food and Drug Administration available at http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022192s000TOC.cfm.. The Drug Approval Package contains several different sections that describe both the preclinical (animal) and the clinical (human) studies conducted that led to the approval of iloperidone, a second-generation antipsychotic medication. Most of this information has not been published in the peer-reviewed literature and much of it had not been previously publicly available. Iloperidone's indication for the acute treatment of schizophrenia in adults is supported by two of the four principal registration studies completed by the manufacturer. The documents made available reveal that there was disagreement between the Food and Drug Administration (FDA) and the manufacturer as to which study was considered 'positive' for iloperidone. There was additional controversy surrounding the appropriateness of combining patients with schizophrenia and schizoaffective disorder in the same study. Questions were also raised by the FDA about the relative efficacy of iloperidone vs. other antipsychotics; the need for an initial titration period was offered as a possible explanation as to why risperidone appeared to have superior efficacy. Moreover, there was disagreement as to what constitutes an appropriate study to test the long-term efficacy of an antipsychotic. Additional information is made available regarding the safety and tolerability of iloperidone, with the FDA acknowledging an overall attractive profile that includes less akathisia and extrapyramidal symptoms than other agents in its class. Of potential clinical utility are the results from FDA analyses of patients where clinical variables shifted from the normal to abnormal range.. Iloperidone is efficacious and reasonably tolerable. The information made publicly available in the Drug Approval Package from the US FDA allows a closer examination as to how the medication was approved and allows for outside clinicians and researchers to appraise the data more carefully. Safety signals generated by FDA analyses of outliers can provide the impetus for the conduct of additional studies and post hoc analyses of registration study data already collected.

Topics: Adult; Antipsychotic Agents; Clinical Trials as Topic; Drug Approval; Humans; Isoxazoles; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Treatment Outcome; United States; United States Food and Drug Administration

Topics: Antipsychotic Agents; Humans; Isoxazoles; Piperidines; Schizophrenia

In schizophrenia, an opioidergic understimulation and a decreased sleep duration are found. The pathogenic significance of these factors is unknown. The present study assessed the influence of the combination of the factors on serotonergic 2A (5-HT(2A)) receptors that are possibly related to psychosis development. 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced head-twitch response in mice was used as a model of 5-HT(2A) receptor functioning. Mice underwent sleep deprivation and/or a blockade of opioidergic receptors with naloxone. To evaluate the involvement of 5-HT(2A) receptor in effects observed, animals were pretreated with MDL 100,907, a potent and selective antagonist of 5-HT(2A) receptor. As was found, 4h of sleep deprivation followed by administration of naloxone significantly increases the frequency of head twitches, with sleep deprivation and naloxone being ineffective alone. The action of the "sleep deprivation-opioid understimulation" combination is antagonized completely by MDL 100,907. Thus, some schizophrenia-associated factors can synergistically enhance the activity of 5-HT(2A) receptors. These results suggest the above factors being pathogenically relevant in schizophrenia.

Topics: Animals; Fluorobenzenes; Head Movements; Male; Mice; Mice, Inbred C57BL; Narcotic Antagonists; Piperidines; Random Allocation; Receptor, Serotonin, 5-HT2A; Receptors, Opioid; Schizophrenia; Serotonin Antagonists; Sleep Deprivation

Several studies have examined the link between the cannabinoid CB1 receptor and several neuropsychiatric illnesses, including schizophrenia. As such, there is a need for in vivo imaging tracers so that the relationship between CB1 and schizophrenia (SZ) can be further studied. In this paper, we present our first human studies in both healthy control patients and patients with schizophrenia using the novel PET tracer, [(11)C]OMAR (JHU75528), we have shown its utility as a tracer for imaging human CB1 receptors and to investigate normal aging and the differences in the cannabinoid system of healthy controls versus patients with schizophrenia. A total of ten healthy controls and nine patients with schizophrenia were included and studied with high specific activity [(11)C]OMAR. The CB1 binding (expressed as the distribution volume; V(T)) was highest in the globus pallidus and the cortex in both controls and patients with schizophrenia. Controls showed a correlation with the known distribution of CB1 and decline of [(11)C]OMAR binding with age, most significantly in the globus pallidus. Overall, we observed elevated mean binding in patients with schizophrenia across all regions studied, and this increase was statistically significant in the pons (p<0.05), by the Students t-test. When we ran a regression of the control subjects V(T) values with age and then compared the patient data to 95% prediction limits of the linear regression, three patients fell completely outside for the globus pallidus, and in all other regions there were at least 1-3 patients outside of the prediction intervals. There was no statistically significant correlations between PET measures and the individual Brief Psychiatry Rating Score (BPRS) subscores (r=0.49), but there was a significant correlation between V(T) and the ratio of the BPRS psychosis to withdrawal score in the frontal lobe (r=0.60), and middle and posterior cingulate regions (r=0.71 and r=0.79 respectively). In conclusion, we found that [(11)C] OMAR can image human CB1 receptors in normal aging and schizophrenia. In addition, our initial data in subjects with schizophrenia seem to suggest an association of elevated binding specific brain regions and symptoms of the disease.

Topics: Adult; Brain; Female; Humans; Male; Middle Aged; Piperidines; Positron-Emission Tomography; Pyrazoles; Radiopharmaceuticals; Receptor, Cannabinoid, CB1; Schizophrenia; Tissue Distribution

Topics: Adult; Antipsychotic Agents; Aripiprazole; Dopamine Antagonists; Female; Humans; Hyperprolactinemia; Piperazines; Piperidines; Quinolones; Schizophrenia

Positive allosteric modulation of metabotropic glutamate receptor 5 (mGluR5) is regarded as a potential novel treatment for schizophrenic patients. Herein we report the synthesis and SAR of 4-aryl piperazine and piperidine amides as potent mGluR5 positive allosteric modulators (PAMs). Several analogs have excellent activity and desired drug-like properties. Compound 2b was further characterized as a PAM using several in vitro experiments, and produced robust activity in several preclinical animal models.

Topics: Allosteric Regulation; Amides; Humans; Microsomes, Liver; Piperazine; Piperazines; Piperidines; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Schizophrenia; Structure-Activity Relationship

SSR103800 and SSR504734 are novel glycine transport 1 (GlyT1) inhibitors with therapeutic potential for the treatment of schizophrenia.. The present studies investigated the effects of GlyT1 inhibitors in acute pharmacological and neurodevelopmental models of schizophrenia using latent inhibition in the rat; these latent inhibition (LI) models are believed to be predictive for treatments of positive, negative, and cognitive aspects of schizophrenia.. LI, the poorer conditioning to a previously irrelevant stimulus, was measured in a conditioned emotional response procedure in male rats. The effects of SSR103800 or SSR504734 (both at 1, 3, and 10 mg/kg, i.p.) were determined on amphetamine-induced disrupted LI, MK-801-induced abnormally persistent LI, and neurodevelopmentally induced abnormally persistent LI in adult animals that had been neonatally treated with a nitric oxide synthase inhibitor.. SSR103800 (1 and 3 mg/kg) and SSR504734 (1 and 10 mg/kg) potentiated LI under conditions where LI was not present in nontreated controls and SSR103800 (1 mg/kg) reversed amphetamine-induced disrupted LI while not affecting LI on its own. Additionally, SSR103800 (1 and 3 mg/kg) and SSR504734 (3 and 10 mg/kg) reversed abnormally persistent LI induced by MK-801. In the neurodevelopmental model, SSR504734 (3 and 10 mg/kg) reverted the LI back to control (normal) levels.. These preclinical data, from acute and neurodevelopmental models, suggest that GlyT1 inhibition may exhibit activity in the positive, negative, and cognitive symptom domains of schizophrenia.

Topics: Aging; Amphetamine; Animals; Animals, Newborn; Antipsychotic Agents; Benzamides; Central Nervous System Stimulants; Cognition; Conditioning, Operant; Dizocilpine Maleate; Dose-Response Relationship, Drug; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Glycine Plasma Membrane Transport Proteins; Haloperidol; Male; Nitroarginine; Piperidines; Rats; Rats, Wistar; Reflex, Startle; Schizophrenia; Schizophrenic Psychology

Cognitive deficits are commonly associated with maintenance electroconvulsive therapy (ECT). Treatment of these cognitive deficits is important but difficult. Cholinergic pathways are involved in these side effects, and donepezil, a cholinesterase inhibitor, may be useful for improvement of cognition. In this case report, we describe for the first time successful use of donepezil in treating cognitive deficits associated with maintenance ECT. The role of cholinesterase inhibitors in the treatment of cognitive deficits caused by ECT needs further studies.

Topics: Adult; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Electroconvulsive Therapy; Female; Humans; Indans; Memory Disorders; Neuropsychological Tests; Nootropic Agents; Piperidines; Schizophrenia

Therapies treating cognitive impairments in schizophrenia especially deficits in executive functioning are not available at present.. The current study evaluated the effect of ampakine CX516 in reversing deficits in executive functioning as represented in two animal models of schizophrenia and assessed by a rodent analog of the intradimensional-extradimensional (ID-ED) attentional set-shifting task. The second generation antipsychotic, sertindole, provided further validation of the schizophrenia-like disease models.. Animals were subjected to (a) sub-chronic or (b) early postnatal phencyclidine (PCP) treatment regimes: (a) Administration of either saline or PCP (5 mg/kg, intraperitonally b.i.d. for 7 days) followed by a 7-day washout period and testing on day 8. (b) On postnatal days (PNDs) 7, 9, and 11, rats were subjected to administration of either saline or PCP (20 mg/kg, subcutaneously (s.c.)) and tested on PNDs 56-95, after reaching adulthood. The single test session required rats to dig for food rewards in a series of discriminations following acute administration of either vehicle, or CX516 (5-40 mg/kg, s.c.), or sertindole (1.25 mg/kg, perorally).. The specific extradimensional deficits produced by sub-chronic or early postnatal PCP treatment were significantly attenuated by sertindole and dose-dependently by CX516.. Findings here further establish PCP treatment as model of executive functioning deficits related to schizophrenia and provide evidence that direct glutamatergic interventions could improve these, when assessed in the ID-ED attentional set-shifting task.

Topics: Animals; Antipsychotic Agents; Attention; Dioxoles; Disease Models, Animal; Dose-Response Relationship, Drug; Imidazoles; Indoles; Male; Phencyclidine; Piperidines; Rats; Schizophrenia

Alterations in muscarinic acetylcholine receptor (CHRM) populations have been implicated in the pathology of schizophrenia. Here we have assessed whether the receptor function of the M(1) subtype (CHRM1) is altered in a sub-population of patients with schizophrenia, defined by marked (60-80%) reductions in cortical [3H]-pirenzepine (PZP) binding, and termed 'muscarinic receptor-deficit schizophrenia' (MRDS). Using a [35S]-GTPgammaS-Galpha(q/11) immunocapture method we have assessed whether CHRM1 signalling in human cortex (Brodmann area 9 (BA9)) is altered in post mortem tissue from a MRDS group compared with a subgroup of patients with schizophrenia displaying normal PZP binding, and controls with no known history of psychiatric or neurological disorders. The CHRM agonist (oxotremorine-M) and a CHRM1-selective agonist (AC-42) increased Galpha(q/11)-[35S]-GTPgammaS binding, with AC-42 producing responses that were approximately 50% of those maximally evoked by the full agonist, oxotremorine-M, in control and subgroups of patients with schizophrenia. However, the potency of oxotremorine-M to stimulate Galpha(q/11)-[35S]-GTPgammaS binding was significantly decreased in the MRDS group (pEC(50) (M)=5.69+/-0.16) compared with the control group (6.17+/-0.10) and the non-MRDS group (6.05+/-0.07). The levels of Galpha(q/11) protein present in BA9 did not vary with diagnosis. Maximal oxotremorine-M-stimulated Galpha(q/11)-[35S]-GTPgammaS binding in BA9 membranes was significantly increased in the MRDS group compared with the control group. Similar, though non-statistically significant, trends were observed for AC-42. These data provide evidence that both orthosterically and allosterically acting CHRM agonists can stimulate a receptor-driven functional response ([35S]-GTPgammaS binding to Galpha(q/11)) in membranes prepared from post mortem human dorsolateral prefrontal cortex of patients with schizophrenia and controls . Furthermore, in a subgroup of patients with schizophrenia displaying markedly decreased PZP binding (MRDS) we have shown that although agonist potency may decrease, the efficacy of CHRM1-Galpha(q/11) coupling increases, suggesting an adaptative change in receptor-G protein coupling efficiency in this endophenotype of patients with schizophrenia.

Topics: Adult; Aged; Cell Membrane; Female; GTP-Binding Protein alpha Subunits, Gq-G11; Guanosine 5'-O-(3-Thiotriphosphate); Humans; Male; Middle Aged; Muscarinic Agonists; Muscarinic Antagonists; Oxotremorine; Phenotype; Piperidines; Pirenzepine; Prefrontal Cortex; Protein Binding; Receptor, Muscarinic M1; Receptors, Muscarinic; Schizophrenia; Sulfur Radioisotopes; Tritium; Young Adult

Recent studies have raised the possibility that antagonists of H(3) histamine receptors possess cognitive-enhancing and antipsychotic properties. However, little work has assessed these compounds in classic animal models of schizophrenia.. The purpose of this study was to determine if a prototypical H(3) antagonist, thioperamide, could alter behavioral deficits caused by the N-methyl-D: -aspartate (NMDA) receptor antagonist, MK-801, in adult male rats. MK-801 was chosen to be studied since it produces a state of NMDA receptor hypofunction in rats that may be analogous to the one hypothesized to occur in schizophrenia.. The interaction between thioperamide and MK-801 was measured in three behavioral tests: locomotor activity, prepulse inhibition (PPI), and delayed spatial alternation. In each test, rats received a subcutaneous injection of saline or thioperamide (3.0 and 10 mg/kg) followed 20 min later by a subcutaneous injection of saline or MK-801 (0.05, 0.10, and 0.30 mg/kg).. Locomotor activity was significantly elevated by MK-801 in a dose-dependent manner. Thioperamide pretreatment alone did not alter locomotor activity; however, its impact on MK-801 was dose-dependent. Each thioperamide dose enhanced the effects of two lower doses of MK-801 but reduced the effect of a higher MK-801 dose. Clear deficits in PPI and delayed spatial alternation were produced by MK-801 treatment, but neither impairment was significantly modified by thioperamide pretreatment.. H(3) receptors modulate responses to NMDA antagonists in behaviorally specific and dose-dependent ways.

Topics: Animals; Dizocilpine Maleate; Drug Interactions; Histamine H3 Antagonists; Injections, Subcutaneous; Male; Memory; Motor Activity; Piperidines; Rats; Rats, Long-Evans; Reflex, Startle; Schizophrenia

Recently, it has been proposed that activation of either metabotropic glutamate receptors e.g. mGlu(5) by positive allosteric modulators or stimulation of mGluR(2/3) receptors by agonists may offer new strategy in schizophrenia treatment. The aim of the present study was to compare the effect of mGlu(5) receptor positive allosteric modulator, ADX47273 (S-(4-Fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone), mGluR(2/3) agonist, LY354740 ((1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate) and selected neuroleptics in animal models for positive schizophrenia symptoms. ADX47273 (3 and 10mg/kgi.p.), the typical antipsychotic haloperidol (0.1 and 0.2mg/kgi.p.), the atypical antipsychotics aripiprazole (1.25-5mg/kgi.p.) and olanzapine (2.5 and 5mg/kgi.p.) all reduced amphetamine-induced hyperlocomotion in Sprague-Dawley rats, unlike the mGlu(2/3) receptor agonist LY354740 (1-10mg/kgi.p.). Interestingly, haloperidol (0.1 and 0.2mg/kgi.p.), aripiprazole (1.25-5mg/kgi.p.) and olanzapine (1.25-5mg/kgi.p.), but not ADX47273 (1-10mg/kgi.p.), all reduced spontaneous locomotion and rearings at doses effective against amphetamine-induced hyperlocomotion. This indicates that the effect of ADX47273 in combination with amphetamine may be specific, and also suggests a lack of sedative side effects. Moreover, ADX47273 (30mg/kgi.p.), haloperidol (0.1 and 0.2mg/kgi.p.) and aripiprazole (5 and 10mg/kgi.p.) reversed apomorphine (0.5mg/kgs.c.)-induced deficits of prepulse inhibition, whereas neither LY354740 (1-10mg/kgi.p.) nor olanzapine (1.25-5mg/kgi.p.) produced this effect. Lack of effect of olanzapine was unexpected and at present no convincing explanation can be provided. In conclusion, in selected rodent models for positive schizophrenia symptoms, ADX47273 showed better efficacy than LY354740.

Topics: Allosteric Regulation; Animals; Antipsychotic Agents; Behavior, Animal; Bridged Bicyclo Compounds; Dopamine Agents; Dose-Response Relationship, Drug; Excitatory Amino Acid Agents; Excitatory Amino Acid Agonists; Male; Motor Activity; Neural Inhibition; Oxadiazoles; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Reflex, Startle; Schizophrenia; Treatment Outcome

Topics: Animals; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Clinical Trials as Topic; Delusions; Drug Administration Schedule; Humans; Lipogenesis; Mice; Mice, Knockout; Models, Biological; Nerve Endings; Obesity; Piperidines; Pyrazoles; Receptors, Cannabinoid; Rimonabant; Schizophrenia; Waist-Hip Ratio; Weight Loss

Decreased muscarinic M1 receptor (CHRM1) mRNA has been reported in Brodmann's area (BA) 6 from subjects with schizophrenia. We have extended this study by measuring levels of CHRM1 ([(3)H]pirenzepine binding), CHRM3 ([(3)H]4-DAMP binding), the transcription factor SP1 and the CHRM1 downstream target beta-site APP-cleaving enzyme 1 (BACE1) in BA 6 from 19 subjects with schizophrenia and 19 control subjects. Radioligand binding was quantified using either in situ radioligand binding with autoradiography or, in cohorts of 10 control subjects and 10 subjects with schizophrenia, membrane enriched fraction (MEF) CNS ([(3)H]pirenzepine binding only). Levels of SP1 and BACE1 were measured by Western blotting. [(3)H]pirenzepine binding to tissue sections was in two layers, binding to tissue sections (Binding layer 1: p<0.01; Binding layer 2: p<0.001) and MEF (p<0.05) were decreased in schizophrenia. Levels of [(3)H]4-DAMP binding, SP1 and BACE1 were not altered in subjects with the disorder. This study shows a decrease in levels of CHRM1 in BA 6 from subjects with schizophrenia; as CHRM1 and BA 6 are important in maintaining normal cognitive function, these data support the hypothesis that decreased levels of cortical CHRM1 may contribute to the cognitive deficits associated with schizophrenia. Our findings on BACE1 suggest that the schizophrenia phenotype reported in BACE(-/-) mice is not simply due to lack of that protein in the cortex.

Topics: Adult; Aged; Autoradiography; Binding Sites; Cathepsin B; Cerebral Cortex; Female; Humans; Male; Middle Aged; Piperidines; Pirenzepine; Radioligand Assay; Receptor, Muscarinic M1; Receptor, Muscarinic M2; Receptor, Muscarinic M3; Receptor, Muscarinic M4; Schizophrenia; Sp1 Transcription Factor

Topics: Akathisia, Drug-Induced; Antipsychotic Agents; Aripiprazole; Basal Ganglia Diseases; Dopamine Agonists; Dopamine Antagonists; Dose-Response Relationship, Drug; Humans; Piperazines; Piperidines; Positron-Emission Tomography; Psychomotor Agitation; Quinolones; Receptor, Serotonin, 5-HT1A; Receptors, Dopamine D2; Schizophrenia; Serotonin 5-HT1 Receptor Agonists; Urea

Topics: Antipsychotic Agents; Humans; Isoxazoles; Piperidines; Schizophrenia

Iloperidone is an atypical antipsychotic in development for the treatment of schizophrenia. This report examines efficacy results from three 6-week, randomized, double-blind, placebo- and active comparator-controlled studies in patients with schizophrenia or schizoaffective disorder. Multiple doses of iloperidone were studied. Active comparators (haloperidol 15 mg/d, or risperidone 4-8 mg/d) were included to confirm trial validity. The primary protocol-defined efficacy variable in Study 1 was change from baseline to end point in Positive and Negative Syndrome Scale total scores; in Studies 2 and 3, it was change in the Positive and Negative Syndrome Scale-derived Brief Psychiatric Rating Scale scores. Results were assessed through analysis of covariance using last observation carried forward in the intent-to-treat population. In total, 1943 patients were randomized. At least 1 iloperidone dosing group in each study demonstrated significantly better efficacy than placebo (Study 1, iloperidone 12 mg/d [P = 0.047]; Study 2, 4-8 mg/d [P = 0.012] and 10-16 mg/d [P = 0.001]; and Study 3, 20-24 mg/d [P = 0.010]). Active controls were also significantly more effective than placebo in each trial, thus validating the trials. Additional analysis in patients who received active treatment for at least 2 weeks indicated comparable efficacy score reductions at 6 weeks for patients receiving iloperidone 20 to 24 mg/d versus those receiving haloperidol or risperidone. Risk for motor-related adverse events (eg, akathisia and extrapyramidal symptoms) was lower with iloperidone than with risperidone and haloperidol and was generally similar to placebo. These trials indicate that iloperidone is effective for the treatment of schizophrenia.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Endpoint Determination; Female; Humans; Isoxazoles; Male; Middle Aged; Piperidines; Psychotic Disorders; Randomized Controlled Trials as Topic; Schizophrenia

Aripiprazole, (+)terguride, OPC-4392 and (-)3-PPP have been classified as dopamine D(2) receptor partial agonists based largely on their activity in second messenger-based assays of dopamine D(2) receptor signalling. Nevertheless, signal transduction amplification might result in these compounds behaving as dopamine D(2) receptor full agonists at a more downstream level of signalling. We compared the intrinsic activity (E(max), expressed as a percentage of the maximal effect of dopamine) of aripiprazole, (+)terguride, OPC-4392 and (-)3-PPP using second (calcium (Ca(2+)) mobilization) and third (extracellular signal-regulated kinase 2 (ERK2) phosphoprotein expression) messenger readouts of cloned human dopamine D(2long) (hD(2L)) receptor signalling in CHO cells. These compounds were all less potent and displayed lower intrinsic activity in the Ca(2+) assay (aripiprazole = 24.3%, (+)terguride = 56.9%, OPC-4392 = 58.6% and (-)3-PPP = 75.1%), and aripiprazole (E(max) = 54.5%) displayed a substantially lower intrinsic activity than (+)terguride (E(max) = 92.3%), OPC-4392 (E(max) = 93.1%) and (-)3-PPP (E(max) = 101.1%) in the more downstream-based ERK2 phosphoprotein expression assay. These drug effects on Ca(2+) mobilization and ERK2 phosphoprotein expression were mediated through dopamine hD(2L) receptors, as they all were blocked by (-)raclopride, whereas (-)raclopride and other dopamine D(2) receptor antagonists (haloperidol, risperidone, ziprasidone, olanzapine, clozapine and quetiapine) were inactive on their own in both assays. These data are consistent with clinical evidence that only dopamine D(2) receptor partial agonists with a sufficiently low enough intrinsic activity will prove effective against the positive symptoms of schizophrenia, and also highlight the importance of using downstream-based assays in the discovery of novel D(2) receptor partial agonist therapeutics.

Topics: Animals; Antipsychotic Agents; Aripiprazole; Calcium Signaling; CHO Cells; Cloning, Molecular; Cricetinae; Cricetulus; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Humans; Immunoblotting; Lisuride; MAP Kinase Signaling System; Microscopy, Confocal; Mitogen-Activated Protein Kinase 1; Phosphorylation; Piperazines; Piperidines; Quinolones; Raclopride; Receptors, Dopamine D2; Schizophrenia; Time Factors; Transfection

The contribution of the endocannabinoid system to dopamine-mediated disorganized behavior in schizophrenia is discussed. We used a model of concurrent stimulation of dopamine D1 and D2 receptors to evaluate the role of this system in dopamine-mediated stereotypies measured in a hole-board test. Pretreatment with the cannabinoid CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A; 1 mg/kg) potentiated stereotyped behavior induced by coadministration of the dopamine D1 receptor agonist SKF 38393 (0.05, 0.1 and 1 mg/kg) and the dopamine D2 receptor agonist quinpirole (0.25 mg/kg). Thus, the endocannabinoid system acts as a brake for abnormal behavior associated with dopaminergic overactivation.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Behavior, Animal; Dopamine Agonists; Dose-Response Relationship, Drug; Male; Piperidines; Pyrazoles; Quinpirole; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Rimonabant; Schizophrenia; Schizophrenic Psychology; Stereotyped Behavior

Clinical and laboratory findings suggest that cannabinoids and their receptors are implicated in schizophrenia. The role of cannabinoids in schizophrenia remains however poorly understood, as data are often contradictory. The primary aim of this study was to investigate whether the cannabinoid CB1 receptor antagonists rimonabant and AM251 are able to reverse deficits of sensorimotor gating induced by phencyclidine and to mimic the 'atypical' antipsychotic profile of clozapine. The prepulse inhibition (PPI) of the startle reflex was used to measure deficits of sensorimotor gating. PPI-disruptive effects of phencyclidine and their antagonism by rimonabant, AM251, and clozapine were studied in rats. The effects of rimonabant were carefully examined taking into account dose ranges, vehicle, and route of administration. We also examined the ability of rimonabant to reduce the PPI-disruptive effects of dizocilpine and apomorphine. Rimonabant as well as AM251 significantly counteracted the phencyclidine-disruptive model of PPI, comparable to the restoring effect of clozapine; no augmentation effect was observed with rimonabant and clozapine as cotreatment. Rimonabant also significantly attenuated the PPI disruptive effects of dizocilpine and apomorphine. Taken together, our results indicate that CB1 receptor antagonists do produce 'atypical' antipsychotic profile mimicking that of clozapine in the phencyclidine disruption of sensorimotor gating. Our findings further suggest that CB1 receptor antagonism may be involved in restoring disturbed interactions between the activity of the endocannabinoid system and glutamate neurotransmitter system implied in schizophrenia.

Topics: Animals; Brain; Cannabinoid Receptor Antagonists; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Drug Synergism; Excitatory Amino Acid Antagonists; Glutamic Acid; Male; Phencyclidine; Piperidines; Psychoses, Substance-Induced; Pyrazoles; Rats; Receptors, Cannabinoid; Reflex, Startle; Rimonabant; Schizophrenia; Sensation Disorders; Synaptic Transmission

BF2.649, a high affinity and selective non-imidazole histamine H(3)-receptor antagonist/inverse agonist, was found to easily enter the brain after oral administration to mice: it displayed a ratio of brain/plasma levels of about 25 when considering either C(max) or AUC values. At low oral doses (2.5-20mg/kg), it elicited in mice a dose-dependent wakening effect accompanied with a shift towards high frequency waves of the EEG, a sign of cortical activation. DOPAC/dopamine ratios were enhanced in the prefrontal cortex but not in the striatum, indicating a selective activation of a sub-population of dopaminergic neurons. BF2.649 showed significant inhibitory activity in several mouse models of schizophrenia. It reduced locomotor hyperactivity elicited by methamphetamine or dizolcipine without significantly affecting spontaneous locomotor activity when administered alone. It also abolished the apomorphine-induced deficit in prepulse inhibition. These observations suggest that H(3)-receptor inverse agonists/antagonists deserve attention as a novel class of antipsychotic drugs endowed with pro-cognitive properties.

Topics: Administration, Oral; Animals; Disease Models, Animal; Histamine Antagonists; Mice; Piperidines; Receptors, Histamine H3; Schizophrenia

[123I]TPCNE (1(trans-[123I]iodopropen-2-yl)-4-[(4-cyanophenoxy)methyl] piperidine; Ki = 0.67 nM; log P = 3.36) is a novel sigma-1 receptor SPET ligand. In this study, we developed an optimized labeling method for [123I]TPCNE and investigated the kinetics, binding characteristics, and whole-body distribution of this tracer for the first time in humans. We also performed a challenge with the sigma-1 receptor antagonist haloperidol against [123I]TPCNE. Seven healthy volunteers were recruited. Dynamic brain SPET scans were performed following i.v. administration of 185 MBq [123I]TPCNE in all seven subjects. Three of the subjects were given oral haloperidol (2.5 mg) approximately 1 h before the scan. The dynamic data were analyzed with both reversible and irreversible compartmental models.[123I]TPCNE showed high uptake in brain and liver. All non-haloperidol-treated subjects showed a high whole-brain uptake (average: 8.7% of injected activity). No significant clearance of the tracer was seen up to 30 h post injection. In the haloperidol-treated subjects, the time-activity curves clearly demonstrated clearance of the tracer from the brain. Regional radioactivity concentrations were reduced by haloperidol from 42% in the cerebellum to 73% in the thalamus.[(123)I]TPCNE demonstrated high brain uptake, with highest binding found in the posterior cingulate. A region in which binding was unaffected by haloperidol pretreatment could not be identified, and the time-activity data were best described by an irreversible model.

Topics: Adult; Binding, Competitive; Brain; Dopamine Antagonists; Drug Interactions; Female; Gyrus Cinguli; Haloperidol; Humans; Iodine Radioisotopes; Liver; Male; Metabolic Clearance Rate; Middle Aged; Piperidines; Radioactive Tracers; Radioligand Assay; Receptors, sigma; Schizophrenia; Sigma-1 Receptor; Time Factors; Tomography, Emission-Computed, Single-Photon

Experimental and clinical evidence points to a role of central histaminergic system in the pathogenesis of schizophrenia. The present study was designed to study the effect of histamine H(3)-receptor ligands on neuroleptic-induced catalepsy, apomorphine-induced climbing behavior and amphetamine-induced locomotor activities in mice. Catalepsy was induced by haloperidol (2 mg/kg p.o.), while apomorphine (1.5 mg/kg s.c.) and amphetamine (2 mg/kg s.c.) were used for studying climbing behavior and locomotor activities, respectively. (R)-alpha-methylhistamine (RAMH) (5 microg i.c.v.) and thioperamide (THP) (15 mg/kg i.p.), per se did not cause catalepsy. Administration of THP (3.75, 7.5 and 15 mg/kg i.p.) 1 h prior to haloperidol resulted in a dose-dependent increase in the catalepsy times (P < 0.05). However, pretreatment with RAMH significantly reversed such an effect of THP (15 mg/kg i.p.). RAMH per se showed significant reduction in locomotor time, distance traveled and average speed but THP (15 mg/kg i.p.) per se had no effect on these parameters. On amphetamine-induced hyperactivity, THP (3.75 and 7.5 mg/kg i.p.) reduced locomotor time, distance traveled and average speed (P < 0.05). Pretreatment with RAMH (5 microg i.c.v.) could partially reverse such effects of THP (3.75 mg/kg i.p.). Climbing behavior induced by apomorphine was reduced in animals treated with THP. Such an effect was, however, reversed in presence of RAMH. THP exhibited an antipsychotic-like profile by potentiating haloperidol-induced catalepsy, reducing amphetamine-induced hyperactivity and reducing apomorphine-induced climbing in mice. Such effects of THP were reversed by RAMH indicating the involvement of histamine H(3)-receptors. Findings suggest a potential for H(3)-receptor antagonists in improving the refractory cases of schizophrenia.

Topics: Amphetamine; Animals; Antipsychotic Agents; Apomorphine; Catalepsy; Dose-Response Relationship, Drug; Haloperidol; Histamine Agonists; Histamine Antagonists; Methylhistamines; Mice; Models, Animal; Motor Activity; Piperidines; Receptors, Histamine H3; Schizophrenia; Stereotyped Behavior; Time Factors

Tardive dyskinesia and other delayed-onset abnormal involuntary movement disorders may occur as a result of the use of psychotropic drugs. A distinction is usually made between classic tardive dyskinesia (TD) (orobuccal-lingual-facial) and tardive dystonia, tardive tremor (TT), tardive akathisia, and other related syndromes. In spite of the development of atypical antipsychotics with fewer side effects, tardive movement disorders nevertheless continue to present a significant clinical and therapeutic challenge. Several reports have suggested that donepezil may be helpful in the treatment of TD.. A preliminary study was conducted of 7 patients (5 women and 2 men) enrolled over a period of 6 months who had been experiencing TT for a period of at least 1 year. The ages of the patients ranged from 64 to 79 years, and all patients were on stable antipsychotic therapy. Donepezil was added to their usual treatment for 8 weeks. The severity of patients' extrapyramidal symptoms was assessed using the tremor subscale of the Simpson-Angus Scale (SAS) and self-rated with a modification of the Clinical Global Impressions scale, the Subjective Clinical Improvement Impression scale. The clinical response was evaluated by comparing the rating scores at baseline prior to donepezil treatment and every 2 weeks thereafter.. The addition of donepezil (up to 10 mg/day) was associated with a clinically significant improvement (from 37.5% to 63.6%) on the SAS tremor subscale following 4 weeks of therapy. Only 1 patient discontinued follow-up due to side effects.. The results suggest that donepezil may be effective in the treatment of TT, and this finding should be evaluated further by a randomized controlled study.

Topics: Aged; Antipsychotic Agents; Basal Ganglia Diseases; Bipolar Disorder; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Dyskinesia, Drug-Induced; Female; Geriatric Assessment; Hospitalization; Humans; Indans; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index; Treatment Outcome

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Data Interpretation, Statistical; Humans; Mianserin; Mirtazapine; Neurotensin; Peptide Fragments; Piperidines; Pyrazoles; Quinolines; Receptors, Neurotensin; Research Design; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Excessive activation of non-NMDA receptors, AMPA and kainate, contributes to neuronal degeneration in acute and progressive pathologies, possibly including schizophrenia. Because 5-HT(1A) receptor agonists have neuroprotective properties (e.g., against NMDA-induced neurotoxicity), we compared the effects of the antipsychotics, clozapine, ziprasidone and aripiprazole, that are partial agonists at 5-HT(1A) receptor, with those of haloperidol, which is devoid of 5-HT(1A) agonist properties, on kainic acid (KA)-induced striatal lesion volumes, in C57Bl/6N mice. The involvement of 5-HT(1A) receptors was determined by antagonist studies with WAY100635, and data were compared with those obtained using the potent and high efficacy 5-HT(1A) receptor agonist, F13714. Intra-striatal KA lesioning and measurement of lesion volumes using cresyl violet staining were carried out at 48 h after surgery. F13714, antipsychotics or vehicle were administered ip twice, 30 min before and 3 1/2 h after KA injection. WAY100635 (0.63 mg/kg) or vehicle were given sc 30 min before each drug injection. Clozapine (2 x 10 mg/kg), ziprasidone (2 x 20 mg/kg) and aripiprazole (2 x 10 mg/kg) decreased lesion volume by 61%, 59% and 73%, respectively. WAY100635 antagonized the effect of ziprasidone and of aripiprazole but only slightly attenuated that of clozapine. In contrast, haloperidol (2 x 0.16 mg/kg) did not affect KA-induced lesion volume. F13714 dose-dependently decreased lesion volume. The 61% decrease of lesion volume obtained with F13714 (2 x 0.63 mg/kg) was antagonized by WAY100635. WAY100635 alone did not affect lesion volume. These results show that 5-HT(1A) receptor activation protects against KA-induced striatal lesions and indicate that some atypical antipsychotic agents with 5-HT(1A) agonist properties may protect against excitotoxic injury, in vivo.

Topics: Aminopyridines; Animals; Antipsychotic Agents; Aripiprazole; Clozapine; Corpus Striatum; Disease Models, Animal; Excitatory Amino Acid Agonists; Haloperidol; Kainic Acid; Male; Mice; Mice, Inbred C57BL; Piperazines; Piperidines; Pyridines; Quinolones; Receptor, Serotonin, 5-HT1A; Schizophrenia; Serotonin 5-HT1 Receptor Agonists; Serotonin Antagonists; Thiazoles

Since H3 receptor (H3R) antagonists/inverse agonists can improve cognitive function in animal models, they may have the potential to be used as add-on therapy in the treatment of schizophrenia, a disease with significant cognitive deficits. However, a recent study showed potentiation of haloperidol-induced catalepsy by ciproxifan, an imidazole-containing H3R antagonist/inverse agonist, suggesting there is a potential risk of exacerbating extrapyramidal symptoms (EPS) if H3R antagonists were used as adjunctive treatment [Pillot, C., Ortiz, J., Heron, A., Ridray, S., Schwartz, J.C. and Arrang, J.M., Ciproxifan, a histamine H3-receptor antagonist/inverse agonist, potentiates neurochemical and behavioral effects of haloperidol in the rat, J Neurosci, 22 (2002) 7272-80]. In order to clarify the basis of this finding, we replicated this result and extended the work with another imidazole and two non-imidazole H3R antagonists. The results indicate that ciproxifan significantly augmented the effects of haloperidol and risperidone on catalepsy. Another imidazole H3R antagonist, thioperamide, also potentiated the effect of risperidone on catalepsy. In contrast, no catalepsy-enhancing effects were observed when selective non-imidazole H3R antagonists, ABT-239 and A-431404, were coadministered with haloperidol and/or risperidone. As ciproxifan and thioperamide are inhibitors of cytochrome P450 enzymes, responsible for metabolizing risperidone and haloperidol, the possibility that the augmentation of antipsychotics by imidazoles resulted from drug-drug interactions was tested. A drug metabolism study revealed that an imidazole, but not a non-imidazole, potently inhibited the metabolism of haloperidol and risperidone. Furthermore, ketoconazole, an imidazole-based CYP 3A4 inhibitor, significantly augmented risperidone-induced catalepsy. Together, these data suggest the potentiation of antipsychotic-induced catalepsy may result from pharmacokinetic drug-drug interactions and support the potential utility of non-imidazole H3R antagonists in treatment of cognitive impairment in schizophrenia without increased risk of increased EPS in patients.

Topics: Animals; Antipsychotic Agents; Benzofurans; Brain Chemistry; Cataplexy; Cytochrome P-450 Enzyme System; Drug Combinations; Drug Synergism; Haloperidol; Histamine; Histamine Antagonists; Imidazoles; Ketoconazole; Male; Metabolic Clearance Rate; Piperidines; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Risperidone; Schizophrenia

Electroconvulsive therapy (ECT) is standard treatment of severe depression. The induction of a seizure is a core event in successful ECT. Although propofol is a frequently used anesthetic agent, one of its limitations is a reduction of seizure duration. No such effects have been reported regarding remifentanil, an ultrarapid-acting opioid that is used to induce and maintain anesthesia. The simultaneous administration of propofol and remifentanil may have similar safety and efficacy in terms of induction of anesthesia during ECT as propofol alone and significantly increase seizure duration.. Twenty-one ECT patients (10 men, 11 women, aged 24 to 81 years) were recruited. Muscle paralysis was achieved with succinylcholine (0.5-0.75 mg/kg intravenously [IV]). Unconsciousness was induced by either propofol (1 mg/kg IV) or propofol (0.5 mg/kg IV) + remifentanil (1 microg/kg) in a crossover format. ECT was administered according to established clinical protocols at the Sheba Medical Center, Israel. No changes in ECT current were permitted in the 2 protocols of each patient. Statistical analysis was based on paired t tests.. In all but 2 cases, seizure duration was significantly longer in the remifentanil group than in the control group (motor seizure 53.7 +/- 28.3 seconds vs. 29.5 +/- 10.9 seconds, t = 4.017, P = 0.0007; Electroencephalographic (EEG) seizures 60.8 +/- 25.1 seconds vs. 40.1 +/- 17.0 seconds, t = 3.971, P = 0.001). No significant differences were found in mean recovery time, post-treatment elevation in blood pressure, heart-beat, or oxygen saturation.. During anesthesia, the addition of remifentanil to propofol appears to be as effective as propofol alone with regard to anesthesia efficacy and cardiovascular function while significantly increasing seizure duration. Whether this discovery is of relevance to the clinical efficacy of ECT remains to be tested.

Topics: Adult; Aged; Aged, 80 and over; Anesthetics, Intravenous; Depressive Disorder, Major; Electroconvulsive Therapy; Female; Hemodynamics; Humans; Male; Middle Aged; Piperidines; Propofol; Remifentanil; Schizophrenia; Seizures; Time Factors

Previous studies suggest that long-term cannabis use causes cognitive impairment, including lack of motivation and impaired attention, conditions that also resemble core negative symptoms of schizophrenia. The anterior cingulate cortex (ACC) plays an important role in normal cognition, particularly in relation to motivation and attention. This could suggest that changes in the cannabinoid (CB) system might be present in the ACC of patients suffering schizophrenia. The present study examined the distribution and density of CB1 cannabinoid receptors in the left ACC taken postmortem from patients with schizophrenia (n=10) and matched control subjects (n=9). Radioligand binding of [3H]SR141716A, an antagonist that specifically targets CB1 receptors of the endogenous cannabinoid system, was examined on ACC sections using quantitative autoradiography. CB1 receptors had a homogeneous distribution among the layers of ACC. A significant 64% increase in [3H]SR141716A specific binding to CB1 receptors was found in the schizophrenia group as compared to the control group (mean+/-S.E.M.: 46.15+/-6.22 versus 28.02+/-4.20 fmol/mg estimated tissue equivalents; p=0.03). The present results support the suggestion that changes in the endogenous cannabinoid system in the ACC may be involved in the pathology of schizophrenia particularly in relation to negative symptoms.

Topics: Adult; Aged; Analysis of Variance; Autoradiography; Female; Gyrus Cinguli; Humans; Male; Middle Aged; Piperidines; Postmortem Changes; Pyrazoles; Radioligand Assay; Receptor, Cannabinoid, CB1; Rimonabant; Schizophrenia

The Carlsson research group has developed a series of compounds capable of stabilising the dopamine system without inducing the deleterious hypodopaminergia that encumbers the currently used antipsychotic drugs. In the present study one of these dopaminergic stabilisers, ACR16, was tested in a mouse model for cognitive deficits of schizophrenia and autism. Since we believe that hypoglutamatergia is a key element in both schizophrenia and autism we used mice rendered hypoglutamatergic by treatment with the N-methyl-D-aspartate (NMDA) antagonist MK-801. MK-801 causes both hyperactivity and a behavioural primitivization. ACR16 attenuated the MK-801-induced hyperactivity and, in addition, caused a marked improvement of behavioural quality with a movement pattern approaching that of control animals. Since we believe that the impoverishment of the behavioural repertoire caused by MK-801 may correspond to the cognitive deficits seen in schizophrenia and autism, these results suggest that ACR16 may improve cognitive status in these disorders.

Topics: Animals; Autistic Disorder; Behavior, Animal; Cognition; Dizocilpine Maleate; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Glutamic Acid; Grooming; Haloperidol; Hyperkinesis; Male; Mice; Motor Activity; Piperidines; Schizophrenia

The antipsychotic efficacy of AD-5423, which has the properties of both a serotonin 5-HT(2) and a dopamine D(2) receptor antagonist, was evaluated using animal models of schizophrenia. Sensitization to phencyclidine (PCP)-induced hyperlocomotion is considered a model of the positive symptoms of schizophrenia, and was significantly antagonized by AD-5423 and haloperidol. The PCP-induced enhancement of immobility induced by the forced swimming test, a model of the negative symptoms of schizophrenia, was attenuated by AD-5423 but not by haloperidol. Since this attenuated effect of AD-5423 was antagonized by DOI, a serotonin 5-HT(2) receptor agonist, it is postulated to be mediated by serotonin 5-HT(2) receptors. These findings suggest that AD-5423 would be clinically effective against both the positive and negative symptoms of schizophrenia.

Topics: Animals; Disease Models, Animal; Immobilization; Male; Mice; Motor Activity; Phencyclidine; Piperazines; Piperidines; Schizophrenia

Topics: Aged; Alzheimer Disease; Antipsychotic Agents; Awareness; Cholinesterase Inhibitors; Delusions; Depressive Disorder; Donepezil; Female; Humans; Indans; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology; Sick Role

Latent inhibition (LI) refers to retarded conditioning to a stimulus as a consequence of its inconsequential preexposure. Amphetamine-induced disruption of LI and its potentiation by antipsychotic drugs (APDs) in the adult rat are well-established models of schizophrenia and antipsychotic drug action, respectively. It is not clear whether LI can be similarly modulated at prepubertal age.. In view of the notion that schizophrenia is a neurodevelopmental disorder whose overt expression depends on postpubertal brain maturational processes, we investigated whether several manipulations known to modulate LI in adult rats, including systemic administration of amphetamine and the atypical APD clozapine, are capable of producing the same effects in prepubertal (35-day-old) rats.. LI was measured in a thirst motivated conditioned emotional response (CER) procedure in which rats received 10 or 40 tone preexposures followed by 2 or 5 tone-footshock pairings.. Like in adults, LI was present with 40 preexposures and 2 conditioning trials. In contrast to findings in adults, LI was resistant to disruption by amphetamine at a dose (1 mg/kg) that significantly increased locomotor activity, as well as by reducing the number of preexposures to ten, increasing the number of conditioning trials to five, or changing the context between preexposure and conditioning. Clozapine (5 mg/kg) and the selective 5HT2A antagonist M100907 (0.3 mg/kg) administered in conditioning were without an effect on "persistent" LI with extended conditioning, but were capable of disrupting LI when administered in the preexposure stage, as found in adults.. The results point to functionality within brain systems regulating LI acquisition but not those regulating LI expression in periadolescent rats, further suggesting that postpubertal maturation of the latter systems may underlie schizophrenia-mimicking LI disruption reported in adult rats following perinatal manipulations and possibly disrupted LI observed in schizophrenia.

Topics: Aging; Amphetamine; Animals; Antipsychotic Agents; Behavior, Animal; Central Nervous System Stimulants; Clozapine; Conditioning, Classical; Disease Models, Animal; Drinking Behavior; Fluorobenzenes; Male; Models, Neurological; Movement; Neural Inhibition; Piperidines; Rats; Rats, Wistar; Schizophrenia; Time Factors

Topics: Aged; Donepezil; Frontal Lobe; Humans; Indans; Male; Piperidines; Psychosurgery; Schizophrenia

Topics: Animals; Brain; Cognition Disorders; Dioxoles; Drug Industry; Humans; Piperidines; Receptors, AMPA; Schizophrenia

A case is reported of a 54-year-old female patient with schizophrenia and cognitive impairment. Her memory dysfunction improved following the addition of donepezil to quetiapine. The possible implications for future studies are reviewed.

Topics: Antipsychotic Agents; Chronic Disease; Dibenzothiazepines; Donepezil; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Indans; Mental Recall; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Quetiapine Fumarate; Retention, Psychology; Schizophrenia; Schizophrenic Psychology

Topics: Animals; Antipsychotic Agents; Dopamine D2 Receptor Antagonists; Humans; Mice; Piperidines; Schizophrenia

The 5-HT(7) receptor is targeted by several new antipsychotics such as clozapine and risperidone. We studied the effect of R-(+)-1-(toluene-3-sulfonyl)-2-[2-(4-methylpiperidin-1-yl)ethyl]-pyrrolidine (SB-258741), a specific 5-HT(7) receptor antagonist, in three models for positive symptoms, D-amphetamine-induced hyperactivity and D-amphetamine- and phencyclidine (PCP)-disrupted prepulse inhibition (PPI) in rats, with the aim of investigating the role of this receptor in the clinical effect of antipsychotics. We also tested this compound in a model for negative symptoms, PCP-disrupted social interaction (SIT) in rats. Induction of side effects by this compound was evaluated by testing its potency to reduce spontaneous motility and to induce catalepsy in rats. The effect of SB-258741 was compared to risperidone in all models. This study showed that SB-258741 had no beneficial effect on PCP-disrupted SIT. SB-258741 did not reverse D-amphetamine-disrupted PPI; however, it dose-dependently normalised PCP-disrupted PPI. SB-258741 antagonised D-amphetamine-induced hyperactivity but reduced motility of rats at similar doses. Thus, this specific 5-HT(7) receptor antagonist brought a clear positive outcome in only one model for positive symptoms of schizophrenia and had no beneficial effect in the model for negative symptoms. Consequently, it is clear that SB-258741 affects the PPI phenomenon but is not expected to have an antipsychotic effect on its own in clinic.

Topics: Animals; Antipsychotic Agents; Catalepsy; Central Nervous System Stimulants; Dextroamphetamine; Dose-Response Relationship, Drug; Male; Motor Activity; Piperidines; Pyrrolidines; Rats; Rats, Wistar; Receptors, Serotonin; Reflex, Startle; Risperidone; Schizophrenia; Serotonin Antagonists; Social Behavior; Tosyl Compounds

Topics: Aged; Antiparkinson Agents; Antipsychotic Agents; Comorbidity; Dementia; Donepezil; Drug Therapy, Combination; Female; Humans; Indans; Mental Status Schedule; Middle Aged; Nootropic Agents; Parkinson Disease; Piperidines; Psychiatric Status Rating Scales; Risperidone; Schizophrenia

Previous research has suggested that serotonin 5-HT(2A) receptors modulate the functioning of the mesocortical dopamine (DA) pathway. However, the specific role of 5-HT(2A) receptors localized within the medial prefrontal cortex (mPFC) is not known. The present study employed in vivo microdialysis to examine the role of this receptor in the modulation of basal and K(+)-stimulated (Ca(2+)-dependent) DA release. The selective 5-HT(2A) antagonist M100,907 was infused directly into the mPFC of conscious rats. This resulted in a concentration-dependent blockade of K(+)-stimulated DA release. Intracortical application of M100,907 also blocked increases in DA release produced by the systemic administration of the 5-HT(2A/2C) agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). These findings demonstrate that local 5-HT(2A) antagonism has an inhibitory effect on stimulated, Ca(2+)-dependent DA release. They suggest that cortical 5-HT(2A) receptors potentiate the phasic release of mesocortical DA.

Topics: Amphetamines; Animals; Brain Chemistry; Dopamine; Fluorobenzenes; Male; Microdialysis; Piperidines; Potassium; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Schizophrenia; Serotonin Antagonists; Serotonin Receptor Agonists

Dysfunction of monoamine neurotransmission seems to contribute to such pathopsychological states as depression, schizophrenia, and drug abuse. The present study examined the effects of the selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI) and antidepressant fluvoxamine on locomotor activity in rats following administration of the catecholamine reuptake inhibitor mazindol. Mazindol (1 mg/kg) did not alter locomotor activity; whereas, fluvoxamine (20 mg/kg) given alone induced a brief period of hypomotility. Hyperactivity was elicited in a dose-related manner when fluvoxamine (5-20 mg/kg) was combined with mazindol (1 mg/kg). The hyperactivity elicited by fluvoxamine (20 mg/kg) plus mazindol (1 mg/kg) was significantly attenuated by the 5-HT(2A) receptor antagonist M100907 (2 mg/kg) and potentiated by the 5-HT(2B/2C) receptor antagonist SB 206553 (2 mg/kg). Neither antagonist significantly altered basal activity. The hyperactivity evoked by the combination of fluvoxamine and mazindol seems to be mediated in part by 5-HT(2A) receptors; whereas, 5-HT(2B/2C) receptors may serve to limit this effect. Thus, the balance of activation between 5-HT(2A) and 5-HT(2B/2C) receptors seems to contribute to the expression of locomotor hyperactivity evoked via combination of a 5-HT and a catecholamine reuptake inhibitor. A disruption in this balance may contribute to the expression of affective disorders, schizophrenia, and drug abuse.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Biogenic Monoamines; Catecholamines; Depression; Dopamine; Drug Synergism; Fluorobenzenes; Fluvoxamine; Indoles; Male; Mazindol; Motor Activity; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2B; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Serotonin; Substance-Related Disorders

Topics: Adult; Aged; Antipsychotic Agents; Cholinesterase Inhibitors; Donepezil; Drug Administration Schedule; Dyskinesia, Drug-Induced; Humans; Indans; Male; Middle Aged; Piperidines; Psychotic Disorders; Schizophrenia; Treatment Outcome

Atypical antipsychotic drugs are thought to show a high degree of 5-HT2A receptor blockade, which may prevent the emergence of extrapyramidal symptoms.. 5-HT2A binding was estimated using 123I-5-I-R91150 and single photon emission tomography (SPET) in six schizophrenic subjects treated with quetiapine at a mean (+/-SD) daily dose of 350+/-123 mg for at least 5 weeks and a matched sample of six healthy volunteers. Clinical and side-effect ratings were performed at baseline and at the time of SPET scanning. The reference region approach was used to define a 5-HT2A binding index in the frontal and temporal cortex.. Quetiapine treatment resulted in a significant decline in 5-HT2A receptor availability in the frontal cortex (mean 0.98+/-0.09) relative to healthy volunteers (mean 1.33+/-0.16). All patients showed improvements in clinical symptom or side-effect ratings. The mean frontal cortex:cerebellum ratio after quetiapine treatment was significantly negatively correlated with reduction in the Abnormal Involuntary Rating scale and Simpson-Angus scores (P<0.05 Bonferroni corrected), but not with the reduction in the scores from the scale for the assessment of positive symptoms, the scale for the assessment of negative symptoms, the Montgomery-Asberg depression rating scale or patient age.. Quetiapine treatment results in significant in vivo blockade of cortical 5-HT2A, similar to other atypical antipsychotic drugs. This effect may contribute to its placebo level extrapyramidal side-effect profile.

Topics: Adult; Dibenzothiazepines; Female; Frontal Lobe; Humans; Iodine Radioisotopes; Male; Piperidines; Prospective Studies; Quetiapine Fumarate; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Receptors, Serotonin; Schizophrenia; Serotonin Antagonists; Tomography, Emission-Computed, Single-Photon

To assess the clinical and cognitive effects of adding donepezil, a reversible acetylcholinesterase inhibitor, to the risperidone treatment of a high functioning stable out-patient with schizophrenia.. Case study using an experimental ABAB design. Assessments were completed objectively by standardized neuropsychological tests and clinical rating scales and subjectively with visual analogue scales.. Strong improvements attributable to donepezil were found for verbal fluency and the patient's subjective response. No adverse changes were noted in psychiatric symptoms or side effects.. Cholinergic enhancement as an adjunctive treatment in schizophrenia should be explored in larger controlled trials.

Topics: Adult; Antipsychotic Agents; Cholinesterase Inhibitors; Cognition; Donepezil; Drug Therapy, Combination; Humans; Indans; Male; Piperidines; Risperidone; Schizophrenia; Treatment Outcome

Tardive dyskinesia (TD) remains a significant clinical problem for which there is no uniformly effective treatment. Earlier trials with acetylcholine precursors may have been disappointing because of underlying damage to striatal cholinergic neurons in patients with TD. In contrast, new cholinesterase inhibitors, developed for the treatment of dementia, may improve TD by directly increasing cholinergic synaptic transmission.. We conducted an 8-week open-label trial of donepezil in the treatment of TD. Ten patients with schizophrenia or schizoaffective disorder who received stable doses of antipsychotics and met DSM-IV criteria for TD were treated with donepezil, 5 to 10 mg/day, for 6 weeks after a 2-week baseline period. Changes in total Abnormal Involuntary Movement Scale (AIMS) scores measured every 2 weeks were assessed for significance. Patients were also assessed using the Brief Psychiatric Rating Scale, the Mini-Mental State Examination, the Barnes Akathisia Scale, and the Simpson-Angus Scale.. Total AIMS scores decreased significantly (p = .0009), with no changes in other measures. Nine patients showed a positive response. Improvement was greatest in orofacial and upper extremity movements. No significant interactions were noted between the total AIMS scores and age (p > .29), duration of TD (p > .38), or duration of antipsychotic treatment (p > .14).. Donepezil appeared to be effective in suppressing TD in this pilot study. However, placebo-controlled, double-blind studies are necessary before donepezil can be recommended as a treatment for TD.

Topics: Adult; Aged; Antipsychotic Agents; Donepezil; Dose-Response Relationship, Drug; Drug Administration Schedule; Dyskinesia, Drug-Induced; Female; Humans; Indans; Male; Mental Status Schedule; Middle Aged; Neurologic Examination; Pilot Projects; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia

Topics: Adult; Antipsychotic Agents; Cerebral Cortex; Dibenzothiazepines; Humans; Iodine Radioisotopes; Male; Piperidines; Quetiapine Fumarate; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Schizophrenia; Tomography, Emission-Computed, Single-Photon

Saturation analyses of [3H]L-689,560, [3H]CGP 39653 and NMDA-specific [3H]ifenprodil binding revealed an equivalent increase (0.7 pmol/mg) in the number of [3H]L-689,560 and [3H]ifenprodil binding sites in superior temporal cortex (BA22) from drug-treated chronic schizophrenic patients and control subjects. No differences were observed between control and schizophrenic subjects for [3H]CGP 39653 binding in BA22, or for any of the radioligands binding to pre-motor cortex (BA6). Since [3H]L-689,560, [3H]CGP 39653 and [3H]ifenprodil label the glycine, glutamate and ifenprodil sites of the NMDA receptor complex, which are associated with NR1, NR1/NR2A and NR1/NR2B subunits respectively, our findings suggest that NR2B-containing receptors are selectively up-regulated in superior temporal cortex in schizophrenia.

Topics: 2-Amino-5-phosphonovalerate; Aminoquinolines; Binding Sites; Cadaver; Excitatory Amino Acid Antagonists; Humans; Isomerism; Piperidines; Receptors, N-Methyl-D-Aspartate; Reference Values; Schizophrenia; Temporal Lobe; Up-Regulation

Previous studies have shown D2-like dopamine receptor involvement in the regulation of phospholipid methylation (PLM), while others have documented impaired methionine and folate metabolism in schizophrenia. Utilizing [14C]formate labeling in cultured neuroblastoma cell lines, we now show that D4 dopamine receptors (D4R) mediate the stimulatory effect of dopamine (DA) on PLM. The effect of DA was potently blocked by highly D4R-selective antagonists and stimulated by the D4R-selective agonist CP-226269. DA-stimulated PLM was dependent upon the activity of methionine cycle enzymes, but DA failed to increase PLM in [3H]methionine labeling studies, indicating that a methionine residue in the D4R might be involved in mediating PLM. A direct role for MET313, located on transmembrane helix No. 6 immediately adjacent to phospholipid headgroups, was further suggested from adenosylation, site-directed mutagenesis and GTP-binding results. A comparison of PLM in lymphocytes from schizophrenia patients vs control samples showed a four-fold lower activity in the schizophrenia group. These findings reveal a novel mechanism by which the D4R can regulate membrane composition. Abnormalities in D4R-mediated PLM may be important in psychiatric illnesses such as schizophrenia.

Topics: Amino Acid Sequence; Aminopyridines; Animals; Benzazepines; Binding Sites; Carbon Radioisotopes; CHO Cells; Clozapine; Cricetinae; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Formates; Guanosine 5'-O-(3-Thiotriphosphate); Humans; Methionine; Mutagenesis, Site-Directed; Neuroblastoma; Phospholipids; Phosphorylation; Piperidines; Psychotic Disorders; Pyridines; Pyrroles; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D4; Recombinant Proteins; S-Adenosylmethionine; Salicylamides; Schizophrenia; Transfection; Tumor Cells, Cultured

EMD 57445 (panamesine) is a high affinity sigma ligand with the profile of an atypical antipsychotic in animal studies. It has been reported recently to have antipsychotic activity in schizophrenia. However, its metabolite, EMD 59983, binds also to D(2) and D(3) dopamine (DA) receptors.. The aim of this study was to test, using single photon emission computed tomography (SPECT) and [(123)I]iodobenzamide (IBZM) as the radiotracer, whether EMD 59983 would pass the blood-brain barrier and to what extent it would contribute to the effects of EMD 57445 in schizophrenia.. Two IBZM SPECT-scans were performed in five neuroleptic-free schizophrenic patients (DSM IV), one before and one after treatment with 60 mg panamesine daily for a treatment duration of 12-26 days.. A high occupancy of striatal D(2)-like DA receptors similar to that induced by typical neuroleptics was observed in all patients treated with EMD 57445.. Our results suggest that a possible antipsychotic activity of EMD 57445 in schizophrenia is not necessarily attributable to its affinity for sigma receptors, but could be simply due to the potent antidopaminergic effects of EMD 59983, its main metabolite.

Topics: Adult; Antipsychotic Agents; Benzamides; Blood-Brain Barrier; Corpus Striatum; Female; Humans; Male; Middle Aged; Oxazoles; Piperidines; Pyrimidines; Pyrrolidines; Receptors, Dopamine D2; Receptors, sigma; Schizophrenia; Tomography, Emission-Computed, Single-Photon

Serotonergic 5-HT2A receptors are of central interest in the complex pathophysiology of schizophrenia. These receptors have also been proposed as putative targets for atypical antipsychotic drugs. Suitable radioligands for 5-HT2A receptors are required to evaluate this hypothesis in vivo with PET. MDL 100,907 is a highly selective 5-HT2A receptor antagonist that is currently being developed as a potential antipsychotic drug. We have previously reported on the preparation of [11C]MDL 100,907 and initial characterization of [11C]MDL 100,907 binding in the monkey brain. In this preliminary PET study, the regional distribution and binding kinetics of [11C]MDL 100,907 were examined in healthy men.. A PET examination was performed in each of three subjects after intravenous injection of [11C]MDL 100,907. The metabolite-corrected arterial input function was used in a kinetic analysis according to the standard three-compartment model.. The highest radioactivity concentration was observed in the neocortex, whereas radioactivity was lower in the cerebellum, pons, thalamus, striatum and white matter. The binding potential (BP) in the neocortical regions was 4-6 times higher, whereas BP in the striatum was slightly higher than that in the cerebellum, demonstrating a regional distribution in good agreement with 5-HT2A receptor densities measured in vitro. The BP in the cerebellum was small but not negligible.. This preliminary study suggests that [11C]MDL 100,907 is a suitable PET radioligand for studies on 5-HT2A receptors in man. The high selectivity of MDL 100,907 represents a major advantage as compared to presently available radioligands with poor selectivity. Thus, [11C]MDL 100,907 is recommended in the future for PET studies in healthy subjects and schizophrenic patients, including the determination of drug-induced 5-HT2A receptor occupancy.

Topics: Adult; Brain; Carbon Radioisotopes; Fluorobenzenes; Humans; Male; Piperidines; Radiopharmaceuticals; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Schizophrenia; Serotonin Antagonists; Tomography, Emission-Computed

5-HT2A receptor antagonism may be crucial to the action of atypical antipsychotics. Previous work has related 5-HT2A receptor blockade to clinical efficacy and protection from extrapyramidal side-effects.. We developed a SPET imaging protocol for assessing 5-HT2A receptor binding using the selective ligand 123I-5-I-R91150. Six healthy volunteers, five clozapine- and five risperidone-treated subjects with DSM-IV schizophrenia were studied. Multi-slice SPET was performed on each subject.. Cortex:cerebellum ratios were significantly lower in both clozapine- and risperidone-treated subjects compared with the healthy volunteers in all cortical regions. There was no difference in occupancy between the two drug-treated groups. No correlation was found between the percentage change in the Global Assessment Scale (GAS) and 5-HT2A receptor binding indices in the drug-treated groups.. Clozapine and risperidone potently block 5-HT2A receptors in vivo. The lack of relationship between receptor binding indices and change in GAS suggests that 5-HT2A receptor blockade may be unrelated to clinical improvement. Future studies will substantiate this finding by studying 5-HT2A receptor binding in large groups of patients treated with both typical and novel atypical antipsychotics.

Topics: Adult; Basal Ganglia Diseases; Clozapine; Female; Humans; Iodine Radioisotopes; Male; Piperidines; Receptors, Serotonin; Risperidone; Schizophrenia; Serotonin Antagonists; Tomography, Emission-Computed, Single-Photon

1. The case of a schizophrenic patient taking bromperidol (18 mg/day), whose psychotic symptoms deteriorated markedly after addition of cisapride (7.5 mg/day), is presented. 2. Retrospective determination of drug concentrations revealed that plasma concentrations of bromperidol and its reduced metabolite were increased after cisapride addition. 3. The present study thus suggests that there is an interaction between cisapride and bromperidol.

Topics: Adult; Cisapride; Drug Interactions; Haloperidol; Humans; Male; Piperidines; Schizophrenia; Sympathomimetics

The apparent antipsychotic action of the selective 5-HT2a receptor antagonist M100907 in MK-801-treated NMRI mice was shown to be markedly counteracted by the 5-HT2a/2c receptor antagonist ritanserin. The mechanism of action and potential implications are discussed.

Topics: Animals; Antipsychotic Agents; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Fluorobenzenes; Male; Mice; Mice, Inbred Strains; Motor Activity; Piperidines; Ritanserin; Schizophrenia; Serotonin Antagonists

By the use of positron emission tomography (PET), high central dopamine D2 receptor occupancy (70 to 90%) has been demonstrated in patients treated with conventional neuroleptics. In patients treated with the atypical antipsychotic clozapine, the D2 occupancy was low (20 to 67%). The effects of clozapine may thus be mediated by a mechanism distinct from D2 occupancy. The observation that low doses of clozapine (125 to 175 mg daily) induced more than 80% (5-hydroxytryptamine) 5-HT2 occupancy supports the view that 5-HT2 antagonism may be related to the atypical effects of clozapine. Risperidone is a new antipsychotic drug with high affinity in vitro for both central 5-HT2 and D2 receptors. In this study, we determined the D2 and 5-HT2 occupancy induced by clinical treatment with risperidone. Four patients with acute exacerbation of schizophrenia were examined by PET after 4 weeks of treatment with risperidone, 6 mg daily. The D2 occupancy in the striatum was 75 to 80%. The 5-HT2 occupancy in the neocortex was 78 to 88%. This study confirms that, in patients with schizophrenia, treatment with risperidone induces a high D2 and 5-HT2 occupancy. Risperidone is, accordingly, a suitable drug for the examination of the clinical benefit of combined serotonin and dopamine antagonism.

Topics: Adult; Antipsychotic Agents; Binding Sites; Brain; Female; Humans; Isoxazoles; Male; Middle Aged; Piperidines; Receptors, Dopamine D2; Receptors, Serotonin; Risperidone; Schizophrenia; Tomography, Emission-Computed

Topics: Antipsychotic Agents; Clozapine; Humans; Isoxazoles; Piperidines; Risperidone; Schizophrenia

Topics: Antipsychotic Agents; Attention Deficit Disorder with Hyperactivity; Child; Drug Therapy, Combination; Humans; Isoxazoles; Male; Methylphenidate; Piperidines; Risperidone; Schizophrenia; Treatment Outcome

Topics: Antipsychotic Agents; Confusion; Creatine Kinase; Drug Therapy, Combination; Fever; Humans; Isoxazoles; Lithium Carbonate; Neuroleptic Malignant Syndrome; Piperidines; Risperidone; Schizophrenia

Topics: Akathisia, Drug-Induced; Antipsychotic Agents; Anxiety; Benzodiazepines; Confusion; Female; Humans; Isoxazoles; Middle Aged; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology; Sleep Initiation and Maintenance Disorders; Substance Withdrawal Syndrome

Topics: Antipsychotic Agents; Clonazepam; Clozapine; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoxazoles; Lorazepam; Piperidines; Risperidone; Schizophrenia; Substance Withdrawal Syndrome

Topics: Antipsychotic Agents; Female; Humans; Hyperprolactinemia; Isoxazoles; Piperidines; Premenopause; Prolactin; Risperidone; Schizophrenia

Topics: Antipsychotic Agents; Cost-Benefit Analysis; Drug Prescriptions; Financing, Government; Health Care Rationing; Humans; Isoxazoles; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology; Virginia

Topics: Dopamine Antagonists; Humans; Isoxazoles; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology

After 9 days of risperidone therapy (2-6 mg/day), a 24-year-old schizophrenic female patient developed a leucopenia with neutropenia < 1000/mm3. A few days after starting the neuroleptic treatment, she suffered from a cold, without fever. All immunological tests performed yielded negative results except for influenza B virus. The cessation of the risperidone therapy was followed within 48 h by a normalisation of the WBC differential count. Therefore, in the absence of a rechallenge with risperidone for ethical reasons, it cannot be excluded that risperidone represents at least a partial cause of the observed neutropenia.

Topics: Adult; Antipsychotic Agents; Cold Temperature; Female; Humans; Influenza, Human; Isoxazoles; Neutropenia; Piperidines; Risperidone; Schizophrenia

Topics: Adult; Antipsychotic Agents; Humans; Isoxazoles; Male; Piperidines; Risperidone; Schizophrenia; Treatment Outcome

In September 1994, the National Institute of Mental Health convened a group of scientists to discuss the clinical effects of rapid clozapine discontinuation, especially in light of the introduction of risperidone for the treatment of schizophrenia. Despite concern over recent reports of clinical deterioration (psychotic exacerbations, somatic withdrawal symptoms, and extrapyramidal side effects) in a few patients abruptly discontinued from clozapine, there is currently insufficient information to determine the magnitude of the problems associated with clozapine withdrawal. However, clinicians are reminded that the withdrawal schedule for clozapine indicates a gradual tapering schedule (unless the patient is experiencing severe side effects); that switching patients from clozapine to risperidone does not mean that such tapering is unnecessary; and that the use of risperidone may not produce all of the same effects as clozapine in some treatment-refractory patients.

Topics: Antipsychotic Agents; Clozapine; Drug Administration Schedule; Humans; Isoxazoles; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology; Substance Withdrawal Syndrome; United States; United States Food and Drug Administration

Topics: Adult; Antipsychotic Agents; Clozapine; Dystonia; Humans; Isoxazoles; Male; Piperidines; Risperidone; Schizophrenia

Topics: Antipsychotic Agents; Drug Therapy, Combination; Humans; Isoxazoles; Piperidines; Risperidone; Schizophrenia; Thioridazine

Risperidone is a recently introduced neuroleptic distinguished by a decreased incidence of extrapyramidal side effects (EPS). The mechanism of its low EPS is unclear. Since it has been shown that EPS is related to the level of D2 receptor occupancy, we studied nine patients receiving 2-6 mg/day of risperidone using [11C]-raclopride PET scans in order to determine the in vivo D2 receptor binding characteristics of risperidone. The mean level of receptor occupancy was 66% at 2 mg; 73% at 4 mg; and 79% at 6 mg. Three patients, those with the highest receptor occupancies, exhibited mild EPS, though none required anitparkinsonian medications. Our results suggest that at doses of 4-6 mg the in vivo D2 receptor occupancy of risperidone is similar to that of typical neuroleptics and higher than that of clozapine. This would suggest that the EPS benefits of risperidone cannot be explained by a low D2 binding but may be related to its high 5-HT2 affinity. However, the emergence of EPS at higher levels of D2 receptor occupancy, in this study and in previous clinical trials, would suggest that risperidone's high 5-HT2 affinity provides only a relative protection from EPS. And once the D2 occupancy exceeds a certain threshold this 'relative' 5-HT2-mediated protection from EPS may be lost.

Topics: Adult; Akathisia, Drug-Induced; Basal Ganglia Diseases; Humans; Isoxazoles; Male; Piperidines; Receptors, Dopamine D2; Risperidone; Schizophrenia; Tomography, Emission-Computed

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Isoxazoles; Male; Piperidines; Recurrence; Risperidone; Schizophrenia; Schizophrenia, Paranoid

Topics: Antipsychotic Agents; Chronic Disease; Clinical Trials as Topic; Humans; Isoxazoles; Piperidines; Risperidone; Schizophrenia

Topics: Adult; Clinical Trials as Topic; Humans; Isoxazoles; Multicenter Studies as Topic; Piperidines; Placebos; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

In 1965 the first study of this series reported different effects of neuroleptics in rats, supporting clinical differences. At the one end, haloperidol presented as a potent and specific antagonist of the psychostimulants amphetamine and apomorphine. Haloperidol-like neuroleptics have marked effects on psychomotor agitation, delusions and hallucinations and bind with high affinity to dopamine-D2 receptors. Pipamperone, at the other end, presented with weak "dopamine" antagonism and more striking tryptamine antagonism. Pipamperone is known to improve disturbed sleep, social withdrawal and other symptoms of chronic schizophrenia in the relative absence of extrapyramidal symptoms. These effects have been attributed to central serotonin-S2 antagonism, on the basis of the clinical effects of ritanserin. As shown by the present analysis of relative tryptamine versus apomorphine antagonism of 57 neuroleptics, in comparison to relative S2 vs. D2 binding, there is a continuity in the series. About 30% of the compounds can be considered to act primarily as serotonin antagonists, but few are markedly more potent than pipamperone. In amphetamine-challenged rats pipamperone-like activity is reflected in preferential inhibition of the excessive oxygen consumption rather than of agitation. Risperidone inhibits oxygen consumption (0.016 mg/kg) at the same dose as haloperidol inhibits agitation. Other low-dose effects of risperidone include reversal of amphetamine-induced withdrawal, antagonism of agitation induced by a sequential tryptamine and apomorphine challenge and LSD-antagonism. In dogs, the antiemetic activity of risperidone is characterized by high oral effectiveness which lasts one day and agrees with pharmacokinetic data when allowance is made for the active metabolite 9-hydroxyrisperidone.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amphetamine; Animals; Antipsychotic Agents; Apomorphine; Butyrophenones; Dogs; Dopamine D2 Receptor Antagonists; Haloperidol; Humans; In Vitro Techniques; Isoxazoles; Lysergic Acid Diethylamide; Motor Activity; Neostriatum; Oxygen Consumption; Piperidines; Rats; Risperidone; Schizophrenia; Serotonin Antagonists; Species Specificity; Tryptamines

Topics: Antipsychotic Agents; Humans; Isoxazoles; Piperidines; Risperidone; Schizophrenia

Topics: Antipsychotic Agents; Humans; Isoxazoles; Piperidines; Risperidone; Schizophrenia

Topics: Adult; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Dystonia; Humans; Isoxazoles; Male; Neurologic Examination; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology; Substance Withdrawal Syndrome

Topics: Antipsychotic Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Approval; Humans; Isoxazoles; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology

Topics: Antipsychotic Agents; Humans; Isoxazoles; Piperidines; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology

We tested risperidone and ritanserin, serotonin-S2 receptor antagonists, for their effects on in vitro polyclonal IgG and IgM synthesis by human peripheral blood mononuclear cells (PBMC) stimulated with pokeweed mitogen (PWM). On the basis of the previously reported effect on immune function in vivo risperidone in this study was tested in three different groups of PBMC: healthy donors as well as schizophrenic patients before risperidone treatment and schizophrenic patients after the treatment with risperidone. IgG and IgM production after 7 days of culture was measured by ELISA. Risperidone decreased IgG synthesis (p < 0.05) in PBMC of healthy subjects only at the highest concentration (10(-6) M) and IgG synthesis enhanced by 5-HT was antagonized by risperidone. This effect, however, was not statistically significant. Neither risperidone nor ritanserin, in the concentration range 10(-8)-10(-6) M, affected IgM synthesis in this group. Risperidone did not affect the production of IgG and IgM by PBMC of schizophrenic subjects in PWM-stimulated cultures both before and after risperidone therapy. The spontaneous production of IgG in PBMC of schizophrenic subjects before therapy was decreased (p < 0.05) at concentrations 10(-6)-10(-7) M of risperidone. We conclude that risperidone and ritanserin did not increase polyclonal IgG and IgM synthesis in vitro in contrast to neuroleptics currently used in clinical practice.

Topics: Antipsychotic Agents; B-Lymphocytes; Enzyme-Linked Immunosorbent Assay; Humans; Immunoglobulin G; Immunoglobulin M; In Vitro Techniques; Isoxazoles; Monocytes; Piperidines; Pokeweed Mitogens; Risperidone; Ritanserin; Schizophrenia

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Humans; Isoxazoles; Piperidines; Receptors, Dopamine; Risperidone; Schizophrenia; Treatment Outcome

Risperidone is rapidly and completely absorbed after oral administration; less than 1% is excreted unchanged in the feces. The principal metabolite was found to be 9-hydroxyrisperidone. Hydroxylation of risperidone is subject to the same genetic polymorphism as debrisoquine and dextromethorphan. In poor metabolizers the half-life of risperidone was about 19 hours compared with about 3 hours in extensive metabolizers. However, becuase the pharmacology of 9-hydroxyrisperidone is very similar to that of risperidone, the half-life for the "active fraction" (risperidone +9-hydroxyrisperidone) was found to be approximately 20 hours in extensive and poor metabolizers. We found that risperidone exhibited linear elimination kinetics and that steady state was reached within 1 day for risperidone and within 5 days for the active fraction.

Topics: Aged; Animals; Antipsychotic Agents; Biotransformation; Dogs; Half-Life; Humans; Isoxazoles; Liver Cirrhosis; Male; Paliperidone Palmitate; Piperidines; Pyrimidines; Rats; Reference Values; Renal Insufficiency; Risperidone; Schizophrenia

Topics: Antipsychotic Agents; Humans; Isoxazoles; Piperidines; Risperidone; Schizophrenia

Topics: Adult; Antipsychotic Agents; Drug Therapy, Combination; Fluvoxamine; Humans; Isoxazoles; Male; Obsessive-Compulsive Disorder; Piperidines; Receptors, Serotonin; Risperidone; Schizophrenia; Schizophrenic Psychology; Serotonin

Topics: Adolescent; Antipsychotic Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Hospitalization; Humans; Isoxazoles; Male; Piperidines; Psychotic Disorders; Risperidone; Schizophrenia; Schizophrenic Psychology

Topics: Adult; Antipsychotic Agents; Clonazepam; Depressive Disorder; Drug Therapy, Combination; Humans; Isoxazoles; Male; Patient Readmission; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology

Topics: Antipsychotic Agents; Delivery of Health Care; Health Services Accessibility; Humans; Isoxazoles; Piperidines; Risperidone; Schizophrenia

Topics: Adult; Ambulatory Care; Antipsychotic Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Isoxazoles; Male; Middle Aged; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology

In this study, we investigated whether risperidone, a serotonin-S2A (5-HT2A)/dopamine-D2 (D2)-receptor antagonist, inhibits phencyclidine (PCP)-induced stereotyped behaviors in comparison with haloperidol and ritanserin. Moreover, we also attempted to investigate the effects of these antipsychotics on the contents of dopamine, serotonin (5-HT) and their metabolites in rat striatum and frontal cortex. In rats, PCP (5 mg/kg, i.p.) caused hyperlocomotion and stereotyped behaviors, including sniffing, head-weaving, backpedalling and turning. Both resperidone (0.8-2.4 mg/kg, p.o.) and haloperidol (0.3-1.0 mg/kg, p.o.) inhibited these behaviors, except for backpedalling, in a dose-dependent manner. PCP (10 mg/kg, i.p.) produced hyperlocomotion and stereotyped behaviors, including rearing, sniffing head-twitch, backpedalling and turning. Risperidone (0.8-2.4 mg/kg, p.o.) inhibited both hyperlocomotion and PCP-induced behaviors, except for backpedalling, while ritanserin (3-10 mg/kg, p.o.) inhibited only the head-twitch. These results suggest that risperidone may have an antipsychotic effect on schizophrenia as well as PCP psychosis in humans by exerting a mixed 5-HT2A/D2 antagonism. Neurochemically, the increasing effects of risperidone on the content of DOPAC and the ratio of DOPAC to dopamine in the striatum were lower than those of haloperidol. These findings may support the view that the extrapyramidal side effects of risperidone are lower than those of haloperidol in clinical situations.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Antipsychotic Agents; Chromatography, High Pressure Liquid; Corpus Striatum; Dopamine; Dose-Response Relationship, Drug; Frontal Lobe; Haloperidol; Homovanillic Acid; Hydroxyindoleacetic Acid; Injections, Intraperitoneal; Isoxazoles; Locomotion; Male; Phencyclidine; Piperidines; Random Allocation; Rats; Rats, Wistar; Risperidone; Ritanserin; Schizophrenia; Serotonin; Stereotyped Behavior

Topics: Antipsychotic Agents; Brain; Clozapine; Humans; Isoxazoles; Piperidines; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology

Topics: Adult; Antipsychotic Agents; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Female; Haloperidol; Humans; Isoxazoles; Neurologic Examination; Piperidines; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology

1. Clozapine and risperidone are revolutionary new neuroleptic drugs that appear to alleviate psychotic symptoms in many patients who are unresponsive to other neuroleptic medications. 2. Alleviation of negative symptoms, although beneficial in many ways, also may create fears, changes, and unknown challenges for both the patient and caregivers. 3. Thorough assessment and diligent community planning may assist patients in fulfilling the basic human need for love and belonging.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Humans; Isoxazoles; Male; Middle Aged; Nursing Assessment; Piperidines; Psychiatric Nursing; Risperidone; Schizophrenia; Socialization

Topics: Agranulocytosis; Anemia, Aplastic; Antipsychotic Agents; Clozapine; Drug Monitoring; Humans; Isoxazoles; Neutropenia; Piperidines; Remoxipride; Risperidone; Schizophrenia

Topics: Adult; Antipsychotic Agents; Benzamides; Brain; Brain Mapping; Contrast Media; Dopamine D2 Receptor Antagonists; Humans; Iodine Radioisotopes; Isoxazoles; Male; Piperidines; Psychiatric Status Rating Scales; Pyrrolidines; Receptors, Dopamine D2; Risperidone; Schizophrenia; Schizophrenic Psychology; Tomography, Emission-Computed, Single-Photon

Topics: Antipsychotic Agents; Female; Humans; Isoxazoles; Piperidines; Remoxipride; Risperidone; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Drug Costs; Humans; Isoxazoles; Piperidines; Risperidone; Schizophrenia

A highly sensitive high-performance liquid chromatography method with electrochemical detection for the determination of risperidone in plasma has been developed. Remoxipride is used as an internal standard. A simple one-step extraction with 25% methylene dichloride in pentane is used to isolate the drug from the plasma. This is followed by high-performance liquid chromatography analysis on a cyano column with electrochemical detection. Under the experimental conditions described here, commonly coadministered drugs and other antipsychotic drugs did not interfere with the analysis of either risperidone or the internal standard. Also, the available two metabolites of risperidone did not interfere in the assay. This method has sufficient sensitivity to quantitate risperidone accurately at 0.1 ng/mL, when 1 mL of plasma was used for the analysis, with a coefficient of variation of < 9%. This method has been successfully used in the determination of plasma levels of risperidone in schizophrenic patients treated with 4-, 6-, and 8-mg oral doses per day.

Topics: Antipsychotic Agents; Chromatography, High Pressure Liquid; Electrochemistry; Humans; Isoxazoles; Piperidines; Remoxipride; Risperidone; Schizophrenia

Risperidone is a new benzisoxazole derivative displaying a very potent serotonin antagonism and a potent dopamine antagonism in pharmacological studies. These properties suggest the hypothesis that risperidone may exert antipsychotic effects and be superior to classic neuroleptics in its beneficial effects on negative and affective symptoms and its low extrapyramidal side-effect propensity. In an open pilot study 13 patients suffering from acute schizophrenic psychosis were treated with risperidone within an individually adapted dose range from 1 to 10 mg per day. A good antipsychotic efficacy could be demonstrated in 6 of the 8 patients who completed the trial. Risperidone was very well tolerated. The substance possesses a low EPS-inducing profile. Future research has to test the suggested advantage of risperidone over other neuroleptic drugs and its performance in the treatment of chronic schizophrenic patients.

Topics: Acute Disease; Adult; Antipsychotic Agents; Chronic Disease; Female; Humans; Isoxazoles; Male; Middle Aged; Pilot Projects; Piperidines; Psychiatric Status Rating Scales; Risperidone; Schizophrenia

The effects of biperiden and piroheptine on the serum level of zotepine were studied in 15 schizophrenic and 6 mentally retarded in-patients. Neither of these anticholinergic drugs affected the serum level of zotepine nor caused significant side-effects. In the schizophrenics the total scores on the BPRS did not change significantly with either combination of drugs.

Topics: Adult; Antipsychotic Agents; Biperiden; Dibenzocycloheptenes; Dibenzothiepins; Drug Therapy, Combination; Female; Humans; Intellectual Disability; Male; Middle Aged; Piperidines; Pyrrolidines; Schizophrenia; Schizophrenic Psychology

It is generally assumed that anticholinergic drugs have no effects on schizophrenic symptomatology. A few studies, however, indicate that anticholinergic agents aggravate psychotic symptoms and antagonize therapeutic effects of neuroleptics in schizophrenic patients; more recently, some investigators have observed that these agents appear to benefit negative symptoms. In an effort to resolve this issue, we studied the effects of 2 days of treatment with biperiden on positive and negative symptoms in 15 medication-free schizophrenic patients. Positive symptoms increased significantly, while there was a trend toward a decrease in negative symptoms. The implications of these findings for the role of the cholinergic system in schizophrenia are discussed.

Topics: Adult; Biperiden; Brain; Female; Humans; Male; Piperidines; Psychiatric Status Rating Scales; Psychometrics; Receptors, Muscarinic; Schizophrenia; Schizophrenic Psychology

Topics: Adult; Aged; Dose-Response Relationship, Drug; Humans; Middle Aged; Piperidines; Ritanserin; Schizophrenia; Serotonin Antagonists

Topics: Adult; Aged; Alzheimer Disease; Arousal; Attention; Biperiden; Electroencephalography; Evoked Potentials, Auditory; Humans; Limbic System; Physostigmine; Piperidines; Reaction Time; Schizophrenia; Signal Processing, Computer-Assisted

Topics: Alpha Rhythm; Biperiden; Electroencephalography; Frontal Lobe; Haloperidol; Humans; Motor Activity; Parietal Lobe; Piperidines; Schizophrenia; Signal Processing, Computer-Assisted; Theta Rhythm

Topics: Adult; Antidepressive Agents; Antipsychotic Agents; Bipolar Disorder; Female; Humans; Imipramine; Male; Neuroleptic Malignant Syndrome; Penfluridol; Piperidines; Schizophrenia

In a schizophrenic patient, hypothermia was caused by combined treatment with zotepine, biperiden, and fluphenazine, although combined treatment with zotepine and biperiden had caused no side effects. Other side effects closely resembled those in neuroleptic malignant syndrome.

Topics: Adult; Biperiden; Dibenzothiepins; Drug Therapy, Combination; Fluphenazine; Humans; Hypothermia; Male; Neuroleptic Malignant Syndrome; Piperidines; Schizophrenia

In searching for reliable animal models of negative schizophrenic symptomatology, we considered the possibility that a deficient response to rewarding stimuli might be the basis for some features of the disease. Apomorphine (0.015 and 0.03 mg/kg) and 3-PPP (1 mg/kg) caused such a reward deficit when rats were shifted from continuous reinforcement to a fixed ratio (FR4) schedule of food delivery. Further experiments indicated that this effect could be accounted for by a decreased ability of secondary reinforcers to sustain responses, rather than by motor impairment, appetite loss, or reduced reward value of the food. If this deficit is due to decreased dopaminergic transmission produced by low doses of dopamine agonists, our model might suggest that some symptoms of schizophrenia (anhedonia for instance) are not incompatible with deficient dopaminergic transmission. Low to moderate doses of sulpiride, amisulpride, pimozide, and pipotiazine, but not fluphenazine, metoclopramide, haloperidol, thioridazine, and chlorpromazine, reversed the apomorphine-induced reward deficit. Although any extrapolation from animal data requires caution, it may be tentatively proposed that only some neuroleptics, at dosages insufficient to block dopamine transmission postsynaptically, can be effective in reducing negative schizophrenic symptoms.

Topics: Amisulpride; Animals; Antipsychotic Agents; Apomorphine; Disease Models, Animal; Male; Phenothiazines; Pimozide; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Reinforcement Schedule; Reinforcement, Psychology; Schizophrenia; Schizophrenic Psychology; Sulpiride

Topics: Antipsychotic Agents; Benzamides; Butyrophenones; Dibenzoxazepines; Humans; Phenothiazines; Piperidines; Schizophrenia; Thioxanthenes

Topics: Administration, Oral; Adult; Delayed-Action Preparations; Drug Administration Schedule; Humans; Penfluridol; Piperidines; Schizophrenia

Topics: Adult; Ambulatory Care; Female; Humans; Male; Penfluridol; Piperidines; Schizophrenia

It is well established that neuroleptic drugs are antagonists of brain dopamine receptors. The role of the reported increase in dopamine receptors (measured as 3H-spiperone binding sites) in post-mortem brain tissue from patients with schizophrenia in the aetiology of the disease is, however, unclear. We have found this increase only in chronically neuroleptic-treated patients, indicating that the increase is probably due to this neuroleptic treatment. Many neuroleptic drugs have a high affinity for a subgroup of 5-hydroxytryptamine receptors, which have also been implicated in schizophrenia. Using the specific ligand 3H-ketanserin, we find that certain neuroleptics have a higher affinity for these 5-HT2 receptors than for the dopamine D2 site. Although changes in these receptors have been reported in schizophrenic brain tissue we have been unable to find any difference in receptor density in cortical tissue from schizophrenics and control subjects.

Topics: Antipsychotic Agents; Cerebral Cortex; Humans; Ketanserin; Piperidines; Receptors, Serotonin; Schizophrenia; Spiperone; Substrate Specificity

Twelve healthy chronic schizophrenic patients were treated with the long-acting oral dopamine (DA) receptor blocker penfluridol (100 mg orally) for 6 weeks. Plasma prolactin (PRL) levels were measured during insulin-tolerance tests (ITT) performed at the end of the drug-free period (7-10 days) and during weeks 1 and 6 of penfluridol treatment. Simultaneous PRL and penfluridol plasma levels were determined just prior to, and at 8, 72 and 120 h after penfluridol administration during weeks 1, 5, and 6. During penfluridol treatment women (N = 4) had a greater increase in their maximal PRL increments after ITT as compared to the men (N = 8). Analyses of (peak) plasma penfluridol and PRL concentrations 8 h after penfluridol administration revealed a trend towards lower plasma penfluridol levels during weeks 5 and 6 and significantly higher PRL levels in women compared to men during weeks 1 (P less than 0.01), 5 (P less than 0.02), and 6 (P less than 0.02). The consistent sex-related differences in the PRL responses to DA blockade, and to insulin-induced hypoglycemia and in the penfluridol plasma levels in our study support the view that sex-related changes need to be considered not only in the hormonal responses to various pharmacological agents, but also in the assessment of the plasma levels of these drugs.

Topics: Adult; Female; Humans; Hypoglycemia; Insulin; Kinetics; Male; Middle Aged; Penfluridol; Piperidines; Prolactin; Receptors, Dopamine; Schizophrenia; Sex Factors

Topics: Adolescent; Adult; Aged; Child; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Penfluridol; Piperidines; Schizophrenia

Topics: Adolescent; Adult; Basal Ganglia Diseases; Double-Blind Method; Fluphenazine; Humans; Male; Middle Aged; Penfluridol; Piperidines; Schizophrenia

Twenty schizophrenic patients were treated for a year with long term neuroleptic Penfluridol to test its antipsychotic and re-socializing effect. They underwent a clinical follow up and an evaluation of psychosocial aspects was also performed by a psychiatric social worker. Their social behaviour and reinsertion to work and family were studied by the use of specially designed scales. Clinical improvement and significant changes in all of the studied aspects of social behaviour were observed after a year of treatment. Also a reduction of treatment abandonment and of frequency of relapse through family handling was detected. Finally a number of preliminary observations on family structure and dynamics as well as changes determined on it by the treatment of the psychotic patient are summarized.

Topics: Adolescent; Adult; Brief Psychiatric Rating Scale; Family; Female; Follow-Up Studies; Humans; Male; Penfluridol; Piperidines; Rehabilitation, Vocational; Schizophrenia; Social Adjustment; Socioeconomic Factors; Surveys and Questionnaires

Topics: Adult; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Penfluridol; Piperidines; Schizophrenia; Time Factors

Topics: Adult; Humans; Male; Penfluridol; Piperidines; Prolactin; Schizophrenia; Testosterone

Topics: Humans; Male; Penfluridol; Piperidines; Prolactin; Schizophrenia; Testosterone

Twenty chronic schizophrenic inpatients who were being treated with high doses of neuroleptics and of whom seven had extra-pyramidal symptoms in spite of anti-Parkinsonian therapy, were given oral domperidone (50 mg t.d.s. for 2 weeks) for the relief of chronic dyspepsia. The dyspepsia symptoms were markedly improved, no side effects were seen and, even at high doses, domperidone did not intensify the existing extra-pyramidal side effects of the neuroleptics or produce new ones.

Topics: Adult; Aged; Antiemetics; Antipsychotic Agents; Benzimidazoles; Drug Interactions; Dyspepsia; Humans; Middle Aged; Piperidines; Schizophrenia

Topics: Butyrophenones; Diazepam; Female; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Methoxyhydroxyphenylglycol; Paranoid Disorders; Piperidines; Prolactin; Schizophrenia; Therapeutic Equivalency; Thiothixene

The study reports about the intravenous application of Biperiden at patients with acute hypokinetic reaction suffering from schizophrenia of the paranoid-hallucinatory type. In all of the six cases examined a fast abolition of the stupor could be observed. The pathophysiological mechanisms deriving from our clinical experiences are discussed. Furthermore, a therapeutic procedure is suggested to treat acute schizophrenic stupor merely with drugs.

Topics: Acute Disease; Adolescent; Adult; Biperiden; Female; Humans; Male; Piperidines; Psychomotor Disorders; Schizophrenia

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Anxiety Disorders; Butyrophenones; Female; Humans; Male; Middle Aged; Piperidines; Psychotic Disorders; Schizophrenia

Twenty patients were treated with penfluridol and 21 with fluphenazine for a period of up to 1 year. Penfluridol, an oral neuroleptic administered weekly was as efficacious as fluphenazine administered twice daily and appeared to be superior to fluphenazine in improving emotional withdrawal and anergia. The low incidence of side effects and other signs of toxicity, coupled with an effective prophylactic activity, suggests that penfluridol is an important addition to our therapeutic armamentarium for the treatment of chronic schizophrenia.

Topics: Adult; Ambulatory Care; Chronic Disease; Female; Fluphenazine; Humans; Male; Middle Aged; Penfluridol; Piperidines; Schizophrenia

In a multicenter collaborative study, 28 newly readmitted schizophrenic patients, stabilized for one week on short-acting neuroleptic drugs, had their medication abruptly changed to penfluridol given once a week on an outpatient basis. The average dose required for maintenance was approximately 40 mg weekly. Analysis of BPRS evaluations carried out during the 16-week trial revealed a significant linear trend toward further improvement. Social functioning, as measured by the KAS questionnaire in the outpatient period of the trial, also revealed a significant linear trend toward improvement. Significant worsening was not found with any psychometric evaluation. Side effects, when observed, were neither frequent nor severe. Three laboratory and vital sign values showed significant changes: increase in BUN concentrations, decrease in pulse rate, and increase in body weight. The changes in weight and pulse appeared to be within relatively normal ranges, and the increase in BUN concentrations did not appear to be clinically significant. During the first part of a long-term study, penfluridol received a high degree of patient acceptability and is a welcome addition to the maintenance treatment of schizophrenia.

Topics: Adult; Brief Psychiatric Rating Scale; Drug Evaluation; Female; Humans; Male; Middle Aged; Penfluridol; Piperidines; Psychiatric Status Rating Scales; Recurrence; Schizophrenia; Time Factors

An open study was carried out in 17 acutely ill, newly admitted, floridly psychotic schizophrenic patients to a city hospital in New York. Penfluridol was given on a daily basis up to doses of 120 mg and patients were rated objectively by means of different psychometric evaluations; vital signs were monitored daily as were side effects. The drug was found to be a rapid acting, well-tolerated, and highly effective antipsychotic agent within the population of patients explored and within the dose range used. It was particularly effective in acutely agitated floridly paranoid schizophrenics; a statistically significant impact was achieved by 7 days and usually within 72 h after initiating treatment. The drug appears unique in that (1) its effects are realized without the untoward and usually troublesome effects of nonspecific sedation attendant upon the use of many other 'neuroleptic' medications, and (2) even within the relatively high doses used it produced no hypotensive effects. It is concluded that this appears to be a unique antipsychotic agent and a potentially important addition to the treatment armamentarium of both acute and chronic schizophrenic individuals.

Topics: Acute Disease; Adult; Drug Evaluation; Female; Humans; Male; Middle Aged; Penfluridol; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenia, Paranoid

Topics: Adult; Antiparkinson Agents; Double-Blind Method; Female; Humans; Male; Middle Aged; Penfluridol; Piperidines; Procyclidine; Schizophrenia; Time Factors

Topics: Administration, Oral; Adult; Aged; Evaluation Studies as Topic; Female; Humans; Male; Middle Aged; Penfluridol; Piperidines; Schizophrenia

The author calls attention to mood-elevation as a side effect of Biperiden HCL and Trihexyphenidyl HCL, two anticholinergic antiparkinsonian agents. This is of significance because of the despondency and anergy often seen in schizophrenics taking antipsychotic medication and because of the difficulty discerning the origin of affective changes in the face of polypharmacy.

Topics: Adolescent; Adult; Antiparkinson Agents; Basal Ganglia Diseases; Biperiden; Emotions; Euphoria; Female; Hallucinations; Humans; Male; Middle Aged; Piperidines; Schizophrenia; Trihexyphenidyl

In a study of 28 schizophrenic in-patients treated with penfluridol or thiothixene, patients were followed with clinical ratings, EEG variables, the mean integrated amplitude (MIA) on both the left and right sides--both with filters with frequency ranges from 7.5 to 13.5 and 0.5 to 25 Hz--as well as its within-patient variance (WPV) on both sides and with both filters, and also with visual averaged evoked responses (V.AER). Moreover, determinations of plasma levels of the drugs were conducted in a search for possible objective measurements of the effects of the treatment, but also to try to find measurements that would make it possible to predict the outcome of treatment. MIA left/right and WPV left/right were found to be the most promising variables to follow the effect of treatment, which were correlated to factors 1 and 2 of the Mårten's S-scale. WPV left/right before treatment was correlated to changes in factor 4 of the S-scale during the trial.

Topics: Adult; Electroencephalography; Evoked Potentials; Female; Humans; Male; Middle Aged; Penfluridol; Piperidines; Schizophrenia; Thiothixene

Topics: Acute Disease; Adult; Female; Humans; Male; Middle Aged; Penfluridol; Piperidines; Psychiatric Status Rating Scales; Schizophrenia

The authors compared penfluridol, a long-acting neuroleptic that can be administered orally once a week, with chlorpromazine in the treatment of 33 newly admitted schizophrenic patients in a brief therapy unit. Patients receiving either drug improved enough to be discharged in 3 weeks. Penfluridol-treated patients experienced less drowsiness than those treated with chlorpromazine, but the severity of extrapyramidal symptoms appeared to be greater with penfluridol.

Topics: Basal Ganglia Diseases; Chlorpromazine; Consciousness Disorders; Humans; Length of Stay; Penfluridol; Piperidines; Psychiatric Status Rating Scales; Schizophrenia

In a controlled trial of penfluridol and thiothixene as maintenance drugs in patients with chronic schizophrenic syndromes, some improvement over previous neuroleptics was seen with both drugs. This improvement was mainly evident in variables concerned with participation in social activities as assessed with the S-scale and by ward behaviour. The drug dosages necessary were very low and gave few and easily manageable side-effects. There was no significant difference between penfluridol and thiothixene. Penfluridol has the clear practical advantage of being the only long-acting drug for oral administration so far available.

Topics: Adolescent; Adult; Aged; Biperiden; Chlorpromazine; Chronic Disease; Drug Evaluation; Female; Humans; Hypnotics and Sedatives; Male; Middle Aged; Penfluridol; Piperidines; Schizophrenia; Thiothixene

Topics: Butyrophenones; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Humans; Piperazines; Piperidines; Professional-Patient Relations; Psychotherapy; Schizophrenia; Thioxanthenes

Longoperidol/Janssen, an orally administered neuroleptic with a five- to seven-day duration of effects, was clinically tested in six mental hospitals in the G.D.R. where the agent was administered to subjects of chronic to subacute schizophrenia. It was not possible for fully consistent results to be obtained in these tests. Workers at mental hospitals in Leipzig and Mühlhausen recommended that the drug should be imported, whereas those at the four other centers (Dresden, Halle, Jena, and Schwerin) did not consider the medication to be indispensable, although they were also able to observe the good effects of the agent.

Topics: Delayed-Action Preparations; Humans; Penfluridol; Piperidines; Schizophrenia

Topics: Acute Disease; Antipsychotic Agents; Basal Ganglia Diseases; Bipolar Disorder; Child; Chronic Disease; Delayed-Action Preparations; Dibenzazepines; Dibenzothiepins; Dosage Forms; Drug Therapy, Combination; Fluphenazine; Humans; Paranoid Disorders; Perphenazine; Pimozide; Piperazines; Piperidines; Schizophrenia; Structure-Activity Relationship; Thioridazine; Thioxanthenes; Tranquilizing Agents

Topics: Delayed-Action Preparations; Humans; Parkinson Disease, Secondary; Penfluridol; Piperidines; Schizophrenia

Penfluridol is a new long-acting neuroleptic drug, first shown by Janssen et al. (1970) and later proved by numerous clinical investigations. The plasma level data are in agreement with these findings since penfluridol is measurable in plasma of the patients 7 days after the oral dose of 120 mg/week. In summary, we have provided for the first time a rapid, accurate and precise gas-chromatographic method for measurement of penfluridol in the plasma of schizophrenic patients.

Topics: Chromatography, Gas; Humans; Male; Penfluridol; Piperidines; Schizophrenia

An open trial of Carpipramine which chemically is a synthesis of a tricyclic antidepressant and the side chain of a butyrophrenone has been performed in 75 acute and chronic schizophrenics over a period of 30 days. The daily dose was 400-800 mg exeeding the recommendations of the manufacturer. The psychopathological changes were documented and evaluated by means of the AMP and the AMPAS-system. In 50 of the patients the trial could be completed. Only the productive symptoms and disturbance of sleep showed a significantly decreased frequency before day 10. It seems remarkable that the symptom of somatic hallucinations responded very rapidly under treatment with Carpipramine. Significant sedative or extrapyramidal side-effects were not observed; anticholinergic effects were moderate. There seems to be evidence of a slight centrally stimulating component. The substance cnnot be classified as a typical neuroleptic nor as an antidepressant drug. A differential action depending on the initial syndrome constellation is discussed.

Topics: Acute Disease; Antidepressive Agents, Tricyclic; Chronic Disease; Dibenzazepines; Drug Evaluation; Humans; Piperidines; Schizophrenia

Topics: Antipsychotic Agents; Depression; Haloperidol; Humans; Kinetics; Perphenazine; Phenothiazines; Piperazines; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenia, Paranoid; Thiothixene; Trifluperidol

Topics: Anemia, Aplastic; Antipsychotic Agents; Female; Humans; Middle Aged; Phenothiazines; Piperidines; Schizophrenia

Topics: Adult; Antiparkinson Agents; Antipsychotic Agents; Basal Ganglia Diseases; Delayed-Action Preparations; Economics; Female; Humans; Hydrocarbons, Halogenated; Male; Middle Aged; Phenothiazines; Piperidines; Schizophrenia; Schizophrenic Psychology; Social Behavior; Time Factors; Toluene; Tranquilizing Agents

Topics: Adult; Ambulatory Care; Antipsychotic Agents; Chronic Disease; Delayed-Action Preparations; Depression; Electrocardiography; Female; Follicle Stimulating Hormone; Humans; Injections, Intramuscular; Male; Middle Aged; Movement Disorders; Outpatient Clinics, Hospital; Palmitic Acids; Phenothiazines; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Self-Assessment; Spermatogenesis; Sulfonamides

Topics: Adult; Aged; Alanine Transaminase; Bipolar Disorder; Blood Pressure; Blood Sedimentation; Butyrophenones; Creatinine; Dementia; Electrocardiography; Female; Hemoglobinometry; Humans; Leukocyte Count; Long-Term Care; Male; Middle Aged; Neurocognitive Disorders; Paranoid Disorders; Piperidines; Schizophrenia; Time Factors; Tranquilizing Agents

Topics: Haloperidol; Humans; Hydrocarbons, Halogenated; Intelligence; Interpersonal Relations; Occupational Therapy; Piperidines; Schizophrenia; Socioenvironmental Therapy; Toluene; Tranquilizing Agents

Topics: Half-Life; Humans; Penfluridol; Piperidines; Schizophrenia

Topics: Administration, Oral; Adult; Chronic Disease; Female; Humans; Hydrocarbons, Halogenated; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Time Factors; Toluene; Tranquilizing Agents

Topics: Antipsychotic Agents; Fecal Incontinence; Humans; Intellectual Disability; Middle Aged; Phenothiazines; Piperidines; Schizophrenia; Urinary Incontinence

Topics: Adolescent; Adult; Anticonvulsants; Antipsychotic Agents; Bipolar Disorder; Brain Diseases; Cerebrovascular Disorders; Child; Epilepsy; Humans; Hypertension; Hypnotics and Sedatives; Intracranial Arteriosclerosis; Middle Aged; Phenothiazines; Piperidines; Schizophrenia; Seizures

Topics: Adolescent; Adult; Antiparkinson Agents; Antipsychotic Agents; Female; Humans; Male; Middle Aged; Palmitic Acids; Paranoid Disorders; Phenothiazines; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Sulfonamides; Time Factors; Tranquilizing Agents

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Delayed-Action Preparations; Female; Humans; Injections, Intramuscular; Male; Middle Aged; Palmitic Acids; Paranoid Disorders; Phenothiazines; Piperidines; Psychoses, Alcoholic; Schizophrenia; Sulfonamides

Topics: Adult; Chemical Phenomena; Chemistry; Chronic Disease; Female; Fluphenazine; Humans; Male; Middle Aged; Palmitic Acids; Phenothiazines; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Sulfonamides

Topics: Adult; Butyrophenones; Female; Humans; Male; Mental Disorders; Piperidines; Schizophrenia; Tranquilizing Agents

Topics: Adult; Chronic Disease; Evaluation Studies as Topic; Female; Fluorobenzenes; Humans; Injections, Intramuscular; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Social Adjustment; Spiro Compounds; Tranquilizing Agents

Topics: Alcoholism; Antipsychotic Agents; Chronic Disease; Delayed-Action Preparations; Female; Fluphenazine; Hallucinations; Humans; Male; Palmitic Acids; Paranoid Disorders; Piperidines; Psychotic Disorders; Schizophrenia; Sulfonamides

Topics: Adult; Antipsychotic Agents; Basal Ganglia Diseases; Female; Humans; Injections, Intramuscular; Male; Middle Aged; Palmitic Acids; Phenothiazines; Piperidines; Schizophrenia; Schizophrenia, Disorganized; Schizophrenia, Paranoid; Sulfonamides; Undecylenic Acids

Topics: Adult; Chronic Disease; Female; Hallucinations; Humans; Hydrocarbons, Halogenated; Male; Motor Skills; Paranoid Disorders; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Spiro Compounds; Thinking; Tranquilizing Agents

Topics: Adult; Aged; Autistic Disorder; Delusions; Depressive Disorder, Major; Female; Humans; Male; Mental Disorders; Paranoid Disorders; Piperidines; Schizophrenia; Spiro Compounds; Time Factors; Tranquilizing Agents

Topics: Adolescent; Adult; Aged; Delusions; Female; Humans; Injections, Intramuscular; Male; Mental Disorders; Middle Aged; Neurotic Disorders; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenia, Disorganized; Schizophrenia, Paranoid; Spiro Compounds; Tranquilizing Agents

Topics: Anxiety; Bipolar Disorder; Cyclohexanes; Humans; Intelligence Tests; Lysergic Acid Diethylamide; Perception; Phencyclidine; Phenothiazines; Piperidines; Psychoses, Substance-Induced; Reaction Time; Schizophrenia; Schizophrenic Psychology; Thinking

Topics: Antidepressive Agents; Cognition Disorders; Dementia; Depression; Humans; Hysteria; Indoles; Male; Paranoid Disorders; Piperidines; Schizophrenia; Schizophrenic Psychology

Topics: Adult; Attention; Benzimidazoles; Chronic Disease; Haloperidol; Humans; Hydrocarbons, Halogenated; Ketones; Male; Memory; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Social Behavior; Time Factors; Tranquilizing Agents

Topics: Anxiety; Benzimidazoles; Chronic Disease; Hallucinations; Humans; Ketones; Mental Disorders; Piperidines; Psychotic Disorders; Schizophrenia; Schizophrenia, Disorganized; Tranquilizing Agents

Topics: 1-Propanol; Adolescent; Adult; Antiparkinson Agents; Basal Ganglia Diseases; Biperiden; Catatonia; Delayed-Action Preparations; Extrapyramidal Tracts; Humans; Male; Middle Aged; Paranoid Disorders; Piperidines; Psychotic Disorders; Schizophrenia; Schizophrenia, Disorganized; Tranquilizing Agents; Tremor

Topics: Adult; Dioxoles; Female; Humans; Indoles; Male; Middle Aged; Piperidines; Schizophrenia; Tranquilizing Agents

Topics: Adult; Analysis of Variance; Benzimidazoles; Chronic Disease; Electroencephalography; Evaluation Studies as Topic; Female; Humans; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Social Adjustment; Statistics as Topic; Tranquilizing Agents

Topics: Benzimidazoles; Humans; Male; Paranoid Disorders; Piperidines; Psychotic Disorders; Schizophrenia

Topics: Humans; Hydrocarbons, Halogenated; Ketones; Piperidines; Schizophrenia; Spiro Compounds; Tranquilizing Agents

Topics: Adolescent; Adult; Evaluation Studies as Topic; Female; Humans; Hydrocarbons, Halogenated; Male; Middle Aged; Neurotic Disorders; Paranoid Disorders; Piperidines; Schizophrenia; Spiro Compounds; Time Factors; Tranquilizing Agents

Topics: Animals; Drug Combinations; Drug Tolerance; Humans; Mental Disorders; Piperidines; Psychotic Disorders; Rats; Schizophrenia; Tranquilizing Agents

Topics: Adult; Chronic Disease; Electroencephalography; Humans; Male; Phenothiazines; Piperidines; Schizophrenia

Topics: Benzimidazoles; Chronic Disease; Delayed-Action Preparations; Humans; Ketones; Mental Disorders; Piperidines; Schizophrenia; Tranquilizing Agents

Topics: Adult; Benzene Derivatives; Female; Humans; Male; Middle Aged; Piperidines; Schizophrenia; Spiro Compounds; Tranquilizing Agents

Topics: Humans; Ketones; Phenothiazines; Piperidines; Schizophrenia

Topics: Adult; Alanine Transaminase; Aspartate Aminotransferases; Autistic Disorder; Autonomic Nervous System; Catatonia; Female; Hallucinations; Humans; Hypnotics and Sedatives; Liver Function Tests; Male; Mental Disorders; Nausea; Neurotic Disorders; Paranoid Disorders; Personality Disorders; Phenothiazines; Piperidines; Schizophrenia; Sleep Wake Disorders; Stimulation, Chemical; Sweating; Tremor; Vascular Diseases; Vomiting

Topics: Acetone; Animals; Brain Chemistry; Chromatography, Paper; Cyclohexanes; Dinitrophenols; Female; Humans; Intestines; Male; Methods; Microchemistry; Piperidines; Schizophrenia; Spectrophotometry; Swine; Tetracycline; Time Factors

Topics: 1-Propanol; Adolescent; Adult; Biperiden; Fluphenazine; Humans; Injections, Intramuscular; Injections, Intravenous; Male; Middle Aged; Parasympatholytics; Piperidines; Prochlorperazine; Schizophrenia; Tranquilizing Agents

Topics: Adolescent; Adult; Antidepressive Agents; Butyrophenones; Female; Fluorine; Humans; Male; Middle Aged; Perphenazine; Piperidines; Schizophrenia; Trifluperidol

Topics: 1-Propanol; Adult; Age Factors; Aged; Bipolar Disorder; Follow-Up Studies; Humans; Middle Aged; Neurologic Manifestations; Parkinson Disease; Piperidines; Psychotic Disorders; Schizophrenia; Tranquilizing Agents

Topics: Adult; Antidepressive Agents; Bipolar Disorder; Butyrophenones; Computers; Dosage Forms; Electroencephalography; Fluorine; Humans; Middle Aged; Piperidines; Schizophrenia; Sleep Stages; Trifluperidol

Topics: Humans; Nitriles; Phenothiazines; Piperidines; Prochlorperazine; Schizophrenia; Tranquilizing Agents

Topics: Adult; Aged; Female; Humans; Middle Aged; Nitriles; Phenothiazines; Piperidines; Schizophrenia; Tranquilizing Agents

Topics: Accommodation, Ocular; Animals; Cats; Chlorpromazine; Cornea; Eye Diseases; Female; Fundus Oculi; Humans; Lens, Crystalline; Male; Penicillamine; Phenothiazines; Pigmentation Disorders; Piperazines; Piperidines; Schizophrenia; Thioridazine; Tranquilizing Agents

Topics: Humans; Paranoid Disorders; Parasympatholytics; Phenothiazines; Piperidines; Schizophrenia; Tranquilizing Agents; Trihexyphenidyl

Topics: Antidepressive Agents; Butyrophenones; Catatonia; Female; Fluorine; Humans; Male; Paranoid Disorders; Piperidines; Schizophrenia; Trifluperidol

Topics: Adult; Aged; Hallucinations; Humans; Male; Mental Disorders; Middle Aged; Paranoid Disorders; Piperidines; Psychotic Disorders; Schizophrenia

Topics: Antidepressive Agents; Butyrophenones; Fluorine; Humans; Mental Disorders; Piperidines; Schizophrenia; Tranquilizing Agents; Trifluperidol

Topics: Adolescent; Adult; Atropine; Female; Humans; Male; Middle Aged; Parasympatholytics; Parkinson Disease; Parkinson Disease, Secondary; Phenothiazines; Piperidines; Schizophrenia; Xanthenes

Topics: Adolescent; Adult; Aged; Female; Humans; Intellectual Disability; Middle Aged; Nitriles; Phenothiazines; Piperidines; Psychotic Disorders; Schizophrenia; Tranquilizing Agents

Topics: Adolescent; Adult; Antidepressive Agents; Butyrophenones; Convulsive Therapy; Electroconvulsive Therapy; Fluorine; Hallucinogens; Humans; Male; Piperidines; Schizophrenia; Trifluperidol

Topics: Antidepressive Agents; Butyrophenones; Chlorpromazine; Female; Fluorine; Humans; Male; Middle Aged; Piperidines; Schizophrenia; Trifluoperazine

Topics: Adolescent; Adult; Antidepressive Agents; Butyrophenones; Fluorine; Humans; Male; Piperidines; Schizophrenia; Trifluperidol

Topics: Adult; Butyrophenones; Depression; Female; Fluphenazine; Humans; Male; Piperidines; Psychotic Disorders; Schizophrenia; Thioridazine

Topics: Blood Glucose; Carbohydrate Metabolism; Diabetes Mellitus; Glucose Tolerance Test; Hallucinations; Hospitals, Psychiatric; Inpatients; Mental Disorders; Piperidines; Placebos; Schizophrenia; Toxicology

Topics: Adolescent; Catatonia; Child; Chlorpromazine; Convulsive Therapy; Electroconvulsive Therapy; Humans; Insulin; Methotrimeprazine; Perphenazine; Piperidines; Reserpine; Schizophrenia; Toxicology

Topics: Antisocial Personality Disorder; Bipolar Disorder; Depression; Drug Combinations; Glycolates; Hallucinogens; Mental Disorders; Piperidines; Psychotic Disorders; Pyrrolidines; Schizophrenia; Toxicology

Topics: Antisocial Personality Disorder; Anxiety; Anxiety Disorders; Atropine; Bipolar Disorder; Depression; Drug Combinations; Drug Therapy; Electroencephalography; Glycolates; Hallucinogens; Mental Disorders; Piperidines; Psychoses, Alcoholic; Psychotic Disorders; Pyrrolidines; Schizophrenia; Toxicology

Topics: Bipolar Disorder; Butyrophenones; Hallucinations; Humans; Hypnotics and Sedatives; Intellectual Disability; Mental Disorders; Paranoid Disorders; Paresis; Parkinsonian Disorders; Piperidines; Psychomotor Agitation; Psychotic Disorders; Schizophrenia

Topics: Humans; Monoamine Oxidase Inhibitors; Piperidines; Schizophrenia

Topics: Adolescent; Child; Electroencephalography; Humans; Piperidines; Schizophrenia

Topics: Humans; Piperidines; Research; Schizophrenia

Topics: Benzhydryl Compounds; Methylphenidate; Piperidines; Schizophrenia

Topics: Hallucinations; Humans; Piperidines; Schizophrenia

Topics: Piperidines; Salts; Schizophrenia

Topics: Humans; Piperidines; Schizophrenia

Topics: Amobarbital; Attention; Humans; Lysergic Acid Diethylamide; Phencyclidine; Piperidines; Proprioception; Schizophrenia; Sodium; Sodium, Dietary

Topics: Humans; Medical Records; Piperidines; Psychoses, Alcoholic; Psychotic Disorders; Schizophrenia

Topics: Chlorpromazine; Convulsive Therapy; Piperidines; Reserpine; Schizophrenia; Seizures

Topics: Humans; Intellectual Disability; Piperidines; Schizophrenia

Topics: Piperidines; Schizophrenia

Topics: Humans; Piperidines; Schizophrenia

Topics: Piperidines; Schizophrenia

Topics: Piperidines; Schizophrenia

Topics: Piperidines; Schizophrenia

Topics: Benzhydryl Compounds; Biomedical Research; Piperidines; Schizophrenia

Topics: Piperidines; Schizophrenia; Suicide

Topics: Piperidines; Schizophrenia

Topics: Double-Blind Method; Piperidines; Salts; Schizophrenia

Topics: Piperidines; Schizophrenia

Topics: Humans; Piperidines; Schizophrenia

Topics: Humans; Mental Disorders; Piperidines; Schizophrenia

Topics: Humans; Piperidines; Schizophrenia

Topics: Mental Disorders; Piperidines; Psychotic Disorders; Schizophrenia