piperidines and Basal-Ganglia-Diseases

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

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

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

The 'second-generation' cholinesterase inhibitors (ChEIs), donepezil, galantamine and rivastigmine, are a class of medications that are currently approved for the treatment of mild-to-moderate Alzheimer's disease (AD). These medications have proven efficacy in improving cognition, behaviour, activities of daily living, and global functioning in mild-to-moderate AD. They have also been shown to reduce caregiver stress and to delay time to nursing home placement. Two separate meta-analyses have indicated that ChEIs confer a modest but significant therapeutic benefit in the treatment of AD, despite higher rates of treatment discontinuation and side effects than placebo. There is growing evidence to support their efficacy in treating moderate-to-severe AD. ChEIs are generally well-tolerated, with side effects that tend to be dose-related and are most problematic during dose titration. The most common adverse effects, related to cholinergic stimulation in the brain and peripheral tissues, include gastrointestinal, cardiorespiratory, extrapyramidal, genitourinary, and musculoskeletal symptoms, as well as sleep disturbances. Few clinically significant drug-drug interactions with ChEIs have been identified. Three head-to-head trials of ChEIs in the treatment of AD have been published to date, but are limited due to their open-label design, rates of titration, and the drug dosage levels utilised. Further study is needed to examine other indications for ChEIs, as well as their combination with newer treatments, such as memantine.

Topics: Aged; Alzheimer Disease; Animals; Basal Ganglia Diseases; Bradycardia; Central Nervous System Diseases; Cholinesterase Inhibitors; Clinical Trials as Topic; Comorbidity; Donepezil; Double-Blind Method; Drug Evaluation; Drug Interactions; Female; Galantamine; Gastrointestinal Diseases; Humans; Indans; Institutionalization; Longitudinal Studies; Male; Memantine; Meta-Analysis as Topic; Mice; Middle Aged; Nootropic Agents; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine; Single-Blind Method; Sleep Wake Disorders; Treatment Outcome

Dementia with Lewy bodies (DLB) is a common cause of dementia with effects on cognition, mood, behavior, and function. Changes in the acetylcholine system have been reported in brains of patients with DLB, which provides a rationale for trials of acetylcholinesterase inhibitors in DLB. This review includes all English-language publications found via Medline and related to the efficacy and/or safety of these compounds in DLB. Preliminary data suggest that these compounds may be efficacious in DLB and that future randomized clinical trials are strongly needed. Methodological limitations of the existing data include small sample sizes, and the paucity of standardized psychometric measures.

Topics: Aged; Basal Ganglia Diseases; Behavior; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition; Cognition Disorders; Donepezil; Humans; Indans; Lewy Body Disease; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine; Tacrine

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

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: Adolescent; Adult; Aged; Basal Ganglia Diseases; Benzamides; Butyrophenones; Child; Drug-Related Side Effects and Adverse Reactions; Dystonia; Extrapyramidal Tracts; Female; Humans; Male; Middle Aged; Muscle Hypertonia; Muscle Rigidity; Parkinson Disease, Secondary; Phenothiazines; Piperazines; Piperidines; Reserpine; Thioxanthenes

Topics: Antiparkinson Agents; Basal Ganglia Diseases; Butyrophenones; Chlorpromazine; Drug Therapy, Combination; Humans; Iatrogenic Disease; Parasympatholytics; Piperazines; Piperidines; Psychotic Disorders; Time Factors

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

The aim of the present study was to determine the efficacy, side-effects and tolerability of blonanserin for treating refractory behavioural psychological symptoms of dementia (BPSD). The present study was a 12-week, prospective, structured clinical trial of blonanserin for the treatment of BPSD. The degree of cognitive function, activities of daily living score, and the degree of BPSD were determined using the Mini-Mental State Examination (MMSE), Disability Assessment for Dementia (DAD), Neuropsychiatric Inventory (NPI) and the Rating Scale for Aggressive Behaviour in the Elderly (RAGE). The severity of extrapyramidal symptoms was assessed using the Drug-Induced Extrapyramidal Symptoms scale (DIEEPS). Five patients were enrolled. These patients met the NINCDS-ADRDA criteria. The patients were prescribed more than two kinds of existing antipsychotic drugs and were considered refractory cases; the drugs were discontinued because they were ineffectual and side-effects appeared. Each drug was prescribed independently for at least 2 weeks. The mean changes (at baseline and at the last week, respectively) in the MMSE (12.25, 9.25), in the DAD (6.5, 6.75), in the RAGE (5.5, 5.3) and in the DIEEPS (0.5, 1.5) were minimal. The mean changes in the NPI were two or fewer points. Some side-effects (one gait abnormality and one pneumonia) were observed. The results of this preliminary study show that blonanserin does not have adequate efficacy for the treatment of refractory BPSD.

Topics: Aged; Aged, 80 and over; Aggression; Alzheimer Disease; Basal Ganglia Diseases; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance; Female; Humans; Japan; Male; Mental Disorders; Mental Status Schedule; Neuropsychological Tests; Piperazines; Piperidines; Prospective Studies; Psychometrics; Receptor, Serotonin, 5-HT2A; Treatment Outcome

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

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

1. In order to verify the hypothesis that risperidone is a useful therapeutic alternative to clozapine the authors carried out a randomized double blind trial in 59 patients with paranoid hallucinatory psychoses. 2. In a treatment lasting 28 days three groups of patients received either 4 mg risperidone (N = 20), 8 mg risperidone (N = 19), or 400 mg clozapine (N = 20) daily. 3. The tolerance of 4 mg risperidone was globally assessed as being better than that of 400 mg clozapine. Drop-outs under clozapine were mostly caused by side effects, whereas under risperidone they tended to occur for therapeutic inefficacy. 4. The antipsychotic effect was highly significant and clinically relevant under both risperidone and clozapine.

Topics: Acute Disease; Adult; Aged; Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Double-Blind Method; Electrocardiography; Electroencephalography; Female; Humans; Infant, Newborn; Isoxazoles; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Risperidone; Schizophrenia, Paranoid

A double-blind placebo-controlled cross-over trial was carried out to evaluate the efficacy and safety of the combined serotonin-dopamine antagonist risperidone in mentally retarded patients with persistent behavioural disturbances. After an observation period of 1 week, risperidone 4-12 mg or placebo was administered during 3 weeks as add-on treatment to the existing medication, followed by a 1-week single-blind placebo wash-out, and another 3 weeks of double-blind treatment with the cross-over medication. Thirty-seven patients participated in the trials; 30 completed the study. Risperidone was significantly superior to placebo in its effect on the Aberrant Behaviour Checklist and the Clinical Global Impression. The Extrapyramidal Symptom Rating Scale did not show any differences between risperidone and placebo. Two patients experienced hypotension at the start of the risperidone administration. Sedation and drowsiness were the most frequently reported treatment-emergent adverse events. The results of this trial warrant further investigation into the therapeutic assets of risperidone in this indication, as add-on therapy and as monotherapy.

Topics: Adolescent; Adult; Antipsychotic Agents; Basal Ganglia Diseases; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Intellectual Disability; Isoxazoles; Male; Mental Disorders; Middle Aged; Piperidines; Placebos; Risperidone

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

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: Adolescent; Adult; Aged; Antiparkinson Agents; Antipsychotic Agents; Basal Ganglia Diseases; Biperiden; Clinical Trials as Topic; Humans; Middle Aged; Parkinson Disease; Parkinson Disease, Secondary; Phenothiazines; Piperidines

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: 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: 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: Administration, Oral; Adult; Antiparkinson Agents; Antipsychotic Agents; Basal Ganglia Diseases; Benzyl Compounds; Delayed-Action Preparations; Drug Evaluation; Humans; Injections, Intramuscular; Male; Middle Aged; Palmitic Acids; Phenothiazines; Piperidines; Piperidones; Placebos; Psychotic Disorders; Remission, Spontaneous; Sulfonamides

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: 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: Administration, Oral; Adult; Antiparkinson Agents; Basal Ganglia Diseases; Benztropine; Benzyl Compounds; Clinical Trials as Topic; Delayed-Action Preparations; Evaluation Studies as Topic; Haloperidol; Humans; Injections, Intramuscular; Intraocular Pressure; Male; Middle Aged; Movement Disorders; Parasympatholytics; Piperidines; Piperidones; Placebos; Psychotic Disorders; Tropanes

Antipsychotics are often used in conjunction with anti-Alzheimer drugs to treat the behavioral and psychological symptoms of dementia (BPSD). Here, we examined the effects of cholinesterase inhibitors (ChEIs), donepezil and galantamine, on antipsychotic-induced extrapyramidal side effects (EPS) in mice. The effects of serotonergic agents on the EPS drug interaction were also evaluated. Donepezil (0.3-3 mg/kg) did not induce EPS signs by itself; however, it significantly potentiated bradykinesia induction with a low dose of haloperidol (0.5 mg/kg) in dose-dependent and synergistic manners. Galantamine (0.3-3 mg/kg) elicited mild bradykinesia at a high dose and dose-dependently augmented haloperidol-induced bradykinesia. The EPS potentiation by galantamine was blocked by trihexyphenidyl (a muscarinic antagonist), but not by mecamylamine (a nicotinic antagonist). In addition, the bradykinesia potentiation by galantamine was significantly reduced by (±)-8-hydroxy-2-(di-n-propylamino)-tetralin (a 5-HT1A agonist), ritanserin (a 5-HT2 antagonist), and SB-258585 (a 5-HT6 antagonist). The present results give us a caution for the antipsychotics and ChEIs interaction in inducing EPS in the treatment of BPSD. In addition, second generation antipsychotics, which can stimulate 5-HT1A receptors or antagonize 5-HT2 and 5-HT6 receptors, seem to be favorable as an adjunctive therapy for BPSD.

Topics: Alzheimer Disease; Animals; Antipsychotic Agents; Basal Ganglia Diseases; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Drug Interactions; Galantamine; Haloperidol; Hypokinesia; Indans; Male; Mice, Inbred Strains; Nootropic Agents; Piperidines; Receptor, Serotonin, 5-HT1A; Receptors, Muscarinic; Serotonin Agents

Blonanserin is a new atypical antipsychotic drug that shows high affinities to dopamine D2 and 5-HT2 receptors; however, the mechanisms underlying its atypicality are not fully understood. In this study, we evaluated the antipsychotic properties of AD-6048, a primary metabolite of blonanserin, to determine if it contributes to the atypicality of blonanserin. Subcutaneous administration of AD-6048 (0.3-1mg/kg) significantly inhibited apomorphine (APO)-induced climbing behavior with an ED50 value of 0.200mg/kg, the potency being 1/3-1/5 times that of haloperidol (HAL). AD-6048 did not cause extrapyramidal side effects (EPS) even at high doses (up to 10mg/kg, s.c.), whereas HAL at doses of 0.1-3mg/kg (s.c.) significantly induced bradykinesia and catalepsy in a dose-dependent manner. Thus, the therapeutic index (potency ratios of anti-APO action to that of EPS induction) of AD-6048 was much higher than that of haloperidol, illustrating that AD-6048 per se possesses atypical antipsychotic properties. In addition, immunohistochemical analysis of Fos protein expression revealed that both AD-6048 and HAL significantly increased Fos expression in the shell part of the nucleus accumbens and the striatum. However, in contrast to HAL which preferentially enhanced striatal Fos expression, AD-6048 showed a preferential action to the nucleus accumbens. These results indicate that AD-6048 acts as an atypical antipsychotic, which seems to at least partly contribute to the atypicality of blonanserin.

Topics: Animals; Antipsychotic Agents; Apomorphine; Basal Ganglia Diseases; Behavior, Animal; Catalepsy; Corpus Striatum; Dose-Response Relationship, Drug; Gene Expression; Haloperidol; Injections, Subcutaneous; Male; Mice; Nucleus Accumbens; Oncogene Proteins v-fos; Piperazines; Piperidines; Pyridines

The low incidence of extrapyramidal side effects associated with the atypical antipsychotic iloperidone may be linked to its unique binding profile of high affinity antagonism of both α1 adrenergic receptors and serotonin 2A receptors.

Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Basal Ganglia Diseases; Corpus Striatum; Dopamine; Humans; Isoxazoles; Piperidines; Serotonin 5-HT2 Receptor Antagonists

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

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

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Antipsychotic Agents; Basal Ganglia Diseases; Donepezil; Drug Interactions; Drug Therapy, Combination; Female; Humans; Indans; Nootropic Agents; Piperidines; Risperidone

The cholinergic hypothesis of Alzheimer's disease is the basis of a new class of drugs: acetylcholinesterase inhibitors. These drugs have few side effects, mainly digestive disorders.. Extra-pyramidal side effects with severe gait disorders were observed in 3 patients with Alzheimer's dementia treated with donepezil. This drug was associated with paroxetine or a neuroleptic. In 2 of the 3 cases, the extra-pyramidal effects disappeared when donepezil was discontinued.. Extra-pyramidal syndromes in elderly subjects with cognitive impairment are difficult to interpret. The possible causes include interactions between acetylcholinesterase inhibitors, neuroleptics and serotonine reuptake inhibitors and Lewy body dementia.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Basal Ganglia Diseases; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Piperidines

The atypical antipsychotic drug olanzapine has been proposed for treatment of dopaminergic psychosis in Parkinson's disease (PD). We report on a 68-year-old patient who developed a severe akinetic-rigid extrapyramidal syndrome, accompanied by additional paranoid symptoms, following olanzapine treatment of optic hallucinosis in PD. Olanzapine may also induce clinically relevant extrapyramidal side effects in PD patients.

Topics: Aged; Antiparkinson Agents; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clozapine; Drug Therapy, Combination; Hallucinations; Humans; Levodopa; Male; Olanzapine; Paranoid Disorders; Parkinson Disease; Piperidines; Pirenzepine; Selegiline; Severity of Illness Index

Topics: Aged; Alzheimer Disease; Antipsychotic Agents; Basal Ganglia Diseases; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Drug Therapy, Combination; Female; Humans; Indans; Piperidines; Risperidone

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

Iloperidone (HP 873; 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy] -3- methoxyphenyl]ethanone) is a compound currently in clinical trials for the treatment of schizophrenia. Iloperidone displays affinity for dopamine D2 receptors and for 5-HT2A receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic. Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5-HT receptor subtypes. We employed receptor binding assays using membranes from cells stably expressing human dopamine D1, D2S, D2L, D3, D4 and D5 and 5-HT2A and 5-HT2C receptors and rat 5-HT6 and 5-HT7 receptors. Iloperidone displayed higher affinity for the dopamine D3 receptor (Ki = 7.1 nM) than for the dopamine D4 receptor (Ki = 25 nM). Iloperidone displayed high affinity for the 5-HT6 and 5-HT7 receptors (Ki = 42.7 and 21.6 nM, respectively), and was found to have higher affinity for the 5-HT2A (Ki = 5.6 nM) than for the 5-HT2C receptor (Ki = 42.8 nM). The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds.

Topics: Animals; Antipsychotic Agents; Basal Ganglia Diseases; CHO Cells; Cricetinae; Humans; Isoxazoles; Kinetics; Piperidines; Rats; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Dopamine D3; Receptors, Dopamine D4; Receptors, Dopamine D5; Receptors, Serotonin

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: Aged; Aged, 80 and over; Antipsychotic Agents; Basal Ganglia Diseases; Dementia; Female; Humans; Isoxazoles; Lewy Bodies; Male; Middle Aged; Parkinson Disease; Piperidines; Risperidone

Iloperidone (1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- piperidinyl]propoxy]-3-methoxyphenyl]ethanone) demonstrated a potent antipsychotic profile in several in vitro and in vivo animal models. Iloperidone displaced ligand binding at D2 dopamine receptors (IC50 = 0.11 microM) and displayed a high affinity for serotonin (5-HT2) receptors (IC50 = 0.011 microM) and alpha-1 receptors (IC50 = 0.00037 microM). In vivo, iloperidone antagonized apomorphine-induced climbing behavior in mice at low doses with good oral bioavailability, prevented 5-HT-induced head twitch in rats at low doses, and inhibited self-stimulation behavior in rats, pole climb avoidance in rats and continuous Sidman avoidance responding in monkeys. The latter assay also demonstrated a good duration of action. Iloperidone was substantially less active in models of extrapyramidal side effect (EPS) liability, such as preventing apomorphine-induced stereotypy and causing catalepsy in rats. In single dopamine neuron sampling studies, iloperidone demonstrated clozapine-like effects on the number of active midbrain dopamine neurons. Based on the significant increase in the open arm time seen after iloperidone treatment in the elevated plus maze assay and increased interaction score in social interaction, iloperidone may also have favorable effects in the clinic on anxiety and, possibly, negative symptoms. Clinical trials are under way of the use of iloperidone for the treatment of schizophrenia.

Topics: Animals; Anti-Anxiety Agents; Antipsychotic Agents; Basal Ganglia Diseases; Behavior, Animal; Clozapine; Dopamine Antagonists; Haloperidol; Isoxazoles; Male; Mice; Piperidines; Radioligand Assay; Rats; Rats, Wistar; Risperidone; Saimiri; Serotonin Antagonists

Several lines of evidence have suggested a link between serotonergic and dopaminergic systems in the brain. The interpretation of much of these early data needs careful reevaluation in light of the recent understanding of the plethora of serotonin receptor subtypes, their distribution in the brain and the new findings with more selective serotonin antagonists. Electrophysiological, biochemical and behavioral evidence obtained using highly selective antagonists of the 5-HT2 or 5-HT3 receptor subtypes, MDL 100,907 or MDL 73,147EF, respectively, supports the thesis that serotonin modulates the dopaminergic system. This modulation is most evident when the dopaminergic system has been activated.

Topics: Animals; Basal Ganglia Diseases; Behavior, Animal; Dopamine; Electrophysiology; Fluorobenzenes; Indoles; Male; Mice; Microdialysis; Motor Activity; N-Methyl-3,4-methylenedioxyamphetamine; Neurons; Piperidines; Quinolizines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Serotonin Antagonists

On the basis of a structural model of the postsynaptic dopaminergic antagonist pharmacophore, a series of 1-[3-(diarylamino)propyl]piperidines and related compounds was synthesized and evaluated for potential antipsychotic activity. For a rapid measure of activity, the target compounds were initially screened in vitro for inhibition of [3H]haloperidol binding and in vivo in a test of locomotor activity. Behavioral efficacy of compounds identified from the initial screens was more accurately measured in rats by using a suppression of high base-line medial forebrain bundle self-stimulation test model. The propensity of these compounds for causing extrapyramidal side effects was evaluated by using a rat catalepsy method. On the basis of these test models, we have shown that the methine carbon of the 1-(4,4-diarylbutyl)piperidines can be advantageously replaced with a nitrogen atom. The 1-[3-(diarylamino)propyl]piperidines were less cataleptic than the corresponding 1-(4,4-diarylbutyl)piperidines. The compounds with the widest separation between efficacious dose and cataleptic dose are 8-[3-[bis(4-fluorophenyl)amino]propyl]-1-phenyl-1,3,8-triazaspiro [4. 5]decan-4-one (6), 1-[1-[3-[bis(4-fluorophenyl)amino]propyl]-4-piperidinyl]-1,3-dihydro- 2H-benzimidazol-2-one (11), 1-[1-[3-[bis(4-fluorophenyl)amino]propyl]-1,2,3,6-tetrahydro-4- pyridinyl]-1,3-dihydro-2H-benzimidazol-2-one (22), and 1-[3-[bis(4-fluorophenyl)amino]propyl]-4-(2-methoxyphenyl)piperazine (26).

Topics: Animals; Antipsychotic Agents; Basal Ganglia Diseases; Binding, Competitive; Catalepsy; Corpus Striatum; Haloperidol; Humans; In Vitro Techniques; Male; Mice; Motor Activity; Piperazines; Piperidines; Rats; Receptors, Dopamine; Self Stimulation; Structure-Activity Relationship

Topics: Adult; Basal Ganglia Diseases; Delusions; Haloperidol; Humans; Male; Neuroleptic Malignant Syndrome; Parasympatholytics; Piperidines; Psychotic Disorders

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Calcium; Humans; Piperidines

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

Topics: Aged; Basal Ganglia Diseases; Female; Humans; Male; Middle Aged; Parkinson Disease; Piperidines; Thioxanthenes; Tremor

Topics: Adult; Antiemetics; Basal Ganglia Diseases; Benzimidazoles; Domperidone; Female; Humans; Infant; Male; Piperidines; Vomiting

Topics: Adult; Age Factors; Alcohol Withdrawal Delirium; Basal Ganglia Diseases; Biperiden; Diagnosis, Differential; Encephalitis; Female; Humans; Male; Piperidines; Psychoses, Alcoholic; Seizures

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

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

Biperiden hydrochloride has been used in the treatment of Parkinson's disease and related disorders within two drugs: --Akinophyl, --and Akineton which is chemically similar but has a slower effect. The first French publications upon its use as a neuroleptic corrector date from 1972. Our study deals with 55 chronic psychotic patients treated with neuroleptics and varied correctors of resulting Parkinson disorders. Akineton has been substituted for the preceding antiparkinson drugs. We may come to the following conclusions = Akineton is effective upon neuroleptic syndrom, gives few or no untoward reactions, has no toxicologic effects, shows no incompatibility with any other drug. It is very satisfactory to have at our disposal a drug effective in small doses and having a slow effect within average of 24 hours.

Topics: Adult; Aged; Basal Ganglia Diseases; Biperiden; Delayed-Action Preparations; Drug Tolerance; Female; Follow-Up Studies; Humans; Middle Aged; Piperidines

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: Aged; Basal Ganglia Diseases; Coronary Disease; Humans; Male; Maleates; Myocardial Infarction; Perhexiline; Piperidines

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; Aged; Antiparkinson Agents; Basal Ganglia Diseases; Female; Humans; Male; Methods; Middle Aged; Parasympatholytics; Piperidines; Psychometrics; Tremor; Xanthenes

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: 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: 1-Propanol; Adjustment Disorders; Adult; Aged; Antidepressive Agents; Antiparkinson Agents; Anxiety Disorders; Basal Ganglia Diseases; Biperiden; Bipolar Disorder; Delayed-Action Preparations; Depression; Depressive Disorder, Major; Female; Humans; Mental Disorders; Middle Aged; Paranoid Disorders; Piperidines; Schizophrenia, Disorganized; Tranquilizing Agents; Tremor