mdl-100907 and Schizophrenia

Negative symptoms have a major impact on the prognosis of schizophrenia, but have proven more difficult to improve or treat with antipsychotic medication. The aim of this meta-analysis is to evaluate the efficacy of 5-HT2A antagonist treatments on negative symptoms in patients with schizophrenia. After a systematic search, all randomized, double-blind and placebo-controlled trials evaluating the efficacy of 5-HT2A antagonists were included. Standardized mean differences were calculated between quantitative data from treatment and placebo groups, and odds ratios were calculated between qualitative data from treatment and placebo groups. Ten studies were included in the analysis. A significantly greater decrease in negative symptoms and global symptomatology was found in the 5-HT2A antagonist group compared with the placebo group, but no difference was found for positive symptoms. At the end of the studies, a lower extra-pyramidal symptoms score was found in the 5-HT2A antagonist group. No significant difference was found for the drop-out rate or for the rate of serious adverse effects, but a higher rate of treatment-emergent adverse effects was found in the 5-HT2A antagonist group. Our meta-analysis shows that 5-HT2A antagonists demonstrate a favorable benefit/risk profile and could be useful in the treatment of negative symptoms in patients with schizophrenia.

Topics: Antipsychotic Agents; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Humans; Randomized Controlled Trials as Topic; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists

Lumateperone (ITI-007) is a tosylate salt with binding affinities to receptors implicated in the therapeutic actions of antipsychotic medications, including the serotonin 5HT2A receptors, dopamine D2 and D1 receptors and the serotonin transporter. It has a unique mechanism of action because it simultaneously modulates serotonin, dopamine, and glutamate neurotransmission, implicated in serious mental illness. It can be considered a multi-target-directed ligand and a multifunctional modulator of serotoninergic system with possible precognitive, antipsychotic, antidepressant and anxiolytic properties. Lumateperone has been investigated as a novel agent for the treatment of schizophrenia, but it represents a new potential option for other psychiatric and neurological diseases, such as behavioural symptoms of dementia or Alzheimer's disease, sleep disturbances, bipolar depression. Besides, it has demonstrated a favourable safety profile without significant extrapyramidal side effects, hyperprolactinemia or changes in cardiometabolic or endocrine factors versus placebo. Additional studies are warranted to confirm and examine the benefit of lumateperone and possible therapeutic targets. This paper is a comprehensive and thorough summary of the most important findings and potential future role of this particular compound in personalized treatments.

Topics: Alzheimer Disease; Bipolar Disorder; Dementia; Dopamine D2 Receptor Antagonists; Drug Partial Agonism; Heterocyclic Compounds, 4 or More Rings; Humans; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D1; Receptors, Dopamine D2; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Serotonin Plasma Membrane Transport Proteins; Sleep Wake Disorders

Topics: Age Factors; Animals; Antipsychotic Agents; Cytochrome P-450 CYP3A; Humans; Kidney; Lurasidone Hydrochloride; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists

Serotonin or 5-hydroxytryptamine (5-HT) is a substance found in plasma, which increases smooth muscle contraction and mediates platelet aggregation. In addition, it is a monoamine neurotransmitter and is implicated in diverse behaviors. The serotonin receptor 2 (5-HT2) subfamily is best known for biased signaling and is strongly expressed mainly in the brain regions postulated to be involved in the modulation of higher cognitive and affective functions. Modulators of the 5-HT2 receptor are currently used to treat a variety of diseases including chronic pain and psychonosema. These properties suggest that 5-HT2 receptors may become an important therapeutic target for the treatment of various pathological conditions.. This review highlights the significant progress that has been made in the discovery and development of 5-HT2 receptor agonists and antagonists based on an analysis of the patent literature between January 2004 and December 2014.. Cumulative evidence over the past decade supports the notion that the modulation of 5-HT2 receptors has a positive effect on human cognition and emotion. Therefore, we suggest that new agonists and antagonists may play an important role in the treatment of disorders such as schizophrenia, addiction and obesity.

Topics: Animals; Drug Design; Humans; Obesity; Patents as Topic; Receptors, Serotonin, 5-HT2; Schizophrenia; Serotonin; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Substance-Related Disorders

Schizophrenia is a chronic psychiatric disease, which is treated by antipsychotic drugs. These drugs are mostly D2 and 5-HT2A antagonists and have extrapyramidal side effects depending on the D2 antagonistic effect. Recently admitted antipsychotic drugs also have systemic side effects. Clozapine, which has the strongest antipsychotic effect, can cause neutropenia. A problem in the treatment of schizophrenia is poor patient compliance leading to the recurrence of psychotic symptoms.. A search was carried out in Medline using the following terms: antipsychotic drugs, antipsychotic effect, risperidone, olanzapine, clozapine, ziprasidone, aripiprazol, asenapine, questiapine, cariprazine, lurasidone, arrythmia, diabetes mellitus, weight gain, epileptic activity, extrapyramidal symptoms, sexual activity, clinical trials and tolerability.. Most clinical trials describe a good antipsychotic effect of the currently used antipsychotic drugs. The efficacy and safety of the antipsychotic drugs also depend on the form of schizophrenia, for example, the chronic recurrent form of schizophrenia. Clozapine and olanzapine have the safest therapeutic effect, while the side effect of neutropenia must be controlled by 3 weekly blood controls. If schizophrenia has remitted and if patients show a good compliance, the adverse effects can be controlled. The pharmacological treatment should be combined with social therapies and psychoeducation in order to reach a good therapeutic outcome.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Dopamine D2 Receptor Antagonists; Humans; Medication Adherence; Olanzapine; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists

Hallucinations are complex misperceptions, that principally occur in schizophrenia or after intoxication induced by three main classes of drugs: psychostimulants, psychedelics, and dissociative anesthetics. There are at least three different pharmacological ways to induce hallucinations: (1) activation of dopamine D2 receptors (D2Rs) with psychostimulants, (2) activation of serotonin 5HT2A receptors (HT2ARs) with psychedelics, and (3) blockage of glutamate NMDA receptors (NMDARs) with dissociative anesthetics. In schizophrenia, the relative importance of NMDAR and D2R in the occurrence of hallucinations is still debated. Slight clinical differences are observed for each etiology. Thus, we investigated whether the concept of hallucination is homogenous, both clinically and neurobiologically. A narrative review of the literature is proposed to synthesize how the main contributors in the field have approached and tried to solve these outstanding questions. While some authors prefer one explanatory mechanism, others have proposed more integrated theories based on the different pharmacological psychosis models. In this review, such theories are discussed and faced with the clinical data. In addition, the nosological aspects of hallucinations and psychosis are addressed. We suggest that if there may be common neurobiological pathways between the different pharmacological systems that are responsible for the hallucinations, there may also be unique properties of each system, which explains the clinical differences observed.

Topics: Hallucinations; Hallucinogens; Humans; Psychotropic Drugs; Receptors, Dopamine D2; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists

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

Hypothermia as an adverse reaction of antipsychotic drug use represents a potentially life-threatening complication. However, the mechanisms by which antipsychotic drugs alter thermoregulatory processes in the human body are far from being fully understood. Here we present a case series of 5 patients developing severe hypothermia after administration of olanzapine and benperidol. Controlled by a network of neural structures, body temperature is physiologically regulated in far more narrow boundaries than are other vital functions, and its homeostasis is critical for survival. The preoptic region in the ventral hypothalamus is assumed to act as a coordinating center that is endowed with thermosensory units that constantly compare actual body temperature with target values and initiate regulatory and compensatory mechanisms in case of mismatch. Hypothermia risk seems to increase in the first days after initiation of antipsychotic drug therapy or increases in the daily dose. Schizophrenic patients bear a higher risk than nonschizophrenic patients treated with antipsychotic drugs (such as patients with dementia or depression). Antipsychotic drugs with strong 5-HT2 antagonism seem to be more frequently associated with hypothermia. These cases demonstrate the clinical relevance of hypothermia as an adverse reaction to antipsychotic treatment and the importance of careful monitoring of body temperature.

Topics: Adult; Aged; Antipsychotic Agents; Benperidol; Benzodiazepines; Body Temperature Regulation; Dose-Response Relationship, Drug; Female; Humans; Hypothermia; Male; Middle Aged; Olanzapine; Risk Factors; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Severity of Illness Index

Despite considerable progress in the pharmacological treatment of schizophrenia, about 30% of patients are minimally responsive to antipsychotics and there is still an excessively high rate of mortality in schizophrenia patients. Clozapine , a D(2)-5HT(2) antagonist, was the first antipsychotic to demonstrate efficacy in treatment-resistant patients, and to be associated with the lowest risk of death.. The pharmacodynamics, pharmacokinetics, clinical efficacy, safety and cost-effectiveness of clozapine are covered in this article, based on a literature review (PubMed) from 1975 to 2012. Pivotal, as well as supporting, randomized controlled trials are reviewed, along with observational and/or naturalistic safety studies. This review of clozapine will allow the reader to determine the place for clozapine in the schizophrenia treatment landscape.. Studies conducted so far suggest that clozapine is the treatment of choice for schizophrenic patients who are refractory to treatment, display violent behaviors, or who are at high risk of suicide. However, it is also the antipsychotic with the worst side effect profile, the highest risk of complications, and the most difficult to prescribe. Experience with clozapine should therefore be included in the education of future physicians.

Topics: Animals; Antipsychotic Agents; Clozapine; Cost-Benefit Analysis; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Drug Resistance; Humans; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Suicide Prevention

Lurasidone is a second-generation antipsychotic newly approved by the U.S. Food and Drug Administration for the treatment of schizophrenia. Similar to most other second-generation antipsychotics, lurasidone is a full antagonist at dopamine D2 and serotonin 5HT2A receptors. Efficacy within the dose range of 40-120 mg/d was established in four 6-week, randomized, controlled trials. The recommended starting dose is 40 mg/d and the maximum recommended dose is 80 mg/d. Doses above 80 mg/d do not appear to confer added benefit and may be associated with a dose-related increase in certain adverse reactions such as somnolence and akathisia. Lurasidone is administered once daily with at least 350 calories of food in order to optimize bioavailability. Lurasidone is primarily metabolized in the liver through the CYP3A4 enzyme system, and coadministration with drugs that are strong inhibitors of CYP3A4 (such as ketoconazole) or strong inducers (such as rifampin) are contraindicated. Lurasidone is associated with minimal weight gain and no clinically meaningful alterations in glucose, lipids, or the ECG QT interval.

Topics: Akathisia, Drug-Induced; Animals; Antipsychotic Agents; Disorders of Excessive Somnolence; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Humans; Isoindoles; Lurasidone Hydrochloride; Randomized Controlled Trials as Topic; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Thiazoles; Treatment Outcome; United States; United States Food and Drug Administration; Weight Gain

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

Serotonin 2C receptors are G protein-coupled receptors expressed by GABAergic, glutamatergic, and dopaminergic neurons. Anatomically, they are present in various brain regions, including cortical areas, hippocampus, ventral midbrain, striatum, nucleus accumbens, hypothalamus, and amygdala. A large body of evidence supports a critical role of serotonin 2C receptors in mediating the interaction between serotonergic and dopaminergic systems, which is at the basis of their proposed involvement in the regulation of mood, affective behavior, and memory. In addition, their expression in specific neuronal populations in the hypothalamus would be critical for their role in the regulation of feeding behavior. Modulation of these receptors has therefore been proposed to be of interest in the search for novel pharmacological strategies for the treatment of various pathological conditions, including schizophrenia and mood disorders, as well as obesity. More precisely, blockade of serotonin 2C receptors has been suggested to provide antidepressant and anxiolytic benefit, while stimulation of these receptors may offer therapeutic benefit for the treatment of psychotic symptoms in schizophrenia and obesity. In addition, modulation of serotonin 2C receptors may offer cognitive-enhancing potential, albeit still a matter of debate. In the present review, the most compelling evidence from the literature is presented and tentative hypotheses with respect to existing controversies are outlined.

Topics: Animals; Cognition; Humans; Mood Disorders; Obesity; Receptor, Serotonin, 5-HT2C; Schizophrenia; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Serotonin Receptor Agonists; Signal Transduction

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 overall outcome in schizophrenia is generally poor, despite the undisputed efficacy of antipsychotics in treating the acute symptoms of psychosis. There remains a subset of patients who are refractory to treatment. Also, for most patients treatment is not effective against the full spectrum of symptoms including negative and cognitive symptoms, and severe functional deficits persist. Further, while the newer drugs produce fewer motor side effects, other safety and tolerability concerns have emerged. Since the advent of antipsychotic therapy in the early 1950s, subsequent advances have been modest. While the mechanism of action of the first-generation antipsychotics appears closely linked to D2 antagonism, the second-generation antipsychotics have broader receptor-binding profiles, particularly 5-HT receptor antagonism. Attempts are now being made to develop antipsychotics with a wider spectrum of efficacy and a more favourable safety and tolerability profile by further exploring the therapeutic potential of D2 and 5-HT2 receptors, as well as investigating other putative mechanisms of action. This article adds to the current literature by providing an up-to-date review of antipsychotic drugs currently in development, focusing on the findings to date for compounds that are presently in Phase III clinical trials. While no exciting breakthroughs appear imminent, several drugs in early development have great potential.

Topics: Antipsychotic Agents; Clinical Trials as Topic; Cognition; Dopamine D2 Receptor Antagonists; Drug Discovery; Drugs, Investigational; Humans; Hyperprolactinemia; Motor Activity; Receptors, Dopamine D2; Schizophrenia; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists; Serotonin 5-HT2 Receptor Antagonists

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

Modulating activity at the 5-HT(2C) receptor holds a tremendous amount of therapeutic promise in multiple psychiatric indications. However, the signaling and regulation of the 5-HT(2C) receptor is highly complex due to multiple signaling pathways and agonist-directed trafficking of this receptor. Moreover, the 5-HT(2C) receptor is differentially regulated via RNA editing in multiple psychiatric disorders and following either pharmacological or environmental manipulation. Direct and indirect data suggest that both agonists and antagonists may provide benefits in several disorders. The current review highlights the underlying complexities of this area and provides the rationale for using 5-HT(2C) agonists in the treatment of both schizophrenia and depressive disorders.

Topics: Animals; Depressive Disorder; Drug Design; Humans; Receptor, Serotonin, 5-HT2C; Schizophrenia; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Serotonin Receptor Agonists; Signal Transduction

Explaining the underlying mechanisms of antipsychotic drug-induced movement disorders remains a substantial challenge. The association of atypical antipsychotic agents with fewer drug-induced movement disorders than conventional agents has engendered several pathophysiologic hypotheses: (1) the hypothesis that, unlike conventional antipsychotic agents, atypical antipsychotics have greater activity in blocking serotonin-2A (5-HT(2A)) receptors than dopamine-2 (D(2)) receptors, which mitigates extrapyramidal symptoms; (2) the hypothesis that atypical antipsychotics block D(2) receptors only long enough to cause an antipsychotic action, but not as long as conventional agents; (3) the hypothesis that, in tardive dyskinesia, the nigrostriatal dopamine receptor system might develop increased sensitivity to dopamine as a result of treatment with conventional antipsychotic drugs, but this may not occur with atypical antipsychotics; and (4) the hypothesis that there might be a genetic association in tardive dystonia relating to the dopamine D(3) allele. A number of factors contribute to the difficult task of gaining insight into the pathophysiologic processes of antipsychotic agents and why these agents may lead to drug-induced movement disorders.

Topics: Age Factors; Antipsychotic Agents; Basal Ganglia Diseases; Dopamine D2 Receptor Antagonists; Dyskinesia, Drug-Induced; Humans; Models, Biological; Psychotic Disorders; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Sex Factors

Topics: Animals; Antipsychotic Agents; Cholinergic Agonists; Disease Models, Animal; Dopamine Antagonists; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Humans; Mice; Mice, Transgenic; Nitric Oxide Synthase; Receptor, Serotonin, 5-HT2A; Receptors, AMPA; Receptors, Dopamine D2; Receptors, Dopamine D4; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotensin; Receptors, Serotonin; Schizophrenia; Serotonin Antagonists

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

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

The paliperidone pharmacokinetics after intramuscular administration of once-monthly paliperidone palmitate in Japanese patients were studied in 3 phase 1 studies and in 2 phase 3 studies performed in Japan, Korea, and Taiwan. These data (Japanese, n = 509; Korean, n = 31; Taiwanese, n = 47) were used to describe the paliperidone palmitate pharmacokinetics in Japanese, to compare with non-Japanese, and to validate the historical population pharmacokinetic (Pop-PK) model for paliperidone palmitate, developed using data from studies in patients with schizophrenia outside Japan. The final historical Pop-PK model, including all significant patient covariates of Japanese studies, was used to simulate paliperidone plasma concentration-time data using nonlinear mixed effects, followed by comparison with actual data. Visual predictive checks displayed considerable overlap between predicted and actual plasma concentrations; the majority of observations were within the 90% prediction interval. Japanese, Korean, and Taiwanese patients had comparable plasma concentrations. Covariate distributions demonstrated comparatively lower median body mass index in Japanese, Korean, and Taiwanese patients versus rest-of-world population. Prediction errors for the data set used for external validation were within cutoff values, confirming accuracy/precision of the model. Paliperidone pharmacokinetics were adequately predicted for Japanese studies using the historical Pop-PK model, confirming its robustness. Pharmacokinetics in Japanese, Korean, and Taiwanese patients with schizophrenia were comparable with rest-of-world population.

Topics: Adult; Aged; Antipsychotic Agents; Body Mass Index; Case-Control Studies; Dopamine D2 Receptor Antagonists; Female; Half-Life; Humans; Injections, Intramuscular; Japan; Male; Middle Aged; Paliperidone Palmitate; Predictive Value of Tests; Republic of Korea; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Taiwan; Treatment Outcome

Schizophrenic patients exhibit impairments in prepulse inhibition (PPI) and habituation of the acoustic startle response (ASR). Recent studies suggested that PPI deficits and habituation deficits are normalized after antipsychotic treatment. Despite clear evidence of gating and habituation mechanisms in animal models, it is still unknown which neurotransmitter systems are involved in schizophrenic patients. Thus, we compared the effects of a combined 5-HT2A/D2 and a pure D2/D3 antagonist on PPI and habituation of ASR in patients with schizophrenia.. The ASR was measured in 37 acute schizophrenic patients who were randomized and double-blinded as to treatment with amisulpride or olanzapine. Patients were assessed during the first week and after four and eight weeks of treatment. Twenty healthy matched control subjects were examined likewise.. Schizophrenic patients showed a significant PPI deficit and significantly decreased startle amplitude at baseline. The gating deficit disappeared after antipsychotic treatment in both treatment groups. Amisulpride sensitized the startle amplitude, whereas startle amplitude was not changed by olanzapine. After correcting for startle amplitude, patients did not show a habituation deficit; however, amisulpride accelerated habituation, whereas olanzapine had no effect.. Our findings suggest that the PPI-restoring effect of antipsychotics is probably attributed to a dopamine D2 receptor blockade.

Topics: Acoustic Stimulation; Adult; Amisulpride; Antipsychotic Agents; Attention; Benzodiazepines; Dopamine D2 Receptor Antagonists; Follow-Up Studies; Habituation, Psychophysiologic; Humans; Longitudinal Studies; Middle Aged; Olanzapine; Receptors, Dopamine D3; Reference Values; Reflex, Startle; Schizophrenia; Schizophrenic Psychology; Serotonin 5-HT2 Receptor Antagonists; Sulpiride

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

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

Neonatal ventral hippocampal-lesioned (NVHL) rats have been shown to display neurochemical and behavioral abnormalities at adulthood, analogous to some of those seen in schizophrenia. Serotonergic neurotransmission is implicated the pathophysiology and treatment of schizophrenia. In this study, we evaluated possible role of serotonergic transmission is the behaviors of NVHL-lesioned rats. Bilateral lesions to the ventral hippocampus (VH) in rat pups were made using the excitotoxin ibotenic acid. We investigated 5-HT

Topics: Age Factors; Animals; Animals, Newborn; Antipsychotic Agents; Autoradiography; Behavior, Animal; Disease Models, Animal; Hippocampus; Prefrontal Cortex; Prepulse Inhibition; Rats; Receptor, Serotonin, 5-HT2A; Reflex, Startle; Schizophrenia; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Plasma Membrane Transport Proteins; Sexual Maturation

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

The extrapyramidal side effects of schizophrenia treatment can be significantly reduced by simultaneously targeting dopamine D

Topics: Catalytic Domain; Dopamine D2 Receptor Antagonists; Drug Design; Drug Evaluation, Preclinical; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Inhibitory Concentration 50; Least-Squares Analysis; Molecular Docking Simulation; Molecular Dynamics Simulation; Quantitative Structure-Activity Relationship; Reproducibility of Results; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Static Electricity

Identifying biomarkers which can be used as a diagnostic tool is a major objective of pharmacogenetic studies. Most mental and many neurological disorders have a compiled multifaceted nature, which may be the reason why this endeavor has hitherto not been very successful. This is also true for tardive dyskinesia (TD), an involuntary movement complication of long-term treatment with antipsychotic drugs. The observed associations of specific gene variants with the prevalence and severity of a disorder can also be applied to try to elucidate the pathogenesis of the condition. In this paper, this strategy is used by combining pharmacogenetic knowledge with theories on the possible role of a dysfunction of specific cellular elements of neostriatal parts of the (dorsal) extrapyramidal circuits: various glutamatergic terminals, medium spiny neurons, striatal interneurons and ascending monoaminergic fibers. A peculiar finding is that genetic variants which would be expected to increase the neostriatal dopamine concentration are not associated with the prevalence and severity of TD. Moreover, modifying the sensitivity to glutamatergic long-term potentiation (and excitotoxicity) shows a relationship with levodopa-induced dyskinesia, but not with TD. Contrasting this, TD is associated with genetic variants that modify vulnerability to oxidative stress. Reducing the oxidative stress burden of medium spiny neurons may also be the mechanism behind the protective influence of 5-HT2 receptor antagonists. It is probably worthwhile to discriminate between neostriatal matrix and striosomal compartments when studying the mechanism of TD and between orofacial and limb-truncal components in epidemiological studies.

Topics: Antipsychotic Agents; Dopamine; Dyskinesia, Drug-Induced; Excitatory Amino Acid Agents; Humans; Neostriatum; Oxidative Stress; Pharmacogenetics; Pyramidal Cells; Receptors, Serotonin, 5-HT2; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Spinal Cord; Tardive Dyskinesia

Serotonin 5-HT

Topics: Animals; Frontal Lobe; Gene Expression; GTP-Binding Protein alpha Subunits, Gi-Go; Humans; Male; Rats; Receptor, Serotonin, 5-HT2A; Schizophrenia; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists

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

Drugs frequently require interactions with multiple targets-via a process known as polypharmacology-to achieve their therapeutic actions. Currently, drugs targeting several serotonin receptors, including the 5-HT

Topics: Ergotamine; HEK293 Cells; Humans; Obesity; Protein Domains; Receptor, Serotonin, 5-HT2C; Ritanserin; Schizophrenia; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Structure-Activity Relationship; Substance-Related Disorders

Brexpiprazole is a new therapeutic agent that was recently approved for the treatment of schizophrenia and for the adjunctive treatment of major depressive disorder. Brexpiprazole has features that both overlap and contrast with a related molecule, aripiprazole, and these features are discussed here.

Topics: Adrenergic alpha-1 Receptor Antagonists; Antipsychotic Agents; Aripiprazole; Depressive Disorder, Major; Dopamine Agonists; Humans; Quinolones; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2A; Receptors, Adrenergic, alpha-1; Receptors, Dopamine D2; Schizophrenia; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Agents; Thiophenes

G protein-coupled receptors (GPCRs) exist as collections of conformations in equilibrium, and the efficacy of drugs has been proposed to be associated with their absolute and relative affinities for these different conformations. The serotonin 2A (5-HT2A) receptor regulates multiple physiological functions, is involved in the pathophysiology of schizophrenia, and serves as an important target of atypical antipsychotic drugs. This receptor was one of the first GPCRs for which the functional selectivity phenomenon was observed, with its various ligands exerting differential effects on the phospholipase A2 (PLA2) and phospholipase C (PLC) signaling pathways. We aimed to develop a multiplex functional assay in 96-well plates for the simultaneous measurement of the PLA2 and PLC pathways coupled to 5-HT2A receptors; this approach enables the detection of either functional selectivity or cooperativity phenomena in early drug screening stages. The suitability of the method for running screening campaigns was tested using the Prestwick Chemical Library, and 22 confirmed hits with activities of more than 90% were identified; 11 of these hits produced statistically significant differences between the two effector pathways. Thus, we have developed a miniaturized multiplex assay in 96-well plates to measure functional selectivity for 5-HT2A receptors in the early stages of the drug discovery process.

Topics: Antipsychotic Agents; Binding Sites; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Humans; Ligands; Phospholipases A2; Receptors, Serotonin, 5-HT2; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Signal Transduction; Type C Phospholipases

Recent studies suggest that the central serotonin2B receptor (5-HT2BR) could be an interesting pharmacological target for treating neuropsychiatric disorders related to dopamine (DA) dysfunction, such as schizophrenia. Thus, the present study was aimed at characterizing the role of 5-HT2BRs in the control of ascending DA pathway activity. Using neurochemical, electrophysiological and behavioral approaches, we assessed the effects of two selective 5-HT2BR antagonists, RS 127445 and LY 266097, on in vivo DA outflow in DA-innervated regions, on mesencephalic DA neuronal firing, as well as in behavioral tests predictive of antipsychotic efficacy and tolerability, such as phencyclidine (PCP)-induced deficit in novel object recognition (NOR) test, PCP-induced hyperlocomotion and catalepsy. Both RS 127445 (0.16 mg/kg, i.p.) and LY 266097 (0.63 mg/kg, i.p.) increased DA outflow in the medial prefrontal cortex (mPFC). RS 127445, devoid of effect in the striatum, decreased DA outflow in the nucleus accumbens, and potentiated haloperidol (0.1 mg/kg, s.c.)-induced increase in mPFC DA outflow. Also, RS 127445 decreased the firing rate of DA neurons in the ventral tegmental area, but had no effect in the substantia nigra pars compacta. Finally, both RS 127445 and LY 266097 reversed PCP-induced deficit in NOR test, and reduced PCP-induced hyperlocomotion, without inducing catalepsy. These results demonstrate that 5-HT2BRs exert a differential control on DA pathway activity, and suggest that 5-HT2BR antagonists could represent a new class of drugs for improved treatment of schizophrenia, with an ideal profile of effects expected to alleviate cognitive and positive symptoms, without eliciting extrapyramidal symptoms.

Topics: Animals; Antipsychotic Agents; Dopamine; Dopaminergic Neurons; Dose-Response Relationship, Drug; Male; Prefrontal Cortex; Pyrimidines; Rats; Rats, Sprague-Dawley; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists

Second-generation antipsychotics, which have become the standard drug therapies for schizophrenia, are known to have a serotonin 5-HT(2A) receptor blocking effect in addition to a dopamine D₂ receptor blocking effect. However, although chlorpromazine (CPZ) has a 5-HT(2A) receptor blocking effect and has the profile of a second-generation antipsychotic in vitro, it loses this pharmacological profile in vivo. In order to elucidate the differences between the in vivo and in vitro pharmacological characteristics of CPZ, we used a radioreceptor assay to measure the anti-D₂ activity and the anti-5-HT(2A) activity of CPZ and five major metabolites of CPZ, and compared the results to the anti-D₂ activity and anti-5-HT(2A) activity of risperidone, zotepine, perospirone, the major metabolites of each of these drugs, and olanzapine, bromperidol, and haloperidol. The subjects were 182 patients who had received diagnoses of schizophrenia based on the DSM-IV criteria. The results revealed that CPZ exhibited little anti-5-HT(2A) activity, regardless of the anti-D₂ activity level, and that none of the metabolites possessed anti-5-HT(2A) activity. However, both the parent compounds and the metabolites of each of the second-generation antipsychotics possessed both anti-D₂ activity and anti-5-HT(2A) activity. This clarified that, unlike second-generation antipsychotics, the reason CPZ loses its second-generation antipsychotic profiles in vivo is because it does not have any metabolites that possess anti-5-HT(2A) activity.

Topics: Adult; Algorithms; Antipsychotic Agents; Biotransformation; Brain; Chlorpromazine; Diagnostic and Statistical Manual of Mental Disorders; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Female; Haloperidol; Humans; Male; Middle Aged; Neurons; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Young Adult

The aim of this prospective observational study was to verify the tolerability and safety profile of risperidone in a sample of antipsychotic-naive children/adolescent patients having a different psychiatric diagnosis. Twenty-two (mean age of 12±3.2) antipsychotic-naive patients who started therapy with risperidone were recruited. The assessment involved anthropometric data (weight, height, BMI, BMI z-score and BMI percentile), cardiovascular parameters (blood pressure and QTc interval) and blood tests (levels of glucose, triglycerides, total cholesterol, glutamic oxaloacetic and pyruvic transaminases, γ-glutamyl transferase, prolactin, free triiodothyronine, free thyroxine, thyroid-stimulating hormone, thyroglobulin, antithyroid peroxidase and antithyroglobulin). After an average follow-up of 6 months of risperidone therapy, a statistically significant increase in weight and body composition was observed. Furthermore, an increase in serum levels of prolactin was observed in 50% of patients. No other significant changes in metabolic and cardiovascular parameters were found. Although an increase in these parameters was detected, it remained in the normal range. This study suggests the use of specific protocols for monitoring children/adolescents treated with second-generation antipsychotics to manage the metabolic long-term complications and progression to more severe disease states.

Topics: Adolescent; Antipsychotic Agents; Attention Deficit and Disruptive Behavior Disorders; Body Composition; Body Mass Index; Child; Child Development Disorders, Pervasive; Diagnostic and Statistical Manual of Mental Disorders; Dopamine Antagonists; Drug Monitoring; Female; Follow-Up Studies; Humans; Male; Prolactin; Risperidone; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Tic Disorders; Up-Regulation; Weight Gain

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

Although the advent of atypical, second-generation antipsychotics (SGAs) has resulted in reduced likelihood of akathisia, this adverse effect remains a problem. It is known that extrapyramidal adverse effects are associated with increased drug occupancy of the dopamine 2 receptors (DRD2). The A1 allele of the DRD2/ANKK1, rs1800497, is associated with decreased striatal DRD2 density. The aim of this study was to identify whether the A1(T) allele of DRD2/ANKK1 was associated with akathisia (as measured by Barnes Akathisia Rating Scale) in a clinical sample of 234 patients who were treated with antipsychotic drugs. Definite akathisia (a score ≥ 2 in the global clinical assessment of akathisia) was significantly less common in subjects who were prescribed SGAs (16.8%) than those prescribed FGAs (47.6%), p < 0.0001. Overall, 24.1% of A1+ patients (A1A2/A1A1) who were treated with SGAs had akathisia, compared to 10.8% of A1- (thus, A2A2) patients. A1+ patients who were administered SGAs also had higher global clinical assessment of akathisia scores than the A1- subjects (p = 0.01). SGAs maintained their advantage over FGAs regarding akathisia, even in A1+ patients who were treated with SGAs. These results strongly suggested that A1+ variants of the DRD2/ANKK1 Taq1A allele do confer an associated risk for akathisia in patients who were treated with SGAs, and these variants may explain inconsistencies found across prior studies, when comparing FGAs and SGAs.

Topics: Adult; Akathisia, Drug-Induced; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Community Mental Health Centers; Cross-Sectional Studies; Diagnostic and Statistical Manual of Mental Disorders; Dopamine D2 Receptor Antagonists; Female; Genetic Association Studies; Genetic Predisposition to Disease; Hospitals, Teaching; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Prevalence; Protein Serine-Threonine Kinases; Queensland; Receptors, Dopamine D2; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists

Topics: Animals; Dopamine D2 Receptor Antagonists; Drug Design; Glycine Plasma Membrane Transport Proteins; Humans; Molecular Targeted Therapy; Receptor, Serotonin, 5-HT2A; Receptors, Metabotropic Glutamate; Research; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists

Deficits in incentive motivation, the energizing of behavior in pursuit of a goal, occur in many psychiatric disorders including schizophrenia. We previously reported deficits in both cognition and incentive motivation in a transgenic mouse model of increased striatal-specific dopamine D2 receptor (D2R) density (D2R-OE mice). This molecular alteration is observed in patients with schizophrenia, making D2R-OE mice a suitable system to study the cellular and molecular mechanisms of motivation and avolition, as well as a tool for testing potential therapies against motivational deficits.. Behavioral studies using operant conditioning methods were performed both to further characterize the incentive motivation deficit in D2R-OE mice and test a novel pharmacological treatment target that arose from an unbiased expression study performed using gene chips and was validated by quantitative reverse transcription polymerase chain reaction, in situ hybridization, and immunohistochemistry.. The reluctance of D2R-OE mice to work is due neither to intolerance for low rates of reward, decreased reactivity to reward, nor increased sensitivity to satiety or fatigue but to a difference in willingness to work for reward. As in patients with schizophrenia, this deficit was not ameliorated by D2R blockade, suggesting that reversal of the motivational deficit by switching off the transgene results from molecular changes downstream of D2R overexpression. We observed a reversible increase in serotonin subtype 2C (5-HT2C) receptor expression in D2R-OE mice. Systemic injection of a 5-HT2C receptor antagonist increased incentive motivation in D2R-OE and control mice.. We propose that targeting 5-HT2C receptors may be a useful approach to modulate incentive motivation in psychiatric illness.

Topics: Affective Symptoms; Aminopyridines; Analysis of Variance; Animals; Conditioning, Operant; Corpus Striatum; Disease Models, Animal; Gene Expression; Indoles; Mice; Mice, Transgenic; Motivation; Receptor, Serotonin, 5-HT2C; Receptors, Dopamine D2; Reward; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Up-Regulation

Abnormalities in both the hippocampal region and in serotonergic transmission are evident in patients with schizophrenia. We previously found that rats with serotonergic lesions targeting the dorsal hippocampus show altered psychotropic drug-induced hyperlocomotion and prepulse inhibition (PPI), behavioural paradigms relevant to aspects of schizophrenia. The present study explored the effect of serotonin depletion (>70%) along the dorsoventral axis of the hippocampus, or of partial serotonin depletion (∼50%) in the ventral hippocampus, on PPI modulation by acute antipsychotic drug treatment. We also used receptor binding autoradiography to investigate the neurochemical basis of behavioural effects. Following micro-injection of 5,7-dihydroxytryptamine, neither hippocampal serotonin depletion or partial serotonin depletion in the ventral hippocampus altered baseline PPI, startle magnitude or startle habituation. Acute treatment with clozapine or haloperidol had minimal effects on PPI in these lesioned rats or sham-operated controls. In contrast, risperidone treatment increased PPI to a significantly greater extent in rats with hippocampal serotonin depletion, an effect which was most prominent at low prepulse intensities. Partial serotonin depletion in the ventral hippocampus did not alter PPI modulation by risperidone. Neither type of serotonergic lesion altered the densities of 5-HT(1A) or 5-HT(2A) receptors in the hippocampus; serotonin transporters or 5-HT(1A) autoreceptors on raphe cell bodies; or dopamine transporters, D(1) or D(2) receptors in forebrain regions efferent to the hippocampus and implicated in schizophrenia, such as the nucleus accumbens. However, levels of [(3)H]mesulergine binding to 5-HT(2C) receptors were increased by approximately 70% in the dorsal hippocampus of rats with serotonin depletion in this region, while those in the ventral hippocampus were unaffected. Therefore, despite intact baseline PPI, abnormal PPI regulation in rats with >70% serotonin depletion in the hippocampus was unmasked by acute risperidone treatment. Selective upregulation of 5-HT(2C) receptors in the dorsal, but not ventral, hippocampus of these lesioned rats suggests that hippocampal 5-HT(2C) receptors vary in their adaptability to changes in serotonergic tone along the dorsoventral axis. These findings suggest that 5-HT(2C) receptors in the dorsal hippocampus may contribute to risperidone-induced enhancement of PPI.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Ergolines; Hippocampus; Male; Nerve Tissue Proteins; Neural Inhibition; Neurons; Organ Specificity; Random Allocation; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2C; Reflex, Startle; Risperidone; Schizophrenia; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists

To document the effects of combining loxapine with aripiprazole for refractory hallucinations in 2 patients with chronic schizophrenia.. Two patients with schizophrenia and auditory hallucinations that were unresponsive to what was considered adequate treatment with multiple typical and atypical antipsychotic medications given over several years were prescribed a combination of aripiprazole 20-30 mg and high-dose loxapine (100-300 mg/day). Both patients had refused clozapine and depot antipsychotics. Aripiprazole/loxapine therapy resolved hallucinations in both patients, and discontinuation of either medication resulted in a return of persecutory voices. Breakthrough hallucinations in both individuals responded to increasing the loxapine dosage. Adverse effects included hypersalivation and tremor, which were treated with benztropine and propranolol. The patients also reported mild sedation, which resolved after several weeks of treatment. Both patients continued to do well during 2 years after starting this combination of medications.. Recent research has indicated serotonergic and dopaminergic abnormalities in the superior temporal gyrus of patients with a history of chronic auditory hallucinations. Both loxapine and aripiprazole have effects on dopaminergic and postsynaptic serotonergic (5-HT₂A) receptor systems, which could account for synergistic effects in treating refractory hallucinations. The combination appears safe, even when loxapine is given in high dosages. Patients should be monitored for the development of parkinsonian tremors.. The combination of aripiprazole and high-dose loxapine should be considered in patients with schizophrenia who develop treatment-refractory hallucinations, particularly those who are unwilling to accept treatment with either depot antipsychotics or clozapine.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Dose-Response Relationship, Drug; Drug Monitoring; Drug Resistance; Drug Therapy, Combination; Hallucinations; Humans; Loxapine; Male; Middle Aged; Piperazines; Quinolones; Schizophrenia; Serotonin 5-HT2 Receptor 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

A recent Finnish study reported that long-term cumulative exposure to any antipsychotic treatment was related to lower mortality than was no drug exposure. We hypothesize that the antipsychotic 5-HT2A receptor blockade might protect from ischemic heart disease and buffer the deleterious metabolic effects of antipsychotics. The 5-HT2A receptor may be involved in vascular smooth muscle contraction, coronary artery spasms, platelet aggregation and thrombus formation. 5-HT2A receptor blockade might protect from ischemic heart disease by decreasing platelet aggregation and myocardium hypertrophy. Long-term follow-up studies are needed to clearly establish the long-term contribution of the various antipsychotic drugs to ischemic heart disease, and to explore our hypothesis that 5-HT2A receptor blockade may be protective for cardiovascular disease.

Topics: Antipsychotic Agents; Cause of Death; Humans; Long-Term Care; Myocardial Ischemia; Receptors, Histamine H1; Risk; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Weight Gain

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

Topics: Animals; Cell Line; Clinical Trials as Topic; Cyclopropanes; Drug Design; High-Throughput Screening Assays; Humans; Ligands; Methylamines; Mice; Phencyclidine; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2B; Receptor, Serotonin, 5-HT2C; Schizophrenia; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Stereoisomerism; Structure-Activity Relationship

Topics: Animals; Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Cognition; Dopamine D2 Receptor Antagonists; Drug Evaluation, Preclinical; Drug Industry; Humans; Perphenazine; Psychotic Disorders; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists

The superior temporal gyrus (STG) is strongly implicated in the pathophysiology of schizophrenia, particularly with regards to auditory hallucinations. In this study, using in situ quantitative autoradiography in postmortem tissue, we investigated the binding of the [3H]ketanserin to 5-HT(2A) receptors and [3H]mesulergine to 5-HT(2C) receptors in the left STG of 8 male schizophrenic patients compared to 8 control subjects. A strong [3H]ketanserin binding was observed in the STG, however there was a very weak [3H]mesulergine binding in the STG. A significant decrease in binding of [(3)H]ketanserin was clearly observed in schizophrenia patients in comparison with control subjects. There were no significant correlations between 5-HT(2A) binding density and age, postmortem intervals, or brain pH. These results suggest that the alterations of the 5-HT(2A) receptors contribute to the pathophysiology of the STG in schizophrenia. Furthermore, there is a clear tendency for a positive correlation between 5-HT(2A) and muscarinic M1 receptor bindings, and for negative correlations between 5-HT(2A) and GABA(A) receptor bindings and between muscarinic M1 and GABA(A) receptor bindings. This provides a possible mechanism of auditory hallucinations through interactions between 5-HT(2A), acetylcholine muscarinic and GABA transmissions in the STG in schizophrenia.

Topics: Adolescent; Adult; Aged; Hallucinations; Humans; Male; Middle Aged; Protein Binding; Receptor, Serotonin, 5-HT2A; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Temporal Lobe

The prefrontal cortex (PFC) is involved in the pathophysiology of schizophrenia. PFC neuronal activity is modulated by monoaminergic receptors for which antipsychotic drugs display moderate-high affinity, such as 5-HT(2A) and alpha(1)-adrenoceptors. Conversely, PFC pyramidal neurons project to and modulate the activity of raphe serotonergic neurons and serotonin (5-HT) release. Under the working hypothesis that atypical antipsychotic drugs may partly exert their action in PFC, we assessed their action on the in vivo 5-HT release evoked by increasing glutamatergic transmission in rat medial PFC (mPFC). This was achieved by applying S-AMPA in mPFC (reverse dialysis) or by disinhibiting thalamic excitatory afferents to mPFC with bicuculline. The application of haloperidol, chlorpromazine, clozapine and olanzapine in mPFC by reverse dialysis (but not reboxetine or diazepam) reversed the S-AMPA-evoked local 5-HT release. Likewise, the local (in mPFC) or systemic administration of these antipsychotic drugs reversed the increased prefrontal 5-HT release produced by thalamic disinhibition. These effects were shared by the 5-HT(2A) receptor antagonist M100907 and the alpha(1)-adrenoceptor antagonist prazosin. However, raclopride (DA D2 antagonist) had very modest effects. These results suggest that, besides their action in limbic striatum, antipsychotic drugs may attenuate glutamatergic transmission in PFC, possibly by interacting with 5-HT(2A) and/or alpha(1)-adrenoceptors.

Topics: Adrenergic alpha-1 Receptor Antagonists; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Antipsychotic Agents; Excitatory Amino Acid Agonists; GABA Antagonists; Glutamic Acid; Male; Microdialysis; Neural Inhibition; Norepinephrine; Prefrontal Cortex; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2A; Receptors, Adrenergic, alpha-1; Receptors, AMPA; Schizophrenia; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Synaptic Transmission; Thalamus

Topics: Anticonvulsants; Antipsychotic Agents; Brain; Brain Chemistry; Dose-Response Relationship, Drug; Electroencephalography; Female; Haloperidol; Humans; Imidazoles; Indoles; Middle Aged; Phenytoin; Receptor, Serotonin, 5-HT2C; Schizophrenia; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Status Epilepticus; Treatment Outcome

Topics: Antipsychotic Agents; Aripiprazole; Drug Therapy, Combination; Haloperidol; Humans; Hyperprolactinemia; Piperazines; Quinolones; Receptors, Dopamine D2; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Synaptic Transmission

Topics: Antipsychotic Agents; Aripiprazole; Dopamine Agonists; Female; Humans; Male; Middle Aged; Paranoid Disorders; Piperazines; Quinolones; Receptor, Serotonin, 5-HT1A; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists

Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at Dopamin D2- and Serotonin-5-HT1A-receptors as well as an antagonism at Serotonin-5-HT2A-receptors. Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability. The special pharmacodynamics of aripiprazole are described herein.

Topics: Antipsychotic Agents; Aripiprazole; Cerebral Cortex; Corpus Striatum; Dopamine Agonists; Humans; Limbic System; Mesencephalon; Neural Pathways; Piperazines; Quinolones; Receptors, Dopamine D2; Schizophrenia; Schizophrenic Psychology; Serotonin 5-HT2 Receptor Antagonists; Treatment Outcome

Topics: Adrenergic beta-1 Receptor Antagonists; Animals; Antipsychotic Agents; Brain; Disease Models, Animal; Dopamine; Dopamine D2 Receptor Antagonists; Humans; Nerve Net; Norepinephrine; Receptor, Serotonin, 5-HT2A; Receptors, Adrenergic, beta-1; Receptors, Dopamine D2; Schizophrenia; Serotonin; Serotonin 5-HT2 Receptor Antagonists

Antipsychotic drugs (APD) are widely prescribed for the treatment of schizophrenia. The APD are differentiated into typical and atypical based on the lower incidence of extra-pyramidal side-effects associated with the newer atypical APD. It was suggested that atypicality may arise from an interaction with the 5-hydroxytryptamine (5-HT)(2) receptor and specifically on the 5-HT(2):dopamine D(2) affinity ratio. It is now realised that multiple subtypes of these receptors exist and that in addition, atypical APD interact with many monoamine receptors. The aim of the present study was to characterise the interaction of APD with a variety of monoamine receptors in terms of both affinity and efficacy. The data produced has highlighted that the atypical profile of APD such as olanzapine and clozapine may reflect antagonism of the 5-HT(2A) and 5-HT(2C) receptors, whilst that of, ziprasidone and quetiapine may reflect partial agonist activity at the 5-HT(1A) receptor, and that of aripiprazole may reflect partial agonist activity at the 5-HT(1A) receptor as well as is its claimed partial agonist activity at the dopamine D(2) receptor.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Binding, Competitive; Biogenic Monoamines; CHO Cells; Clozapine; Cricetinae; Dibenzothiazepines; Dopamine; Humans; Olanzapine; Piperazines; Quetiapine Fumarate; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Receptors, Dopamine; Receptors, Serotonin; Schizophrenia; Serotonin; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Serotonin Receptor Agonists; Synaptic Transmission; Thiazoles

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

Risperidone is a widely used atypical antipsychotic with certain advantages over typical antipsychotics. Although variations in the efficacy of treatment with risperidone have been observed, no specific predictable marker has been identified as of yet. In all, 73 Japanese patients with schizophrenia were given risperidone for 8 weeks, and clinical symptoms were evaluated using the Positive and Negative Syndrome Scale (PANSS). Six candidate polymorphisms (HTR2A -1438G>A, 102T>C, H452Y; DRD2 -141delC, Taq I A; COMT V158M) were genotyped. The diplotype configuration for each individual was estimated by the maximum-likelihood method. Multiple linear regressions were used to analyze the effects of these haplotypes/genotype and other prognostic factors on PANSS scale performance. After adjustment for the effects of patient-related variables, HTR2A diplotype and COMT genotype, as well as other potential prognostic factors, did not significantly influence the clinical performance. A DRD2 haplotype tended to correlate with better clinical performance. Compared with patients who had Ins-A2/Ins-A2 diplotype (n=25), PANSS total scores of patients with Ins-A2/Del-A1 diplotype (n=10) showed 40% greater improvement (P=0.03). The PANSS total scores of patients with HTR2A A-T/A-T diplotype (n=22) tended to show 15% worse improvement compared with A-T/G-C diplotype (n=33) (P=0.06). These results should be treated with caution because of limitations due to small sample size, heterogeneity of patients with respect to past antipsychotic use history, and no correction for multiple corrections. However, the present findings generate important hypotheses in a sample of Japanese schizophrenia patients that may lay the foundation for future pharmacogenomics investigations in other populations.

Topics: Adult; Antipsychotic Agents; Catechol O-Methyltransferase; Chi-Square Distribution; Dopamine D2 Receptor Antagonists; Female; Humans; Male; Middle Aged; Polymorphism, Genetic; Psychotic Disorders; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Risperidone; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Statistics, Nonparametric

With the introduction of conventional antipsychotics in the 1950s, clinicians began to expect effective treatment of positive symptoms of schizophrenia. However, these drugs do not resolve negative and cognitive symptoms of schizophrenia and are also associated with serious side effects, including extrapyramidal side effects (EPS) and tardive dyskinesia. In 1989, clozapine was introduced and labeled the first new antipsychotic owing to its improved efficacy and side-effect profile. Clozapine proved effective in alleviating many of the positive, negative, and cognitive symptoms of schizophrenia, without causing inevitable EPS or tardive dyskinesia. Over the past decade, a number of different new antipsychotics have been developed. These drugs have an affinity for multiple dopamine-receptor subtypes as well as serotonin, norepinephrine, and glutamate receptors, allowing for better treatment outcomes. The antagonism of the 5-HT2A receptor may be responsible for improvement in negative symptoms and decrease in EPS. In addition to providing enhanced efficacy, the affinity of the new drugs for multiple receptors introduces new side effects not seen with the conventional agents, including weight gain. Each new antipsychotic has a unique receptor-binding profile that corresponds to its pharmacologic and side-effect profile. Understanding the differences in mechanisms of action of new antipsychotics will allow physicians to better choose treatment that meets the needs of each individual patient.

Topics: Antipsychotic Agents; Brain; Dopamine D2 Receptor Antagonists; Dyskinesia, Drug-Induced; Humans; Schizophrenia; Schizophrenic Psychology; Serotonin 5-HT2 Receptor Antagonists; Treatment Outcome; Weight Gain

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

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

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