clozapine and Mental-Disorders

There have been concerns that clozapine treatment may undermine the capacity of the body to fight infection and increase the vulnerability to contracting COVID-19. This review of recent cohort studies investigated (1) whether people with a severe psychiatric disorder are at increased risk of COVID-19 and complications, (2) the immunological response of clozapine-users who contract COVID-19, and (3) patients' perspectives on COVID-19 and the pandemic response.. A systematic search of EMBASE, Medline, Pubmed, and PsycINFO databases using PRISMA guidelines using "COVID-19", "clozapine", and "vaccination" terms.. 18 studies (out of 330 identified) met all criteria (N = 119 054 including 8045 on clozapine). There was no strong evidence that clozapine users may be at increased risk of contracting COVID-19 or developing complications after adjusting for medical comorbidities. Hematological studies showed temporary reductions in neutrophils in COVID-19-positive patients and vaccination suggesting a clozapine effect in defence against infection. Vaccination studies did not report major adverse effects. Increased plasma levels of clozapine and neutropenia however point to COVID-19-related interference of clozapine metabolism. Patient surveys reported limited impact on mental health and positive attitudes regarding pandemic response.. This review did not find compelling evidence that the immune system of clozapine users put them at risk of COVID-19 and further complications. Evidence of drug-infection interactions however points to the importance of adhering to consensus guidelines about clozapine therapy during the pandemic. More evidence using longitudinal designs is required to examine the longer-term effects of COVID-19 and vaccination in this vulnerable population.

Topics: Antipsychotic Agents; Clozapine; COVID-19; Humans; Mental Disorders; Outcome Assessment, Health Care; Prevalence

Previous research has investigated the efficacy of clozapine in reducing suicidality in patients with schizophrenia and schizoaffective disorder. We aimed to systematically review published evidence, including studies concerning clozapine administration to treat: (a) refractory suicidality in other mental disorders, including bipolar disorder and borderline and other personality disorders; and (b) refractory cases of non-suicidal self-injury.. We performed a PUBMED-search (last day: July 17, 2022) of English-language studies, combining the keywords "clozapine", "suicidality", and "suicide" with various psychopathological terms (e.g. "schizophrenia"). All duplications were eliminated.. Fifty-one studies were eligible for inclusion in the review. Most studies suggest a superior anti-suicide effect of clozapine in schizophrenia/schizoaffective disorder, compared to other antipsychotics, or no antipsychotic therapy, which is not due to the close monitoring of patients for blood dyscrasias. No consensus exists as to whether other antipsychotic drugs share this effect. Discontinuation of clozapine is associated with increases in suicidality. Reductions in refractory suicidality/NSSI are observed in clozapine-treated patients with bipolar disorder or borderline personality disorder, but the evidence is limited. Potential biological underpinnings of the anti-suicide effect of clozapine include its unique profile of modulation of brain neurotransmitters; its non-selectivity for neurotransmitter receptors; specific genetic and hormonal factors; effects on neuroinflammation; and ability to elicit epileptiform activity.. The superior anti-suicide effect of clozapine in schizophrenia/schizoaffective disorder patients is well established. It may have a role in severe and refractory cases of suicidality and non-suicidal self-injury in patients with bipolar disorder or borderline personality disorder, but the level and quality of supporting evidence is limited.

Topics: Antipsychotic Agents; Clozapine; Humans; Mental Disorders; Schizophrenia; Suicide

Pharmacological treatments used for psychiatric disorders, such as clozapine, demonstrate large interindividual variability in terms of possible adverse effects and therapeutic benefit. This variability can be explained by multiple factors, including pharmacogenetic factors. Clozapine efficacy can be impacted by CYP polymorphisms. A growing body of literature on pharmacogenetics suggests the clinical benefit of concomitant use of clozapine and fluvoxamine to improve global pharmacotherapeutic management. This article reviews and discusses available clinical and pharmacological data and limitations of clozapine augmentation with fluvoxamine based on pharmacogenetic rationale and clinical experience. The aim is to provide an updated approach on how to use the pharmacological and pharmacogenetic profile to improve clozapine efficacy and tolerance in severely ill patients.

Topics: Antipsychotic Agents; Clozapine; Fluvoxamine; Humans; Mental Disorders; Pharmacogenetics; Psychiatry

Though clozapine is recommended for treatment of tardive dyskinesia (TD) relating to the use of antipsychotic medications, studies comprehensively investigating the treatment effect of clozapine on TD are still limited.. This review examines the effectiveness of clozapine as an intervention for tardive dyskinesia and dystonia in patients with all psychiatric conditions. Effectiveness of clozapine, duration to exert the effect and dosage used were also analysed.. A search in the PubMed, PsycINFO and clinicaltrials databases was performed, using the search terms "Clozapine" AND "dyskinesia" OR "dystonia". Full-text articles that reported the use of clozapine to treat abnormal involuntary movements and were written in English were included.. A total of 48 studies were identified, of which 13 were clinical trials and 35 were case reports. Significant improvement was seen in 86.7% of patients with schizophrenia spectrum disorders (average dose of clozapine = 355 mg/day) and 93% of patients with other psychiatric disorders (average dose of clozapine = 152.5 mg/day). Patients with other psychiatric diagnoses had faster improvement than the patients with schizophrenia spectrum disorders. Variation in improvements and dosage were also seen in the clinical trials.. Results suggested an overall effectiveness of clozapine in the treatment of TD for patients with a range of psychiatric conditions. Different response time and clozapine dosage were seen in patients with different psychiatric conditions, suggesting different treatment protocols are required for different conditions. Most of the studies identified are of inadequate qualities, highlighting the need for high quality studies to provide clearer evidence.

Topics: Antipsychotic Agents; Clozapine; Humans; Mental Disorders; Schizophrenia; Tardive Dyskinesia

The COVID-19 pandemic is a particularly relevant threat to mentally ill patients, and it constitutes a new challenge for health care providers. To the best of our knowledge, there is not any embracing published review about the use of psychotropic drugs during the COVID-19 pandemic.. Non-systematic literature review. A search in the PubMed database was performed, with the terms 'psychotropic drugs', 'COVID-19', 'psychiatry' and 'pandemic'. Consensus and clinical guidelines about psychotropic drugs and COVID-19 approach, published by scientific societies, governmental entities and drug regulatory agencies were included.. We present the recommendations about the use of psychotropic drugs during the COVID-19 pandemic, in the outpatient and inpatient settings. The treatment of affective bipolar disorder and schizophrenia have now added increased difficulties. Some psychotropic drugs interfere with the pathophysiology of the novel coronavirus infection and they could interact with the drugs used in the treatment of COVID-19. Some patients will need pharmacological interventions due to the presence of delirium. Smoking cessation changes the serum levels of some psychotropic drugs and may influence their use.. The COVID-19 pandemic has created new challenges in clinical practice. Psychiatric patients are a vulnerable population and often a careful clinical, laboratorial and electrocardiographic evaluation may be needed, particularly in those diagnosed with COVID-19. The regular treatment of mentally ill patients with COVID-19 presents increased complexity.. Introdução: A pandemia de COVID-19 constitui uma ameaça particularmente relevante para os portadores de doença mental e um novo desafio para os profissionais que os acompanham. Até à data, tanto quanto sabemos, não existe qualquer revisão abrangente publicada relativamente à utilização de fármacos psicotrópicos durante a pandemia COVID-19. Material e Métodos: Revisão não sistemática da literatura. A pesquisa na PubMed foi realizada com os termos ‘psychotropic drugs’, ‘COVID-19’, ‘psychiatry’ e ‘pandemic’. Foram incluídos os consensos e as normas publicadas pelas sociedades científicas, entidades governamentais e agências regulamentares de medicamentos. Resultados e Discussão: Apresentam-se recomendações relativamente à utilização de psicofármacos durante a pandemia COVID-19, em contexto de ambulatório e de internamento. O tratamento da perturbação afetiva bipolar e da esquizofrenia tem agora dificuldades acrescidas. Alguns psicofármacos interferem com os mecanismos fisiopatológicos envolvidos na infeção pelo novo coronavírus e têm interações com os fármacos utilizados no tratamento da COVID-19. Em doentes com COVID-19 e com delirium, a utilização de psicofármacos poderá ser necessária. A cessação tabágica altera os níveis séricos de alguns psicofármacos e pode condicionar a sua utilização. Conclusão: A pandemia de COVID-19 coloca novos desafios na prática clínica. Os doentes psiquiátricos constituem uma população vulnerável, sendo frequentemente necessária uma avaliação clínica, laboratorial e eletrocardiográfica cuidadosa, naqueles com o diagnóstico de COVID-19. Os doentes mentais com COVID-19 apresentam uma complexidade acrescida na gestão da sua terapêutica habitual.

Topics: Antiviral Agents; Benzodiazepines; Betacoronavirus; Bipolar Disorder; Body Temperature Regulation; Buprenorphine; Clozapine; Coronavirus Infections; COVID-19; Delayed-Action Preparations; Drug Interactions; Hospitalization; Humans; Lithium Compounds; Mental Disorders; Methadone; Narcotic Antagonists; Pandemics; Pneumonia, Viral; Psychotropic Drugs; SARS-CoV-2; Schizophrenia; Smoking Cessation Agents; Valproic Acid

BACKGROUND AND OBJECTIVE: Individuals with severe mental illness experience increased morbidity and mortality as a result of metabolic problems that may partly be related to the adverse effects of antipsychotics. Compared with first-generation antipsychotics, second-generation antipsychotics collectively are considered to have stronger associations with lipid abnormalities, but evidence for this specific claim has not been systematically reviewed. The objective of this review was to evaluate the risk of dyslipidaemia with second-generation versus first-generation antipsychotics amongst individuals with severe mental illness.. Major electronic databases were searched until November 2018. Studies were eligible if they were cross-sectional, cohort, case-control or interventional, where any individual second-generation antipsychotic was directly compared with first-generation antipsychotics in individuals with severe mental illness, and where lipid metabolism was a primary or secondary outcome. The evidence was reviewed and appraised according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.. In total, 18 studies were eligible. The reported associations between second-generation antipsychotics vs. first-generation antipsychotics with dyslipidaemia were inconsistent, with high variability between studies and only a full qualitative synthesis was feasible. We had sufficient data, however, to undertake limited meta-analyses for clozapine, olanzapine and risperidone, all showing mildly elevated associations with dyslipidaemia "caseness" (clozapine, odds ratio 1.26, 95% confidence interval 1.16-1.38; olanzapine, odds ratio 1.29, 95% confidence interval 0.89-1.87; risperidone, odds ratio 1.05, 95% confidence interval 0.80-1.37) compared with first-generation antipsychotics, but heterogeneity was high (all I. There was considerable variation in study design and methodologies. Determining the comparative risk of second-generation vs. first-generation antipsychotics as a group of antipsychotics for lipid dysregulation may be of limited clinical utility, as drugs from either group have the potential to cause such adversity to varying degrees. It is therefore more valuable to consider the metabolic risks of specific antipsychotics rather than focusing on collective metabolic effects belonging to either antipsychotic group.

Topics: Antipsychotic Agents; Clozapine; Humans; Lipids; Mental Disorders; Olanzapine; Risperidone

This is a comprehensive review of antipsychotic (AP)-induced dysphagia and its complications: choking and pneumonia. Areas covered: Four PubMed searches were completed in 2018. The limited literature includes: 1) 45 case reports of AP-induced dysphagia with pharmacological mechanisms, 2) a systematic review of APs as a risk factor for dysphagia, 3) reviews suggesting adult patients with intellectual disability (ID) and dementia are prone to dysphagia (APs are a risk factor among multiple others), 4) studies of the increased risk of choking in patients with mental illness (APs are a contributing factor), 5) naturalistic pneumonia studies suggesting that pneumonia may contribute to AP-increased death in dementia, and 6) naturalistic studies suggesting that pneumonia may be a major cause of morbidity and mortality in clozapine patients. Expert commentary: The 2005 Food and Drug Administration requirement that package inserts warn of AP-induced dysphagia jumpstarted this area, but current studies are limited by: 1) its naturalistic nature, 2) the lack of dysphagia studies of patients with IDs and dementia on APs, and 3) the assumed indirect association between dysphagia with choking and pneumonia. Future clozapine studies on pneumonia, if they lead to a package insert warning, may have high potential to save lives.

Topics: Adult; Airway Obstruction; Antipsychotic Agents; Clozapine; Deglutition Disorders; Dementia; Drug Labeling; Humans; Intellectual Disability; Mental Disorders; Pneumonia; Risk Factors

Up to 75% of people with serious mental illness (SMI) such as schizophrenia and bipolar disorder have co-occurring substance use disorders (dual diagnosis). Dual diagnosis can have an adverse effect on treatment and prognosis of SMI.. To evaluate the effects of risperidone compared to treatment with other antipsychotics (first-generation and other second-generation antipsychotics) used in people with serious mental illness and co-occurring substance misuse.. On 6 January 2016 and 9 October 2017, we searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (including trial registers).. We selected randomised trials of risperidone versus any other antipsychotic in people with SMI and substance abuse (dual diagnosis). We included trials meeting our inclusion criteria and reporting useable data. We excluded trials that either did not meet our inclusion criteria or met our inclusion criteria but did not report any useable data.. We independently inspected citations and selected studies. For included studies, we independently extracted data and appraised study quality. For binary outcomes we calculated the risk ratios (RRs) and their 95% confidence intervals. For continuous outcomes we calculated the mean differences (MDs) and their 95% confidence intervals. We pooled data using random-effects meta-analyses and assessed the quality of evidence, creating a 'Summary of findings' table using the GRADE approach.. We identified eight randomised trials containing a total of 1073 participants with SMI and co-occurring substance misuse. Seven of these contributed useable data to the review. There was heterogeneity in trial design and measurement. Risperidone was compared to clozapine, olanzapine, perphenazine, quetiapine and ziprasidone. Few trials compared risperidone with first-generation agents. Few trials examined participants with a dual diagnosis from the outset and most trials only contained separate analyses of subgroups with a dual diagnosis or were secondary data analyses of subgroups of people with a dual diagnosis from existing larger trials.For risperidone versus clozapine we found no clear differences between these two antipsychotics in the reduction of positive psychotic symptoms (1 randomised controlled trial (RCT), n = 36, mean difference (MD) 0.90, 95% CI -2.21 to 4.01, very low quality evidence), or reduction in cannabis use (1 RCT, n = 14, risk ratio (RR) 1.00, 95% CI 0.30 to 3.35, very low quality evidence), improvement in subjective well-being (1 RCT, n = 36, MD -6.00, 95% CI -14.82 to 2.82, very low quality evidence), numbers discontinuing medication (1 RCT, n = 36, RR 4.05, 95% CI 0.21 to 78.76, very low quality evidence), extrapyramidal side-effects (2 RCTs, n = 50, RR 2.71, 95% CI 0.30 to 24.08; I² = 0%, very low quality evidence), or leaving the study early (2 RCTs, n = 45, RR 0.49, 95% CI 0.10 to 2.51; I² = 34%, very low quality evidence). Clozapine was associated with lower levels of craving for cannabis (1 RCT, n = 28, MD 7.00, 95% CI 2.37 to 11.63, very low quality evidence).For risperidone versus olanzapine we found no clear differences in the reduction of positive psychotic symptoms (1 RCT, n = 37, MD -1.50, 95% CI -3.82 to 0.82, very low quality evidence), reduction in cannabis use (1 RCT, n = 41, MD 0.40, 95% CI -4.72 to 5.52, very low quality evidence), craving for cannabis (1 RCT, n = 41, MD 5.00, 95% CI -4.86 to 14.86, very low quality evidence), parkinsonism (1 RCT, n = 16, MD -0.08, 95% CI -1.21 to 1.05, very low quality evidence), or leaving the study early (2 RCT, n = 77, RR 0.68, 95% CI 0.34 to 1.35; I² = 0%, very low quality evidence).For risperidone versus perphenazine, we found no clear differences in the number of participants leaving the study early (1 RCT, n = 281, RR 1.05, 95% CI 0.92 to 1.20, low-quality evidence).For risperidone versus quetiapine, we found no clear differences in the number of participants leaving th. There is not sufficient good-quality evidence available to determine the effects of risperidone compared with other antipsychotics in people with a dual diagnosis. Few trials compared risperidone with first-generation agents, leading to limited applicability to settings where access to second-generation agents is limited, such as in low- and middle-income countries. Moreover, heterogeneity in trial design and measurement of outcomes precluded the use of many trials in our analyses. Future trials in this area need to be sufficiently powered but also need to conform to consistent methods in study population selection, use of measurement scales, definition of outcomes, and measures to counter risk of bias. Investigators should adhere to CONSORT guidelines in the reporting of results.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Diagnosis, Dual (Psychiatry); Humans; Mental Disorders; Olanzapine; Patient Dropouts; Perphenazine; Piperazines; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Substance-Related Disorders; Thiazoles

New clozapine optimization strategies are warranted, as some patients do not achieve sufficient response and experience various adverse effects. Fluvoxamine is a potent CYP1A2 inhibitor and may increase the ratio of clozapine to its primary metabolite N-desmethylclozapine (NDMC).. This study aims to review all pharmacodynamic effects and the adverse effect profile of changing the clozapine/NDMC ratio with adjunctive fluvoxamine.. MEDLINE, Embase, and the Cochrane Library were searched with the search terms "clozapine" and "fluvoxamine" without any time limit. Language was restricted to English, Scandinavian, Polish, and German. Studies were sorted for relevance based on title and abstract. Clinical recommendations of potential indications/effects were graded as level A, B, C, or D depending on studies of high, moderate, low, or very low quality, respectively.. Based on data from 24 case reports/series, seven cohort studies, and two randomized controlled trials, 241 patients were studied. Evidence (A) supported that adjunctive fluvoxamine increased clozapine plasma levels. This may increase the probability of response in patients, where sufficient clozapine plasma levels cannot be achieved. Adjunctive fluvoxamine reduced metabolic adverse effects of clozapine (B) but not agranulocytosis risk (B). Although depressive or obsessive-compulsive symptoms may improve, a SSRI with no CYP1A2 inhibition should rather be used (C). No studies investigated the effect of adjunctive fluvoxamine to minimize clozapine rebound psychosis (D) or to reduce the effects of smoking on clozapine plasma levels (D).. Adjunctive fluvoxamine may have clinical potentials for optimizing clozapine treatment but further clinical studies are warranted to explore the clinical implications.

Topics: Antidepressive Agents, Second-Generation; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Fluvoxamine; Humans; Mental Disorders

Clozapine (CLZ) is the prototype atypical antipsychotic and it has many advantages over other antipsychotic drugs. Several data suggest that both CLZ response and induced weight gain are strongly determined by genetic variability. However, results remain mainly inconclusive. We aim to review the literature data about pharmacogenetics studies on CLZ efficacy, focusing on pharmacodynamic genes. Further, we performed meta-analyses on response when at least three studies for each polymorphism were available. Sensitivity analyses were conducted on Caucasian population when feasible. Electronic literature search was performed to identify pertinent studies published until May 2014 using PubMed, ISI Web of Knowledge and PsycINFO databases. For meta-analyses, data were entered and analyzed through RevMan version 5.2 using a random-effect model. Our literature search yielded 9266 articles on CLZ; among these, we identified 59 pertinent pharmacogenetic studies. Genotype data were retrieved for 14 polymorphisms in 9 genes. Among these, we had available data from at least three independent samples for 8 SNPs in 6 genes to perform meta-analyses: DRD2 rs1799732, DRD3 rs6280, HTR2A rs6313, rs6311, rs6314, HTR2C rs6318, HTR3A rs1062613, TNFa rs1800629. Although literature review provided conflicting results, in meta-analyses three genetic variants within serotonin genes resulted associated to CLZ response: rs6313 and rs6314 within HTR2A gene and rs1062613 within HT3A gene. On the other hand, no clear finding emerged for CLZ-induced weight gain. Our results suggest a possible serotonergic modulation of CLZ clinical response.

Topics: Antipsychotic Agents; Clozapine; Databases, Factual; Humans; Mental Disorders; Pharmacogenetics; Weight Gain

Ever since clozapine was first synthesized and tested, it showed the unique property of having antipsychotic action but no Parkinson-like motor side effects. The antipsychotic basis of clozapine is to transiently occupy dopamine D2 receptors in the human striatum, in contrast to haloperidol and chlorpromazine, which have a prolonged occupation of D2 receptors. The chemical structure of clozapine facilitates a relatively rapid dissociation from D2 receptors. After short-term occupation of D2 receptors, peak neural activity raises synaptic dopamine, which then displaces clozapine. While clozapine also occupies other types of receptors, they may not have a significant role in preventing parkinsonism. Clozapine's transient occupation of D2 receptors permits patients to move easily and comfortably.

Topics: Animals; Antipsychotic Agents; Clozapine; Corpus Striatum; Humans; Mental Disorders; Protein Binding; Receptors, Dopamine D2

To review recent work on the haematological toxicity of clozapine and some other drugs used in psychiatry concerning especially (i) the mechanism of antipsychotic-induced neutropenia/agranulocytosis, (ii) criteria for clozapine prescribing in benign ethnic neutropenia, (iii) options in the event of worrying falls in white cell count (WCC), including measures to boost WCC with or without continued clozapine administration, (iv) criteria for clozapine rechallenge in the event that treatment was suspended because of a fall in WCC and (v) safety concerns regarding clozapine in children/adolescents.. There remain several difficult areas, including the criteria for clozapine rechallenge. Experience has emphasised (i) the role of appropriate timing of WCC sample collection to ensure that clozapine is not withdrawn unnecessarily and (ii) the success of agents such as filgrastim in promoting rapid production of granulocytes if the situation so demands. On the other hand, the use of lithium to promote a leucocytosis has taken hold without a clear risk: benefit analysis. Be this as it may, should patients decide that they no longer wish to undergo WCC monitoring after 12 months on clozapine, cessation of monitoring is probably preferable to stopping the drug since overall mortality is decreased in patients treated with clozapine.

Topics: Agranulocytosis; Animals; Antipsychotic Agents; Clozapine; Hematologic Diseases; Humans; Mental Disorders; Neutropenia

Atypical antipsychotic drugs have less extra pyramidal side effects and are more effective to control the clinical manifestations of schizophrenia. However, their use may be associated to a higher incidence of weight gain, dyslipidemia, metabolic syndrome, glucose intolerance and type 2 diabetes mellitus. We performed a systematic literature search to evaluate the risk of type 2 diabetes mellitus incidence associated to the use of atypical antipsychotic drugs, compared to conventional treatment. If users of all types of atypical antipsychotic drugs are compared with users of conventional treatment, no significant differences in the incidence of type 2 diabetes mellitus were observed. If individual drugs are evaluated, clozapine and risperidone are associated with a higher risk of diabetes than haloperidol. Quetiapine is associated with a lower risk of diabetes than conventional treatment. The quality of the evidence found was low; therefore, new studies should been performed.

Topics: Antipsychotic Agents; Chronic Disease; Clozapine; Diabetes Mellitus, Type 2; Humans; Mental Disorders; Risk Factors; Risperidone

Clozapine was the first atypical 'broad spectrum' antipsychotic drug to be marketed and the first agent approved for the treatment of schizophrenia refractory to other medications. It is also effective for the treatment of aggressive behaviour in schizophrenic and demented patients and in the management of psychosis and aggression in Parkinson's disease and Lewy body dementia.. The aim of this review is to study the safety of clozapine for use in elderly patients.. An extensive Medline search was made. Some studies that were referenced in reports from our pharmacovigilance centre and from regulatory agencies such as the FDA, EMEA and WHO were included.. Clozapine treatment in the elderly requires a careful geriatric assessment. However, its use is strongly limited by the possibility of onset of severe adverse effects such as potentially fatal agranulocytosis, myocarditis and others such as seizures, weight gain and metabolic adverse effects.

Topics: Aged; Agranulocytosis; Antipsychotic Agents; Clozapine; Geriatric Assessment; Humans; Mental Disorders; Myocarditis; Parkinson Disease

Clozapine remains one of the most commonly used antipsychotic medications in China. As China has the largest population internationally on clozapine treatment, its experience and research findings are of keen interest to Western psychiatrists. However, most of the related papers have hitherto been published only in Chinese language journals. Here we review mainly Chinese-language publications on the use of clozapine in China. A descriptive study based on literature identified from searches of Medline and the China National Knowledge Infrastructure (CNKI) databases (1979-2007), and other hand-picked references. Unlike the situation in other countries, clozapine is still widely used for a number of psychiatric disorders in China, though the prescription of other second-generation antipsychotics (SGAs) is also increasing. About 25-60% of all treated patients with schizophrenia receive clozapine; and clozapine is preferred by some as a first-line treatment for schizophrenia. Clozapine is also used for other conditions such as mania, treatment-resistant depression and drug abuse. The average daily dose is between 200 and 400 mg. The incidence of leukopenia is 3.92% and agranulocytosis 0.21% in China, with about one third of reported cases of patients with agranulocytosis dying. Weight gain and clozapine-associated diabetes are also commonly reported in the Chinese population. Clozapine is currently the most commonly used treatment for schizophrenia in China. Chinese psychiatrists need to pay more attention to its potential toxic side effects when they make drug choices.

Topics: Antipsychotic Agents; China; Clozapine; Dose-Response Relationship, Drug; Drug Utilization; History, 20th Century; History, 21st Century; Humans; Mental Disorders

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clozapine; Diabetes Mellitus; Dibenzothiazepines; Dyslipidemias; Glucose Metabolism Disorders; Humans; Insulin Resistance; Mental Disorders; Obesity; Olanzapine; Phenothiazines; Piperazines; Quetiapine Fumarate; Quinolones; Risperidone; Schizophrenia; Thiazoles

Behavioural symptoms such as anxiety, depression and psychosis are common in Parkinson's disease (PD), and dementia occurs in about 90% of the patients. These symptoms can be more disabling than the motor dysfunction and they negatively impact quality of life, increase caregiver distress and are more frequently associated with nursing home placement. Depression can be treated with counselling and pharmacotherapy. Tricyclic antidepressants or selective serotonin reuptake inhibitors are widely used, but there is still need for controlled clinical trials. Management of psychosis in PD is complex and includes elimination of identifiable risk factors, reduction of polypharmacy and administration of atypical neuroleptics, which can alleviate psychotic symptoms without worsening motor functions. Clozapine is the best documented atypical neuroleptic shown to be effective against psychosis in PD patients. Cholinesterase inhibitors may prove additional benefit in psychotic PD patients. Recent evidence from small double-blind and open-label trials suggests that cholinesterase inhibitors may be effective in the treatment of dementia associated with PD.

Topics: Antipsychotic Agents; Anxiety Disorders; Cholinesterase Inhibitors; Clozapine; Dementia; Depressive Disorder; Humans; Mental Disorders; Parkinson Disease; Psychotic Disorders

Genetic factors play a significant role in predicting an individual's response to a drug. The response may be the desired therapeutic effect of the drug and also may be the undesirable development of adverse effects. This relationship between genes and drug response interests the pharmacogeneticist. This article aims to give an overview of the exciting discoveries made so far in the field of psychiatry, particularly concerning the response to antidepressants and antipsychotics, as well as to mention some of the more recent findings. The ultimate goal of pharmacogenetics is to provide medication "tailored" to the individual based on their genetic profile, and although this may currently seem a distant target, it has already begun to raise ethical questions, which also are discussed.

Topics: Antidepressive Agents; Antipsychotic Agents; Clozapine; Forecasting; Humans; Mental Disorders; Pharmacogenetics; Psychiatry; Treatment Outcome

Atypical antipsychotics offer superior safety and similar efficacy compared with conventional agents in adults with psychotic disorders. Consequently, atypical antipsychotics have been increasingly used in children and adolescents. Because most information now available on pediatric use comes from case reports and small open-label studies rather than large controlled trials, treatment in pediatric patients is often guided by experience with adults or based on limited evidence in youths. Although the literature contains reports on the use of each agent in this class in children, risperidone has been the focus of the greatest number of reports. However, the atypical antipsychotics are not interchangeable; each has a unique pharmacologic profile and may differ considerably in terms of adverse effects. Evidence on the use of atypical antipsychotics in children and adolescents is summarized in this review.

Topics: Adolescent; Age Factors; Antipsychotic Agents; Attention Deficit and Disruptive Behavior Disorders; Benzodiazepines; Bipolar Disorder; Child; Child Development Disorders, Pervasive; Clozapine; Dibenzothiazepines; Humans; Mental Disorders; Olanzapine; Piperazines; Quetiapine Fumarate; Risperidone; Schizophrenia; Thiazoles; Tic Disorders

Topics: Anti-Bacterial Agents; Antipsychotic Agents; Clozapine; Comorbidity; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP1A2 Inhibitors; Drug Administration Schedule; Drug Interactions; Humans; Mental Disorders; Respiratory Tract Infections

Five new antipsychotic drugs introduced in the United States in the last decade offer physicians the ability to treat patients with schizophrenia and bipolar mania without the adverse effects of the first-generation antipsychotics. In this article, the authors discuss the advantages and side effects of these agents and present a guide to help physicians choose the optimal drug in the most favorable formulation for each patient.

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clozapine; Diabetes Mellitus, Type 2; Dibenzothiazepines; Drug Administration Schedule; Humans; Hyperprolactinemia; Mental Disorders; Olanzapine; Patient Compliance; Piperazines; Practice Guidelines as Topic; Prescription Fees; Quetiapine Fumarate; Quinolones; Risk Assessment; Risperidone; Thiazoles; Torsades de Pointes; Treatment Outcome; Weight Gain

Topics: Adolescent; Adult; Age Factors; Aged; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Clinical Trials as Topic; Clozapine; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dibenzothiazepines; Female; Glucose; Haloperidol; Humans; Intellectual Disability; Male; Mental Disorders; Metabolic Syndrome; Middle Aged; Olanzapine; Quetiapine Fumarate; Retrospective Studies; Risk Factors; Risperidone; Schizophrenia; Sex Factors; Time Factors; Weight Gain

The atypical antipsychotics have been shown to have superior efficacy compared with typical antipsychotics such as haloperidol, particularly in the treatment of negative symptoms of schizophrenia. Furthermore, they induce less extrapyramidal effects. However, following clinical use, marked bodyweight gain has been frequently observed with some of the atypical antipsychotic drugs. In order to examine and compare the frequency, amount and conditions of bodyweight gain during treatment with atypical antipsychotics, studies concerning bodyweight gain with these agents were identified through a MEDLINE search from 1966 to March 2000. Although comparison is limited by the different designs and recruitment procedures of the reviewed studies, the available data support the notion that the frequency as well as the amount of bodyweight gain is high in patients treated with olanzapine (average bodyweight gain 2.3 kg/month), clozapine (1.7 kg/month), quetiapine (1.8 kg/month), and possibly also zotepine (2.3 kg/month). Moderate changes in bodyweight have been observed in the treatment with risperidone (average bodyweight gain 1.0 kg/month). Ziprasidone seems to induce only slight bodyweight changes (0.8 kg/month). Bodyweight gain most frequently occurs in the first 12 weeks of treatment. Patients who were underweight at the beginning of treatment are at highest risk of gaining bodyweight. The underlying pathomechanism still remains largely unclear. The relative receptor affinities of the atypical antipsychotics for histamine H1 receptors as well as the ratio of their affinity for serotonin 5-HT2 and dopamine D2 receptors appear to be the most robust correlate of bodyweight gain. Furthermore, the induction of leptin secretion may have an important impact on bodyweight gain in patients treated with atypical antipsychotics. Although many questions concerning the pathogenesis of bodyweight gain remain unresolved, this adverse effect has to be taken into consideration when prescribing the atypical antipsychotics, particularly in view its affect on compliance during long term treatment and the long term effects of obesity on mortality and morbidity.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Humans; Mental Disorders; Olanzapine; Pirenzepine; Quetiapine Fumarate; Receptors, Dopamine D2; Receptors, Histamine H1; Receptors, Serotonin; Risk Factors; Smoking Cessation; Weight Gain

As generic products become more available for the treatment of psychiatric disorders, clinicians must stay abreast of the U.S. Food and Drug Administration (FDA) requirements for the approval of generic drug products. The FDA declares that pharmaceutical equivalents only are therapeutically equivalent, and pharmacokinetic data are all that is usually required to determine therapeutic equivalence. The rationale behind the overall concept of bioequivalence is that if 2 pharmaceutical equivalents provide identical plasma concentration-time profiles in humans, there is no evidence to demonstrate that the 2 identical dosage forms will exhibit a difference in safety and efficacy. This article reviews current terminology used in abbreviated new drug applications for generic products, typical bioequivalence study designs, and FDA bioequivalence guidance for clozapine.

Topics: Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Approval; Drugs, Generic; Mental Disorders; Research Design; Therapeutic Equivalency; United States; United States Food and Drug Administration

The management of agitation and aggression in psychiatric inpatients is a significant clinical dilemma. Establishing a clear diagnosis and distinguishing whether aggression is an acute manifestation or a long-standing or repetitive problem are fundamental antecedents of medication treatment. For acute aggression, either benzodiazepines or antipsychotic medications (typical and atypical) are recommended choices. Currently, on the basis of efficacy, ease of use, and availability in multiple (tablet, liquid, intramuscular) preparations, typical antipsychotics such as loxapine should be considered as first choice for acute aggression (in psychosis). On the other hand, atypical antipsychotics, particularly clozapine, should be considered when aggression in psychosis persists and/or is repetitive. Typical antipsychotics are indicated for persistent aggression in psychosis when medication noncompliance is the obstacle to effective treatment.

Topics: Aggression; Antipsychotic Agents; Benzodiazepines; Clozapine; Humans; Loxapine; Mental Disorders; Olanzapine; Pirenzepine; Psychomotor Agitation; Psychotic Disorders; Risperidone; Schizophrenia; Schizophrenic Psychology

This article reviews the published clinical experience with atypical neuroleptics in children and adolescents.. A computerized literature search was conducted (MEDLINE, 1974-1998) to retrieve all reports on the use of atypical neuroleptics in children and adolescents. A hand search was performed as well. All relevant clinical data were collated by type of drug.. We found 5 blind placebo-controlled clinical trials (105 patients), 24 open-label clinical trials (387 patients), and 33 case series (115 patients) describing the use of the atypical neuroleptics clozapine, risperidone, olanzapine, sulpiride, tiapride, amisulpride, remoxipride, and clothiapine in children and adolescents. Some of these agents, especially clozapine, risperidone, and olanzapine, were found to be efficacious in the treatment of schizophrenia, bipolar disorders, and pervasive developmental disorders. The role of atypical neuroleptics as augmenters of serotonin reuptake inhibitors in obsessive-compulsive disorder is unclear. Risperidone appears to possess anti-tic properties in patients with Tourette's disorder.. The most convincing evidence of the efficacy of atypical neuroleptics in children and adolescents concerns clozapine in the treatment of schizophrenia. Data on other atypical neuroleptics in other disorders are still sparse, and further research is needed. Some of the atypical neuroleptics may become the first-line treatment for childhood schizophrenia and pervasive developmental disorders.

Topics: Adolescent; Adult; Age Factors; Antipsychotic Agents; Benzodiazepines; Child; Child Development Disorders, Pervasive; Clinical Trials as Topic; Clozapine; Dibenzothiazepines; Humans; Mental Disorders; Olanzapine; Pirenzepine; Psychiatric Status Rating Scales; Remoxipride; Risperidone; Schizophrenia; Treatment Outcome

Medical treatment of Parkinsonian syndromes is often complicated by psychiatric side effects such as confusional states, hallucinations and psychosis. Recent pilot studies report good clinical results with the atypical neuroleptic clozapine.. We report on 15 patients with Parkinsonian syndromes: 11 with idiopathic Parkinson's disease (IPD), 3 with multiple system atrophy (MSA) and 1 with postencephalitic Parkinsonism (SPP). The mean age was 68.8 +/- 10 years; the mean duration of Parkinsonian symptoms was 6.8 +/- 5.7 years. The Hoehn & Yahr grade was: 3.5 +/- 0.8. Eleven patients were suffering from psychotic episodes, 10 from hallucinations, 8 from confusional states. Clozpine was introduced at nighttime and dosage was modified until the appearance of clinical effect or intolerable side effects.. We report on an observed cumulative duration of clozapine treatment of 13 patient-years. The average treatment duration was 10.5 +/- 10.4 months. The mean daily dose was 33.3 +/- 30 mg (range: 6.2-100). There was at least transitory improvement of psychiatric symptoms in all patients. There was constant and complete improvement in 7 patients (46%) and satisfactory improvement in 5 patients (33.3%). The levodopa dosage was unchanged (mean dosage 563 +/- 232 mg), and the dosage of dopamine agonists was significantly increased. None of our patients experienced motor deterioration. Side effects comprised sialorrhoea, sedation, orthostatic hypotension, and delirium tremens and an epileptic seizure in one patient each. Two patients died suddenly at the 63rd and at the 86th day of treatment respectively, outside the hospital. These deaths seemed to be unrelated to the treatment. There was no agranulocytosis.. Clozapine is an efficient antipsychotic drug in Parkinsonian patients with no motor side effects in the dosages used. The effective dosage is very low in comparison to psychiatric patients. However various side effects may occur and close monitoring is required.

Topics: Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Clozapine; Female; Humans; Male; Mental Disorders; Middle Aged; Parkinson Disease

This article reviews the literature on the use of psychotropic drugs in pregnancy and lactation.. Medline search yielded more than five hundred titles. Articles were reviewed and ninety-one were selected for reference.. Fetal physiology and teratogenicity are discussed and the effects of specific drugs on the fetus and newborn are presented. When possible, recommendations for use or non-use are presented.. Though no controlled studies have ever been done in pregnant women to truly prove their safety, it appears that most, but not all, current psychotropic drugs appear fairly safe for use in pregnancy.

Topics: Clozapine; Embryonic and Fetal Development; Female; Fluoxetine; Humans; Lactation; Lithium; Mental Disorders; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Psychotropic Drugs; Puerperal Disorders

Topics: AIDS Dementia Complex; Clozapine; HIV Infections; HIV-1; Humans; Mental Disorders; Neuroleptic Malignant Syndrome; Parkinson Disease

Clozapine is a new antipsychotic drug that displays antipsychotic efficacy of the classic neuroleptics without the associated extrapyramidal side effects. This article briefly reviews the action and use of clozapine in order to help nurse clinicians become familiar with the drug usage. Clozapine is presently in use only in clinical trials, but is expected to be marketed by Sandoz Pharmaceutical Corporation (Hanover, NJ) in 1990.

Topics: Clozapine; Humans; Mental Disorders; Patient Discharge

Topics: Antidepressive Agents; Clozapine; Depressive Disorder; Dopamine; Electroconvulsive Therapy; Female; Homovanillic Acid; Humans; Levodopa; Male; Mental Disorders; Nomifensine; Nortriptyline; Parkinson Disease; Personality; Psychotic Disorders; Serotonin; Tryptophan

Nocturnal sialorrhea is one of the most frequent adverse events in clozapine treatment. Symptomatic management of sialorrhea usually consists of off-label treatment with anticholinergic agents. The aim of the current study is to evaluate the efficacy and safety of glycopyrrolate in patients using clozapine that experience sialorrhea.. In a double-blind randomized crossover trial, patients with nocturnal sialorrhea (n = 32) were randomized to treatment with glycopyrrolate 1 mg or placebo. This double-blinded phase was followed by an optional open label extension phase with glycopyrrolate 2 mg. Exposure periods consisted of 6 consecutive days and were separated with 1 washout week. The primary outcome was clinical improvement of nocturnal sialorrhea assessed by the Patient Global Impression of Improvement (PGI-I).. The proportion of patients with a clinical improvement according to PGI-I did not significantly differ between 1 mg and placebo (18.8% vs 6.3%, P = 0.289); however, in patients using glycopyrrolate 2 mg once daily versus placebo, it did (43.5% vs 6.3%, P = 0.039). Glycopyrrolate was not associated with severe adverse events or worsening of cognitive adverse events.. Glycopyrrolate 1 mg was not superior to placebo, whereas 2 mg showed a significant clinical improvement of nocturnal sialorrhea compared with placebo. Glycopyrrolate seemed to be a tolerable anticholinergic agent in the treatment of clozapine-associated sialorrhea.

Topics: Adult; Antipsychotic Agents; Clozapine; Cross-Over Studies; Double-Blind Method; Female; Glycopyrrolate; Humans; Male; Mental Disorders; Middle Aged; Muscarinic Antagonists; Outcome Assessment, Health Care; Sialorrhea

Clozapine remains the drug of choice for patients with treatment-resistant schizophrenia, who show a response rate of about 50% despite their unresponsiveness to other antipsychotics. Although treatment with clozapine can lead to considerable savings on bed days, the drug is underutilized for several reasons, perhaps most importantly because of the mandatory hematological monitoring. The Chempaq Express Blood Counter (Chempaq XBC) is a point-of-care device providing counts of white blood cells (WBC) and granulocytes based on a capillary blood sampling. A randomized cross-over trial design was used comparing capillary blood sampling using a point-of-care device with traditional venous blood sampling. Patients were randomized to two sequences starting with either capillary or venous blood sampling followed by a repeated sequence. Primary outcome was measured on a 10-cm visual analog scale. Eighty-five patients were included in the test. Eight (9.4%) dropped out before completion. Patients indicated that they found capillary blood monitoring less painful than venous sampling (VAS ratings: 0.55 cm 25-75 percentiles: 0.1-1.4 cm vs. 1.75 cm 25-75 percentiles: 0.7-2.6, p<0.001). They also felt less inconvenienced by the point-of-care method than the traditional blood sampling, which involved traveling to the laboratory clinical (0.3 cm 25-75 percentiles: 0.05-0.7 vs. 2.3 cm 25-75 percentiles: 0.75-4.5, p<0.001). For hematological monitoring of clozapine patients a point-of-care device based on capillary blood sampling is better tolerated than traditional venous blood sampling.

Topics: Adult; Blood Specimen Collection; Clozapine; Cross-Over Studies; Female; Hematology; Humans; Longitudinal Studies; Male; Mental Disorders; Middle Aged; Pain Measurement; Surveys and Questionnaires

To evaluate the effect of melperone, a butyrophenone with atypical antipsychotic properties, on plasma prolactin (PRL) concentrations compared with clozapine and typical neuroleptics.. Analysis of pre- and post-treatment PRL levels collected prospectively per protocol in a non-randomized study of 26 melperone-, 76 clozapine-, and 66 neuroleptic-treated patients with schizophrenia or schizoaffective disorder. Cross-sectional analysis of a larger sample of patients with PRL data was also performed.. For males, post-treatment PRL levels were significantly higher in the typical neuroleptic group compared with the melperone (p = 0.0001) and clozapine (p = 0.0001) groups, with no significant difference between clozapine and melperone. For females, post-treatment PRL levels were significantly higher in the melperone group as compared to the clozapine group (p = 0.004). There were too few typical neuroleptic-treated females to permit analysis of this sample. However, the cross-sectional analysis of PRL data confirmed the results for melperone- and clozapine-treated females, and showed higher PRL levels in typical neuroleptic-treated females as compared with those who received melperone and clozapine.. Melperone did not significantly increase PRL levels in male patients. However, melperone and typical neuroleptics caused increase in PRL levels in females. Further study of melperone's effects on PRL concentration is warranted.

Topics: Adult; Antipsychotic Agents; Butyrophenones; Clozapine; Female; Humans; Male; Mental Disorders; Prolactin; Sex Factors

The aim of this study was to improve and evaluate the practibility of a method for the assessment of drug-associated side effects, and we implemented a clinical drug monitoring for atypical neuroleptics.. Side effects of initially hospitalized patients treated with clozapine (n = 16), olanzapine (n = 16), and risperidone (n = 19) were prospectively monitored on a weekly basis for the first 3 weeks. In the case of stable medication, measurements of all variables were made every 4 weeks or upon discharge. We used the Dosage Record Treatment Emergent Symptom Scale (DOTES) in a supplemented version to measure the presence and severity of side effects.. Drowsiness and decreased motor activity were common, especially in the first 2 weeks. Orthostatic hypotension, increased salivation, constipation, and nasal congestion were seen in more than 30% to 60% of patients treated with clozapine and were less common in adolescents treated with olanzapine and risperidone. Rigidity, tremor, and dystonia were seen in 5% to 15% of patients treated with risperidone and olanzapine. The average weight gain after 6 weeks of treatment with the atypical neuroleptics was significantly higher for the olanzapine group (4.6 +/- 1.9 kg) than for the risperidone (2.8 +/- 1.3 kg) and clozapine (2.5 +/- 2.9 kg) groups.. The authors' supplemented DOTES version is generally applicable to clinical use in mental health centers. The differences among the side effects of these three agents may affect compliance with medication and medical risks of metabolic syndrome, diabetes, and cardiovascular disease. More research on the short- and long-term safety of psychotropic drugs in children and adolescents, using standardized methods, should be considered.

Topics: Adolescent; Adolescent Psychiatry; Adult; Antipsychotic Agents; Benzodiazepines; Child; Child Psychiatry; Clozapine; Drug Monitoring; Female; Humans; Male; Mental Disorders; Olanzapine; Risperidone

We report on dyspeptic complaints among patients hospitalized in the long-stay ward of a general psychiatric hospital.. A representative sample of the patients was interviewed using a structured questionnaire.. Eighty percent of the patients reported one or more symptoms of dyspepsia, and 68 % reported symptoms of reflux-like dyspepsia.. Significant positive associations were found for dyspepsia complaints and clozapine (OR = 3.4), laxatives (OR = 4.4), and heavy smoking (OR = 2.3).

Topics: Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Cathartics; Chronic Disease; Clozapine; Confidence Intervals; Dyspepsia; Female; Humans; Male; Mental Disorders; Middle Aged; Odds Ratio; Sex Factors; Smoking

Antipsychotic medications are associated with weight gain and metabolic dysregulation, yet little is known about the management of obesity among individuals with severe and persistent mental illness. Thus we sought to evaluate the potential utility of a behavioral weight control program for this population.. Outpatients receiving psychiatric care at a university medical center who had a body mass index (BMI; weight in kg/[height in m](2)) >or= 30 and were currently taking antipsychotic medication participated in a 12-week group behavioral weight control program. A medical chart review was conducted for each participant's body weight over the 10 months prior to beginning the program. A multiple baseline design was used to determine the impact of the intervention on BMI through 12-month posttreatment follow-up. We also assessed self-reported eating behavior, physical activity, and health-related quality of life. Data were collected from October 2000 to July 2003.. Among 35 patients who began the program, 29 (83%) completed treatment, with mean (+/- SD) weight loss of 5.04 (+/- 7.52) pounds (p = .001) and improvements in eating, activity, and quality of life. At 3-month posttreatment follow-up (N = 27; 77%), total mean weight loss was 7.14 (+/- 11.47) pounds (p = .003). Results of a longitudinal model based on general estimating equations indicated that, relative to the pretreatment period, BMI decreased significantly during treatment and remained stable through 12-month posttreatment follow-up.. Behavioral weight control is a promising approach to the treatment of obesity among outpatients taking antipsychotic medications, but longer and more robust interventions are needed.

Topics: Adult; Ambulatory Care; Antipsychotic Agents; Behavior Therapy; Body Mass Index; Clozapine; Comorbidity; Feasibility Studies; Feeding Behavior; Female; Health Status; Humans; Male; Mental Disorders; Obesity; Quality of Life; Treatment Outcome; Weight Loss

Topics: Antipsychotic Agents; Clozapine; Humans; Mental Disorders; Patient Compliance; Patient Education as Topic; Pilot Projects; Self Administration

Delusions and other manifestations of psychotic behavior are common side effects in Parkinson's disease (PD) patients chronically treated with dopaminergic drugs. Clozapine, a dibenzodiazepine derivative, is an antipsychotic drug largely devoid of extrapyramidal side effects. We evaluated the effects of low doses of clozapine on the mental and motor functions in PD patients requiring antipsychotic treatment. Twenty-seven PD patients taking dopaminergic drugs and who had psychotic behavior received clozapine at 12.5 to 75 mg/d. Fifteen patients received clozapine for 1 to 11 months (mean, 6.8 months) and seven received it for 12 to 24 months (mean, 18 months). No patient exhibited motor deterioration, and the psychotic features disappeared immediately, allowing discontinuation of clozapine after several months in 10 patients. Fifteen patients are still receiving clozapine and are free of psychiatric symptoms. The clozapine treatment was discontinued after 5 days (25 mg/d) in two patients because of somnolence. No patient developed neutropenia. Clozapine in low doses is effective in the treatment of drug-induced delusions and hallucinations in PD.

Topics: Aged; Aged, 80 and over; Clozapine; Female; Humans; Levodopa; Male; Mental Disorders; Middle Aged; Parkinson Disease

The adverse drug reaction profile of 3-fluoro-6-(4-methyl-piperazinyl)- 11H -dibenz[b,e]azepine ( fluperlapine -NB 106-689), a possible successor drug of clozapine, is presented based on, first, the results of the open multicentre trial of the AMDP group, and second, on two open multicentre trials initiated by the manufacturers. In general, side-effects of fluperlapine seem to be very similar to those of clozapine, i.e. anticholinergic and sedative effects as well as marked EEG-changes can be observed in most of the patients. However, in contrast to clozapine, so far no evidence for the occurrence of hypersalivation, or increase of body temperature has been obtained, although an increased white blood cell count around day 15 could be seen in quite a number of patients. Hypotensive effects were less than expected from corresponding trials with clozapine.

Topics: Animals; Antipsychotic Agents; Appetite; Blood Pressure; Body Weight; Clinical Trials as Topic; Clozapine; Depression; Electrocardiography; Electroencephalography; Hematopoietic System; Humans; Hypnotics and Sedatives; Lipids; Liver Function Tests; Mental Disorders; Parasympatholytics; Rats; Schizophrenia

Among the newer psychoactive compounds, clozapine is classified by some authors as an antipsychotic compound, but it exhibits differences in pharmacology and clinical effects that clearly distinguish it from established antipsychotic compounds. It represents an anomaly in the EEG classification scheme as well. In normal volunteers and in psychotic patients, it elicits EEG effects that are more like those of sedative thymoleptic antidepressants than the established antipsychotic compounds. It is probable that the antipsychotic activity reported by some observers reflected the sedative qualities of the compound and not a prototypic antipsychotic activity. Further testing in other psychiatric populations, particularly patients with depressive illnesses, is warranted.

Topics: Adult; Clinical Trials as Topic; Clozapine; Dibenzazepines; Electroencephalography; Humans; Male; Mental Disorders; Psychiatric Status Rating Scales

Topics: Clinical Trials as Topic; Clozapine; Dibenzazepines; Humans; Mental Disorders; Tranquilizing Agents

Few researchers have investigated the incidence of and risk factors for hospital-acquired pneumonia (HAP) among inpatients with mental disorders in a general hospital.. This study included patients with mental disorders hospitalized in a large mental health center (situated in a general hospital) between January 1, 2017, and July 31, 2021 (excluding January 1, 2020- May 31, 2020). Risk factors for HAP were identified by logistic regression analysis after propensity score matching (PSM, 1:4) for gender, age, duration of observation, and hospital ward.. The study included 16,864 patients. HAP incidence rate was 1.15% overall, 2.11% in closed wards, 0.75% in open wards, 4.45% in patients with organic mental disorders, 1.80% in patients with schizophrenia spectrum disorders, and 0.84% in patients with mood disorders. Risk factors for HAP after PSM were hypoproteinemia, chronic liver disease, use of clozapine, hospitalization during the previous 180 days, body mass index (BMI) ≤18.5 kg/m. HAP was common among inpatients with mental disorders. Risk factors for HAP in patients with mental disorders include hypoproteinemia, chronic liver disease, hospitalization during the past 180 days, BMI ≤18.5 kg/m

Topics: Clozapine; Cross Infection; Healthcare-Associated Pneumonia; Hospitals, General; Humans; Hypoproteinemia; Inpatients; Mental Disorders; Mental Health; Pneumonia; Risk Factors

Advanced psychiatric treatments remain uncertain in preventing suicide among adolescents. Across the 21 Swedish regions, using nationwide registers between 2016-2020, we found negative correlation between adolescent excess suicide mortality (AESM) and regional frequencies of clozapine, ECT, and lithium (CEL) usage among adolescents (β = -0.613, p = 0.0003, 95% CI: -0.338, -0.889) and males (β = -0.404, p = 0.009, 95% CI: -0.130, -0.678). No correlation was found among females (p = 0.197). Highest CEL usage among male adolescents was seen in regions with lowest quartile (Q1) AESM (W = 74, p = 0.012). Regional CEL treatment frequency in 15-19-year-olds was related to lower AESM in males, reflecting potential treatment efficacy, treatment compliance or better-quality mental health care. Suicide prevention may benefit from early recognition and CEL treatment for severe mental illness in male adolescents. The results indicate association but further research, using independent samples and both prospective and observational methodologies, is needed to confirm causality.

Topics: Adolescent; Clozapine; Female; Humans; Lithium; Male; Mental Disorders; Prospective Studies; Suicide

Clozapine is the most effective drug for treatment-resistant schizophrenia, and the dosage and concentration of clozapine in the treatment of mental illness vary greatly in different populations and are affected by many factors.. The serum clozapine concentration of 3734 psychiatric patients was detected, and data on daily dose, sex, age and other medical records were collected for statistical analysis.. The mean daily dose, mean serum concentration and mean C/D (concentration/dose) ratio of clozapine were 191.02 ± 113.47 mg/day, 326.15 ± 235.66 ng/mL and 1.94 ± 1.25 ng/mL per mg/day, respectively. There was difference in daily dose between sexes, and females had higher daily dose (p <0.01), higher serum clozapine concentrations (p < 0.01) and higher C/D ratios (p < 0.01). There were significant differences in daily dose (p < 0.001), serum drug concentration (p < 0.001) and C/D ratio (p < 0.001) among different age groups. The daily dose decreased with age (p for trend < 0.001), and the C/D ratio increased with age (p for trend < 0.001). Inpatients and outpatients had no difference in daily dose, but inpatients had higher serum concentration (p < 0.001) and C/D ratio (p < 0.001). There was no difference in daily dose among different occupations, but there were significant differences in serum concentration (p < 0.001) and C/D ratio (p < 0.001), and unemployed patients may have higher serum concentration and C/D ratio. Duration of disease, comorbidity, marital status, and psychotic type may influence the daily dose and serum concentration.. The effective daily dose and serum concentration of clozapine in the study area may be lower than recommended levels, and women have higher serum concentrations and slower metabolic rates. With increasing age, the daily dose decreases, and the metabolic rate slows. Inpatient status and occupation of patients may influence the serum concentration and metabolic rate of clozapine.

Topics: Antipsychotic Agents; Clozapine; Female; Humans; Inpatients; Mental Disorders; Outpatients

The goal of the study was to examine clozapine (CLZ) and norclozapine (NCLZ) therapeutic drug monitoring (TDM) data and associated sources of pharmacokinetic variability, particularly the impact of valproic acid (VPA) use.. This study included 126 patients with psychiatric disorders on mono- or co-therapy with CLZ. Patients' data during routine TDM were collected retrospectively from clinical records. The descriptive and statistical analysis was computed using IBM SPSS Statistics software (version 22, NY, USA). Multiple linear regression, based on the last observations, was used to assess correlation between demographic characteristics, life habits and co-therapy with dose-corrected serum levels (C/D) of CLZ and NCLZ, as well as CLZ/NCLZ.. A total of 295 CLZ concentrations were measured in 126 patients, with a mean of 275.5 ± 174.4 µg/L, while 124 NCLZ concentrations were determined in 74 patients, with a mean of 194.6 ± 149.8 µg/L. A statistically significant effect on ln-transformed CLZ C/D was confirmed for sex and smoking, whereas sex, smoking and VPA therapy were associated with ln-transformed NCLZ C/D. According to the final models, lower values of NCLZ C/D for about 45.9% can be expected in patients receiving VPA. Concomitant use of VPA was the only factor detected to contribute in CLZ/NCLZ variability.. The results of this study may help clinicians interpret TDM data and optimize CLZ dosing regimens, especially in patients concomitantly treated with VPA. Our results show that VPA primarily decreases NCLZ levels, while alteration of the parent drug is not statistically significant.

Topics: Clozapine; Humans; Mental Disorders; Retrospective Studies; Valproic Acid

Antipsychotics are widely used to manage mental illnesses. They have, however, been reported to cause various adverse events. Two studies were conducted to resolve clinical questions related to adverse events caused by antipsychotic medications in clinical practice. The first adverse event studied was clozapine-induced sialorrhea (CIS), a common adverse event. There is no established standard treatment for CIS because the underlying mechanism remains unclear. Therefore, this study aimed to identify the cause of CIS. Results of clinical and basic studies suggest that N-desmethylclozapine (NDMC), the active metabolite of clozapine, is the causative agent of CIS. Furthermore, the action of NDMC on salivary gland cells via muscarinic receptors is one of the proposed mechanisms of CIS. The second adverse event was hyperglycemia. Antipsychotics increase the incidence of hyperglycemia. However, the incidence of antipsychotic-induced hyperglycemia is difficult to predict because many factors are involved. This study aimed to examine the effect of antipsychotic treatment-associated factors on hyperglycemic progression after adjustment for the effect of background factors suggested to be associated with hyperglycemic progression. A national multicenter prospective observational study of 631 newly initiated patients showed that initiation of clozapine and zotepine treatment significantly increased the incidence of hyperglycemia. In addition, obesity has been shown to significantly increase the incidence of antipsychotic-induced hyperglycemia. Because these studies were conducted to resolve questions that arose in actual clinical practice, the study results obtained are considered to have clinical applicability.

Topics: Antipsychotic Agents; Clozapine; Humans; Hyperglycemia; Mental Disorders

The present study aimed to measure the prevalence and severity of food insecurity in people with a severe mental illness, defined as schizophrenia and related psychoses, and bipolar disorder; and explore relationships between food insecurity status, and sociodemographic and clinical characteristics.. This cross-sectional study recruited community-dwelling people with severe mental illness receiving clozapine and/or a long-acting injectable antipsychotic medication within three mental health services in Sydney, Australia. Participants completed the 18-item Household Food Insecurity Access Scale. Sociodemographic and medical information was obtained from participants' medical records. Independent samples t-test and chi-square analyses were used to test for between group differences based on food insecurity status. Binary logistic regression analyses adjusting for age and gender were used to determine the odds ratio.. One-hundred and eighty-eight people completed the assessment: 63% were male, mean age was 49.2 ± 12.4 years, and the majority (85%) had a diagnosis of schizophrenia. Food insecurity was detected in 31% of participants. Of those who were food insecure, 12% were classified as severe, 13% as moderate and 7% as mild. Tobacco smoking was higher in food insecure people compared to food secure people (odds ratio = 3.1, 95% CI 1.3 to 7.1, p = 0.01). Food insecurity status was not associated with demographic, diagnostic or other clinical data.. Food insecurity is highly prevalent among community-dwelling people with severe mental illness receiving clozapine and/or long-acting injectable antipsychotic medication. Food security screening should be considered as routine care for this population group.

Topics: Adult; Antipsychotic Agents; Clozapine; Cross-Sectional Studies; Female; Food Insecurity; Food Supply; Humans; Independent Living; Male; Mental Disorders; Middle Aged; Prevalence

The Psychiatric Consultation Service at Massachusetts General Hospital sees medical and surgical inpatients with comorbid psychiatric symptoms and conditions. During their twice-weekly rounds, Dr Stern and other members of the Consultation Service discuss diagnosis and management of hospitalized patients with complex medical or surgical problems who also demonstrate psychiatric symptoms or conditions. These discussions have given rise to rounds reports that will prove useful for clinicians practicing at the interface of medicine and psychiatry.

Topics: Clozapine; Hospitals, General; Humans; Mental Disorders; Primary Health Care; Psychiatry; Referral and Consultation

Initially, it had been assumed that in cases of SARS-CoV-2 infection comorbidity with psychiatric disorders worsens clinical outcomes. This was attributed to patients' poor overall health conditions, concomitant illnesses and unhealthy lifestyles. However, only schizophrenia is in a statistically significant correlation with very serious conditions leading to death, possibly as a result of underlying immune dysfunctions. Clozapine (an antipsychotic used in therapy of treatment resistant schizophrenia) seems to decrease the likelihood of recovery in COVID-19 patients, however admi nistration of antidepressant medications appears to increase it. It has also been justified that among these antidepressant drugs, fluvoxamin shows to have an effect in inhibiting cytokine storms and reducing the severity of the COVID-19 infection. Most recent data suggest that the well-known antiviral effect of lithium is also present in patients with COVID-19 infection.

Topics: Antipsychotic Agents; Clozapine; COVID-19 Drug Treatment; Humans; Mental Disorders; SARS-CoV-2

The Clozapine Plus Working Group is frequently consulted for advice on measures in case of infection with SARSCoV-2 and on vaccination against COVID-19 in patients receiving clozapine.

AIM: Inform about risks of infection with SARS-CoV-2 in patients with severe mental illness (SMI), patients with schizophrenia spectrum disorders (SSD), and patients treated with clozapine. Advise on monitoring of clozapine plasma levels and white blood cell count and differential in COVID-19 and after vaccination, as well as measures to be taken.

METHOD: Literature research and case studies.

RESULTS: SMI patients and in particular SSD patients have an increased risk of infection with SARS-CoV-2 with more hospitalizations and higher mortality than non-psychiatric patients. Patients using clozapine may be at greater risk of infection. SARS-CoV-2 infection may cause a dangerous increase of clozapine plasma levels and generally mild and short-term granulocytopenia and lymphocytopenia, which are usually not a result of clozapine treatment.

CONCLUSION: In case of COVID-19 extra alertness is required in patients with SMI and especially SSD. In clozapine users, in case of COVID-19, reduction in dose by half to three quarters of the original dose is recommended. When patients develop granulocytopenia, SARS-CoV-2 should be considered as the cause and not immediately clozapine. SMI patients and clozapine users in particular belong to a high risk group with a medical indication for early vaccination.

Topics: Clozapine; COVID-19; Humans; Mental Disorders; SARS-CoV-2; Schizophrenia

Most defendants found incompetent to stand trial have psychotic illnesses. Clozapine has been shown to be superior to other antipsychotic medications in treatment-resistant schizophrenia. It is vastly underutilized, however, including in forensic settings. To our knowledge, there have been no studies exploring the risks and benefits of clozapine for incompetent to stand trial defendants with severe mental illness. We sought to explore the characteristics of patients who were prescribed clozapine in a retrospective sample of defendants deemed incompetent to stand trial with diagnoses of psychotic and bipolar disorders. We found that 25 of 240 defendants (10%) were prescribed clozapine, with 15 (60%) eventually being discharged on it. Of those 15, 8 defendants were successfully restored to competency to stand trial. The restoration rate in the clozapine group was much lower than in the non-clozapine group (32% versus 87%). Our results emphasize the need for prospective comparative studies assessing the efficacy and tolerability of clozapine and other antipsychotic medications related to restoration of competency to stand trial.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Forensic Psychiatry; Humans; Insanity Defense; Male; Mental Competency; Mental Disorders; Retrospective Studies

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Health Equity; Hematopoietic Stem Cell Transplantation; Humans; Mental Disorders

The clinical applications of antipsychotics for symptoms unrelated to schizophrenia, such as behavioral and psychological symptoms, in patients with Alzheimer's disease, and the likelihood of doctors prescribing antipsychotics for elderly people are increasing. In elderly people, drug-induced and aging-associated urinary disorders are likely to occur. The most significant factor causing drug-induced urinary disorders is a decrease in urinary bladder smooth muscle (UBSM) contraction induced by the anticholinergic action of therapeutics. However, the anticholinergic action-associated inhibitory effects of antipsychotics on UBSM contraction have not been sufficiently assessed. In this study, we examined 26 clinically available antipsychotics to determine the extent to which they inhibit acetylcholine (ACh)-induced contraction in rat UBSM to predict the drugs that should not be used by elderly people to avoid urinary disorders. Of the 26 antipsychotics, six (chlorpromazine, levomepromazine (phenothiazines), zotepine (a thiepine), olanzapine, quetiapine, clozapine (multi-acting receptor targeted antipsychotics (MARTAs))) competitively inhibited ACh-induced contractions at concentrations corresponding to clinically significant doses. Further, 11 antipsychotics (perphenazine, fluphenazine, prochlorperazine (phenothiazines), haloperidol, bromperidol, timiperone, spiperone (butyrophenones), pimozide (a diphenylbutylpiperidine), perospirone, blonanserin (serotonin-dopamine antagonists; SDAs), and asenapine (a MARTA)) significantly suppressed ACh-induced contraction; however, suppression occurred at concentrations substantially exceeding clinically achievable blood levels. The remaining nine antipsychotics (pipamperone (a butyrophenone), sulpiride, sultopride, tiapride, nemonapride (benzamides), risperidone, paliperidone (SDAs), aripiprazole, and brexpiprazole (dopamine partial agonists)) did not inhibit ACh-induced contractions at concentrations up to 10

Topics: Acetylcholine; Aging; Animals; Antipsychotic Agents; Chlorpromazine; Cholinergic Antagonists; Clozapine; Dibenzothiepins; Male; Mental Disorders; Methotrimeprazine; Muscle Contraction; Muscle, Smooth; Olanzapine; Quetiapine Fumarate; Rats, Wistar; Urinary Bladder; Urologic Diseases

Patients with a severe mental illness have higher rates of infection with blood-borne viruses (BBVs) but are less likely to access testing and treatment. Enhanced testing of this population is therefore warranted.. In this single centre, prospective study, we sought to offer testing for BBVs to all patients who attended an appointment in the clozapine clinic (CC) over a six-month period. Those who consented were tested for HIV antigen/antibody, hepatitis C virus (HCV) antibody and hepatitis B virus surface antigen (HBsAg).. During the study period, 192 patients attended an appointment, of which 164 were offered testing. Of those, 134 (81.7%) accepted and 30 declined. Among patients who agreed to be tested, results were returned for 96 (71.6%). There were no positive results for HBsAg or HIV. Seven patients (7.2%) were positive for HCV antibody. Of those, three were newly identified exposures of which two were found to be chronically infected and were referred for treatment.. A routine offer of BBV testing for people with severe mental illness in the outpatient setting is feasible and may detect treatable infections.

Topics: Adult; Aged; Aged, 80 and over; Clozapine; Coinfection; Female; Hepatitis B; Hepatitis C; HIV Infections; Humans; Male; Mass Screening; Mental Disorders; Middle Aged; New South Wales; Outpatients; Prevalence; Prospective Studies; Young Adult

Topics: Betacoronavirus; Clozapine; Coronavirus Infections; COVID-19; Delivery of Health Care; Evidence-Based Medicine; Humans; Mental Disorders; Mental Health; Pandemics; Pneumonia, Viral; SARS-CoV-2; Systematic Reviews as Topic; Vulnerable Populations

Behavioural and psychological symptoms of dementia (BPSD) are common and contribute significantly to caregiver burden and institutionalization of the patient. Unfortunately, current guideline-based interventions are sometimes ineffective and BPSD can become extreme.. A 75-year-old man with dementia was admitted to a psychogeriatric unit because of very severe BPSD in a nursing home. Different kinds of pharmaceutical and psychological interventions had been tried but turned out to be ineffective. Therefore, we started with low dose clozapine which improved his behavior. We reduced the dose twice, whereupon the behavior deteriorated. By reintroducing the proper dose, his behavior became better again.. Our case is in accordance with the available literature on Clozapine for BPSD: Six uncontrolled studies have shown a positive effect of clozapine for BPSD, even if other interventions failed. We conclude that clozapine may be tried in cases of serious refractory BPSD when guideline-based interventions are ineffective.

Topics: Aged; Antipsychotic Agents; Clozapine; Dementia; Hospitalization; Humans; Male; Mental Disorders; Nursing Homes

To assess the extent to which therapeutic drug monitoring during maintenance phase treatment with lithium and clozapine was performed according to an agreed protocol and to identify strategies that may support monitoring.. Data concerning the prescribing and monitoring patterns of lithium for 31 patients and clozapine for 53 patients were collected retrospectively over a period of 2 years.. Adherence to clozapine monitoring throughout the study period was 90.5%, while the monitoring of lithium was less likely at 58.1% (. Despite the initiatives established to improve adherence to monitoring, there was a significantly lower level of lithium monitoring compared to that of clozapine. Strategies that are likely to support monitoring include the use of labels to clarify tests required, the use of a database to keep track of those requiring pathology tests and allocation of time each week for a nurse to work with medical staff and case managers to support monitoring.

Topics: Adult; Clozapine; Community Mental Health Centers; Community Mental Health Services; Drug Monitoring; Humans; Lithium Compounds; Medication Adherence; Mental Disorders; Psychotropic Drugs; Retrospective Studies; Secondary Prevention

Topics: Adult; Antipsychotic Agents; Austria; Clozapine; Epilepsy, Tonic-Clonic; Female; Germany; Hospitals, Psychiatric; Humans; Male; Mental Disorders; Middle Aged; Pharmacovigilance; Risk; Seizures; Switzerland

Topics: Animals; Antipsychotic Agents; Brain; Brain-Derived Neurotrophic Factor; Cell Adhesion Molecules, Neuronal; Chromatin; Chromatin Assembly and Disassembly; Clozapine; Disease Models, Animal; DNA Methylation; Epigenesis, Genetic; Extracellular Matrix Proteins; Female; Glutamate Decarboxylase; Male; Mental Disorders; Mice; Nerve Tissue Proteins; Phthalimides; Pregnancy; Prenatal Exposure Delayed Effects; Promoter Regions, Genetic; Reelin Protein; Serine Endopeptidases; Tryptophan

Antipsychotic-induced weight gain has been especially related to clozapine and olanzapine. Underlying mechanisms in relation to food preferences with an increased food craving and consumption of specific nutrients have not been extensively studied in patients with serious mental illness (SMI). We aim to describe specific food preferences (craving) and subsequent food consumption in SMI patients starting clozapine, as well as their possible relation to weight and body mass index (BMI).. An observational prospective follow-up study (18 weeks) was conducted in a cohort of 34 SMI patients who started clozapine due to resistant-psychotic symptoms. Anthropometric measures, Food Craving Inventory (FCI), and a food consumption frequency questionnaire were evaluated at baseline, weeks 8 and 18 of treatment. Statistical analysis included generalized estimating equations models with adjustment for potential confounding factors.. No longitudinal changes over time were found across the different food craving scores after 18 weeks of treatment. However, adjusted models according to BMI status showed that the normal weight (NW) group presented an increased score for the "complex carbohydrates/proteins" food cravings (- 0.67; 95% CI [- 1.15, - 0.19]; P = 0.010), while baseline scores for "fast-food fats" cravings were significantly higher in the overweight/obese (OWO) group in comparison with NW patients (NW, 2.05; 95% CI [1.60, 2.49]; OWO, 2.81, 95% CI [2.37, 3.25]; P = 0.016). When considering if food craving could predict weight gain, only increments in "fast-food fats" cravings were associated (β = - 5.35 ± 1.67; 95% CI [- 8.64, - 2.06]; P = 0.001).. No longitudinal differences were found for any of the food craving scores evaluated; however, in the NW group, food craving for "complex carbohydrates/proteins" changed. Thus, changes in "fast-food fats" cravings predicted weight increase in this sample. Interventions targeting food preferences may help to mitigate weight gain in patients starting treatment with clozapine.

Topics: Adult; Antipsychotic Agents; Body Weight; Clozapine; Cohort Studies; Craving; Eating; Female; Follow-Up Studies; Food Preferences; Humans; Longitudinal Studies; Male; Mental Disorders; Middle Aged; Prospective Studies; Treatment Outcome; Weight Gain; Young Adult

Numerous genetic and functional studies implicate variants of Neuregulin-1 (NRG1) and its neuronal receptor ErbB4 in schizophrenia and many of its endophenotypes. Although the neurophysiological and behavioral phenotypes of NRG1 mutant mice have been investigated extensively, practically nothing is known about the function of NRG2, the closest NRG1 homolog. We found that NRG2 expression in the adult rodent brain does not overlap with NRG1 and is more extensive than originally reported, including expression in the striatum and medial prefrontal cortex (mPFC), and therefore generated NRG2 knockout mice (KO) to study its function. NRG2 KOs have higher extracellular dopamine levels in the dorsal striatum but lower levels in the mPFC; a pattern with similarities to dopamine dysbalance in schizophrenia. Like ErbB4 KO mice, NRG2 KOs performed abnormally in a battery of behavioral tasks relevant to psychiatric disorders. NRG2 KOs exhibit hyperactivity in a novelty-induced open field, deficits in prepulse inhibition, hypersensitivity to amphetamine, antisocial behaviors, reduced anxiety-like behavior in the elevated plus maze and deficits in the T-maze alteration reward test-a task dependent on hippocampal and mPFC function. Acute administration of clozapine rapidly increased extracellular dopamine levels in the mPFC and improved alternation T-maze performance. Similar to mice treated chronically with N-methyl-d-aspartate receptor (NMDAR) antagonists, we demonstrate that NMDAR synaptic currents in NRG2 KOs are augmented at hippocampal glutamatergic synapses and are more sensitive to ifenprodil, indicating an increased contribution of GluN2B-containing NMDARs. Our findings reveal a novel role for NRG2 in the modulation of behaviors with relevance to psychiatric disorders.

Topics: Animals; Behavior, Animal; Brain; Clozapine; Dopamine; ErbB Receptors; Male; Mental Disorders; Mice; Mice, Knockout; Nerve Growth Factors; Neuregulin-1; Receptor, ErbB-4; Signal Transduction; Synapses; Transcriptome

Schizophrenia is a severely debilitating neurodevelopmental disorder. Establishing a causal link between circuit dysfunction and particular behavioral traits that are relevant to schizophrenia is crucial to shed new light on the mechanisms underlying the pathology. We studied an animal model of the human 22q11 deletion syndrome, the mutation that represents the highest genetic risk of developing schizophrenia. We observed a desynchronization of hippocampal neuronal assemblies that resulted from parvalbumin interneuron hypoexcitability. Rescuing parvalbumin interneuron excitability with pharmacological or chemogenetic approaches was sufficient to restore wild-type-like CA1 network dynamics and hippocampal-dependent behavior during adulthood. In conclusion, our data provide insights into the network dysfunction underlying schizophrenia and highlight the use of reverse engineering to restore physiological and behavioral phenotypes in an animal model of neurodevelopmental disorder.

Topics: 22q11 Deletion Syndrome; Action Potentials; Animals; Animals, Newborn; CA1 Region, Hippocampal; Clozapine; Disease Models, Animal; Female; Humans; Male; Mental Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Net; Neuregulins; Neurons; Nonlinear Dynamics; Parvalbumins; Prepulse Inhibition; Reflex, Startle; Schizophrenia

Antipsychotics produce electroencephalogram (EEG) modifications and increase the risk of epileptic seizure. These modifications remain sparsely studied specifically for atypical antipsychotics. In this context, our study focuses on EEG modifications associated with atypical strict antipsychotic monotherapies.. Electroencephalogram recordings of 84 psychiatric patients treated with atypical antipsychotics in strict monotherapy (clozapine, n = 22; aripiprazole, n = 22; olanzapine, n = 17; risperidone, n = 9; quetiapine, n = 8; risperidone long-acting injection, n = 4; and paliperidone long-acting injection, n = 2) were analyzed. The modifications were ranked according to both slowing and excitability scores.. Electroencephalogram modifications (in 51 subjects, 60.71%) were graded according to 4 stages combining general slowing and sharp slow waves and/or epileptiform activities. The presence of sharp or epileptiform activities was significantly greater for clozapine (90.9%) compared with other second-generation antipsychotics (aripiprazole, 50%; olanzapine, 58.8%; quetiapine, 37.5%; risperidone, 44.4%). Age, duration of disease progression, and diagnosis were not associated as risk factors. Electroencephalogram modifications were associated with lower doses for treatment with quetiapine but not for specific antipsychotics. Electroencephalogram modifications and severe excitability were associated with higher chlorpromazine equivalent doses.. Atypical antipsychotics (clozapine, aripiprazole, quetiapine, olanzapine, and risperidone) induce EEG modifications, and these are significantly greater for clozapine and appear dependent on chlorpromazine equivalent dose. No encephalopathy was observed in these antipsychotic monotherapies, whatever dose.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Aripiprazole; Bipolar Disorder; Cerebral Cortex; Clozapine; Depressive Disorder, Major; Electroencephalography; Female; Humans; Male; Mental Disorders; Middle Aged; Olanzapine; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Schizophrenia; Young Adult

The present study is a review of a cardiometabolic clinic for consumers taking clozapine. This clinic was recently established and co-located with the clozapine clinic at a regional hospital in New South Wales, Australia, to enhance engagement and improve the physical health outcomes of consumers taking antipsychotic medication. A descriptive analysis of clients' (n = 73) information collected during routine care for the first 6 months of the clinic's operation, from January 2016 to July 2016, was conducted. First-visit data were analysed to establish a client profile, consisting of weight, height, blood pressure, pulse, a range of blood measurements, smoking status, alcohol consumption, and eating and exercise habits. Data collected for clients who had three or more visits with the general practitioner (n = 40) were analysed separately for outcomes. Two case studies are used to depict the service received and client profile. At the first appointment, the majority of clients had metabolic syndrome that was mostly left untreated; many of these clients were commenced on metformin. The outcomes are positive, and show that the majority of clients lost weight (82.5%) and had a reduction in body mass index (84.6%); nearly half (44.4%) had a reduction in waist circumference. The majority of clients self-reported increased physical activity (72.5%, n = 29) and positive dietary changes (77.5%, n = 31) since their first appointment. The model trialled by the cardiometabolic clinic integrated a specialist mental health and primary care service, and demonstrates success in engaging clients with severe mental illness in physical health care. Co-location is conceptualized as critical for positive patient outcomes and high levels of engagement.

Topics: Adult; Aged; Cardiovascular Diseases; Clozapine; Female; General Practitioners; Health Status; Humans; Male; Mental Disorders; Middle Aged; New South Wales; Program Evaluation; Psychotropic Drugs; Risk Reduction Behavior; Treatment Outcome; Young Adult

Prescription of clozapine is complicated by the occurrence of clozapine-induced reduction of neutrophils. The aim of this study was to identify genetic risk factors in a population of 310 Dutch patients treated with clozapine, including 38 patients developing neutropenia and 31 patients developing agranulocytosis. NQO2 1541AA (NRH quinone oxidoreductase 2; protects cells against oxidative metabolites) was present at a higher frequency in agranulocytosis patients compared with control (23% versus 7%, P=0.03), as was ABCB1 (ABC-transporter-B1; drug efflux transporter) 3435TT (32% versus 20%, P=0.05). In patients developing neutropenia, ABCB1 3435TT and homozygosity for GSTT1

Topics: Adult; Agranulocytosis; Antipsychotic Agents; ATP Binding Cassette Transporter, Subfamily B; Case-Control Studies; Clozapine; Female; Genotype; Humans; Male; Mental Disorders; Middle Aged; Netherlands; Neutropenia; Pharmacogenomic Variants; Quinone Reductases; Retrospective Studies; Risk Factors

Cholesterol metabolism is vital for brain function. Previous work in cultured cells has shown that a number of psychotropic drugs inhibit the activity of 7-dehydrocholesterol reductase (DHCR7), an enzyme that catalyzes the final steps in cholesterol biosynthesis. This leads to the accumulation of 7-dehydrocholesterol (7DHC), a molecule that gives rise to oxysterols, vitamin D, and atypical neurosteroids. We examined levels of cholesterol and the cholesterol precursors desmosterol, lanosterol, 7DHC and its isomer 8-dehydrocholesterol (8DHC), in blood samples of 123 psychiatric patients on various antipsychotic and antidepressant drugs, and 85 healthy controls, to see if the observations in cell lines hold true for patients as well. Three drugs, aripiprazole, haloperidol and trazodone increased circulating 7DHC and 8DHC levels, while five other drugs, clozapine, escitalopram/citalopram, lamotrigine, olanzapine, and risperidone, did not. Studies in rat brain verified that haloperidol dose-dependently increased 7DHC and 8DHC levels, while clozapine had no effect. We conclude that further studies should investigate the role of 7DHC and 8DHC metabolites, such as oxysterols, vitamin D, and atypical neurosteroids, in the deleterious and therapeutic effects of psychotropic drugs. Finally, we recommend that drugs that increase 7DHC levels should not be prescribed during pregnancy, as children born with DHCR7 deficiency have multiple congenital malformations.

Topics: Adult; Animals; Antidepressive Agents; Antipsychotic Agents; Body Mass Index; Cholestadienols; Clozapine; Dehydrocholesterols; Female; Haloperidol; Humans; Lipid Metabolism; Male; Mental Disorders; Psychiatric Status Rating Scales; Random Allocation; Rats, Sprague-Dawley; Weight Gain

While it is recommended that clozapine be administered in a divided dosing regimen, it is unclear whether this recommendation is followed in real-world clinical practice. In two large datasets, we examined clozapine dosing frequency and patient characteristics across different dosing regimens.. We conducted a cross-sectional survey, collecting data on patients receiving clozapine in August/September 2015 from the Centre for Addiction and Mental Health (CAMH) in Toronto, Canada, and The Zucker Hillside Hospital (ZHH) in New York, United States.. Of 676 and 308 patients included in CAMH and ZHH datasets, clozapine was prescribed once daily in 75.1% and 74.4%, even though doses exceeding 200 mg/day were administered in 88.6% and 84.4% of the respective samples. No significant difference was found in the rates of positive symptom remission between once-daily vs. divided dosing (79.7% vs. 80.5%, P = 1.00). Higher clozapine dose and use of anticholinergic medications were significantly associated with divided dosing in both datasets. Older age or male gender was related to divided dosing in CAMH or ZHH dataset respectively.. Despite the product monograph recommendation, clozapine is frequently prescribed once daily in North America. Further studies are needed to compare clinical outcomes between once-daily vs. divided clozapine dosing.

Topics: Adult; Antipsychotic Agents; Canada; Clozapine; Cross-Sectional Studies; Drug Administration Schedule; Drug Prescriptions; Female; Health Surveys; Humans; Male; Mental Disorders; Middle Aged; New York; Treatment Outcome

Information on dose- and concentration-related clinical effects of clozapine treatment in children and adolescents is scarce. This study aimed to examine the relationship between dose, serum concentration, and clinical outcome as well as the influencing factors thereof in paediatric patients treated with clozapine. Data from a routine Therapeutic Drug Monitoring (TDM) service between 2004 and 2014 were studied in 68 patients, aged 11-18 years. Severity of illness, therapeutic effectiveness and adverse drug reactions (ADRs) were assessed by standardized means. A relationship between the daily dose (mean 319 mg, 4.9 mg/kg) and serum concentration (mean 387 ng/ml) of clozapine was found with the variation in dose explaining 30 % of the variability in clozapine serum concentrations. Also gender contributed to the variability, however, no influence of age or concomitant medications was detected. Furthermore, a significant association was found between clozapine serum concentration and the occurrence of ADRs. Patients without ADRs had a lower mean serum concentration than those with mild (261.4 vs 407.3 ng/ml, P = 0.018) and moderate ADRs (261.4 vs 416.3 ng/ml, P = 0.028). As clozapine was estimated to be effective in lower blood concentrations, guidance on a possibly lower therapeutic range of clozapine serum levels in paediatric patients is provided. With ADRs increasing under higher concentrations, TDM is strongly recommended in paediatric clozapine therapy for individualized dosing. Dose adjustment in females also might be reasonable according to gender-related differences in serum concentrations. However, regarding the limitations of this study results should be validated in larger studies with more standardized designs.

Topics: Adolescent; Antipsychotic Agents; Child; Clozapine; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Longitudinal Studies; Male; Mental Disorders; Retrospective Studies; Treatment Outcome

To examine the frequency of hyperprolactinemia and the socio-demographic, clinical, and quality of life (QOL) correlates. The frequency of prolactin-related side effects and associated subjective experiences were also examined.. A cohort of 1364 psychiatric inpatients were consecutively recruited and evaluated. Basic socio-demographic and clinical data were collected. Psychopathology, prolactin-related side effects were measured using standardized instruments. QOL was assessed using the Medical Outcomes Study Short Form 12.. The frequency of hyperprolactinemia was 61.3% in the whole sample; 61.6% in female and 60.8% in male patients. There was no significant association between hyperprolactinemia and any QOL domain. In the whole sample, 15.1% of patients reported moderately severe breast symptoms and lactation, and 53.9% reported moderate or severe discomfort. Nearly a third of female patients (30.4%) reported at least moderate menstrual changes and 50.2% moderate or severe discomfort, while 24.2% of male patients reported at least moderate erectile dysfunction and 52.6% moderate or severe discomfort. Multiple logistic regression analysis revealed that patients with hyperprolactinemia were less likely to be married, diagnosed with mood disorders, or treated with clozapine, aripiprazole, or antidepressants but more likely to receive risperidone.. Effective measures to lower the frequency of hyperprolactinemia and the related side effects should be considered in Chinese psychiatric facilities.

Topics: Adult; Antidepressive Agents; Antipsychotic Agents; Aripiprazole; Case-Control Studies; China; Clozapine; Female; Humans; Hyperprolactinemia; Male; Mental Disorders; Quality of Life; Risperidone; Sexual Dysfunction, Physiological; Young Adult

Antipsychotic drugs (APs) are of great benefit in several psychiatric disorders, but they can be associated with various adverse effects, including seizures. To investigate the effects of chronic antipsychotic treatment on seizure susceptibility in genetically epilepsy-prone rats, some APs were administered for 7 weeks, and seizure susceptibility (audiogenic seizures) was evaluated once a week during treatment and for 5 weeks after drug withdrawal. Furthermore, acute and subchronic (5-day treatment) effects were also measured. Rats received haloperidol (0.2-1.0 mg/kg), clozapine (1-5 mg/kg), risperidone (0.03-0.50 mg/kg), quetiapine (2-10 mg/kg), aripriprazole (0.2-1.0 mg/kg), and olanzapine (0.13-0.66 mg/kg), and tested according to treatment duration. Acute administration of APs had no effect on seizures, whereas, after regular treatment, aripiprazole reduced seizure severity; haloperidol had no effects and all other APs increased seizure severity. In chronically treated rats, clozapine showed the most marked proconvulsant effects, followed by risperidone and olanzapine. Quetiapine and haloperidol had only modest effects, and aripiprazole was anticonvulsant. Finally, the proconvulsant effects lasted at least 2-3 weeks after treatment suspension; for aripiprazole, a proconvulsant rebound effect was observed. Taken together, these results indicate and confirm that APs might have the potential to increase the severity of audiogenic seizures but that aripiprazole may exert anticonvulsant effects. The use of APs in patients, particularly in patients with epilepsy, should be monitored for seizure occurrence, including during the time after cessation of therapy. Further studies will determine whether aripiprazole really has a potential as an anticonvulsant drug and might also be clinically relevant for epileptic patients with psychiatric comorbidities.

Topics: Animals; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clozapine; Disease Models, Animal; Epilepsy; Haloperidol; Mental Disorders; Olanzapine; Quetiapine Fumarate; Rats; Risperidone; Seizures

Clozapine's association with agranulocytosis led to the implementation of stringent and mandatory hematologic monitoring guidelines in most countries. Although other hematologic aberrations such as eosinophilia and neutropenia have been previously described, clozapine's impact on the erythroid lineage has not been studied. There is a suspicion that a higher rate of anemia is observed in patients receiving clozapine; therefore, we hypothesized that there would be a higher rate of anemia in patients receiving clozapine therapy.. All individuals initiated on clozapine at our center from 2009 to 2010 were recruited. Information on age, gender, medical comorbidities, and smoking status was extracted from the medical records. Data from complete blood counts over a 2-year follow-up period were extracted, with anemia defined as a hemoglobin value below 120 g/L for women and 130 g/L for men. Time to anemia event was calculated and Cox regression was employed to identify predictors of anemia.. We found a high incidence of anemia in the first 2 years following clozapine initiation; of the 94 individuals (68 men, 26 women) recruited, 23 (24.5%) developed anemia. Higher baseline hemoglobin level (hazard ratio [HR] = 0.86, P = .002) and smoking status (HR = 0.21, P = .021) were identified as significant protective factors against anemia in men but not in women (HR = 0.92, P = .184, and HR = 0.52, P = .467 for baseline hemoglobin and smoking, respectively).. Although smoking appears to lower the risk of anemia, we believe this is due to smoking's up-regulation of hemoglobin levels. Further studies are warranted in light of the present findings; for example, we cannot exclude the possibility that anemia was an epiphenomenon, characterizing instead a population with severe mental illness.

Topics: Adult; Anemia; Antipsychotic Agents; Clozapine; Female; Follow-Up Studies; Hemoglobins; Humans; Incidence; Male; Mental Disorders; Regression Analysis; Sex Factors; Smoking; Time Factors

To assess the attitude of psychiatrists towards clozapine and also to evaluate the prescription practices of psychiatrists for clozapine.. An email survey was sent to 3381 psychiatrists from India, of whom 548 (16.2%) responded.. Mean number of years in clinical practice was 12.59 (SD-10.1) for participating psychiatrists. Majority of the participants rated their knowledge about clozapine to be good (61.5%)/very good (34.5%). The primary indication for use of clozapine for almost all the participants was treatment resistance and most of the psychiatrists initiated clozapine either in the dose of 25mg OD (44.3%) or 12.5mg OD (37%). Half (51.8%) of the psychiatrists preferred to use clozapine as BD dosing schedule, and median doses required to stabilize the patients ranged from 137.5 to 400mg/day. Once the clozapine dose had been stabilized, about half (51%) of the psychiatrists advised blood monitoring at monthly intervals. Almost all psychiatrists rated effectiveness of clozapine to be better than other antipsychotics. In terms of tolerability, 45.3% of the psychiatrists rated it as 'same as other antipsychotics' and 15.9% rated it as better than other antipsychotics. Most common patient and therapist related factors associated with reluctance to start clozapine were history of poor medication compliance and need for monitoring, respectively. Upon reviewing the prescription of other psychiatrists, participating psychiatrists reported that in about 28.46% of patients clozapine was not prescribed though indicated.. This survey suggests that clozapine is underused in India, although psychiatrists have adequate knowledge about the drug but many psychiatrists have negative attitude towards clozapine.

Topics: Adult; Antipsychotic Agents; Attitude of Health Personnel; Clozapine; Dose-Response Relationship, Drug; Drug Monitoring; Female; Health Care Surveys; Humans; India; Male; Medication Adherence; Mental Disorders; Psychiatry; Treatment Outcome

We report the synthesis and structure-activity relationships of a class of tetracyclic butyrophenones that exhibit potent binding affinities to serotonin 5-HT(2A) and dopamine D2 receptors. This work has led to the discovery of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluorophenyl)-butan-1-one 4-methylbenzenesulfonate (ITI-007), which is a potent 5-HT(2A) antagonist, postsynaptic D2 antagonist, and inhibitor of serotonin transporter. This multifunctional drug candidate is orally bioavailable and exhibits good antipsychotic efficacy in vivo. Currently, this investigational new drug is under clinical development for the treatment of neuropsychiatric and neurological disorders.

Topics: Adrenergic Uptake Inhibitors; Animals; Behavior, Animal; Biological Availability; Drug Discovery; Electroshock; Indicators and Reagents; Male; Mental Disorders; Nervous System Diseases; Quinoxalines; Quipazine; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Recombinant Proteins; Schizophrenia; Serotonin Antagonists; Serotonin Plasma Membrane Transport Proteins; Structure-Activity Relationship

Psychiatric disorders have been hypothesized to originate during development, with genetic and environmental factors interacting in the etiology of disease. Therefore, developmentally regulated genes have received attention as risk modulators in psychiatric diseases. Reelin is an extracellular protein essential for neuronal migration and maturation during development, and its expression levels are reduced in psychiatric disorders. Interestingly, several perinatal insults that increase the risk of behavioral deficits alter Reelin signaling. However, it is not known whether a dysfunction in Reelin signaling during perinatal stages increases the risk of psychiatric disorders. Here we used a floxed dab1 allele to study whether a transient decrease in Dab1, a key component of the Reelin pathway, is sufficient to induce behavioral deficits related to psychiatric disorders. We found that transient Dab1 downregulation during perinatal stages leads to permanent abnormalities of structural layering in the neocortex and hippocampus. In contrast, conditional inactivation of the dab1 gene in the adult brain does not result in additional layering abnormalities. Furthermore, perinatal Dab1 downregulation causes behavior impairments in adult mice, such as deficits in memory, maternal care, pre-pulse inhibition, and response to cocaine. Some of these deficits were also found to be present in adolescence. We also show that D-cycloserine rescues the cognitive deficits observed in floxed dab1 mice with layering alterations in the hippocampus and neocortex. Our results indicate a causal relation between the downregulation of Dab1 protein levels during development and the structural and behavioral deficits associated with psychiatric diseases in the adult.

Topics: Animals; Animals, Newborn; Antipsychotic Agents; beta-Galactosidase; Brain; Clozapine; Corticosterone; Disease Models, Animal; Down-Regulation; Female; Gene Expression Regulation, Developmental; Male; Mental Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor Activity; Mutation; Nerve Tissue Proteins; Reelin Protein; Tamoxifen

Prior clozapine studies indicated no effects, mild inhibition or induction of valproic acid (VPA) on clozapine metabolism. The hypotheses that (i) VPA is a net inducer of clozapine metabolism, and (ii) smoking modifies this inductive effect were tested in a therapeutic drug monitoring study.. After excluding strong inhibitors and inducers, 353 steady-state total clozapine (clozapine plus norclozapine) concentrations provided by 151 patients were analyzed using a random intercept linear model.. VPA appeared to be an inducer of clozapine metabolism since total plasma clozapine concentrations in subjects taking VPA were significantly lower (27% lower; 95% confidence interval, 14-39%) after controlling for confounding variables including smoking (35% lower, 28-56%).. Prospective studies are needed to definitively establish that VPA may (i) be an inducer of clozapine metabolism when induction prevails over competitive inhibition, and (ii) be an inducer even in smokers who are under the influence of smoking inductive effects on clozapine metabolism.

Topics: Antimanic Agents; Chromatography, High Pressure Liquid; Clozapine; Drug Monitoring; Female; Humans; Linear Models; Male; Mental Disorders; Sex Factors; Smoking; Valproic Acid

Psychiatric hospital readmissions correlate with illness severity, drug selection, and compliance with treatment in the outpatient setting. The risk factors for psychiatric rehospitalization have been mainly assessed in databases lacking information regarding somatic comorbidity and anthropometric variables, such as body mass index (BMI), which are known to predict readmissions in nonpsychiatric settings.. To determine independent predictors of 1-year readmission occurring among unselected adults consecutively admitted for treatment of severe mental illness to an academic, freestanding psychiatric hospital in New York City from August 2010 through January 2011.. After identifying univariate correlates of readmission, we used logistic regression with backward elimination to identify independent predictors of readmissions within 1 year after the index psychiatric hospitalization.. Among 224 (23.7%) of 945 readmitted patients, psychiatric readmission was significantly associated with age (P = .0029), length of stay (P = .036), schizophrenia/schizoaffective disorder (P < . 0001), dementia (P = .027), major depressive disorder (P = .0006), treatment with atypical antipsychotic drugs (P = .0054), electroconvulsive therapy (P < .0001), and BMI (P = .0079), but not with physical comorbidities and routine laboratory data.The independent predictors of readmission were higher BMI (median = 28.5 kg/ m2; odds ratio [OR] = 3.6; Cl, 1.2-10.6), a diagnosis of schizophrenia/schizoaffective disorder (OR = 2.2; Cl, 1.5-3.4), clozapine treatment (OR = 2.8; CI, 1.1-6.9), no electroconvulsive therapy (OR = 0.13; Cl, 0.02-0.45), and shorter length of stay (median = 18 days; OR = 0.08; Cl, 0.01-0.42).. Body mass index was identified, for the first time, as an independent predictor of psychiatric rehospitalization. Enhanced outpatient treatment programs for overweight and obese psychiatric patients might influence readmission rates and should be explored in prospective studies.

Topics: Adult; Age Factors; Antipsychotic Agents; Body Mass Index; Clozapine; Combined Modality Therapy; Depressive Disorder, Major; Electroconvulsive Therapy; Female; Hospitals, Psychiatric; Humans; Length of Stay; Male; Mental Disorders; Middle Aged; Patient Readmission; Prognosis; Psychotherapy; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Young Adult

Increasing evidence suggests that clock genes may be implicated in a spectrum of psychiatric diseases, including sleep and mood related disorders as well as schizophrenia. The bHLH transcription factors SHARP1/DEC2/BHLHE41 and SHARP2/DEC1/BHLHE40 are modulators of the circadian system and SHARP1/DEC2/BHLHE40 has been shown to regulate homeostatic sleep drive in humans. In this study, we characterized Sharp1 and Sharp2 double mutant mice (S1/2-/-) using online EEG recordings in living animals, behavioral assays and global gene expression profiling. EEG recordings revealed attenuated sleep/wake amplitudes and alterations of theta oscillations. Increased sleep in the dark phase is paralleled by reduced voluntary activity and cortical gene expression signatures reveal associations with psychiatric diseases. S1/2-/- mice display alterations in novelty induced activity, anxiety and curiosity. Moreover, mutant mice exhibit impaired working memory and deficits in prepulse inhibition resembling symptoms of psychiatric diseases. Network modeling indicates a connection between neural plasticity and clock genes, particularly for SHARP1 and PER1. Our findings support the hypothesis that abnormal sleep and certain (endo)phenotypes of psychiatric diseases may be caused by common mechanisms involving components of the molecular clock including SHARP1 and SHARP2.

Topics: Animals; Anxiety; Basic Helix-Loop-Helix Transcription Factors; Circadian Rhythm; Clozapine; Endophenotypes; Exploratory Behavior; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; Male; Mental Disorders; Mice, Inbred C57BL; Prepulse Inhibition; Repressor Proteins; Sleep; Transcription Factors; Wakefulness

Topics: Adult; Cerebral Angiography; Clozapine; Electrocardiography; Humans; Male; Mental Disorders; Pulmonary Embolism; Serotonin Antagonists; Tomography, X-Ray Computed

In this retrospective study, we aimed to evaluate platelet changes in patients taking clozapine for a variety of psychiatric disorders and hypothesized that there would be any changes in the course of the treatment.. Diagnoses were based on Diagnostic and Statistical Manual of Mental Disorders 4(th) edition. Forty-three patients, with the mean age of 36.23 ± 6.35 years were included into final analysis. Morning venous blood samples were used for platelet counts. Correlation analyses were performed between platelet counts and clozapine doses.. Paired t test did not reveal a significant change in platelet counts at the end visit compared to those of first assessment (p>0.05). Seven (17.9%) of 39 patients had platelet count below 180000 per cubic millimeter at least one time during their clozapine use. In five of these patients, the platelet count returned to a level above 180000 per cubic millimeter, without any dose change or other interventions. On the other hand, as for the issue of increased platelet count, results demonstrated that seven (17.9%) had platelet count above 400000 per cubic millimeter at least one time during clozapine use.. The present investigation revealed that platelet changes beyond WBC changes should be taken into consideration when using clozapine. Clinicians should be aware of the deviations from absolute threshold values.

Topics: Adult; Antipsychotic Agents; Blood Platelets; Clozapine; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Male; Mental Disorders; Middle Aged; Platelet Count; Prognosis; Retrospective Studies; Thrombocytopenia; Thrombocytosis; Young Adult

The clinical severity, impact on development, and poor prognosis of childhood onset schizophrenia may represent a more homogeneous group. Positive symptoms in children are necessary for the diagnosis and hallucinations are more often multimodal. In healthy children and children with a variety of other psychiatric illnesses, hallucinations are not uncommon and diagnosis should not be based on these alone. Childhood onset schizophrenia is an extraordinarily rare illness that is poorly understood but seems continuous with the adult onset disorder. Once a diagnosis is affirmed, aggressive medication treatment combined with family education and individual counseling may defer further deterioration.

Topics: Adolescent; Adult; Antipsychotic Agents; Brain; Child; Child, Preschool; Clozapine; Cohort Studies; Comorbidity; Diagnosis, Differential; Diagnostic and Statistical Manual of Mental Disorders; Humans; Incidence; Mental Disorders; National Institute of Mental Health (U.S.); Practice Guidelines as Topic; Prodromal Symptoms; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index; United States; Young Adult

A functional analysis examined the relation between consequences that maintained episodic problem behavior (aggression, property destruction, and elopement) in the presence and absence of manic behaviors (MB). Results suggested that the presence of MB was correlated with the sensitivity of problem behavior to attention as a reinforcer during a functional analysis and that problem behaviors were maintained by attention. Noncontingent reinforcement was subsequently implemented and demonstrated to be effective in reducing problem behavior during the presence of manic behaviors.

Topics: Antimanic Agents; Antipsychotic Agents; Attention Deficit Disorder with Hyperactivity; Behavioral Symptoms; Clozapine; Diagnosis, Dual (Psychiatry); Female; Humans; Mental Disorders; Middle Aged; Psychiatric Status Rating Scales; Valproic Acid

We assessed the predictors of clozapine initiation among youth 18 years and younger within a state psychiatric hospital. Administrative data (n = 358) were evaluated of inpatients from a long-term state child and adolescent psychiatric hospital. We investigated 25 background and clinical patient characteristics to determine which factors predicted clozapine initiation following the first 21 days of hospital admission. A Cox proportional model was used to evaluate factors that independently predicted the hazard rate of clozapine initiation. Emergency medication administration during the first 3 weeks of admission, which was more common among the clozapine (84.9 %) than control (61.7 %) patients (p < 0.001), was associated with a significantly increased probability of clozapine initiation (Hazard Ratio = 1.9, 95 % Confidence Interval = 1.2-3.1). Use of a mood stabilizer during the first 3 weeks of the inpatient was non-significantly related to an increased probability of clozapine initiation (Hazard Ratio = 1.7, 95 % Confidence Interval = 1.0-2.9). In this setting, emergency medication use predicts clozapine initiation suggesting that it may be used to treat patients with aggressive behavior.

Topics: Adolescent; Antipsychotic Agents; Child; Child, Preschool; Clozapine; Cohort Studies; Female; Hospitals, Psychiatric; Humans; Infant; Male; Mental Disorders; Proportional Hazards Models; Psychiatric Status Rating Scales

To investigate the influence of a single episode of psychiatric inpatient treatment on metabolic parameters.. A total of 294 consecutive patients of an Upper Austrian psychiatric department were assessed at admission and discharge regarding bodyweight, body mass index (BMI), high density cholesterol (HDL), low density cholesterol (LDL), triglycerides (TG) and fasting glucose (FG), and the TG/HDL ratio.. Patients showed an increase of BMI of 0.35 kg/m² (+ 1.3%) during a mean duration of inpatient stay of 25.8 days. LDL rose by 10.7 mg/dl (+ 8.1%), triglycerides by 23.0 mg/dl (+ 17%), HDL decreased by 4.4 mg/dl (-7.4%). Fasting glucose decreased by 3.6 mg/dl (-3.8%), yet the TG/HDL ratio, as a marker for insulin resistance, increased significantly from 2.86 to 3.58 (+ 25.2%) on average. Patients with psychotic disorders gained about three times more weight than patients with other diagnoses. Negative alterations of serum lipids were to be found in all diagnostic groups but were especially pronounced in patients with psychotic disorders who were treated with second-generation antipsychotics clozapine, olanzapine and quetiapine.. Psychiatric inpatient treatment leads to clinically relevant deterioration of metabolic parameters within a short time, most pronouncedly in patients with psychotic disorders.

Topics: Antipsychotic Agents; Austria; Benzodiazepines; Biomarkers; Body Mass Index; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Clozapine; Dibenzothiazepines; Female; Glucose; Hospitalization; Humans; Insulin Resistance; Length of Stay; Lipid Metabolism; Male; Mental Disorders; Middle Aged; Multivariate Analysis; Olanzapine; Polypharmacy; Prospective Studies; Psychiatric Department, Hospital; Psychotic Disorders; Quetiapine Fumarate; Regression Analysis; Triglycerides; Weight Gain

Weight gain is a common problem of treatment with atypical antipsychotics. However, the dimension of body weight change differs interindividually, and various genetic factors are considered to be associated with this effect. Peroxisome proliferator-activated receptor gamma (PPARG) Pro12Ala polymorphism and its reported relationship to type 2 diabetes susceptibility and body mass accumulation prompted us to investigate the impact of this single nucleotide polymorphism (SNP) on antipsychotic-induced changes of body weight and body mass index (BMI) in a naturalistic study design.. Included were 138 olanzapine- and 32 clozapine-treated psychiatric inpatients whose demographic data, medical anamnesis, and drug treatment were assessed at admission to hospital and 4 weeks thereafter. The PPARG Pro12Ala SNP was determined with a validated real-time PCR assay.. In contrast to previous investigations, we did not detect significant variations of weight gain among the different PPARG Pro12Ala genotypes.. Our results suggest that the examined polymorphism appears to play a minor or no role in clinical practice concerning antipsychotic drug-induced weight gain.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Clozapine; Female; Genetic Association Studies; Humans; Male; Mental Disorders; Middle Aged; Olanzapine; Polymorphism, Single Nucleotide; PPAR gamma; Weight Gain; Young Adult

To investigate the effect of dose and other factors on plasma clozapine concentrations in patients aged 65 years and over.. Audit of clozapine therapeutic drug monitoring data, 1996-2010.. There were 1930 samples [778 patients, 363 men aged (median, range) 67 (65-100) years and 415 women aged 68 (65-90) years]. There was no significant difference in the mean plasma clozapine concentration between men (0.56 mg/l) and women (0.58 mg/l), although the mean dose was higher in men (323 mg/d) than women (264 mg/d). The higher proportion of men (46%) compared with women (37%) smokers could explain this finding. Overall, 32% of samples had plasma clozapine below, and 37% above, a target range of 0.35-0.60 mg/l. Overall, the median dose decreased from 300 (65-70 years) to 200 mg/d (age 85 years and over). However, prescription of >350 mg/d was associated with a 50% likelihood that the plasma clozapine would exceed 0.60 mg/l. For a subgroup of 196 patients (114 men, 82 women), mean plasma clozapine was significantly higher after age 65 despite significantly lower dosage.. Clozapine dosage in elderly patients should be reviewed regularly to minimise the risk of adverse effects.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Longitudinal Studies; Male; Mental Disorders; Middle Aged; Retrospective Studies; Sex Factors

Adverse events early in life, including maternal separation and social isolation, profoundly affect brain development and adult behaviour and may contribute to the occurrence of psychiatric disorders such as schizophrenia and mood disorders in genetically predisposed individuals. The molecular mechanisms underlying these environmentally induced developmental adaptations are unclear and best evaluated in animal paradigms with translational salience. In this study, we examined the effects in mice of maternal separation and/or social isolation for 6 h/d between postnatal days 15 and 21 on performance during adulthood in the open-field, social interaction, elevated plus-maze, forced swimming, Y-maze, novel object recognition, conditioned fear-learning, prepulse inhibition, and locomotor activity tests, to investigate whether this animal model could show the phenotypes for schizophrenia and mood disorders. The stress of maternal separation and isolation led to adult behavioural deficits, activation of the hypothalamic-pituitary-adrenal axis, and decreases in the levels of norepinephrine and dopamine in the frontal cortex and metabolites of dopamine and serotonin in the amygdala, showing the involvement of endocrine and neuronal risk in behavioural deficits. The results suggest that the frontal cortex and amygdala undergo structural remodelling induced by the stress of maternal separation and isolation, which alters behavioural and physiological responses in adulthood, including anxiety, memory and other cognitive processes. Further, social isolation enhanced the behavioural dysfunctions induced by maternal separation. These findings indicate that maternal separation and social isolation early in life can lead to long-lasting abnormal behaviour and pathophysiological impairments including schizophrenia and mood disorders.

Topics: Animals; Antipsychotic Agents; Anxiety; Behavior, Animal; Clozapine; Disease Models, Animal; Environment; Fear; Hypothalamo-Hypophyseal System; Male; Maternal Deprivation; Maze Learning; Mental Disorders; Mice; Mice, Inbred C57BL; Motor Activity; Neurotransmitter Agents; Pituitary-Adrenal System; Social Isolation; Swimming

Few studies on the association between atypical antipsychotic drug (AAP) administration and metabolic dysfunction have concurrently evaluated the general population (GP), other psychotropic drug treatments and drug-free psychiatric patients.. We assessed the frequency of the metabolic syndrome (MS) according to the National Cholesterol Education Program criteria (NCEP) and its constituting variables in a GP sample (n=271) and in patients receiving, for at least three consecutive months, antiepileptic drugs (n=93), olanzapine (n=162), clozapine (n=105), typical antipsychotics (n=117), other AAP (n=58), other psychotropic drugs (n=185), and drug-free individuals (n=636). Subjects were clinically classified as schizophrenia, bipolar or other axis I disorders (DSM-IV-RT), and as first-degree relatives of each diagnostic group.. The MS was detected in 26.6% of the GP (95% confidence interval: 21.5-31.8). No diagnostic or treatment group had a significantly higher age-adjusted frequency than the GP (p>0.05). Treatment duration did not significantly affect the results. However, significant differences were observed in the frequency of abnormal MS constituting variables in comparison to the GP. For example, schizophrenia patients and their relatives, bipolar subjects and olanzapine- and clozapine-treated patients had higher abnormal waist circumference values. In addition, bipolar patients and their relatives and subjects treated with olanzapine and other AAPs had higher frequencies of abnormal glucose levels. Neither schizophrenia nor bipolar patients in the diagnostic categories nor the olanzapine or the clozapine groups displayed higher proportions of abnormal triglycerides, high density cholesterol or blood pressure levels than the GP.. While we did not demonstrate an increased frequency of the MS in AAP-treated subjects, our results confirm that specific metabolic variables must be monitored in psychiatric patients. Besides they stress the importance, in epidemiological studies, of concurrently comparing the figures recorded in AAP-treated patients with those obtained in the local GP, other drug treatment groups and drug-free subjects when referring to the magnitude of the metabolic effects of specific antipsychotic agents.

Topics: Adult; Age Factors; Aged; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Cholesterol; Clozapine; Community Health Planning; Confidence Intervals; Family; Female; Humans; Male; Mental Disorders; Metabolic Diseases; Middle Aged; Olanzapine; Retrospective Studies; Treatment Outcome; Venezuela; Young Adult

Topics: Adult; Aged; Clozapine; Female; Humans; Male; Mental Disorders; Middle Aged; Retrospective Studies; Smoking; Smoking Cessation; Young Adult

The aim of this study was to review the use of clozapine in a Sydney area old age psychiatry service. Data were extracted from case files of all people who were treated in a health area's old age psychiatry units with clozapine during a 15-year period. Additional details were obtained from clinicians who provided ongoing care after discharge from the hospital. Note was made of psychiatric diagnoses, length of time taking clozapine, dosage, side effects and outcome. Sixteen patients aged over 65 years commenced or continued taking clozapine while inpatients of the service. Of the 13 patients who had a history of schizophrenia or schizoaffective disorder, four patients (all female) developed neutropenia and therefore clozapine was stopped. In one case, neutropenia was first diagnosed 6 years after commencing the medication. Two women died; the nine other women, and one of the deceased, stopped taking clozapine, usually because of side effects. The mean daily dose at cessation was 236 mg. All five men were still taking clozapine (mean 260 mg daily) when followed at a mean age of 72 years, having taken it for an average of 10 years. This case review adds to evidence of the risk of neutropenia when older people are prescribed clozapine.

Topics: Age of Onset; Aged; Clozapine; Dementia; Drug Utilization; Female; Humans; Inpatients; Male; Mental Disorders; Middle Aged; Neutropenia; New South Wales; Psychiatry; Psychotic Disorders; Retrospective Studies; Schizophrenia; Treatment Outcome

Topics: Adult; Antipsychotic Agents; Causality; Clozapine; Cytochrome P-450 CYP1A2; Humans; Male; Mental Disorders; Young Adult

Available information regarding clozapine-related cardiomyopathy is limited to reports of severe left ventricular dysfunction not rarely with fatal clinical evolution. A subclinical cardiotoxic effect might be diagnosed using echocardiography and N-terminal pro-B-type natriuretic peptide assay.. Thirty-eight patients with psychotic disorder in chronic therapy with clozapine (24 male and 14 female subjects; mean age, 38.4 years) were enrolled. Left ventricular ejection fraction (LVEF) was measured by area-length method (average of 5 measurements).. Twelve patients showed a mild depression of left ventricular function (LVEF between 50% and 55%), 2 LVEF less than 50% and 1 less than 30%. The area under the receiver operating characteristic curve for N-terminal pro-B-type natriuretic peptide as a predictor of left ventricular dysfunction was 0.87.. A subclinical left ventricular dysfunction was found in 3 of 38 patients, whereas a mild impairment of the left ventricular systolic function occurred in 1 of 3 of young, previously healthy, clozapine-treated patients A prospective study in clozapine-naive patients may be useful to better understand cardiotoxic effects of clozapine.

Topics: Adult; Antipsychotic Agents; Biomarkers; Cardiomyopathies; Clozapine; Female; Humans; Male; Mental Disorders; Natriuretic Peptide, Brain; Peptide Fragments; ROC Curve; Ultrasonography; Ventricular Dysfunction, Left

Consumers with a mental illness have a significantly higher risk of physical health problems than the general population. The role of health behaviour beliefs and their part in the health of consumers with a mental illness has been poorly explored in the literature.. To understand the relationship between physical health risk factors and health behaviour beliefs in consumers with schizophrenia.. A cross-sectional survey study design using the European Health and Behaviour Survey and assessing (n=99) consumer's blood pressure, waist circumference, body mass index, smoking history, exercise levels, demographics, family history of diabetes and cardiovascular disease was used.. The study was conducted in a 76-bed psychiatric facility located within a 550-bed metropolitan generalist hospital in Sydney, Australia.. Patients attending an outpatient clozapine clinic at the mental health service were asked to participate in the survey by a nurse working in the clinic during the study period.. Of the 163 consumers asked to be involved in the study, n=99 agreed to participate. Mean waist circumference and body mass index for both males and females were significantly above normal population limits. Overall, consumer's beliefs toward their health on the European Health and Behaviour Survey were positive, having statistically significantly more positive attitudes to the statements 'avoiding too much sugar', 'drinking no alcohol' and 'yearly blood pressure checks' than a previously published non-mental health consumer sample. Whilst having positive attitude toward their healthcare, consumers' physical health risk parameters were higher than general population norms.. Consumers with a mental illness have a significantly higher risk for serious physical health problems, yet possess high positive attitudes toward their physical health care. Models of care need to explore this contradiction within mental health services to improve patient outcomes.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Attitude to Health; Cardiovascular Diseases; Clozapine; Cross-Sectional Studies; Female; Health Behavior; Humans; Hypertension; Life Style; Male; Mental Disorders; Models, Psychological; New South Wales; Obesity; Outpatients; Risk Assessment; Risk Factors; Self Care; Smoking; Surveys and Questionnaires

The purpose of this study was to identify children in a state Medicaid population who were newly treated with second-generation antipsychotics from 2001 through 2005, to classify each use of these agents as evidence based or not depending on the child's diagnoses, and to identify factors associated with the likelihood of evidence-based use of the medication.. A Medicaid claims database was used to retrospectively identify enrollees receiving initial outpatient treatment with a second-generation antipsychotic between 2001 and 2005. To capture all relevant treatments and diagnoses, claims were examined from January 2000 through December 2006. The final sample included 11,700 children under age 18. The primary measure of interest was the proportion for whom use of the antipsychotic was based on evidence. Evidence-based use (categorized as strong, plausible, or weak evidence) was defined as any use of the agent for a diagnosis supported by a clinical trial published before the end of 2005. Trend analysis and logistic regression were used.. The number of children newly treated with second-generation antipsychotics increased from 1,482 in 2001 to 3,110 in 2005. Of the new users of these agents during the study period, 41.3% had no diagnosis for which such treatment was supported by a published study. The medication with the highest level of non-evidence-based use was aripiprazole (77.1%), and risperidone had the lowest (30.6%).. The number of children receiving second-generation antipsychotics doubled in this Medicaid population between 2001 and 2005, and a large proportion of the treatments were not supported by evidence from clinical studies.

Topics: Adolescent; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Child; Child, Preschool; Clozapine; Dibenzothiazepines; Drug Utilization; Evidence-Based Medicine; Female; Humans; Infant; Insurance Claim Review; Male; Medicaid; Mental Disorders; Off-Label Use; Olanzapine; Piperazines; Quetiapine Fumarate; Quinolones; Risperidone; Thiazoles; United States; United States Food and Drug Administration

Patterns of discontinuation of atypical antipsychotic drugs, including the return to therapy after an interruption, have not been examined longitudinally.. This study was conducted to describe discontinuation patterns of atypical antipsychotic drugs across a spectrum of outpatients in the province of Québec.. This retrospective, inception cohort study employed data from the Québec health insurance board databases and the Québec hospitalization registry on Québec Drug Plan beneficiaries between the ages of 20 and 64 years who first filled a prescription for any antipsychotic drug between January 1, 2000, and December 31, 2007. Five subcohorts were constructed according to the initial antipsychotic received: either 1 of the 4 atypical antipsychotics covered by the Québec drug plan at the time of the study-olanzapine, quetiapine, risperidone, and clozapine-or polytherapy (>1 atypical antipsychotic, or 1 atypical and 1 typical antipsychotic). Discontinuation was defined as a failure to refill the initial prescription within 2 times the days' supply of the preceding claim. In individuals who discontinued initial drug treatment, a new course of treatment was defined as initiation of treatment with any antipsychotic drug after a first treatment discontinuation. Discontinuation of a second course of treatment was defined as failure to refill a prescription for the second drug within 2 times the days' supply of the preceding claim. Patients were followed from initiation to December 31, 2004, ineligibility for the drug plan, or death, whichever came first. Kaplan-Meier curves and Cox regression models were used to compare discontinuations and new courses of treatment by initial atypical antipsychotic.. The overall cohort consisted of 46,074 drug plan beneficiaries who had initiated antipsychotic treatment during the specified period. The majority of individuals were female (54.6%) and lived in urban areas (79.2%); the median age ranged from 40 to 44 years. The mean (SD) duration of follow-up was 2.67 (1.91) years. Compared with individuals whose initial therapy was olanzapine, those whose initial therapy was quetiapine had a significantly higher likelihood of discontinuing initial treatment (adjusted hazard ratio [AHR] = 1.06; 95% CI, 1.04-1.09; P < 0.001). The likelihood of discontinuing initial treatment was significantly lower among those whose initial therapy was risperidone (AHR = 0.93; 95% CI, 0.90-0.95; P < 0.001), clozapine (AHR = 0.56; 95% CI, 0.46-0.68; P < 0.001), or polytherapy (AHR = 0.69; 95% CI, 0.64-0.74; P < 0.001). Those whose initial therapy was quetiapine were significantly less likely than those whose initial therapy was olanzapine to begin a second course of treatment (AHR = 0.95; 95% CI, 0.90-0.99; P = 0.02). Compared with individuals who initiated a second course of treatment with olanzapine, those who initiated a second course with quetiapine were more likely to discontinue again (AHR = 1.09; 95% CI, 1.04-1.14; P < 0.001), whereas those who initiated a second course with risperidone were less likely to discontinue again (AHR = 0.95; 95% CI, 0.90-1.00; P = 0.04).. This study population had a high risk of discontinuing initial atypical antipsychotic therapy within 1 year. Those who discontinued had a low likelihood of returning to treatment, and those who did return to treatment had a high likelihood of discontinuing again. These patterns of use may have serious consequences for patients' health and for the utilization of health services.

Topics: Adult; Age Distribution; Antipsychotic Agents; Benzodiazepines; Clozapine; Cohort Studies; Databases, Factual; Dibenzothiazepines; Drug Prescriptions; Drug Therapy, Combination; Drug Utilization; Drug Utilization Review; Female; Humans; Kaplan-Meier Estimate; Male; Mental Disorders; Middle Aged; Olanzapine; Patient Compliance; Quebec; Quetiapine Fumarate; Registries; Retrospective Studies; Risperidone; Sex Distribution; Young Adult

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Humans; Mental Disorders; Schizophrenia; Schizophrenic Psychology

A sensitive and specific GC/MS method for the determination of clozapine (CLZ) and its major metabolite norclozapine (NCLZ), in plasma has been developed, optimized and validated. Specimen preparation includes solid-phase extraction of both analytes using Bond-Elut Certify cartridge and further derivatization with TFAA. Clozapine-d8 was used as internal standard for the determination of CLZ and NCLZ. Limits of detection were 0.45 ng/mL for CLZ and 1.59 ng/mL for NCLZ, while limits of quantification were 1.37 ng/mL for CLZ and 4.8 ng/mL for NCLZ, as calculated by the calibration curves. The calibration curves were linear up to 600 ng/mL for CLZ and NCLZ. Absolute recovery ranged from 82.22% to 95.35% for both analytes. Intra- and interday accuracy was less than 7.13% and --12.52%, respectively, while intra- and interday precision was between 9.47% and 12.07%, respectively, for CLZ and NCLZ. The method covers all therapeutic range and proved suitable for the determination of CLZ and NCLZ not only in psychiatric patients but also in forensic cases with clozapine implication.

Topics: Clozapine; Gas Chromatography-Mass Spectrometry; Humans; Linear Models; Mental Disorders; Reproducibility of Results; Sensitivity and Specificity; Solid Phase Extraction

Usher syndrome, the most common case of deaf - blindness, may be associated with various psychiatric disorders. Inability of communication through spoken language in association with progressive visual impairment affects diagnostics and management in case of co-morbidity with mental disorder. A patient with Usher syndrome and psychiatric symptoms is described and the difficulties in psychiatric assessment in her case are discussed. A 28 years old woman with hearing impairment diagnosed at the age of 3 months and progressive pigmentary retinopathy diagnosed at the age of 19 years, has been treated for ADHD in childhood, eating disorder in adolescence and psychosis-like disorder in adult life. Direct observation of patient behavior and the effects of pharmacotherapy were the main diagnostic procedures, since the use of sign language and handwriting was very limited. The limitations of management are discussed.

Topics: Adult; Anorexia Nervosa; Anti-Anxiety Agents; Antipsychotic Agents; Clozapine; Comorbidity; Diagnosis, Differential; Drug Therapy, Combination; Female; gamma-Aminobutyric Acid; Humans; Mental Disorders; Obsessive-Compulsive Disorder; Pregabalin; Psychotic Disorders; Recurrence; Social Isolation; Usher Syndromes; Violence

Cognitive deficits in schizophrenia are a major source of dysfunction for which more effective treatments are needed. The vasopressin-deficient Brattleboro (BRAT) rat has been shown to have several natural schizophrenia-like deficits, including impairments in prepulse inhibition and memory. We investigated BRAT rats and their parental strain, Long-Evans (LE) rats, in a social discrimination paradigm, which is an ethologically relevant animal test of cognitive deficits of schizophrenia based upon the natural preference of animals to investigate conspecifics. We also investigated the effects of the atypical antipsychotic, clozapine, and the putative antipsychotic, PD149163, a brain-penetrating neurotensin-1 agonist, on social discrimination in these rats. Adult rats were administered saline or one of the three doses of clozapine (0.1, 1.0, or 10 mg/kg) or PD149163 (0.1, 0.3, or 1.0 mg/kg), subcutaneously. Following drug administration, adult rats were exposed to a juvenile rat for a 4-min learning period. Animals were then housed individually for 30 min and then simultaneously exposed to the juvenile presented previously and a new juvenile for 4 min. Saline-treated LE rats, but not BRAT rats, exhibited intact social discrimination as evidenced by greater time spent exploring the new juvenile. The highest dose of clozapine and the two highest doses of PD149163 restored social discrimination in BRAT rats. These results provide further support for the utility of the BRAT rat as a genetic animal model relevant to schizophrenia and drug discovery. The potential of neurotensin agonists as putative treatments for cognitive deficits of schizophrenia was also supported.

Topics: Animals; Antipsychotic Agents; Brain; Clozapine; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Exploratory Behavior; Male; Mental Disorders; Neurotensin; Rats; Rats, Brattleboro; Rats, Long-Evans; Receptors, Neurotensin; Schizophrenia; Schizophrenic Psychology; Social Behavior

The purpose of this study was to examine the association between atypical antipsychotics, including the newer agents, aripiprazole and ziprasidone, and newly treated diabetes, using the largest post-marketing cohort of patients exposed to these newer treatments that has been studied to date.. Identified two overlapping cohorts-a simple cohort (all antipsychotic users) and an inception cohort (new users of antipsychotics)-using automated data from three United States sites (60.4 million covered lives). Patients exposed to antipsychotics > or = 45 days were identified and followed for incident diagnoses of treated diabetes. Data analysis accounted for drug switching and non-consistent drug use.. In the 55 287-member inception cohort, 357 cases of newly treated diabetes were identified. Compared with current use of typical antipsychotics, current users of aripiprazole (adjusted hazard ratio (aHR) 0.93, 95% confidence interval (CI) 0.50-1.76), quetiapine (aHR 1.04, 95%CI, 0.67-1.62), risperidone (aHR 0.85, 95%CI, 0.54-1.36) and ziprasidone (aHR 1.05, 95%CI, 0.54-2.08) had similar low risk of diabetes. Patients exposed to olanzapine had an increased risk of diabetes (aHR 1.71, 95%CI, 1.12-2.61), and although the effect estimate is imprecise, clozapine-exposed patients had a trend towards an elevated hazard ratio (aHR 2.58, 95%CI, 0.76-8.80). Results for the simple cohort were similar.. Relative to typical antipsychotics, aripiprazole, ziprasidone, risperidone and quetiapine were not associated with an increased risk of diabetes; olanzapine and clozapine were associated with an increased risk. This analysis constitutes the largest post-marketing pharmacoepidemiologic study to date that includes the newer agents.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clozapine; Cohort Studies; Diabetes Mellitus; Female; Humans; Male; Mental Disorders; Middle Aged; Olanzapine; Piperazines; Quinolones; Retrospective Studies; Thiazoles; United States

A methodological problem arises when efficacy of clozapine is compared with other antipsychotic medication in double blind randomized studies. Due to the risk of leucopenia and agranulocytosis, patients in the clozapine condition need to have regular blood testing. The problem is that in order to maintain blinding, patients in the comparison conditions need to undergo blood testing as well and this can lead to underestimation of treatment acceptability and efficacy of the comparators.. A thought experiment considering all possible solutions for the methodological problem.. We propose a special study design that preserves randomization and blinding while at the same time prevents underestimation of the effect in the comparator treatments. In addition, the necessity for blood testing is limited to only a small number of patients who receive comparative treatments. The design involves initial randomization to a sub-study including clozapine and a small comparator arm or to a sub-study that includes only comparator arms. Blood testing is only necessary in the first sub-study.. Limitations of the proposed design are discussed. It is noted that this study design may offer a solution to similar situations where blood testing or other types of monitoring (e.g. as with lithium) is required in one but not in all of the treatment arms of a double blind randomized study.

Topics: Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Double-Blind Method; Humans; Mental Disorders; Outcome Assessment, Health Care; Research Design

Topics: Antidepressive Agents, Second-Generation; Antipsychotic Agents; Bupropion; Clozapine; Humans; Male; Mental Disorders; Middle Aged; Sialorrhea

Medication is a necessary part of treatment for severe psychiatric illnesses such as schizophrenia and nonadherence to prescribed medication is one of the most important public health issues in psychiatry today. The devastating consequences of nonadherence have motivated the development of novel therapeutic strategies, including a new long-term implantable medication delivery system.. The current study assesses attitudes towards implantable medication in psychiatric patients and their family members. Patients included in the study had diagnoses of Schizophrenia, Schizoaffective Disorder, Mood or Anxiety related disorders.. 49.62% of patients and 74.47% of family members endorse support for implantable medication.. This study demonstrates that implants may be an acceptable alternative to oral and injectable medication for a subset of psychiatric patients and their families.

Topics: Adult; Attitude to Health; Clozapine; Cross-Cultural Comparison; Data Collection; Drug Implants; Family; Female; Haloperidol; Humans; Male; Mental Disorders; Middle Aged; Mood Disorders; Patient Compliance; Psychotic Disorders; Psychotropic Drugs; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; United States

Topics: Adult; Antimanic Agents; Antipsychotic Agents; Clozapine; Humans; Lithium Chloride; Male; Mental Disorders; Neutropenia

Leptin dysregulation has been implicated in the body weight gain and metabolic dysfunction observed with the second generation antipsychotic drugs (SGAD) olanzapine and clozapine.. This study quantified the frequency of subjects with abnormal correlation between leptin and the body mass index controlling for gender (defined as being out of the upper or lower 95% confidence interval in the regression line when combining each group with the drug-free subjects) after prolonged treatment with olanzapine (n=126), clozapine (n=62), first generation antiypsychotics (n=91), other SGAD (n=22), other psychotropic drugs (n=65) and drug-free subjects (n=229).. None of the analysis was significant (p>0.05). In fact, in 17 out of 20 comparisons, the drug-free group had numerically higher frequencies of outliers than the corresponding treatment group. There were 28 outliers (4.7% of the total sample). In agreement with previous studies, cross-sectional analysis did not report gross alterations in serum leptin levels during olanzapine or clozapine administration.. Longitudinal studies should focus on leptin regulation early on treatment, on the frequency of abnormal leptin receptor sensitivity and/or specific polymorphisms in the leptin allele and on several confounding factors in order to design personalized preventive and therapeutic measures.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Body Mass Index; Body Weight; Clozapine; Cross-Sectional Studies; Female; Humans; Insulin Resistance; Leptin; Male; Mental Disorders; Middle Aged; Olanzapine; Outliers, DRG; Receptors, Leptin; Schizophrenia; Sex Factors; Weight Gain

The effects of in utero exposure to atypical antipsychotics on infant birth weight are unknown.. To determine whether atypical and typical antipsychotics differ in their effects on birth weight after maternal exposure during pregnancy.. Prospective data on gestational age and birth weight collected by the National Teratology Information Service for infants exposed to typical (n=45) and atypical (n=25) antipsychotics was compared with data for a reference group of infants (n=38).. Infants exposed to atypical antipsychotics had a significantly higher incidence of large for gestational age (LGA) than both comparison groups and a mean birth weight significantly heavier than those exposed to typical antipsychotics. In contrast those exposed to typical antipsychotics had a significantly lower mean birth weight and a higher incidence of small for gestational age infants than the reference group.. In utero exposure to atypical antipsychotic drugs may increase infant birth weight and risk of LGA.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Birth Weight; Clozapine; Female; Fetal Macrosomia; Gestational Age; Humans; Infant, Newborn; Male; Mental Disorders; Olanzapine; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Prospective Studies; Statistics, Nonparametric

The study was aimed at the evaluation of weight gain associated with atypical antipsychotics and its clinical risk factors in children and adolescents. Weight and body mass index (BMI) of initially hospitalised patients treated with clozapine (n = 15), olanzapine (n = 15), and risperidone (n = 15) were prospectively monitored on a weekly basis for the first 6 weeks. Different clinical risk factors were tested for their association with weight gain in the three groups. All three groups experienced significant weight gain between baseline and endpoint (p < 0.0001). For all weight measures, planned comparisons were all significant between olanzapine vs. clozapine and risperidone, respectively. Average weight gain was significantly higher for the olanzapine group (mean = 4.6 kg, SD = 1.9) than for the risperidone (mean = 2.8 kg, SD = 1.3) and clozapine (mean = 2.5 kg, SD = 2.9) groups. Olanzapine and risperidone, but not clozapine, caused a disproportionately higher weight gain in children and adolescents in comparison to adults.

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Body Weight; Child; Clozapine; Female; Humans; Male; Mental Disorders; Olanzapine; Risperidone; Weight Gain

To report and comment upon two cases of suspected pharmacological interaction between the "classical" neuroleptic levomepromazine (LMP) and the "atypical" antipsychotic clozapine (CLZ).. The patients who simultaneously took the two drugs had unusually low plasma levels of CLZ and its metabolites, even though they took high doses of CLZ. The patients were considered "non-responders" to the treatment by the psychiatrist. When LMP was withdrawn from the therapy, plasma concentrations of CLZ returned to therapeutic levels and one of the two patients experienced the anticipated therapeutic response.. No information can be found in the literature regarding possible interactions between LMP and CLZ. However, the results of the two cases reported herein point out to a possible lack of therapeutic efficacy of CLZ therapy during this kind of polypharmacy.. While two cases are too few to draw any conclusion, it would be prudent on the part of psychiatrists to consider a possible drug interaction in patients receiving both CLZ and LMP who fail to respond to the therapy.

Topics: Adolescent; Antipsychotic Agents; Clozapine; Drug Interactions; Humans; Male; Mental Disorders; Methotrimeprazine; Middle Aged

Topics: Alzheimer Disease; Antipsychotic Agents; Clozapine; Dibenzothiazepines; Humans; Mental Disorders; Quetiapine Fumarate

This study was conducted to estimate the prevalence of antipsychotic polypharmacy among fee-for service state Medicaid beneficiaries initiating antipsychotic drug therapy and to investigate psychiatric and demographic predictors of such polypharmacy.. This was a retrospective cohort study employing Medicaid claims data from California, Nebraska, Oregon, Utah, and Wyoming for patients who filled >1 antipsychotic prescription between 1998 and 2003 and who were continuously eligible for benefits from 180 days before to 1 year after the index antipsychotic claim. Antipsychotic Polypharmacy was defined as initiation of multiple antipsychotic medications or at least 60 consecutive days of concomitant antipsychotic medication overlapping the index antipsychotic prescription at any time during the 365 days after the index drug claim. Primary and secondary diagnosis codes (International Classification of Diseases, Ninth Revision, Clinical Modification) were used to identify patients with mental disorders and mental health-related hospitalizations. Multivariate logistic regression, with adjustment for sex, age, race/ethnicity, state, mental health diagnoses, hospitalization, year, and type of index antipsychotic, was performed to identify predictors of polypharmacy. A multivariate Cox proportional hazards model was used to compare the cumulative incidence of polypharmacy by index antipsychotic drug.. The study cohort consisted of 55,481 individuals with > or =1 prescription claim for an antipsychotic drug. The mean prevalence of long-term antipsychotic polypharmacy in the year after initiating antipsychotic medication was 6.4%. Approximately half of those with polypharmacy were started on multiple antipsychotic drugs and half were started on monotherapy but received > or =2 antipsychotic drugs concomitantly in the year after drug initiation. Among the stronger predictors of polypharmacy were a diagnosis of schizophrenia (odds ratio [OR] = 2.95; 95% Cl, 2.43-3.58), recent mental health hospitalization (OR = 1.17; 95% Cl, 1.02-1.33), and the number of mental health diagnoses (OR = 1.07 per diagnosis; 95% CI, 1.06-1.08). Polypharmacy was more likely among male than female patients (OR = 1.26; 95% Cl, 114-1.39) and among those between the ages of 18 and 24 years. The cumulative incidence of polypharmacy was greater among patients initiating clozapine compared with those initiating other antipsychotics (P < 0.001).. In these fee-for-service Medicaid beneficiaries from 5 states, the prevalence of chronic antipsychotic polypharmacy was low in the year after the initiation of therapy. Polypharmacy was more common in patients with indicators of more severe mental illness.

Topics: Adolescent; Adult; Age Factors; Aged; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Drug Utilization Review; Female; Hospitalization; Humans; Male; Medicaid; Mental Disorders; Middle Aged; Multivariate Analysis; Polypharmacy; Prevalence; Proportional Hazards Models; Retrospective Studies; Risk Factors; Schizophrenia; Sex Factors; Time Factors

Approximately one third of schizophrenia patients show partial or no response to pharmacotherapy. Despite intensive investigations, the phenomenological and biological characteristics of such patients are far from elucidated. This study examined the premorbid behavioral and intellectual functioning of schizophrenia patients who showed poor response to antipsychotic treatment.. One hundred twenty-nine schizophrenia patients who showed poor response to treatment were ascertained from a national register and matched by gender, age and education to 129 patients who showed adequate response. The groups were compared on premorbid measures of behavioral and intellectual functions.. As a group, treatment-resistant male patients had significantly lower (worse) social functioning [p=0.002], and individual autonomy [p<0.0001] scores before the onset of the illness compared to treatment non-resistant patients. Male and female treatment-resistant patients did not differ from non-resistant patients in premorbid intellectual functioning [p>0.1].. Low premorbid social functioning and individual autonomy, but not intellectual functioning, could serve as predictors of poor treatment response in schizophrenia.

Topics: Adult; Antipsychotic Agents; Clozapine; Cognition Disorders; Drug Resistance; Female; Humans; Male; Mental Disorders; Neuropsychological Tests; Registries; Schizophrenia; Social Behavior

To study the prescribing practices of atypical antipsychotic drugs in French psychiatric hospitals.. A 1-day cross-sectional observational survey was performed in seven psychiatric hospitals to study prescribing practices of the four atypical antipsychotics (AAP) marketed in France. These hospitals are members of the PIC network, a pharmacists' working group based in southwestern France.. Type and dosages of prescribed atypical antipsychotics, indication and concomitant prescriptions.. The study included 1475 adult inpatients' prescriptions with an antipsychotic drug; 647 prescriptions included an AAP with risperidone and olanzapine accounting for about 70% cases. AAP prescriptions concerned psychotic patients in 65% of cases. Patients receiving an AAP in this indication were more likely to be male, were younger, and received higher daily doses than patients treated for other troubles. They were also more likely to receive associated neuroleptic and anticholinergic antiparkinsonian agents. There were 59 prescriptions (9.1%) for bipolar disorders. Clozapine wasn't used in this indication. In 76.3% of cases, mood stabilizers were associated to the AAP prescribed in this indication.. This observational survey underlines the significant place taken by AAP for the treatment of psychiatric diseases in hospital prescribing practices. They show usage patterns of these drugs: dose, indications and concomitant medications, in line or not with current recommendations and reference guidelines. In bipolar disorders, AAPs seem more likely to be associated to an ongoing therapy using mood stabilizer than to replace it.

Topics: Adult; Age Factors; Amisulpride; Antimanic Agents; Antiparkinson Agents; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Clozapine; Cross-Sectional Studies; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; France; Hospitals, Psychiatric; Humans; Male; Mental Disorders; Middle Aged; Olanzapine; Practice Patterns, Physicians'; Psychotic Disorders; Risperidone; Sex Factors; Sulpiride

Topics: Aged; Antipsychotic Agents; Clozapine; Epilepsy; Humans; Male; Mental Disorders; Middle Aged

Changes in dopamine (DA) D(1), D(2), D(3), and D(4) receptors and serotonin 5-HT(1A) and 5-HT(2A) receptors in rat forebrain regions were autoradiographically quantified after continuous infusion of JL 13 [(5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]benzoxazepine fumarate] for 28 days with osmotic minipumps and compared with the effects of other typical (fluphenazine) and atypical (clozapine, olanzapine, and risperidone) antipsychotic drugs from previous studies. Similar to other typical and atypical antipsychotics, JL 13 increased labeling of D(2) receptors in medial prefrontal cortex (MPC) and hippocampus (HIP) and D(4) receptors in nucleus accumbens (NAc), caudate-putamen (CPu), and HIP. In addition, JL 13 increased 5-HT(1A) and decreased 5-HT(2A) receptors in MPC and dorsolateral frontal cortex (DFC), an effect shared by atypical antipsychotics, and may contribute to their psychopharmacological properties. Clozapine and JL 13, but not other antipsychotics, spared D(2) receptors in CPu, which may reflect their ability to induce minimal extrapyramidal side effects. In addition, JL 13 but not other typical and atypical antipsychotic drugs increased abundance of D(1) receptors in CPu and NAc. JL 13 as well as other antipsychotic agents did not alter levels of forebrain D(3) receptors. An atypical-like profile of JL 13 on DA and 5-HT receptor subtypes should encourage further development of this compound as a novel atypical antipsychotic drug.

Topics: Animals; Antipsychotic Agents; Brain Chemistry; Clozapine; Dopamine; Down-Regulation; Mental Disorders; Oxazepines; Piperazines; Prosencephalon; Pyridines; Rats; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Dopamine D4; Serotonin; Synaptic Transmission; Time; Up-Regulation

To outline the prescribing patterns of atypical antipsychotics for adult mental health outpatients in Auckland and Northland in 2004.. All community files were reviewed retrospectively (n = 6165). Patient characteristics, diagnosis, and antipsychotic and concurrent medication were recorded and analysed.. Overall, 71.3% of outpatients were prescribed an antipsychotic, of which 82.5% were atypicals: oral risperidone (30.9%), olanzapine (30.3%), quetiapine (17.1%), clozapine (26.3%), and depot risperidone (0.4%). Psychotic disorders accounted for 73.2% of outpatients on atypicals, and schizophrenia was the most common disorder overall (62.5%). Combination antipsychotic treatment occurred in 13.5% of those prescribed atypicals; 4.8% had another atypical and 8.7% had a typical co-prescribed. Clozapine was least likely to be combined with a typical antipsychotic. Those receiving combination typical and atypical antipsychotics had a greater likelihood of being prescribed an anticholinergic medication.. Atypical antipsychotics are the preferred treatment for outpatients with psychotic illness and are being prescribed in a manner consistent with clinical practice guidelines. Co-prescribing of antipsychotics was low, but may be causing unnecessary adverse effects and risks.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Ambulatory Care; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Drug Prescriptions; Drug Therapy, Combination; Drug Utilization Review; Female; Humans; Male; Mental Disorders; Middle Aged; New Zealand; Olanzapine; Practice Patterns, Physicians'; Quetiapine Fumarate; Retrospective Studies; Risperidone

Topics: Adolescent; Antipsychotic Agents; Clozapine; Female; Humans; Intellectual Disability; Mental Disorders; Ocular Motility Disorders; Substance Withdrawal Syndrome

Violent behavior is a significant problem in the psychiatric hospital setting. Persistently violent patients often require seclusion and/or restraints and typically receive high doses of medication and polypharmacy. Clozapine has been found to be effective in reducing aggression in patients with psychosis. Thus, we examined the effects of clozapine in a heterogeneous group of persistently violent patients. A chart review of the effect of clozapine in persistently violent patients was performed. Changes in the number of violent episodes and the need for seclusion and restraint were assessed for a 3-month period before and after receiving clozapine. In this group of five, carefully selected, persistently violent patients, clozapine treatment resulted in marked decreases in violent episodes and the use of seclusion and restraint. These data suggest a role for clozapine in the treatment of persistently violent patients irrespective of DSM-IV diagnosis.

Topics: Adolescent; Adult; Analysis of Variance; Brain Injuries; Clozapine; Female; Humans; Male; Meningitis; Mental Disorders; Retrospective Studies; Violence

The purpose of this study is to determine sociodemographic, clinical, and pharmacotherapeutic characteristics, especially use of atypical antipsychotics, associated with incident diabetes mellitus in a population of privately insured patients with mental health diagnoses. Patients with a mental health diagnosis stably medicated for a 3-month period during January 1999 through October 2000 and having no diabetes were followed through December 2000. Cox proportional hazards models were developed to identify antipsychotic medications associated with newly diagnosed diabetes. Of the 7381 patients identified, 339 developed diabetes, representing an annual incidence rate of 4.7%. Diabetes risk among the entire sample was lowest for risperidone (hazard ratio [HR] = 0.69; p < 0.05), while quetiapine (HR = 0.74), olanzapine (HR = 0.95), and clozapine (HR = 1.22) were not significantly different from first-generation antipsychotics. Diabetes risk was significantly lower among males receiving risperidone (HR = 0.49; p < 0.01) or quetiapine (HR = 0.50; p < 0.10), while diabetes risk among females did not differ significantly from first-generation antipsychotics for any atypical examined. These findings are substantially different from other reports.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Diabetes Mellitus; Dibenzothiazepines; Female; Follow-Up Studies; Humans; Incidence; Insurance Coverage; Male; Mental Disorders; Olanzapine; Proportional Hazards Models; Quetiapine Fumarate; Risk Factors; Risperidone; Sex Factors; United States

The use of atypical antipsychotics has been associated with abnormalities of glucose metabolism in patients with schizophrenia. This study was designed to determine the proportion of undiagnosed hyperglycemia in patients receiving a broad range of atypical antipsychotics.. All outpatients treated at an urban Veterans Affairs medical center who received a prescription for clozapine, risperidone, olanzapine, quetiapine, or ziprasidone were identified, and an attempt was made to obtain a fasting plasma glucose (FPG) test. Testing took place October 2000 to November 2002. Patients previously diagnosed as diabetic were excluded.. Of the 647 patients who received antipsychotic prescriptions and were not diagnosed as diabetic, 494 (76.4%) had a random glucose result, while 153 (23.6%) had an FPG result. Within the FPG group, 107 (69.9%) had a normal FPG level, while 46 (30.1%) had an abnormally elevated FPG. There were no differences between these 2 groups in terms of race/ethnicity, age, body mass index, or comorbid diagnoses. However, significantly more patients receiving clozapine were found to have occult hyperglycemia (p = .001); no significant differences in the percentage of patients with FPG levels > or = 100 mg/dL and those with FPG levels < 100 mg/dL were observed for any of the other medications.. Hyperglycemia is common in patients treated with atypical antipsychotics and thought to be euglycemic. Screening for elevated FPG is indicated for patients receiving atypical antipsychotics.

Topics: Ambulatory Care; Antipsychotic Agents; Blood Glucose; Clozapine; Comorbidity; Connecticut; Diabetes Mellitus; Drug Therapy, Combination; Female; Glucose Tolerance Test; Hospitals, Veterans; Humans; Hyperglycemia; Male; Mass Screening; Mental Disorders; Middle Aged; Sampling Studies; Schizophrenia

The incidence of neuroleptic malignant syndrome (NMS) is not known, but the frequency of its occurrence with conventional antipsychotic agents has been reported to vary from 0.02% to 2.44%.. MEDLINE search conducted in January 2003 and review of references within the retrieved articles.. Our MEDLINE research yielded 68 cases (21 females and 47 males) of NMS associated with atypical antipsychotic drugs (clozapine, N = 21; risperidone, N = 23; olanzapine, N = 19; and quetiapine, N = 5). The fact that 21 cases of NMS with clozapine were found indicates that low occurrence of extrapyramidal symptoms (EPS) and low EPS-inducing potential do not prevent the occurrence of NMS and D(2) dopamine receptor blocking potential does not have direct correlation with the occurrence of NMS. One of the cardinal features of NMS is an increasing manifestation of EPS, and the conventional antipsychotic drugs are known to produce EPS in 95% or more of NMS cases. With atypical antipsychotic drugs, the incidence of EPS during NMS is of a similar magnitude.. For NMS associated with atypical antipsychotic drugs, the mortality rate was lower than that with conventional antipsychotic drugs. However, the mortality rate may simply be a reflection of physicians' awareness and ensuing early treatment.

Topics: Adult; Aged; Antipsychotic Agents; Benzodiazepines; Bromocriptine; Clozapine; Dantrolene; Dibenzothiazepines; Dopamine Agonists; Female; Humans; Intubation; Male; MEDLINE; Mental Disorders; Middle Aged; Muscle Relaxants, Central; Neuroleptic Malignant Syndrome; Olanzapine; Quetiapine Fumarate; Respiration, Artificial; Risperidone; Treatment Outcome

Therapeutic drug monitoring (TDM) of the atypical antipsychotic drug clozapine is recommended. Clinical studies have indicated a therapeutic window for clozapine serum levels in schizophrenic and schizo-affective patients during acute treatment, i.e. for patients who do not respond to treatment with typical antipsychotics. However, despite the frequent use of clozapine also in maintenance treatment, very few data are available showing the relationship between serum levels of clozapine and the prevention of relapse. Thus, the primary objective of the study was to investigate the relationship between serum levels ofclozapine and relapse during maintenance treatment.. A retrospective study of routine TDM-data was conducted. Samples obtained on an acute treatment ward from patients with < 4 days hospitalization (recent admissions) were regarded as samples associated with relapse. Samples which can be attributed to an intoxication were identified as described in the TDM-form. The serum level of clozapine, as well as age, gender, smoking habits, concurrent drugs, psychiatric diagnosis and dose of clozapine were evaluated. Data analysis was performed on individual samples and, alternatively, on multiple samples from a single patient which are summarized according to a typical clinical situation.. 404 serum levels were measured in 86 patients. After exclusion of patients receiving acute treatment, 65 relevant clinical situations were identified in 50 patients: 12 relapses, 8 intoxications (a total of 20 situations with poor outcome) and 45 situations involving patients with good maintenance outcome. Samples involving relapse had serum levels of 198 +/- 211 ng/ml (10-624), intoxications had serum levels of 1,969 +/- 705 ng/ml (900-2,900) and those with good outcome had serum levels of 384 +/- 255 ng/ml (56-1,028) (mean +/- SD (range)). By means of sensitivity of receiver operating characteristic curves (ROC) a lower limit of the therapeutic window can be estimated at about 50-250 ng/ml and an upper limit at about 745-1,050 ng/ml. The frequencies of good and poor outcome were significantly different within and outside these ranges, e.g. chi2 = 11.8 and p < 0.001 for 250 to 745 ng/ml. Comparison of only good outcome and relapse provided a significant difference in the serum level of clozapine (Student's t-test p = 0.024). However, 67% of relapses were predicted in a model of logistic regression only if the variables serum level and concurrent treatment with other psychotropic drugs were included simultaneously as independent variables. Neither variable was able to predict relapse if used as a single variable in separate models. Finally, it was found that serum levels of clozapine were increased in women, in aged patients and in nonsmokers.. It is tentatively concluded that serum levels of clozapine < 50 ng/ml are related to relapse irrespective of concurrent psychotropic drugs. In cases where there are no concurrent psychotropic drugs, serum levels of clozapine < 250 ng/ml are associated with relapse. The risk of relapse is low for serum levels of clozapine > 250 ng/ml irrespective of concurrent psychotropic drugs. The risk of intoxication is increased with serum levels > 750 ng/ml. The TDM of clozapine is recommended during maintenance treatment.

Topics: Adult; Age Factors; Aged; Antipsychotic Agents; Clozapine; Drug Administration Schedule; Drug Interactions; Drug Monitoring; Female; Humans; Inpatients; Male; Mental Disorders; Middle Aged; Retrospective Studies; Sex Factors; Smoking; Treatment Outcome

Increasingly, atypical antipsychotic drugs are prescribed for elderly patients with symptoms of psychosis and behavioral disturbances. These symptoms often occur in patients with Alzheimer's disease, other dementias, or Parkinson's disease. As the average age of Americans increases, the prevalence of Alzheimer's disease and Parkinson's disease will rise accordingly. Although nonpharmacologic treatments for behavioral disturbances should be tried first, medications often are needed to enable the patient to be adequately cared for. Current guidelines recommend using risperidone and olanzapine to treat psychosis in patients with Alzheimer's dementia. Quetiapine and clozapine are recommended for treatment of psychosis in patients with Parkinson's disease. Additional research is needed for a recently approved agent, ziprasidone. To minimize side effects, these medications should be started at low dosages that are increased incrementally. Drug interactions, especially those involving the cytochrome P450 system, must be considered. Clozapine's potentially lethal side effects limit its use in the primary care setting. Informed use of atypical antipsychotic drugs allows family physicians to greatly improve quality of life in elderly patients with dementia and behavior disturbances.

Topics: Aged; Antipsychotic Agents; Benzodiazepines; Clozapine; Comorbidity; Dementia; Dibenzothiazepines; Humans; Mental Disorders; Olanzapine; Pirenzepine; Quetiapine Fumarate; Risperidone

Topics: Adult; Antipsychotic Agents; Clozapine; Ego; Female; Humans; Life Change Events; Mental Disorders; Psychotic Disorders

Given that we are celebrating the 50th birthday of neuroleptics introduction in psychiatry, the author proposes to take a look at certain results related to therapeutic practice. After a brief chronological literature review of the clinical practices and theoretical models that have controlled drug treatment of schizophrenia, the author presents a critical review of four meta-analyses. Since Delay, Deniker and Harl's initial report, the story of neuroleptics comprises several periods. In 1963, the hyper-dopaminergic theory of psychoses was proposed. Another period began with models mainly based on the serotonin/dopamine relative blockade receptor hypothesis. More recently, a new framework to understand the differential effect of antipsychotics is related to the appropriate modulation (e.g., fast dissociation) of the D2 receptor alone. The concept of atypicality has become a new vista for research and to market new compounds. However, after 50 years of neuroleptic drugs, are we able to answer the following simple questions: Are neuroleptics effective in treating schizophrenia? Is there a difference between atypical and conventional neuroleptics? How do the efficacy and safety of newer antipsychotic drugs compare with those of clozapine? Actually, the answers yielded by these simple questions by meta-analysis should elicit in us a good deal of humility. If we wish to base psychiatry on evidence-based medicine, we run a genuine risk in taking a closer look at what has long been considered fact. Each psychiatrist must continue to be critical, sceptical, optimistic (not overoptimistic) and to learn in order to integrate the positive aspects of our growing knowledge base.

Topics: Antipsychotic Agents; Clozapine; Evidence-Based Medicine; History, 20th Century; Humans; Mental Disorders; Pharmacology; Serotonin Antagonists

Topics: Adult; Antipsychotic Agents; Clozapine; Counseling; Female; Humans; Male; Mental Disorders; Patient Education as Topic; Pilot Projects; Treatment Outcome; Treatment Refusal

In 200 inpatients on regular neuroleptics, point prevalence of extrapyramidal syndromes, including Parkinson syndrome, akathisia and tardive dyskinesia (TD), was studied and found to be 20, 11 and 22%, respectively. A total of 46 patients have currently, and for a longer time, (average about 3years, median over 1year) been treated with clozapine, and 127 with typical neuroleptics (NLs). Comparing both groups, higher TD scores were found in the clozapine sample. Investigating the influence of a set of seven clinical variables on the TD score with the help of multiple regression analysis, the influence of the treatment modality disappeared, whereas the age proved to be the only significant variable. Studying the role of past clozapine therapy in patients currently on typical NLs and comparing 10 matched pairs of chronic patients with and without TD in whom a complete life-time cumulative dose of NLs was identified, a relationship between TD and length of current typical NL therapy and life-time typical NL dosage could be demonstrated. On the whole, long-term relatively extensive use of clozapine has not markedly reduced the prevalence of extrapyramidal syndromes in our psychiatric inpatient population. In particular, we failed to demonstrate a beneficial effect of clozapine on prevalence of TD. There are certainly patients who suffer from TD in spite of a long-term intensive clozapine treatment.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Chronic Disease; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Male; Mental Disorders; Middle Aged; Prevalence; Time Factors

Topics: Antipsychotic Agents; Clozapine; Cross-Sectional Studies; Humans; Mental Disorders; Retrospective Studies; Urinary Incontinence

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Drug Monitoring; Humans; Mental Disorders; Neutropenia

The Forensic Algorithm Project (FAP) was born of the need for a holistic approach in the treatment of the inmate with schizophrenia. Schizophrenia was chosen as the first entity to be addressed by the algorithm because of its refractory nature and high rate of recidivism in the correctional setting. Schizophrenia is regarded as a spectrum disorder, with symptom clusters and behaviors ranging from positive to negative symptoms to neurocognitive dysfunction and affective instability. Furthermore, the clinical picture is clouded by Axis II symptomatology (particularly prominent in the inmate population), comorbid Axis I disorders, and organicity. Four subgroups of schizophrenia were created to coincide with common clinical presentations in the forensic inpatient facility and also to parallel 4 tracks of intervention, consisting of pharmacologic management and programming recommendations. The algorithm begins with any antipsychotic medication and proceeds to atypical neuroleptic usage, augmentation with other psychotropic agents, and, finally, the use of clozapine as the common pathway for refractory schizophrenia. Outcome measurement of pharmacologic intervention is assessed every 6 weeks through the use of a 4-item subscale, specific for each forensic subgroup. A "floating threshold" of 40% symptom severity reduction on Positive and Negative Syndrome Scale and Brief Psychiatric Rating Scale items over a 6-week period is considered an indication for neuroleptic continuation. The forensic algorithm differs from other clinical practice guidelines in that specific programming in certain prison environments is stipulated. Finally, a social commentary on the importance of state-of-the-art psychiatric treatment for all members of society is woven into the clinical tapestry of this article.

Topics: Algorithms; Ambulatory Care; Clozapine; Crisis Intervention; Decision Trees; Forensic Psychiatry; Hospitalization; Humans; Mental Disorders; Outcome Assessment, Health Care; Patient Care Planning; Patient Compliance; Prisoners; Prisons; Psychiatric Status Rating Scales; Psychotropic Drugs; Schizophrenia; Schizophrenic Psychology

Leptin is produced by fat cells and is presumed to signal the size of the adipose tissue to the brain. The authors investigated whether antipsychotic drugs that often induce weight gain affect circulating levels of leptin.. Weight, body mass index, and leptin plasma level were measured weekly over 4 weeks in psychiatric inpatients who received clozapine (N = 11), olanzapine (N = 8), haloperidol (N = 13), or no psychopharmacological treatment (N = 12).. In patients receiving clozapine or olanzapine, significant increases in weight, body mass index, and leptin level were found, whereas these measures remained stable in patients who received haloperidol or no pharmacological treatment.. Weight gain induced by clozapine or olanzapine appears to be associated with an increase in leptin level that cannot be attributed to dietary changes upon hospitalization.

Topics: Adipose Tissue; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Clozapine; Haloperidol; Hospitalization; Humans; Leptin; Mental Disorders; Olanzapine; Pirenzepine; Proteins; Weight Gain

In spite of some inherent limitations, naturalistic data can provide information on populations that have greater heterogeneity than can controlled clinical trials and on functional outcomes that may be especially important in clinical practice. In the present retrospective naturalistic study, we evaluated key clinical outcomes among the first wave of risperidone-treated patients at a state psychiatric hospital.. Outcome data were extracted from the charts of 142 patients 2 years after initiation of treatment with risperidone. Their diagnoses included DSM-III-R schizophrenia (57%), schizoaffective disorder (22%), dementia and other organic conditions (7%), bipolar disorder (5%), and other psychiatric disorders (9%).. During the 2-year period, 92 of 142 patients were discharged from the hospital: 61 (43%) were discharged on risperidone treatment and 31 (22%) were discharged on treatment with other drugs. At the time of the study, 50 of 142 patients were still in the hospital: of these, 18 (13%) were still receiving risperidone. The modal maximum daily dose of risperidone was 4.1 mg in patients discharged on risperidone treatment and 7.5 mg in patients still in the hospital. All groups were granted more ward privileges after starting risperidone, the most being granted to patients discharged from the hospital on risperidone treatment (p<.05 versus patients discharged on treatment with other drugs) and those still receiving risperidone in the hospital. Significantly fewer patients discharged on risperidone treatment than on treatment with other drugs were readmitted to the hospital within 2 years after discharge (p<.01).. Improved privilege levels and a reduced readmission rate indicate that risperidone was an effective antipsychotic agent among a heterogeneous patient population in a state hospital. These factors may be especially important to justify use of this agent in the current fiscal climate.

Topics: Adult; Antiparkinson Agents; Antipsychotic Agents; Bipolar Disorder; Clozapine; Dementia; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Hospitalization; Hospitals, Psychiatric; Hospitals, State; Humans; Length of Stay; Male; Mental Disorders; Patient Readmission; Psychotic Disorders; Retrospective Studies; Risperidone; Schizophrenia

110 patients (52 men, 58 women) in a state of acute intoxication were examined in emergency department of psychoneurologic hospital. Neuroleptics of different groups were used to commit a suicide (91.3% of the cases), to obtain a toxicomanic effect (6.3%) and accidentally (1.8%). The patients suffered from borderline mental disorders (39.2%), schizophrenia (40.9%), manic-depressive psychosis in depressive phase (10.9%), chronic alcoholism (4.5%) and organic damages of CNS (4.5%). The patients with borderline states used various drugs and had more light disorders of consciousness (deafness). Meanwhile, the patients with endogenic mental disorders used strong neuroleptics, as a rule, that resulted in coma. In residual period there were different syndromes from asthenic to psychoorganic ones. They were more severe after poisoning with aminazinum, haloperidol, leponex.

Topics: Acute Disease; Adult; Age Distribution; Antipsychotic Agents; Chlorpromazine; Clozapine; Female; Haloperidol; Humans; Male; Mental Disorders; Middle Aged; Suicide, Attempted

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Humans; Mental Disorders; Middle Aged; Risperidone; Schizophrenia; Treatment Outcome; Violence

Recent case reports suggest the association of the emergence of diabetes mellitus with clozapine treatment, although conventional neuroleptics have also been implicated. This study was conducted to determine if there is an increased risk of diabetes mellitus and/or impaired glucose tolerance (IGT) during clozapine treatment compared with treatment with conventional depot neuroleptics.. In a district hospital in northern Sweden, blood glucose tests and, if necessary an oral glucose tolerance test were used to assess the prevalence of diabetes mellitus or IGT in 63 patients treated with clozapine compared with 67 patients treated with conventional depot neuroleptics (haloperidol, zuclopenthixol, fluphenazine, perphenazine, or flupenthixol). Diabetes mellitus and impaired glucose tolerance were classified according to World Health Organization criteria.. There were 3 dropouts in the clozapine group and 4 in the control group. Of subjects treated with clozapine, 12% (7/60) had type 2 diabetes mellitus, and 10% (6/60) had IGT. Of subjects treated with depot injections of neuroleptics, 6% (4/63) had type 2 diabetes mellitus and 3% (2/63) had IGT. None in either group had type 1 diabetes mellitus. Subjects in the clozapine group were significantly (p < .001) younger than subjects in the control group, whereas the 2 groups did not differ with respect to body weight, body mass index, or prevalence of diabetes mellitus in first-degree relatives.. Subjects treated with clozapine were more often classified as having type 2 diabetes mellitus or IGT compared with subjects in the control group. This difference did not, however, achieve statistical significance (p=.06).

Topics: Adult; Aged; Antipsychotic Agents; Blood Glucose; Clozapine; Comorbidity; Delayed-Action Preparations; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Male; Mental Disorders; Middle Aged; Prevalence; Schizophrenia; Sweden

Topics: Antipsychotic Agents; Bipolar Disorder; Clozapine; Cost-Benefit Analysis; Drug Costs; Health Care Costs; Humans; Mental Disorders; Schizophrenia

Topics: Abnormalities, Drug-Induced; Benzodiazepines; Clozapine; Contraindications; Female; Humans; Mental Disorders; Pregnancy; Pregnancy Complications; Psychotropic Drugs; Research Design; Schizophrenia

This paper presents the results of a case study exploring the subjective experience of Clozapine treatment in 10 clients at a major Australian psychiatric hospital. Data were categorized into: subjective improvements, observed improvements, subjective expression of concerns, side effects, and goals for the future. Responses provide direction for individualized mental health nursing care. For example, rehabilitation is ideally focused on each person's needs and goals. Such needs can best be identified by ongoing exploration of subjective and objective information.

Topics: Antipsychotic Agents; Clozapine; Female; Humans; Male; Mental Disorders; Nursing Methodology Research; Patient Satisfaction; Quality of Life

Topics: Antipsychotic Agents; Budgets; Clozapine; Costs and Cost Analysis; Drug Monitoring; Humans; Mental Disorders; Psychotropic Drugs; Risperidone

Topics: Antipsychotic Agents; Clozapine; Guidelines as Topic; Humans; Mental Disorders; Patient Selection; Risperidone

Topics: Aggression; Clozapine; Dose-Response Relationship, Drug; Humans; Mental Disorders; Self-Injurious Behavior; Treatment Outcome

This study evaluated recent and current use of antipsychotics by psychiatric inpatients.. Computer-based hospital pharmacy records identified prescriptions for antipsychotics in 1993. Medical records were reviewed to verify prescription and clinical data, and these were compared with similar data from 1989.. In 1993, antipsychotics were prescribed for 299 (42%) of 709 hospitalized patients. Treatment usually started within 24 hours of admissions averaging 18 days. High-potency agents were used 2.4 times more frequently than low-potency drugs; 13% received clozapine. The mean chlorpromazine-equivalent daily dose, corrected for as-needed supplements, was 305 mg; peak doses were 32% higher. Doses of the most potent agents (fluphenazine and haloperidol) were only 22%-33% above the overall mean. Rarely were two neuroleptics given simultaneously, but cotreatment with an anticonvulsant (84% of patients, 92% of whom received valproate), a potent benzodiazepine (81%), lithium (70%), one CNS depressant (84%), or more (45%) was common. Doses averaged 20% higher for men, 42% lower at age > 50 years versus 20-30 years, and 53% greater for schizophrenia or schizoaffective disorder versus other conditions. Comparison with 1989 admissions (N = 50) averaging 73 days indicated few differences in use of neuroleptics or benzodiazepines but less frequent use of anticonvulsants and lithium.. High-potency antipsychotic agents and clozapine were used most often in 1993; doses of high-potency agents were only slightly higher than doses of low-potency agents, but combinations with mood stabilizers were more common in 1993, when length of stay was one-fourth that in 1989.

Topics: Adult; Age Factors; Anticonvulsants; Antipsychotic Agents; Clozapine; Drug Administration Schedule; Drug Prescriptions; Drug Therapy, Combination; Drug Utilization; Female; Hospitalization; Humans; Length of Stay; Lithium; Male; Mental Disorders; Pharmacy Service, Hospital

Topics: Adult; Clozapine; Constipation; Humans; Male; Mental Disorders; Prevalence

Akathisia is a common side effect of traditional neuroleptic drugs and is associated with medication refusal and impulsive behavior. While our previous experience indicates that clozapine is effective in treating persistent akathisia, two controlled studies indicate vastly different prevalence rates of akathisia (7% vs. 40%) in patients receiving clozapine.. We used the Barnes Rating Scale for Drug-Induced Akathisia to estimate the prevalence of akathisia in patients receiving stable doses of clozapine alone (N = 29) in a state hospital. Measurements were also made of manifest psychopathology (Brief Psychiatric Rating Scale) and tardive dyskinesia (Abnormal Involuntary Movement Scale).. Two patients (6.8%) receiving clozapine were rated as having akathisia. Only 4 (28.6%) of the 14 subjects with a history of moderate-to-severe tardive dyskinesia on traditional neuroleptic drugs continued to show current evidence of tardive dyskinesia, and in 10 patients (71.4%) there was no evidence of the syndrome (p < .002). In the 4 subjects with tardive dyskinesia there was amelioration to a milder form of the syndrome. There were no new cases of tardive dyskinesia among clozapine-treated subjects.. These data support the low prevalence of akathisia in patients receiving stable doses of clozapine monotherapy. There is further support that clozapine has an ameliorating effect on tardive dyskinesia associated with traditional neuroleptic drugs. These and other data indicate the need for a controlled trial of clozapine in patients experiencing persistent and disabling akathisia on traditional neuroleptic drugs.

Topics: Adult; Akathisia, Drug-Induced; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Male; Mental Disorders; Prevalence; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia

The main objective of the pharmacotherapy of schizophrenia has been, and still is, to obtain optimal therapeutic efficacy, which is seconded by the aim to restrict as far as possible the sometimes severe collateral effects which are acknowledged as being the major drawback to the regular use of neuroleptic agents. Tight from the start, some "atypical neuroleptics" were identified as being of interest for this reason; these included Clothiapine and Clozapine, a more recently discovered drug which is not yet commercially available in Italy. Both of these neuroleptics have been found to offer extremely interesting advantages. The authors now report data referring to the clinical use of these drugs during 1989-1990 in addition to those published in the literature on this subject.

Topics: Adolescent; Adult; Aged; Antidepressive Agents, Tricyclic; Clozapine; Dibenzothiazepines; Drug Tolerance; Extrapyramidal Tracts; Female; Humans; Male; Mental Disorders; Middle Aged; Receptors, Serotonin; Schizophrenia; Schizophrenic Psychology; Serotonin

Topics: Agranulocytosis; Carbamazepine; Clozapine; Drug Interactions; Hematologic Diseases; Humans; Mental Disorders; Risk

After noting a dramatic reduction in aggression and agitation in five psychotic inpatients residing on a specialized unit for the severely aggressive, the authors conducted a retrospective chart review to assess the possible role of clozapine treatment in this change.. The authors culled 12 months of nursing data, including progress notes, orders for seclusion, and mechanical and chemical restraint, to tabulate the frequency of aggression before and after the initiation of clozapine treatment, and looked at ratings on the Brief Psychiatric Rating Scale and periodic review reports to assess overall clinical change.. The results of the review indicate that although psychotic symptoms were not greatly affected by the drug, the overall frequency of assaults, self-abuse, and the use of seclusion, mechanical restraint, and chemical restraint was reduced in the subjects.. The authors conclude that because the reduction of aggression and agitation coincided with clozapine treatment, it is likely that clozapine was responsible for the change. The authors propose possible reasons for this effect and suggest that controlled studies are needed to substantiate these preliminary results.

Topics: Adult; Aggression; Clozapine; Hospital Records; Hospitalization; Hospitals, State; Humans; Male; Mental Disorders; Psychiatric Status Rating Scales; Restraint, Physical; Retrospective Studies; Social Isolation

The past decade has brought extraordinarily rapid changes to the treatment of patients with severe mental illnesses. Changes evolved from advances in technologic and pharmacologic understanding as well as from complex fiscal and political pressures. Increasingly, regimented standardization in approach narrows the range of treatment options. Both within and outside of psychiatry, some disparage psychodynamic approaches. Psychiatrists are required to accept as plausible standardized and constricted time frames for evaluation and treatment. Thus we are asked to view the mind's storms as strictly neuronally based and to view our patients as passively compliant. By implication, treatment alliance is to be cemented by a prescription and authority. This paper presents clinical material drawn from hospital-based experience at The Chestnut Lodge Hospital, Rockville, Maryland, meant to place current trends in an historic context. The author offers possible alternatives to resignation in the face of current pressures.

Topics: Adult; Clozapine; Female; Hospital Bed Capacity, 100 to 299; Hospitals, Psychiatric; Humans; Maryland; Mental Disorders; Organizational Innovation; Psychiatry; Schizophrenia

Topics: Clozapine; Drug Therapy; Humans; Mental Disorders

Topics: Clozapine; Humans; Mental Disorders; Wit and Humor as Topic

The authors investigated the clozapine plasma levels of 148 psychiatric inpatients. Multiple regression analysis revealed a linear relationship between dose of clozapine and plasma concentrations. The analysis showed a significant influence of dose, sex, smoking, weight, and age on the plasma concentrations of clozapine under clinical conditions. These results remained significant when clozapine doses below 150 mg/day and above 500 mg/day were excluded from the analysis.

Topics: Adult; Age Factors; Analysis of Variance; Body Weight; Clozapine; Dose-Response Relationship, Drug; Female; Hospitalization; Humans; Male; Mental Disorders; Sex Factors; Smoking

Topics: Azepines; Chemical Phenomena; Chemistry; Clozapine; Desipramine; Diazepam; Dibenzazepines; Family Practice; Humans; Mental Disorders; Phenothiazines; Tranquilizing Agents

Plasma levels of perazine, clozapine, amitriptyline and imipramine and of their demethylated metabolites can be measured in patients receiving therapeutic doses by UV reflectance photometry of thin-layer chromatograms of plasma extracts, Large inter-individual variations were observed in unselected psychiatric patients treated with comparable doses. An investigation into the relationship between plasma levels and therapeutc effect in acutely schizophrenic patients was carried out for perazine and clozapine. With perazine, a group of patients exhibiting an unsatisfactory response had a tendency to show lower plasma levels than a group with a good response; in some patients of the former group, increase of the dose with concomitant increase of the plasma level led to a satisfactory therapeutic effect. In patients treated with clozapine, such a relationship could not be demonstrated.

Topics: Antidepressive Agents, Tricyclic; Chromatography, Thin Layer; Clozapine; Humans; Mental Disorders; Perazine; Psychotropic Drugs

An experimental analysis of the psychotropic activity of Leponex (in a chronic experiment on II cats) in conditions of a group interaction depicted that the preparation processes a definite tranquillizing and antipsychotic effect. In conditions of zoosocial interactions this drug promotes disappearance of neurotic reactions and a resocialization of animals in the zoosocial ierarchy. In tranquillizing doses the preparation has an antihypertensive effect and prevents the development of a long-term tonic hypertension due to emotional stress.

Topics: Animals; Antipsychotic Agents; Cats; Clozapine; Diazepam; Dibenzazepines; Disease Models, Animal; Haloperidol; Humans; Mental Disorders; Neurotic Disorders; Psychotic Disorders; Social Behavior; Tranquilizing Agents