clozapine and Drug-Related-Side-Effects-and-Adverse-Reactions

Although clozapine is much researched in western literature, a review on Indian research on clozapine published in 2010 reported limited data and need for further research in this area.. We aimed to conduct a systematic review of research on clozapine from India from 2010 to mid-2022 and also compare the same with research output before 2010.. A systematic various search engines, i.e., PUBMED, Medknow, Hinari and Google Scholar was done using the key words clozapine and India. Published articles with clozapine in the title and having an author from India, published during 2010 to July 2022 were included.. Initial Internet and hand searches yielded 280 articles, out of which 126 articles were excluded due to various reasons and 154 articles, were included for the review. This included 84 case reports, 49 original articles, 11 review articles and 10 letters to the editor as comments. We found an increase in the number of publications during the period of 2010-2022 compared to 1997-2009 in all types of publications. Over the years a significant proportion of the articles focused on various side effects of clozapine, factors associated with response and non-response to clozapine and evaluation of outcomes other than efficacy/effectiveness. However, all the studies were limited to a single centre with no multicentric studies on clozapine.. Over the last 12 years or so, there is increase in the number of publications on clozapine. However, there is lack of multicentric studies.

Topics: Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; India; Publications; PubMed

Treatment-resistant schizophrenia (TRS) is often associated with severe burden of disease, poor quality of life and functional impairment. Clozapine is the gold standard for the treatment of TRS, although it is also known to cause significant side effects in some patients. In view of the burgeoning interest in the role of genetic factors in precision psychiatry, we conducted a scoping review to narratively summarize the current genetic factors associated with TRS, clozapine resistance and side effects to clozapine treatment. We searched PubMed from inception to December 2022 and included 104 relevant studies in this review. Extant evidence comprised associations between TRS and clozapine resistance with genetic factors related to mainly dopaminergic and serotoninergic neurotransmitter systems, specifically, TRS and rs4680, rs4818 within COMT, and rs1799978 within DRD2; clozapine resistance and DRD3 polymorphisms, CYP1A2 polymorphisms; weight gain with LEP and SNAP-25 genes; and agranulocytosis risk with HLA-related polymorphisms. Future studies, including replication in larger multi-site samples, are still needed to elucidate putative risk genes and the interactions between different genes and their correlations with relevant clinical factors such as psychopathology, psychosocial functioning, cognition and progressive changes with treatment over time in TRS and clozapine resistance.

Topics: Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Psychiatry; Quality of Life; Schizophrenia; Schizophrenia, Treatment-Resistant

Antipsychotic drug-induced myocarditis is a serious and potentially fatal adverse drug reaction characterized by inflammation of the heart muscle (myocardium) that typically develops within the first month after commencing an antipsychotic drug. Although the precise mechanism of this severe adverse drug reaction is unknown, multiple theories have been proposed with varying levels of support from cellular or animal studies. We conducted a systematic review, in accordance with PRISMA guidelines, of published preclinical and clinical studies investigating the cellular mechanism by which antipsychotic drugs induce myocarditis. A literature search including all studies available before December 10, 2022, yielded 15 studies that met our inclusion criteria. Antipsychotics examined in the included studies included clozapine (n = 13), ziprasidone (n = 1), amisulpride (n = 1), haloperidol (n = 1), levomepromazine (n = 1), olanzapine (n = 1), and sertindole (n = 1). The evidence suggests several overlapping mechanistic cascades involving: (1) increased levels of catecholamines, (2) increased proinflammatory cytokines, (3) increased reactive oxygen species (ROS), (4) reduced antioxidant levels and activity, and (5) mitochondrial damage. Notable limitations such as, a focus on clozapine, sample heterogeneity, and use of supratherapeutic doses will need to be addressed in future studies. Discovery of the mechanism by which antipsychotic drugs induce myocarditis will allow the development of clinically-useful biomarkers to identify those patients at increased risk prior to drug exposure. The development or repurposing of therapeutics to prevent or treat drug-induced myocarditis will also be possible and this will enable increased and safe use of antipsychotics for those patients in need.

Topics: Animals; Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Myocarditis; Schizophrenia

Topics: Acetylcysteine; Chemical and Drug Induced Liver Injury; Clozapine; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Liver Failure, Acute; Middle Aged

Clozapine is substantially underutilized in most countries and clinician factors including lack of knowledge and concerns about adverse drug effects (ADEs) contribute strongly to treatment reluctance. The aim of this systematic review was to provide clinicians with a comprehensive information source regarding clozapine ADEs.. PubMed and Embase databases were searched for English language reviews concerned with clozapine ADEs; publications identified by the automated search were manually searched for additional relevant citations. Following exclusion of redundant and irrelevant reports, pertinent information was summarized in evidence tables corresponding to each of six major ADE domains; two authors reviewed all citations for each ADE domain and summarized their content by consensus in the corresponding evidence table. This study was conducted in accordance with PRISMA principles.. Primary and secondary searches identified a total of 305 unique reports, of which 152 were included in the qualitative synthesis. Most clozapine ADEs emerge within 3 months, and almost all appear within 6 months, after initiation. Notable exceptions are weight gain, diabetic ketoacidosis (DKA), severe clozapine-induced gastrointestinal hypomotility (CIGH), clozapine-induced cardiomyopathy (CICM), seizures, and clozapine-induced neutropenia (CIN). Most clozapine ADEs subside gradually or respond to dose reduction; those that prompt discontinuation generally do not preclude rechallenge. Rechallenge is generally inadvisable for clozapine-induced myocarditis (CIM), CICM, and clozapine-induced agranulocytosis (CIA). Clozapine plasma levels >600-1000 μg/L appear more likely to cause certain ADEs (e.g., seizures) and, although there is no clear toxicity threshold, risk/benefit ratios are generally unfavorable above 1000 μg/L.. Clozapine ADEs rarely require discontinuation.

Topics: Antipsychotic Agents; Cardiomyopathies; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Myocarditis; Neutropenia; Seizures

Clozapine (CLZ) is an atypical antipsychotic reserved for patients with refractory psychosis, but it is associated with a significant risk of severe adverse reactions (ADRs) that are potentiated with the concomitant use of alcohol. Additionally, pharmacogenetic studies have explored the influence of several genetic variants in CYP450, receptors and transporters involved in the interindividual response to CLZ. Herein, we systematically review the current multiomics knowledge behind the interaction between CLZ and alcohol intake, and how its concomitant use might modulate the pharmacogenetics.

Topics: Alcohol Drinking; Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmacogenetics; Schizophrenia

Clozapine-induced myocarditis in children (age ≤18 yo) was studied from a PubMed search (18 July 2022) (9 cases) and from the World Health Organization's pharmacovigilance database, called Vigibase, of adverse drug reaction (ADR) reports (72 non-duplicated cases). VigiBase uses a logarithmic measure of disproportionality called the information component (IC). A logistic regression model of presence/absence (40/32) of seriousness in VigiBase was developed.. VigiBase provided a significant myocarditis IC = 4.2 with an IC. These 41 cases of at least possible clozapine-induced myocarditis indicated that this ADR can definitively occur in children, particularly in the first 30 days of up-titration. Children's and adult cases appeared similar.

Topics: Adolescent; Australia; Child; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Myocarditis; Pharmacovigilance

Clozapine is underutilized due, in part, to concerns about rare but severe adverse drug reactions, including cardiac inflammation and injury (myocarditis). Risk factors for clozapine-induced myocarditis are limited and predictors for the successful rechallenge of clozapine after an episode of myocarditis are even more poorly understood. We conducted a systematic review, in accordance with the PRISMA recommendation, of published case reports to describe demographic and clinical characteristics of patients with clozapine-induced myocarditis and identify potential markers of clozapine rechallenge success. A total of 180 cases from 88 articles were evaluated. Male cases of clozapine-associated myocarditis were more frequently reported than female cases by a ratio of 6:1. Less than half of patients reported the presence of chest pain (35%) or flu-like symptoms (43%) but increases in troponin or C-reactive protein were present in 87% of cases. Clozapine rechallenge was carried out in 34 (2 female) cases, with successful reintroduction in 22 (2 female) cases (64.7%) and one fatality (2.9%). No demographic or clinical markers were significantly associated with rechallenge success after correction for multiple testing. Standardized reporting of clozapine-induced myocarditis cases is needed to facilitate the identification of factors associated with successful rechallenge.

Topics: Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Myocarditis; Schizophrenia

Clozapine is the most effective antipsychotic for treatment-refractory schizophrenia for reducing positive psychotic symptoms. It is associated with a reduction in hospitalisation and overall mortality. In spite of this, clozapine remains underutilised due to its complex adverse drug reaction (ADR) profile.. This systematic review aims to investigate the association of clozapine and norclozapine serum levels, and peripheral ADRs.. Studies were searched from four electronic databases (PubMed, EMBASE, PsycINFO and CINAHL) from inception to 12 June 2020. Studies were included if they had adult patients, provided data on steady-state trough clozapine or norclozapine levels and reported on clozapine-associated ADRs. Pregnant women, case reports and series were excluded.. A statistically significant correlation was found for clozapine serum levels and triglycerides (n = 70; r = 0.303, 95% CI 0.0119-0.546, p = 0.042), heart rate (n = 137; r = 0.269, 95% CI 0.0918-0.486, p = 0.035), and overall combined ADRs (n = 160; r = 0.264, 95% CI 0.110-0.405, p = 0.001), but not for absolute neutrophil count (n = 223; r = - 0.164, 95% CI - 0.529-0.253, p = 0.444) or total white cell count (n = 18; r = 0.0176, 95% CI - 0.203-0.237, p = 0.878). Interestingly, norclozapine serum levels were found to be statistically correlated to triglycerides (n = 120; r = 0.211, 95% CI 0.0305-0.378, p = 0.022), total cholesterol (n = 120; r = 0.272, 95% CI 0.0948-0.432, p = 0.003) and weight gain (n = 118; r = 0.208, 95% CI 0.0261-0.377, p = 0.025).. Heart rate, triglycerides and combined ADRs are significantly correlated with clozapine levels, and triglycerides, total cholesterol and weight gain with norclozapine levels. Future prospective, randomised controlled studies are needed to identify the cause-effect relationship between clozapine levels and peripheral ADRs.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Female; Heart Rate; Humans; Pregnancy; Schizophrenia; Schizophrenic Psychology; Triglycerides; Weight Gain

The second generation antipsychotic drug clozapine represents the most effective pharmacotherapy for treatment-resistant psychosis. It is also associated with low rates of extrapyramidal symptoms and hyperprolactinemia compared to other antipsychotic drugs. However, clozapine tends to be underutilized in clinical practice due to a number of disabling and serious side-effects. These are characterized by a constellation of metabolic side-effects which include dysregulation of glucose, insulin, plasma lipids and body fat. Many patients treated with clozapine go on to develop metabolic syndrome at a higher rate than the general population, which predisposes them for Type 2 diabetes mellitus and cardiovascular disease. Treatments for the metabolic side-effects of clozapine vary in their efficacy. There is also a lack of knowledge about the underlying physiology of how clozapine exerts its metabolic effects in humans. In the current review, we focus on key studies which describe how clozapine affects each of the main symptoms of the metabolic syndrome, and cover some of the treatment options. The clinical data are then discussed in the context of preclinical studies that have been conducted to identify the key biological substrates involved, in order to provide a better integrated overview. Suggestions are provided about key areas for future research to better understand how clozapine causes metabolic dysregulation.

Topics: Animals; Antipsychotic Agents; Clozapine; Diabetes Mellitus, Type 2; Drug-Related Side Effects and Adverse Reactions; Humans; Hyperprolactinemia; Metabolic Syndrome; Psychotic Disorders; Risk Factors

Clozapine levels may be a more useful predictor of therapeutic response than the dose, given the variability in clozapine metabolism between individuals. We therefore systematically reviewed and meta-analysed the impact of clozapine levels on response and/or relapse to provide guidance on optimal clozapine levels.. We systematically searched PubMed, PsycInfo and Embase for studies exploring clozapine levels and response and/or relapse. Our primary meta-analysis was rates of response above and below clozapine level thresholds of 350 ng/ml and 600 ng/ml. Secondary analyses were undertaken of mean clozapine levels, dose and concentration/dose (C/D) ratio and response and/or relapse. A meta-regression by study duration was conducted.. Twenty studies met inclusion criteria. Clozapine levels above 350 ng/ml were associated with statistically significantly higher rates of response (OR 2.27 95% CI 1.40-3.67, p < 0.001), but not above 600 ng/ml (OR 1.40 95% CI 0.85-2.31, p = 0.19). Higher mean clozapine levels were associated with better rates of response (SMD 0.24, 95% CI 0.00-0.49, p = 0.05), and lower rates of relapse (SMD -0.72, 95% CI -1.26 to -0.19, p = 0.008). By contrast, neither clozapine dose nor C/D ratio was associated with differing rates of response. Similarly, study duration did not affect outcome.. Our findings are in keeping with current guidelines that recommend targeting clozapine levels above 350 ng/ml before augmentation is considered. As some clozapine associated ADRs are dose dependent, levels above 600 ng/ml may have an unfavourable risk-benefit ratio.

Topics: Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Schizophrenia

Clozapine treatment increases the risk of agranulocytosis, but findings on the epidemiology of agranulocytosis have been inconsistent. This meta-analysis examined the prevalence of agranulocytosis and related death in clozapine-treated patients.. A literature search in the international (PubMed, PsycINFO, and EMBASE) and Chinese (WanFang, Chinese National Knowledge Infrastructure, and Sinomed) databases was conducted. Prevalence estimates of agranulocytosis and related death in clozapine-treated patients were synthesized with the Comprehensive Meta-Analysis program using the random-effects model.. Thirty-six studies with 260 948 clozapine-treated patients published between 1984 and 2018 were included in the meta-analysis. The overall prevalence of agranulocytosis and death caused by agranulocytosis were 0.4% (95% CI 0.3-0.6%) and 0.05% (95% CI 0.03-0.09%), respectively. The prevalence of agranulocytosis was moderated by sample size, study quality, year of publication, and that of data collection.. The prevalence of clozapine-associated agranulocytosis is low. Agranulocytosis-related death appears rare.

Topics: Agranulocytosis; Antipsychotic Agents; Cause of Death; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Observational Studies as Topic; Prevalence

The purpose of this article is to review the current literature on drug-induced thrombocytosis with the goal of critically assessing causality and providing a comprehensive review of the topic. Thrombopoietic growth factors, such as thrombopoietin-receptor agonists (romiplostim and eltrombopag) and erythropoietin are not included in our review.. The literature search included published articles limited to the English language and humans in MEDLINE, EMBASE, and Web of Science databases. MEDLINE/PubMed (1966 to September 2018) was searched using the MeSH terms thrombocytosis/chemically-induced and thrombocytosis/etiology. EMBASE (1980 to September 2018) was searched using the EMTAGS thrombocytosis/side effect. Web of Science (1970 to September 2018) was searched using the search term thrombocytosis. References of all relevant articles were reviewed for additional citations and information.. Review articles, clinical trials, background data, case series, and case reports of drug-induced thrombocytosis were collected, and case reports were assessed for causality using a modified Naranjo nomogram.. Drug-induced thrombocytosis, a form of reactive thrombocytosis cannot be easily differentiated from more common etiologies of reactive thrombocytosis. In all, 43 case reports of drug-induced thrombocytosis from a wide variety of drugs and drug classes were reviewed using a modified Naranjo probability scale that included criteria specific for thrombocytosis.. Drug-induced thrombocytosis is a relatively rare adverse drug reaction. The strongest evidence of causality supports low-molecular-weight heparins and neonatal drug withdrawal. Weaker evidence exists for all-trans retinoic acid, antibiotics, clozapine, epinephrine, gemcitabine, and vinca alkaloids.

Topics: Anti-Bacterial Agents; Antineoplastic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Epinephrine; Humans; Thrombocytosis

Recent meta-analyses of randomized clinical trials (RCTs) comparing clozapine with nonclozapine second-generation antipsychotics (NC-SGAs) in schizophrenia have challenged clozapine's superiority in treatment-resistant patients. However, patients in RCTs are not necessarily generalizable to those in clinical practice.. To conduct a systematic review and meta-analysis to compare various outcomes of clozapine vs oral NC-SGAs in cohort studies.. Systematic literature search in PubMed, PsycINFO, and CINAHL without language restriction from database inception until December 17, 2018.. Nonrandomized cohort studies reporting effectiveness and/or safety outcomes comparing clozapine with NC-SGAs in schizophrenia or schizoaffective disorder.. Independent investigators assessed studies and extracted data. Using a random-effects model, the study calculated risk ratio (RR) unadjusted for covariates and follow-up duration, number needed to treat/number needed to harm (NNT/NNH) for dichotomous data, and standardized mean difference (SMD) or mean difference (MD) for continuous data.. Coprimary outcomes were hospitalization and all-cause discontinuation. Secondary outcomes included all effectiveness and safety outcomes reported in at least 3 analyzable studies.. Of 8446 hits, 68 articles from 63 individual cohort studies (n = 109 341) (60.3% male; mean [SD] age of 38.8 [6.5] years, illness duration of 11.0 [5.1] years, and study duration of 19.1 [23.3] months) were meta-analyzed. Compared with NC-SGAs, despite greater illness severity (17 studies [n = 38 766]; Hedges g, 0.222; 95% CI, 0.013-0.430; P = .04), clozapine was significantly associated with lower hospitalization risk (19 studies [n = 49 453]; RR, 0.817; 95% CI, 0.725-0.920; P = .001; NNT, 18; 95% CI, 12-40) and all-cause discontinuation (16 studies [n = 56 368]; RR, 0.732; 95% CI, 0.639-0.838; P < .001; NNT, 8; 95% CI, 6-12). Associations were statistically significant for comparisons with quetiapine fumarate and aripiprazole regarding hospitalization and all NC-SGAs, except aripiprazole, for all-cause discontinuation. Clozapine was also significantly associated with better outcomes regarding overall symptoms (SMD, -0.302; 95% CI, -0.572 to -0.032; P = .03) and Clinical Global Impressions scale severity (SMD, -1.182; 95% CI, -2.243 to -0.122; P = .03). Clozapine was significantly associated with increases in body weight (MD, 1.70; 95% CI, 0.31-3.08 kg; P = .02), body mass index (MD, 0.96; 95% CI, 0.24-1.68; P = .009), and type 2 diabetes (RR, 1.777; 95% CI, 1.229-2.570; P = .002; NNH, 27; 95% CI, 13-90).. In cohort studies, despite more severely ill patients being treated with clozapine, use of clozapine was associated with better key efficacy outcomes and higher cardiometabolic-related risk outcomes vs NC-SGAs.

Topics: Adult; Antipsychotic Agents; Clozapine; Cohort Studies; Drug-Related Side Effects and Adverse Reactions; Female; Hospitalization; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Schizophrenia

Clozapine is one of the most effective atypical antipsychotic drugs prescribed to patients with treatment-resistant schizophrenia. Approximately 1% of patients experience potential life-threatening adverse effects in the form of agranulocytosis, greatly hindering its applicability in clinical practice. The etiology of clozapine-induced agranulocytosis (CIA) remains unclear, but is thought to be a heritable trait. We reviewed the genetic studies of CIA published thus far. One recurrent finding from early candidate gene study to more recent genome-wide analysis is that of the involvement of human leukocyte antigen locus. We conclude that CIA is most likely a complex, polygenic trait, which may hamper efforts to the development of a genetic predictor test with clinical relevance. To decipher the genetic architecture of CIA, it is necessary to apply more rigorous standards of phenotyping and study much larger sample sizes.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Genome-Wide Association Study; HLA Antigens; Humans; Schizophrenia

Clozapine is a second-generation antipsychotic which has proven efficacy in treating the symptoms of schizophrenia. Although clozapine therapy is associated with a number of adverse drug reactions, it is frequently used. One of the most common adverse drug reactions is gastroesophageal reflux disease which is an indication for treatment with proton pump inhibitors (PPIs). Coadministration of clozapine and PPIs increases the risk of hematological adverse drug reactions, including neutropenia and agranulocytosis. The mechanism in idiosyncratic agranulocytosis is not dose related and involves either a direct toxic or an immune-allergic effect. It is suspected that the clozapine metabolites nitrenium ion and N-desmethylclozapine may cause apoptosis or impair growth of granulocytes. Formation of N-desmethylclozapine is correlated with activity of the cytochrome P450 enzymes 1A2 and 3A4 (CYP1A2 and CYP3A4). Nitrenium ion is produced by the flavin-containing monooxygenase system of leukocytes. A drug interaction between clozapine and a PPI is a consequence of the induction of common metabolic pathways either by the PPI or clozapine. Findings to date suggest that indirect induction of flavin-containing monooxygenase by omeprazole through the aryl hydrocarbon receptor increases the expression of the enzyme mRNA and in the long term may cause the increase in activity. Moreover, induction of CYP1A2, especially by omeprazole and lansoprazole, may increase the serum concentration of N-desmethylclozapine, which can accumulate in lymphocytes and may achieve toxic levels. Another hypothesis that may explain hematological adverse drug reactions is competitive inhibition of CYP2C19, which may contribute to increased serum concentrations of toxic metabolites.

Topics: Antipsychotic Agents; Clozapine; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Humans; Proton Pump Inhibitors

Patients exposed to second-generation antipsychotics (SGAs) have approximately 10 times increased risk of diabetic ketoacidosis (DKA) compared with the general population. However, as DKA is a rare complication of type 2 diabetes mellitus, and susceptible patients exposed to antipsychotics may rapidly develop DKA independently of treatment duration and weight gain, this is rather suggestive of type 1 diabetes mellitus (T1DM) or latent autoimmune diabetes in adults.. We performed a systematic review of current studies regarding antipsychotic-associated DKA with type 1 etiology and analyzed Danish adverse drug event (ADE) reports (previously unpublished cases).. PubMed, Embase, and the Cochrane Library were searched for all relevant studies, and the Danish Medicines Agency retrieved ADE reports using the Danish ADE database (up to date as of June 28, 2016). Diagnosis of antipsychotic-associated DKA with type 1 etiology was either considered confirmed or possible depending on authors' conclusions in the studies and/or clinical aspects. In addition, clinico-demographic risk factors were extracted.. A total of 655 records and 11 ADE reports were identified, and after screening for eligibility, we included 21 case reports/series and two ADE reports (n = 24). No relevant clinical studies were included. Although fatal cases were identified, these were excluded because of diagnostic uncertainties (n = 15). DKA occurred in 15 males (62.5 %) and nine females (37.5 %), with a mean age ± standard deviation of 34.8 ± 12.4 years. Median time to DKA was 5 months (interquartile range: 1.4-11 months). Associated antipsychotics were olanzapine (n = 9, 36 %), aripiprazole (n = 6, 24 %), risperidone (n = 6, 24 %), clozapine (n = 3, 12 %), and quetiapine (n = 1, 4 %). Nine patients (37.5 %) were confirmedly diagnosed with T1DM following DKA resolution, whereas 15 patients (62.5 %) had possible T1DM. In 22 patients (91.7 %), ongoing insulin treatment was required for glycemic control.. Increased awareness of the potential risk of antipsychotic-associated DKA and subsequent T1DM diagnosis, with insulin requirements for glycemic control, is warranted. The underlying mechanisms are poorly understood but most probably multifactorial. Certainly, further studies are warranted. Clinicians must utilize appropriate monitoring in susceptible patients and consider the possibility of continuing antipsychotic treatment with appropriate diabetic care.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Blood Glucose; Clozapine; Denmark; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Olanzapine; Risk Factors; Risperidone; Young Adult

Schizophrenia is a severe disorder that significantly affects the quality of life and total functioning of patients and their caregivers. Clozapine is the first atypical antipsychotic with fewer adverse effects and established efficacy. As a rule of thumb, risperidone is one of the most reliable and effective antipsychotics for newly diagnosed and chronic schizophrenics. Pharmacogenetic studies have identified genomic variants of candidate genes that seem to be important in the way a patient responds to treatment. The recent progress made in pharmacogenomics will improve the quality of treatment, since drug doses will be tailored to the special needs of each patient. In this article, we review the available literature attempting to delineate the role of genomic variations in clozapine and risperidone response in schizophrenic patients of various ethnicities. We conclude that pharmacogenomics for these two drugs is still not ready for implementation in the clinic.

Topics: Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmacogenetics; Precision Medicine; Risperidone; Schizophrenia; Treatment Outcome

Research into the use of clozapine in older people is somewhat scarce. Clozapine is associated with serious adverse effects such as agranulocytosis, seizures, myocarditis and metabolic syndrome. Other common undesirable effects such as sedation, constipation (which can be fatal), urinary incontinence and hypersalivation further limit its use. These adverse effects are particularly important for the use of clozapine in older people, who are generally more susceptible to medication-related adverse effects. Whilst clozapine should be used with caution in elderly people, strict monitoring procedures can help to prevent harmful effects through early detection, and certain management techniques exist to minimise them. This review outlines the epidemiology of clozapine-related adverse effects in older people and discusses potential prevention and management strategies.

Topics: Aged; Clozapine; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Humans

Antipsychotic-induced extrapyramidal adverse effects are well recognized in the context of first-generation antipsychotic drugs. However, the introduction of second-generation antipsychotics, with atypical mechanism of action, especially lower dopamine receptors affinity, was met with great expectations among clinicians regarding their potentially lower propensity to cause extrapyramidal syndrome. This review gives a brief summary of the recent literature relevant to second-generation antipsychotics and extrapyramidal syndrome. Numerous studies have examined the incidence and severity of extrapyramidal syndrome with first- and second-generation antipsychotics. The majority of these studies clearly indicate that extrapyramidal syndrome does occur with second-generation agents, though in lower rates in comparison with first generation. Risk factors are the choice of a particular second-generation agent (with clozapine carrying the lowest risk and risperidone the highest), high doses, history of previous extrapyramidal symptoms, and comorbidity. Also, in comparative studies, the choice of a first-generation comparator significantly influences the results. Extrapyramidal syndrome remains clinically important even in the era of second-generation antipsychotics. The incidence and severity of extrapyramidal syndrome differ amongst these antipsychotics, but the fact is that these drugs have not lived up to the expectation regarding their tolerability.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Receptors, Dopamine D2; Schizophrenia

The efficacy of antipsychotic use in children and adolescents with psychosis has been shown in an increasing number of randomized controlled trials. Chronic use of second-generation and third-generation antipsychotics has the potential for significant side effects, especially metabolic syndrome. A review of the literature on side effect profiles of antipsychotic medications used in children and adolescents is provided to help clinicians develop treatment plans for their patients. Clozapine has the best efficacy of all antipsychotic medications in adults as well as children and adolescents who are treatment resistant. Guidance is provided for the management of clozapine side effects.

Topics: Adolescent; Age Factors; Age of Onset; Antipsychotic Agents; Child; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Polypharmacy; Psychopharmacology; Psychotic Disorders; Randomized Controlled Trials as Topic; Risk Factors; Schizophrenia; Secondary Prevention; Treatment Outcome

Clozapine is a uniquely efficacious antipsychotic drug in treatment-resistant schizophrenia. Its use is restricted due to adverse effects including a rare but dangerous reduction in neutrophils (agranulocytosis) and the mandatory hematological monitoring this entails in many countries. We review the statistical, ethical and legal issues arising from a hypothetical pharmacogenetic test for clozapine, using the UK as an exemplary case for consideration. Our key findings include: a consideration of the probabilistic results that a pharmacogenetic test may return; the impact on drug licensing; and the potential for pharmacogenetic tests for clozapine being used without consent under the UK's legal framework. We make recommendations regarding regulatory changes applicable to the special case of pharmacogenetic testing in clozapine treatment.

Topics: Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmacogenetics; Schizophrenia; United Kingdom

Numerous publications have provided evidence for clinically important metabolic adverse effects of antipsychotics, but there is no systematic evaluation as to whether weight gain and other metabolic changes are dose dependent.. This review of the available literature aimed to explore a possible relationship between dosage of second-generation antipsychotics (SGAs) and the degree of metabolic side effects.. A literature review was conducted in 3 steps: (1) Articles published between 1975 and 2004 were identified on the basis of the bibliography of an extensive review of the metabolic effects of SGAs. (2) Articles published between 2004 and 2008 were identified by a PubMed search with the keywords weight gain, metabolic, glucose, insulin, and lipid AND dose combined with amisulpride, aripiprazole, clozapine, quetiapine, risperidone, sertindole, and ziprasidone. (3) A hand search was conducted based on the bibliography of the identified articles.. All studies that provided information on metabolic side-effects in different dose ranges were selected. Data extraction was carried out independently by 2 observers.. Preliminary evidence suggests a dose-response relationship between clozapine and olanzapine serum concentrations and metabolic outcomes, although the association between administered daily dose and metabolic outcomes is not clear. Data are controversial with regard to risperidone, and no study has as yet assessed risperidone serum concentrations in association with metabolic outcomes. For the other SGAs, there was little evidence to suggest a dose-response relationship, although, in these agents also, no assessment of serum concentrations was conducted.. The finding that metabolic complications may be associated with clozapine and olanzapine plasma concentrations provides further evidence for a causal contribution to the metabolic disturbances observed with these agents. Further well-designed, prospective studies investigating a possible association between SGA serum concentrations and metabolic outcomes are needed.

Topics: Adolescent; Adult; Antipsychotic Agents; Child; Clozapine; Controlled Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Insulin; Male; Metabolic Syndrome; Risperidone; Treatment Outcome; Triglycerides; Weight Gain

The present review focuses on atypical antipsychotics and tardive dyskinesia.. We have known for many years that clozapine has a diminished risk of tardive dyskinesia compared with typical antipsychotics. The last decade has seen the introduction of a number of other atypical antipsychotics, allowing us to begin evaluating whether they too share this attribute. In addition, the opportunity to use these drugs as first-line treatment permits a more precise means of establishing risk. While longer-term data are required, the limited evidence available clearly indicates that the atypical antipsychotics have a decreased liability of tardive dyskinesia, approximately 1% compared with 5% for typical agents annually. Like clozapine, the other atypical antipsychotics also demonstrate antidyskinetic properties in individuals with preexisting tardive dyskinesia. The underlying mechanisms remain unclear, and without such information it is not possible to say what clinical conditions, if any, might diminish or even eliminate these advantages.. An update is provided regarding the atypical antipsychotics and tardive dyskinesia. This information is critical in our decision-making regarding choice of antipsychotic and optimal use in the clinical setting.

Topics: Antipsychotic Agents; Brain; Clozapine; Drug-Related Side Effects and Adverse Reactions; Dyskinesia, Drug-Induced; Evidence-Based Medicine; Humans; Neurologic Examination; Product Surveillance, Postmarketing; Risk

The use of clozapine, a unique antipsychotic drug, has been restricted due to a 1 to 2% incidence of drug-induced agranulocytosis. Many other drugs, including paracetamol (acetaminophen), can cause agranulocytosis, although with a much lower incidence. Metabolic activation of these drugs by neutrophils or stem cells could be the molecular mechanism underlying this adverse effect. Drug oxidation by myeloperoxidase leads to free radical metabolite formation; these reactive free radicals can oxidise glutathione to a thiyl free radical, which in the presence of oxygen forms oxygen-derived free radicals. In contrast to glutathione, when these free radical metabolites oxidise ascorbate an unreactive free radical is formed, which does not even react with oxygen. In both reactions, the free radical metabolite is reduced to the original drug, although ascorbate is the more effective reducing agent. Thus ascorbate, when coadministered with agranulocytosis-causing drugs, may inhibit free radical chain reactions and other free radical-mediated reactions, such as protein adduct formation, and thereby prevent drug-induced agranulocytosis.

Topics: Agranulocytosis; Clozapine; Drug-Related Side Effects and Adverse Reactions; Free Radicals; Humans; Oxidation-Reduction; Peroxidases; Pharmaceutical Preparations

Emerging evidence suggests an important role of the human gut microbiome in psychiatry and neurodevelopmental disorders. An increasing body of literature based on animal studies has reported that the gut microbiome influences brain development and behavior by interacting with the gut-brain axis. Furthermore, as the gut microbiome has an important role in metabolism and is known to interact with pharmaceuticals, recent evidence suggests a role for the microbiome in antipsychotic-induced metabolic side effects in animals and humans.. Here we present the protocol for a two-phase study investigating the gut microbiome in healthy controls and in patients with schizophrenia treated with antipsychotics.. Phase I of our study involves humans exclusively. We recruit 25 patients who are chronically treated with clozapine and compare them with 25 healthy controls matched for age, sex, BMI, and smoking status. A second cohort consists of 25 patients newly starting on clozapine, and a third cohort includes 25 antipsychotic-naive patients. The patients in the second cohort and third cohort are prospectively assessed for up to 6 and 12 weeks, respectively. Phase II of this study will incorporate microbiota humanized mouse models to examine the influence of human fecal transplant on metabolic parameters and the gut-brain axis. Progress and Future Directions: We are underway with the first participants enrolled in all phase I treatment cohorts. This study will contribute to elucidating the role of the gut microbiome in schizophrenia and metabolic side effects. In addition, its results may help to explore potential therapeutic targets for antipsychotic-induced metabolic side effects.

Topics: Adult; Animals; Antipsychotic Agents; Clozapine; Disease Models, Animal; Drug-Related Side Effects and Adverse Reactions; Fecal Microbiota Transplantation; Female; Gastrointestinal Microbiome; Humans; Male; Mice; Prospective Studies; Schizophrenia; Weight Gain

Topics: Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Italy; Olanzapine; Pharmacovigilance

Among antipsychotics, clozapine is associated with a high risk of seizures. This study aimed to generate novel hypotheses regarding trends in the onset of clozapine-induced seizures using the JADER (Japanese Adverse Drug Event Report) database. Seizures were defined according to the Standardized MedDRA Queries (SMQ) for convulsions (SMQ20000079). Trends in the onset of clozapine-induced seizures were assessed using multivariate logistic regression analysis with covariates of sex, age, clozapine dose, antipsychotic polypharmacy, concomitant medications, and history of convulsive disorder. In addition, we assessed the time-to-onset of clozapine-induced seizures using the median time, interquartile range, and Weibull shape parameter. The JADER database registered 2,745 cases of adverse events with clozapine, and 1,784 cases were included in the analysis after excluding cases for which clinical information was not available. Medium (200-400 mg) and high (> 400 mg) doses of clozapine had a significantly higher reporting rate of seizures than low doses (< 200 mg) (adjusted reporting odds ratio [aROR] = 3.05, 95% confidence interval [CI]: 1.86-4.99 and aROR = 9.81, 95% CI: 6.06-15.89, respectively). Younger age, antipsychotic polypharmacy, and concomitant use of lithium were also significantly associated with reports of seizures. The time-to-onset analysis of 222 cases of clozapine-induced seizures showed that the median time was 134 (interquartile range, 72-295) days. The 95% CI of the WSP β-value for clozapine-induced seizures included 1 and was classified as a random failure type. In conclusion, the results suggest that clozapine-induced seizures are dose-dependent adverse events that should be monitored with consideration of the effects of age and concomitant medications. Further epidemiological research is needed to strengthen and validate our hypotheses.

Topics: Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; East Asian People; Humans; Japan; Seizures

Clozapine is an anti-psychotic agent, reserved for treatment-resistant schizophrenia, with demonstrated efficacy in an otherwise therapeutically challenging patient population. We aimed to review the full spectrum casemix of clozapine presentations to our tertiary toxicology service.. In this retrospective study, we reviewed consecutive clozapine related toxicity presentations to a tertiary medical toxicology inpatient and consultation service-including deliberate self-poisoning (DSP), adverse drug reaction (ADR), recreational use, and therapeutic misadventure over a 10-year period from 2011 to 2021. Data were extracted for demographics, ingested dose, exposure characteristics, and patient outcome.. We identified 83 patients with clozapine-related presentations over the 10-year period. Twenty-two patients were excluded. Of the remaining 61 patients, 28 patients presented with DSP, 20 patients with accidental overdose, and 13 patients with an ADR; no patients presented with recreational use. It was noted that ADRs were largely idiosyncratic reactions and not always related to dose adjustments. In the context of therapeutic misadventure and DSP, we noted that a lower mean dose achieved a higher poison severity score (PSS) in clozapine-naive patients when compared to those patients on regular clozapine.. The presentation of clozapine-related toxicity differs depending on the modality of ingestion, whether DSP, accidental, or as a result of ADR. Patients naive to clozapine therapy tend to experience higher PSS with lower doses ingested either in a deliberate self-poisoning or accidental ingestion context. This is likely due to tolerance to the sedative properties of clozapine. No patients manifested clinical toxicity greater than 8 hours after ingestion, with an observation period of 6 hours accurately identifying toxicity in most patients.

Topics: Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Hypnotics and Sedatives; Retrospective Studies

Topics: Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Urinary Retention

Tubulointerstitial nephritis is a common cause of acute renal failure, in two thirds of cases it is associated with drugs (mostly antimicrobials and NSAIDs), in 5-10% of cases it is associated with infections (bacterial/viral/parasitic), in 5-10% of cases it is idiopathic (this is the case of the TINU syndrome characterized by interstitial nephritis and bilateral uveitis, and the anti-glomerular basal membrane antibody syndrome), and finally in 10% of cases it is associated with systemic diseases (sarcoidosis, by Sjogren, LES). The pathogenesis is based on a cell-mediated immune response and in most cases removing the causative agent is the gold standard of therapy. However, a percentage of patients, in a variable range from 30% to 70% of cases, do not fully recover renal function, due to the rapid transformation of the interstitial cell infiltrate into vast areas of fibrosis. Clozapine is a second generation atypical antipsycothic usually used for the treatment of schizophrenia resistant to other types of treatment; it can cause severe adverse effects among which the best known is a severe and potentially fatal neutropenia, furthermore a series of uncommon adverse events are recognized including hepatitis, pancreatitis, vasculitis. Cases of acute interstitial tubular nephritis associated with the use of clozapine have been described in the literature, although this complication is rare. Medical personnel using this drug need to be aware of this potential and serious side effect. We describe the case of a 48-year-old man who developed acute renal failure after initiation of clozapine.

Topics: Acute Kidney Injury; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Male; Middle Aged; Nephritis, Interstitial; Uveitis

Clozapine is often underused due to concerns about adverse drug reactions (ADRs) but studies into their prevalences are inconclusive. We therefore comprehensively examined prevalences of clozapine-associated ADRs in individuals with schizophrenia and demographic and clinical factors associated with their occurrence. Data from a multi-center study (n = 698 participants) were collected. The mean number of ADRs during clozapine treatment was 4.8, with 2.4 % of participants reporting no ADRs. The most common ADRs were hypersalivation (74.6 %), weight gain (69.3 %), and increased sleep necessity (65.9 %), all of which were more common in younger participants. Participants with lower BMI prior to treatment were more likely to experience significant weight gain (>10 %). Constipation occurred more frequently with higher clozapine blood levels and doses. There were no differences in ADR prevalence rates between participants receiving clozapine monotherapy and polytherapy. These findings emphasize the high prevalence of clozapine-associated ADRs and highlight several demographic and clinical factors contributing to their occurrence. By understanding these factors, clinicians can better anticipate and manage clozapine-associated ADRs, leading to improved treatment outcomes and patient well-being.

Topics: Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Prevalence; Sex Characteristics; Weight Gain

Clozapine, an antipsychotic medication used to treat treatment-refractory schizophrenia, has been associated with various dangerous side effects, including myocarditis. However, there have been few published cases reporting on patients with clozapine-induced myocarditis confirmed by cardiac magnetic resonance imaging or the management, treatment, and follow-up of these patients.. This report describes 2 cases of patients with treatment-refractory schizophrenia evidencing transient clozapine-induced myocarditis. Detailed information including laboratory values, imaging results, and clinical notes were gathered.. The 2 cases demonstrated differing manifestations of clozapine-induced myocarditis. Both cases showed that such myocarditis can be transient and can be treated clinically with close observation without discontinuation of clozapine.. These cases show that clozapine-induced myocarditis is transient at times and can self-resolve without discontinuation of clozapine. These observations may suggest a change in clinical practice so that, with close observation, we can avoid risking psychiatric decompensation in select patients with a history of treatment-resistant schizophrenia.

Topics: Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Magnetic Resonance Imaging; Myocarditis

Retrospective studies using spontaneous reporting system databases have provided a great understanding of adverse drug reactions (ADRs) in the real world, complementing the data obtained from randomized controlled trials. However, there have been few reports on large-scale epidemiological studies on the adverse effects of antipsychotics in Asia.. This study aimed to investigate the characteristics of antipsychotic ADRs using a nationwide pharmacovigilance database.. Data were collected from the Korea Adverse Event Reporting System database between 2010 and 2019. The study subjects were selected using the International Classification of Disease codes for diseases related to psychosis and Electronic Data Interchange codes for amisulpride, aripiprazole, clozapine, haloperidol, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone. The causality assessment of "possible," "probable," or "certain" by the World Health Organization-Uppsala Monitoring Center System causality category was selected. All data were descriptively analyzed.. In total, 5067 adverse events associated with antipsychotic drugs were reported. The antipsychotics that commonly resulted in ADRs were quetiapine (47.7%), olanzapine (11.3%), and clozapine (10.7%). Serious ADRs were most commonly observed with clozapine. Gastrointestinal and central nervous system problems occurred within a month when ADRs were classified according to the time of onset. In contrast, metabolic and bone marrow-related symptoms occurred after long-term use. Sedation and nausea were the most common ADRs in children and adolescents, whereas constipation and dizziness were common in adults and the elderly.. This study extends our knowledge of antipsychotic ADRs in the Asian population.

Topics: Adolescent; Adult; Aged; Amisulpride; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Child; Clozapine; Drug-Related Side Effects and Adverse Reactions; Haloperidol; Humans; Olanzapine; Paliperidone Palmitate; Quetiapine Fumarate; Retrospective Studies; Risperidone; Schizophrenia

Topics: Adverse Drug Reaction Reporting Systems; Antipsychotic Agents; Appendicitis; Clozapine; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmacovigilance

Topics: Adolescent; Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Schizophrenia

Clozapine is associated with increased risk of myocarditis. However, many common side-effects of clozapine overlap with the clinical manifestations of myocarditis. As a result, there is uncertainty about which signs, symptoms and investigations are important in distinguishing myocarditis from benign adverse effects of clozapine. Clarity on this issue is important, since missing a diagnosis of myocarditis or discontinuing clozapine unnecessarily may both have devastating consequences.. To examine the clinical characteristics of clozapine-induced myocarditis and to identify which signs and symptoms distinguish true myocarditis from other clozapine adverse effects.. A retrospective analysis of the record database for 247 621 patients was performed. A natural language processing algorithm identified the instances of patients in which myocarditis was suspected. The anonymised case notes for the patients of each suspected instance were then manually examined, and those whose instances were ambiguous were referred for an independent assessment by up to three cardiologists. Patients with suspected instances were classified as having confirmed myocarditis, myocarditis ruled out or undetermined.. Of 254 instances in 228 patients with suspected myocarditis, 11.4% (n = 29 instances) were confirmed as probable myocarditis. Troponin and C-reactive protein (CRP) had excellent diagnostic value (area under the curve 0.975 and 0.896, respectively), whereas tachycardia was of little diagnostic value. All confirmed instances occurred within 42 days of clozapine initiation.. Suspicion of myocarditis can lead to unnecessary discontinuation of clozapine. The 'critical period' for myocarditis emergence is the first 6 weeks, and clinical signs including tachycardia are of low specificity. Elevated CRP and troponin are the best markers for the need for further evaluation.

Topics: Antipsychotic Agents; Biomarkers; Clozapine; Drug-Related Side Effects and Adverse Reactions; Electronics; Humans; Incidence; Myocarditis; Retrospective Studies; Tachycardia; Troponin

An association between antipsychotic drugs and pneumonia has been demonstrated in several studies; however, the risk for pneumonia caused by specific antipsychotics has not been extensively studied. The underlying mechanism is still unknown, and several receptor mechanisms have been proposed. Therefore, using a combined pharmacovigilance-pharmacodynamic approach, we aimed to investigate safety signals of US Food and Drug Administration (FDA)-approved antipsychotics for reporting pneumonia and the potential receptor mechanisms involved. A disproportionality analysis was performed to detect a signal for reporting "infective-pneumonia" and "pneumonia-aspiration" and antipsychotics using reports submitted between 2004 and 2019 to the FDA adverse events spontaneous reporting system (FAERS) database. Disproportionality was estimated using the crude and the adjusted reporting odds ratio (aROR) and its 95% confidence interval (CI) in a multivariable logistic regression. Linear regressions investigated the relationship between aROR and receptor occupancy, which was estimated using in vitro receptor-binding profiles. Safety signals for reporting infective-pneumonia were identified for clozapine (LL = 95% 3.4, n = 546 [aROR: 4.8]) as well as olanzapine (LL = 95% 1.5, n = 250 [aROR: 2.1]) compared with haloperidol, while aRORs were associated with higher occupancies of muscarinic receptors (beta = .125, P-value = .016), yet other anti-muscarinic drugs were not included as potential confounders. No safety signals for reporting pneumonia-aspiration were detected for individual antipsychotics. Multiple antipsychotic use was associated with both reporting infective-pneumonia (LL 95%: 1.1, n = 369 [aROR:1.2]) and pneumonia-aspiration (LL 95%: 1.7, n = 194 [aROR: 2.0]). Considering the limitations of disproportionality analysis, further pharmacovigilance data and clinical causality assessment are needed to validate this safety signal.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Aged, 80 and over; Antipsychotic Agents; Clozapine; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Female; Haloperidol; Humans; Male; Middle Aged; Olanzapine; Pharmacovigilance; Pneumonia; Pneumonia, Aspiration; Receptors, Muscarinic; United States; United States Food and Drug Administration; Young Adult

Clozapine (CLZ) is an atypical antipsychotic and the gold standard for refractory psychosis treatment. However, there is little information regarding pharmacogenetics of CLZ in patients with refractory psychosis and its clinical correlation with alcohol intake. Although neurological effects of CLZ in patients with concomitant alcohol intake are documented, its use is very common in patients with psychosis. We explored the impact of CYP1A2, CYP2D6, CYP2C19, and CYP3A4 genetic variants on CLZ pharmacokinetics and side effects, along with coffee/alcohol/tobacco consumption habits and clinical data of 48 adult patients with refractory psychosis on CLZ antipsychotic monotherapy. Relevant CYP variants in CLZ metabolism were evaluated by targeted genotyping and multiplex ligation-dependent probe amplification. CLZ and its main metabolite plasma concentrations were determined by high performance liquid chromatography. Biochemical and molecular data, along with other potential confounders, were included in the analysis by linear regression. Overall, CYP variants showed no effect on CLZ pharmacokinetics. The rs2069514 variant in homozygous genotype (also known as CYP1A2*1C/*1C) was associated with CLZ adverse reactions in Mexican patients with refractory psychosis (OR = 3.55 CI

Topics: Adult; Alcohol Drinking; Antipsychotic Agents; Clozapine; Cross-Sectional Studies; Cytochrome P-450 CYP1A2; Drug-Related Side Effects and Adverse Reactions; Female; Genetic Variation; Genotype; Humans; Male; Pharmacogenetics; Psychotic Disorders

Topics: Antipsychotic Agents; Clozapine; COVID-19; Drug-Related Side Effects and Adverse Reactions; Humans; Inflammation; Male; Middle Aged; SARS-CoV-2

Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.. A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.. This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.

Topics: Antipsychotic Agents; Clozapine; Constipation; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Middle Aged; Schizophrenia

Topics: Antipsychotic Agents; C-Reactive Protein; Clozapine; COVID-19 Vaccines; Drug-Related Side Effects and Adverse Reactions; Humans; Male; Middle Aged; mRNA Vaccines; Psychotic Disorders; Vaccines, Synthetic

The current coronavirus pandemic (COVID-19) has led mental health systems to uncertainty regarding safe continuation of clozapine monitoring protocols. Clozapine is without doubt the only antipsychotic available with repeatedly proven efficacy in treatment resistant schizophrenia.1 Replacing clozapine with an alternative antipsychotic in patients stabilized with clozapine can potentially lead to higher risk of relapse or exacerbation of severity of illness.1 Clozapine, as already known, has a number of side effects, some of which can be serious, thus patients receiving clozapine require ongoing scheduled monitoring. Side effects of clozapine include neutropenia or agranulocytosis, myocarditis, fever, hypersalivation, weight gain and constipation. These side effects can be detected and treated when recognized on time decreasing the possibility of serious consequences making the implementation of an ongoing treatment monitoring protocol for patients on clozapine mandatory.2 Since it was advised for all mental health providers in most countries worldwide to limit non-urgent hospital visits and procedures to reduce the risk of contamination a challenge arose for patients' ability to access health care facilities for their routine clozapine monitoring. Nevertheless, the majority of Mental Health Care Authorities decided to ensure access for all patients on clozapine to their routine monitoring protocol.3,4 To date, no data exist on any potential relationship between antipsychotic use and the risk of contamination with SARS-CoV-2 or the development of severe symptoms of the infection. The literature suggests that patients receiving antipsychotics, especially clozapine, have an increased risk of developing pneumonia, leading to the assumption that patients receiving clozapine are at higher risk to develop COVID-19. 1 Balancing the importance of monitoring continuation against the increased risk for COVID-19, an International Consensus Statement was recently published addressing a monitoring protocol with reduced visits. The Consensus suggested reduced hematologic monitoring frequency of every 3 months with a prescription of 90 days clozapine supply (if safe). The above applies to patients receiving clozapine for at least one year without neutropenia. Τhe risk of neutropenia after 12 months of clozapine treatment falls significantly.4 Based on the above it is suggested to all clozapine clinics to implement a guidance monitoring protocol for all patients on clozap

Topics: Antipsychotic Agents; Clozapine; COVID-19; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Health Services Accessibility; Health Services Needs and Demand; Humans; Infection Control; Mental Health Services; Organizational Innovation; Risk Management; SARS-CoV-2; Schizophrenia

To evaluate the incidence of clozapine induced haematological side effects among patients receiving clozapine.. Data of 333 patients who were on clozapine for a mean duration of 52.96 (45.18) months were reviewed for haematological abnormalities.. Clozapine is associated eosinophilia and thrombocytopenia, which are often benign and in majority of the patients these normalize with time.

Topics: Adolescent; Adult; Aged; Anemia; Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Eosinophilia; Female; Hematologic Diseases; Humans; Incidence; India; Male; Middle Aged; Neutropenia; Psychotic Disorders; Retrospective Studies; Schizophrenia; Thrombocytopenia; Young Adult

Topics: Antipsychotic Agents; Clozapine; Databases, Factual; Deglutition Disorders; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmacovigilance; Pneumonia; World Health Organization

Topics: Adult; Antipsychotic Agents; Bias; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Mortality; Schizophrenia

Clozapine, an antipsychotic reserved for management of treatment-resistant schizophrenia, is associated with severe adverse effects, including myocarditis. This study aims to determine the incidence of clozapine-induced myocarditis at a large tertiary hospital compared to what is reported in the literature.. Medical records of adult patients admitted to psychiatry units receiving clozapine between January 1, 2010, and July 31, 2016, were retrospectively reviewed. Cases of clozapine-induced myocarditis were defined as having elevated C-reactive protein (CRP) or detectable troponin and at least 1 sign or symptom of myocarditis, in the absence of alternative plausible aetiologies. The primary outcome was incidence of clozapine-induced myocarditis during the study period. Secondary outcomes included rate and description of the management of clozapine-induced myocarditis.. In total, 316 patients were screened; 10 patients met the case definition for clozapine-induced myocarditis. The incidence of this adverse drug reaction over the study period was 3.16%. Reduced left ventricular ejection fraction was observed in 60% of cases, and electrocardiography changes were noted in 60% of cases. Clozapine was discontinued in all cases. Rechallenge was performed in 2 patients; recurrent CRP elevation resulted in discontinuation in each case. Medications for management of myocarditis were used in 50% of cases. Although 2 patients required transfer to critical care, the in-hospital mortality rate was 0%.. The incidence of clozapine-induced myocarditis at the study hospital was consistent with the higher range reported in the literature. Further research is necessary to elucidate risk factors, definitive diagnostic criteria, and effective management of clozapine-induced myocarditis.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Incidence; Male; Middle Aged; Myocarditis; Retrospective Studies; Schizophrenia; Tertiary Care Centers

To review and analyse medication errors related to clozapine, an atypical antipsychotic, that were reported to the National Reporting and Learning System (NRLS).. Following extraction of one year of clozapine related errors from the NRLS, a qualitative analysis (thematic analysis and re-classification) and quantitative analysis was performed. An incident was considered a clozapine error if there was a failure in its medication process (i.e. an error in the prescribing, dispensing, preparing, administering, monitoring or advising of clozapine).. "Issues with stock/supply/ordering" was the most common theme derived from the qualitative thematic analysis (n = 338), followed by wrong dose/strength/frequency (n = 221) and medication omissions (n = 202). Most errors occurred in the "administration/supply" medication stage. Over half of reported clozapine incidents involved people 26 to 55 years old (n = 830) and 82% of errors were reported by mental health services (n = 1270). Only 1.5% of reports were classed as moderate/severe harm.. Issues with availability, stock, and supply were found to be the most common causes. This usually entailed a lack of stock to fulfil a patient's dose/supply. Such incidents could potentially be reduced by improved management of the supply process, and liaison between pharmacy and clinical staff. The implementation of emergency drug cupboards at the discretion of an on-call pharmacist may prove to be a preventative measure for such errors. Despite the potential adverse effects associated with clozapine, very few incidents led to moderate/severe harm. Encouragement of NRLS reporting is recommended for incidents of all degrees of harm.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Incidence; Medication Errors; Middle Aged; United Kingdom; Young Adult

The present study aimed to investigate the incidence of agranulocytosis and leukopenia and its associated factors in Thai schizophrenia patients treated with clozapine and the rate of hematologic adverse events monitored in clinical practice. Data were collected from the medical records of 641 outpatients at two hospitals. The results showed no cases of agranulocytosis and 20 cases of leukopenia (3.1%), 85% of which were observed after 1 year of prescription. The associated factors were female (p = 0.019) and duration of clozapine prescription (p = 0.026). According to the guideline for safety monitoring, 23.6% of cases had neutrophils count monitoring.

Topics: Adult; Adverse Drug Reaction Reporting Systems; Agranulocytosis; Ambulatory Care; Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Incidence; Leukopenia; Male; Mental Health Services; Middle Aged; Prescription Drug Monitoring Programs; Retrospective Studies; Schizophrenia; Thailand

Some medications are more rapidly metabolized by smokers; upon smoking cessation, medication metabolism may be significantly reduced, resulting in medication-related adverse events. Clozapine, olanzapine and theophylline have been deemed to have potentially highly significant interactions with smoking cessation, which could lead to seizures, extrapyramidal effects and tachycardia, respectively. This study examined the period prevalence and characteristics of patients at risk of highly significant medication-smoking cessation interactions when admitted to a smoke-free hospital.. A retrospective cross-sectional study was undertaken in an Australian tertiary-referral hospital with a well-established electronic prescribing system. Smokers prescribed clozapine, olanzapine or theophylline prior to and during a hospital admission in 2015 were included. Length of hospital stay, daily doses, and recognition of the potential interaction by treating clinicians were determined from medical records.. The period prevalence of patients at risk of a potentially highly significant medication-smoking cessation interaction was 23/48 (48%), 66/256 (26%) and 1/16 (6%) amongst smokers prescribed clozapine, olanzapine or theophylline, respectively. These interactions were poorly recognized by healthcare professionals during the admission.. Up to one in two patients receiving medications that have potentially highly significant interactions with smoking cessation may be experiencing clinically significant potential interactions. Such interactions, however, were commonly overlooked by hospital staff. Interventions to improve awareness of this issue are warranted.

Topics: Adult; Aged; Australia; Clozapine; Cross-Sectional Studies; Delivery of Health Care; Drug-Related Side Effects and Adverse Reactions; Female; Hospitalization; Humans; Length of Stay; Male; Middle Aged; Olanzapine; Prevalence; Retrospective Studies; Smokers; Smoking Cessation; Theophylline

Topics: Adverse Drug Reaction Reporting Systems; Antipsychotic Agents; Australia; Clozapine; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Humans; Myocarditis

Topics: Adult; Antipsychotic Agents; Clinical Protocols; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Male; Myocarditis; Schizophrenia

Clozapine is the most effective medication for treatment refractory schizophrenia. However, descriptions of the mental health and comorbidity profile and care experiences of people on clozapine in routine clinical settings are scarce. Using data from the 2010 Australian Survey of High Impact Psychosis, we aimed to examine the proportion of people using clozapine, and to compare clozapine users with other antipsychotic users on demographic, mental health, adverse drug reaction, polypharmacy and treatment satisfaction variables.. Data describing 1049 people with a diagnosis of schizophrenia or schizoaffective disorder, who reported taking any antipsychotic medication in the previous 4 weeks, were drawn from a representative Australian survey of people with psychotic disorders in contact with mental health services in the previous 12 months. We compared participants taking clozapine (n = 257, 22.4%) with those taking other antipsychotic medications, on a range of demographic, clinical and treatment-related indicators.. One quarter of participants were on clozapine. Of participants with a chronic course of illness, only one third were on clozapine. After adjusting for diagnosis and illness chronicity, participants taking clozapine had significantly lower odds of current alcohol, cannabis and other drug use despite similar lifetime odds. Metabolic syndrome and diabetes were more common among people taking clozapine; chronic pain was less common. Psychotropic polypharmacy did not differ between groups.. Consistent with international evidence of clozapine underutilisation, a large number of participants with chronic illness and high symptom burden were not taking clozapine. The lower probabilities of current substance use and chronic pain among clozapine users warrant further study.

Topics: Adult; Antipsychotic Agents; Australia; Clozapine; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Medication Adherence; Polypharmacy; Psychotic Disorders; Schizophrenia; Treatment Outcome

Atypical antipychotics are linked to a higher incidence of metabolic side effects, including weight gain, dyslipidemia, and diabetes. In this study, we examined the prevalence and potential genetic predictors of metabolic side effects in 60 adult patients on clozapine.. Genetic variants of relevance to clozapine metabolism, clearance, and response were assessed through targeted genotyping of cytochrome P450 enzymes CYP1A2 and CYP2C19, the efflux transporter ABCB1, the serotonin receptor (HTR2C), leptin (LEP), and leptin receptor (LEPR). Clozapine levels and other potential confounders, including concurrent medications, were also included in the analysis.. This study confirms a high prevalence of metabolic side effects with clozapine and suggests higher clozapine level and pharmacogenetic markers in CYP2C19, LEP, LEPR, and HTR2C receptors as important predictors of BMI and metabolic syndrome.

Topics: Adult; Aged; Antipsychotic Agents; Clozapine; Cross-Sectional Studies; Cytochrome P-450 Enzyme System; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Obesity; Overweight; Pharmacogenomic Testing; Prevalence; Psychotic Disorders; Schizophrenia; Young Adult

Driven by the need of pharmacovigilance centres and companies to routinely collect and review all available data about adverse drug reactions (ADRs) and adverse events of interest, we introduce and validate a computational framework exploiting dominant as well as emerging publicly available data sources for drug safety surveillance.. Our approach relies on appropriate query formulation for data acquisition and subsequent filtering, transformation and joint visualization of the obtained data. We acquired data from the FDA Adverse Event Reporting System (FAERS), PubMed and Twitter. In order to assess the validity and the robustness of the approach, we elaborated on two important case studies, namely, clozapine-induced cardiomyopathy/myocarditis versus haloperidol-induced cardiomyopathy/myocarditis, and apixaban-induced cerebral hemorrhage.. The analysis of the obtained data provided interesting insights (identification of potential patient and health-care professional experiences regarding ADRs in Twitter, information/arguments against an ADR existence across all sources), while illustrating the benefits (complementing data from multiple sources to strengthen/confirm evidence) and the underlying challenges (selecting search terms, data presentation) of exploiting heterogeneous information sources, thereby advocating the need for the proposed framework.. This work contributes in establishing a continuous learning system for drug safety surveillance by exploiting heterogeneous publicly available data sources via appropriate support tools.

Topics: Adverse Drug Reaction Reporting Systems; Antipsychotic Agents; Cardiotoxicity; Cerebral Hemorrhage; Clozapine; Drug-Related Side Effects and Adverse Reactions; Factor Xa Inhibitors; Haloperidol; Humans; Information Storage and Retrieval; Pharmacovigilance; Pyrazoles; Pyridones

In this study, we describe a simple and rapid method for the determination of the antipsychotic drug clozapine and five commonly co-administered antidepressants - bupropion, mirtazapine, sertraline, clomipramine and citalopram - in serum, plasma and whole blood. Sample preparation includes solid phase extraction of analytes and determination of drug concentrations by gas chromatography-mass spectrometry without any derivatization steps. The method was fully validated according to international criteria and can be successfully applied for routine analyses. Correlation coefficients of calibration curves for the tested drugs in the three specimens were in the range 0.9977-0.9999. Intra-day and inter-day precisions ranged from 0.81-7.85% and 3.60-12.91% respectively for the studied analytes and matrices. Recoveries were satisfactory for different concentrations of each drug in each specimen allowing accurate determinations in the range from sub-therapeutic to toxic levels. The presented method shows acceptable sensitivity, linearity in wide concentration ranges (sub-therapeutic, therapeutic, supra-therapeutic/toxic levels), it is simple and rapid and it is applicable for qualitative and quantitative routine toxicological analyses of clinical and postmortem cases.

Topics: Antidepressive Agents; Antipsychotic Agents; Clozapine; Diagnosis; Drug-Related Side Effects and Adverse Reactions; Gas Chromatography-Mass Spectrometry; Humans; Limit of Detection; Substance Abuse Detection

The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it serves as the primary route of elimination for monovalent bile acids (BAs) into the bile canaliculi. The most compelling evidence linking dysfunction in BA transport with liver injury in humans is found with carriers of mutations that render BSEP nonfunctional. Based on mounting evidence, there appears to be a strong association between drug-induced BSEP interference and liver injury in humans; however, causality has not been established. For this reason, drug-induced BSEP interference is best considered a susceptibility factor for liver injury as other host- or drug-related properties may contribute to the development of hepatotoxicity. To better understand the association between BSEP interference and liver injury in humans, over 600 marketed or withdrawn drugs were evaluated in BSEP expressing membrane vesicles. The example of a compound that failed during phase 1 human trials is also described, AMG 009. AMG 009 showed evidence of liver injury in humans that was not predicted by preclinical safety studies, and BSEP inhibition was implicated. For 109 of the drugs with some effect on in vitro BSEP function, clinical use, associations with hepatotoxicity, pharmacokinetic data, and other information were annotated. A steady state concentration (C(ss)) for each of these annotated drugs was estimated, and a ratio between this value and measured IC₅₀ potency values were calculated in an attempt to relate exposure to in vitro potencies. When factoring for exposure, 95% of the annotated compounds with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 were associated with some form of liver injury. We then investigated the relationship between clinical evidence of liver injury and effects to multidrug resistance-associated proteins (MRPs) believed to play a role in BA homeostasis. The effect of 600+ drugs on MRP2, MRP3, and MRP4 function was also evaluated in membrane vesicle assays. Drugs with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 and a C(ss)/MRP IC₅₀ ratio ≥ 0.1 had almost a 100% correlation with some evidence of liver injury in humans. These data suggest that integration of exposure data, and knowledge of an effect to not only BSEP but also one or more of the MRPs, is a useful tool for informing the potential for liver injury due to altered BA transport.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Biological Transport; Chemical and Drug Induced Liver Injury; Cluster Analysis; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Male; Multidrug Resistance-Associated Proteins; Pharmacokinetics; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Risk Assessment; Risk Factors; Toxicity Tests

Inhibition of the activity of the human bile salt export pump (BSEP: ABCB11) has been proposed to play a role in drug-induced liver injury (DILI). To enhance understanding of the relationship between BSEP inhibition and DILI, inhibition of human BSEP (hBSEP) and its rat ortholog (rBsep) by 85 pharmaceuticals was investigated in vitro. This was explored using assays that quantified inhibition of ATP-dependent [(3)H]taurocholate uptake into inverted plasma membrane vesicles from Sf21 insect cells, which expressed the proteins. Of the pharmaceuticals, 40 exhibited evidence of in vitro transporter inhibition and overall a close correlation was observed between potency values for inhibition of hBSEP and rBsep activity (r(2) = 0.94), although 12 drugs exhibited >2-fold more potent inhibition of hBSEP than rBsep. The median potency of hBSEP inhibition was higher among drugs that caused cholestatic/mixed DILI than among drugs that caused hepatocellular or no DILI, as was the incidence of hBSEP inhibition with IC(50) <300 μM. All drugs with hBSEP IC(50) <300 μM had molecular weight >250, ClogP >1.5, and nonpolar surface area >180Å. A clear distinction was not evident between hBSEP IC(50) or unbound plasma concentration (C(max, u)) of the drugs in humans and whether the drugs caused DILI. However, all 17 of the drugs with hBSEP IC(50) <100 μM and C(max, u) >0.002 μM caused DILI. Overall, these data indicate that inhibition of hBSEP/rBsep correlates with the propensity of numerous pharmaceuticals to cause cholestatic DILI in humans and is associated with several of their physicochemical properties.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Bile Acids and Salts; Cell Line; Chemical and Drug Induced Liver Injury; Cholestasis; Drug-Related Side Effects and Adverse Reactions; Humans; Insecta; Rats; Risk Factors

Phospholipidosis (PLD) is a lysosomal storage disorder induced by compounds, notably cationic amphiphilic drugs, which although reversible interferes with cellular phospholipids.The in silico method described utilizes the amphiphilic moment ΔΔG(AM) (kJ/mol) together with basic pK(a) values to assign PLD inducing potential to a compound. The new model was accurate and sensitive (85% and 82%, respectively) when compared to other data sets. Therefore, the parallel in vitro assay for PLD was discontinued. The data reinforce our view that the amphiphilic moment is far more informative for determining a compound's potential to induce PLD than the combined use of basic pK(a) and ClogP values.

Topics: Animals; Cattle; Cells, Cultured; Computer Simulation; Cornea; Drug-Related Side Effects and Adverse Reactions; Fibroblasts; Lipidoses; Lysosomal Storage Diseases; Models, Molecular; Pharmaceutical Preparations; Phospholipids; Structure-Activity Relationship; Thermodynamics

Drug-induced liver injury is the most common cause of market withdrawal of pharmaceuticals, and thus, there is considerable need for better prediction models for DILI early in drug discovery. We present a study involving 223 marketed drugs (51% associated with clinical hepatotoxicity; 49% non-hepatotoxic) to assess the concordance of in vitro bioactivation data with clinical hepatotoxicity and have used these data to develop a decision tree to help reduce late-stage candidate attrition. Data to assess P450 metabolism-dependent inhibition (MDI) for all common drug-metabolizing P450 enzymes were generated for 179 of these compounds, GSH adduct data generated for 190 compounds, covalent binding data obtained for 53 compounds, and clinical dose data obtained for all compounds. Individual data for all 223 compounds are presented here and interrogated to determine what level of an alert to consider termination of a compound. The analysis showed that 76% of drugs with a daily dose of <100 mg were non-hepatotoxic (p < 0.0001). Drugs with a daily dose of ≥100 mg or with GSH adduct formation, marked P450 MDI, or covalent binding ≥200 pmol eq/mg protein tended to be hepatotoxic (∼ 65% in each case). Combining dose with each bioactivation assay increased this association significantly (80-100%, p < 0.0001). These analyses were then used to develop the decision tree and the tree tested using 196 of the compounds with sufficient data (49% hepatotoxic; 51% non-hepatotoxic). The results of these outcome analyses demonstrated the utility of the tree in selectively terminating hepatotoxic compounds early; 45% of the hepatotoxic compounds evaluated using the tree were recommended for termination before candidate selection, whereas only 10% of the non-hepatotoxic compounds were recommended for termination. An independent set of 10 GSK compounds with known clinical hepatotoxicity status were also assessed using the tree, with similar results.

Topics: Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Decision Trees; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Glutathione; Humans; Liver; Pharmaceutical Preparations; Protein Binding

Approximately 30% of individuals diagnosed with schizophrenia suffer from treatment-resistant or refractory schizophrenia. The gold standard for treatment of refractory schizophrenia is clozapine. However, a significant number of patients cease clozapine therapy; therefore this study explores patient's motives for cessation.. The motives for cessation and duration of clozapine treatment from a retrospective database of 151 patients with schizophrenia or schizo-affective disorder who had ceased clozapine once or more were reviewed, with the motives for cessation coded. The general motives for cessation were non-compliance, own decision, medical, poor response and other. In addition, the medical reasons for cessation were further codified: cardiac complications, neutropenia, fevers, other side effects and pregnancy.. The majority of patients ceased clozapine owing to non-compliance with medical protocols or citing their own decision. Approximately half ceased after a period of 6 months or less. Seventeen per cent of patients ceased owing to medical reasons, with the largest proportions discontinuing treatment because of other side effects or neutropenia.. Future research should seek to further investigate why patients decide to be non-compliant and formulate their own decision to cease treatment, as this will facilitate strategies to promote adherence amongst these two groups that are potentially the most amenable to change.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Resistance; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Medication Adherence; Motivation; Neutropenia; Physician-Patient Relations; Pregnancy; Pregnancy Complications, Hematologic; Psychotic Disorders; Retrospective Studies; Schizophrenia; Schizophrenic Psychology

Drug-induced liver injury (DILI) is a leading cause of drugs failing during clinical trials and being withdrawn from the market. Comparative analysis of drugs based on their DILI potential is an effective approach to discover key DILI mechanisms and risk factors. However, assessing the DILI potential of a drug is a challenge with no existing consensus methods. We proposed a systematic classification scheme using FDA-approved drug labeling to assess the DILI potential of drugs, which yielded a benchmark dataset with 287 drugs representing a wide range of therapeutic categories and daily dosage amounts. The method is transparent and reproducible with a potential to serve as a common practice to study the DILI of marketed drugs for supporting drug discovery and biomarker development.

Topics: Animals; Benchmarking; Biomarkers, Pharmacological; Chemical and Drug Induced Liver Injury; Drug Design; Drug Labeling; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmaceutical Preparations; Reproducibility of Results; United States; United States Food and Drug Administration

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60-70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the "Rule of Three" was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Chemical and Drug Induced Liver Injury; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Models, Biological; Predictive Value of Tests

In the era of personalized medical practice, understanding the genetic basis of patient-specific adverse drug reaction (ADR) is a major challenge. Clozapine provides effective treatments for schizophrenia but its usage is limited because of life-threatening agranulocytosis. A recent high impact study showed the necessity of moving clozapine to a first line drug, thus identifying the biomarkers for drug-induced agranulocytosis has become important. Here we report a methodology termed as antithesis chemical-protein interactome (CPI), which utilizes the docking method to mimic the differences in the drug-protein interactions across a panel of human proteins. Using this method, we identified HSPA1A, a known susceptibility gene for CIA, to be the off-target of clozapine. Furthermore, the mRNA expression of HSPA1A-related genes (off-target associated systems) was also found to be differentially expressed in clozapine treated leukemia cell line. Apart from identifying the CIA causal genes we identified several novel candidate genes which could be responsible for agranulocytosis. Proteins related to reactive oxygen clearance system, such as oxidoreductases and glutathione metabolite enzymes, were significantly enriched in the antithesis CPI. This methodology conducted a multi-dimensional analysis of drugs' perturbation to the biological system, investigating both the off-targets and the associated off-systems to explore the molecular basis of an adverse event or the new uses for old drugs.

Topics: Agranulocytosis; Benzodiazepines; Biomarkers; Cell Line, Tumor; Clozapine; Computational Biology; Drug-Related Side Effects and Adverse Reactions; GABA Antagonists; HSP70 Heat-Shock Proteins; Humans; Olanzapine; Protein Interaction Mapping; Proteomics; Reactive Oxygen Species; Retrospective Studies; Risk Factors

Topics: Adolescent; Adult; Antipsychotic Agents; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Infant; Internet; Pertussis Vaccine; Safety; Seizures; Selective Serotonin Reuptake Inhibitors; Spasms, Infantile; Suicide

Previously published case reports have noted severe adverse reactions such as cardiac arrest, respiratory arrest, and sudden death when clozapine (CLZ) and benzodiazepines (BZDs) are used concomitantly. As CLZ and BZD are both used regularly to treat psychiatric illness, it is important to have additional information concerning this potential interaction. The objective of this study was to contribute to the evolving literature by evaluating the occurrence of sudden deaths and cardiac or respiratory events leading to death in patients treated concurrently with CLZ and BZD.. A retrospective chart review was conducted at a 240-bed New York State mental health facility. Most patients in this facility have been diagnosed with refractory schizophrenia, resulting in high rates of CLZ use. Electronic and hard copy records of the 490 patients who had been treated with CLZ in this facility at any time from 2001 to 2006 were selected, and the medication records of these patients were assessed for concomitant BZD use. Information on 152 patients who were treated with CLZ and a BZD concomitantly during this time period are included in this study. Data from the facility's mortality review committee were obtained to determine sudden deaths and cardiac or respiratory events leading to death in patients treated with CLZ and BZD concomitantly. Secondary parameters also recorded during the chart review included average duration of CLZ therapy, BZD therapy, and concomitant therapy; average doses of agents used; specific BZD used; number of patients treated with a specific BZD; psychiatric diagnosis; and use of other medications that depress the central nervous system.. No deaths occurred as a result of concomitant BZD and CLZ use in the sample examined in this study, suggesting that CLZ and BZD may be safely used concomitantly in many cases. Further study is needed to determine patient characteristics or predisposing factors that might put patients at higher risk of death from this interaction. Our findings are limited by the small sample size and suboptimal frequency of side effect measurements (e.g., measurements of blood pressure and heart rate, reports of hypotensive episodes). Confounding variables that might also play a role in interactions between CLZ and BZDs, but which were not measured in this study, include other types of respiratory compromise, cognitive dysfunction, and organ dysfunction. Precautionary measures that may be used when initiating concomitant CLZ and BZD therapy include slow titration of CLZ, blood pressure monitoring, and/or nightly pulse oximeter measurements.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Cross-Sectional Studies; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Heart Arrest; Humans; Male; Medical Records; Middle Aged; Respiratory Insufficiency; Retrospective Studies; Schizophrenia

The FDA's Spontaneous Reporting System (SRS) database contains over 1.5 million adverse drug reaction (ADR) reports for 8620 drugs/biologics that are listed for 1191 Coding Symbols for Thesaurus of Adverse Reaction (COSTAR) terms of adverse effects. We have linked the trade names of the drugs to 1861 generic names and retrieved molecular structures for each chemical to obtain a set of 1515 organic chemicals that are suitable for modeling with commercially available QSAR software packages. ADR report data for 631 of these compounds were extracted and pooled for the first five years that each drug was marketed. Patient exposure was estimated during this period using pharmaceutical shipping units obtained from IMS Health. Significant drug effects were identified using a Reporting Index (RI), where RI = (# ADR reports / # shipping units) x 1,000,000. MCASE/MC4PC software was used to identify the optimal conditions for defining a significant adverse effect finding. Results suggest that a significant effect in our database is characterized by > or = 4 ADR reports and > or = 20,000 shipping units during five years of marketing, and an RI > or = 4.0. Furthermore, for a test chemical to be evaluated as active it must contain a statistically significant molecular structural alert, called a decision alert, in two or more toxicologically related endpoints. We also report the use of a composite module, which pools observations from two or more toxicologically related COSTAR term endpoints to provide signal enhancement for detecting adverse effects.

Topics: Adverse Drug Reaction Reporting Systems; Artificial Intelligence; Computers; Databases, Factual; Drug Prescriptions; Drug-Related Side Effects and Adverse Reactions; Endpoint Determination; Models, Molecular; Quantitative Structure-Activity Relationship; Software; United States; United States Food and Drug Administration

The aim of this paper is to demonstrate the usefulness of the Bayesian Confidence Propagation Neural Network (BCPNN) in the detection of drug-specific and drug-group effects in the database of adverse drug reactions of the World Health Organization Programme for International Drug Monitoring.. Examples of drug-adverse reaction combinations highlighted by the BCPNN as quantitative associations were selected. The anatomical therapeutic chemical (ATC) group to which the drug belonged was then identified, and the information component (IC) was calculated for this ATC group and the adverse drug reaction (ADR). The IC of the ATC group with the ADR was then compared with the IC of the drug-ADR by plotting the change in IC and its 95% confidence limit over time for both.. The chosen examples show that the BCPNN data-mining approach can identify drug-specific as well as group effects. In the known examples that served as test cases, beta-blocking agents other than practolol are not associated with sclerosing peritonitis, but all angiotensin-converting enzyme inhibitors are associated with coughing, as are antihistamines with heart-rhythm disorders and antipsychotics with myocarditis. The recently identified association between antipsychotics and myocarditis remains even after consideration of concomitant medication.. The BCPNN can be used to improve the ability of a signal detection system to highlight group and drug-specific effects.

Topics: Adverse Drug Reaction Reporting Systems; Bayes Theorem; Captopril; Clozapine; Databases, Factual; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Humans; Information Storage and Retrieval; Pharmaceutical Preparations; Practolol; Terfenadine; World Health Organization

Cytochrome P450 expression in liver is influenced by several factors, including species, sex and strain. We compared metabolism formation of clozapine in different species (rat, mouse, guinea-pig, dog, monkey and man) so as to choose between species to further validate interaction studies. Liver microsomes of male and female Sprague-Dawley rats, hairless rats, OF1 mice, Balb C mice and Dunkin-Hartley albino guinea-pigs, male beagle dogs, male cynomolgus monkeys and man were used to investigate in vitro metabolism of clozapine. This process was dependent on the presence of NADPH and on the presence of microsome protein. In addition, we observed the formation of desmethyl- and N-oxide metabolites, with the rate of formation of each of these compounds varying with species, sex and strain of microsomes incubated. The desmethyl- and N-oxide metabolites formed were statistically greater in male than in female rats, mice in the two strains studied, as well as for the guinea-pigs. Levels of desmethyl clozapine formed were high for the rats and no significant difference in clozapine biotransformation was observed between Sprague-Dawley and hairless rats. For man, the formation of metabolites of clozapine was comparable with guinea-pig, dog and monkey. In addition, we screened the effect of 52 molecules, representative of 11 different therapeutic classes, on the metabolism of clozapine by rat liver microsomes. We found that most of the calcium channel blockers (diltiazem, felodipine, isradipine, lacidipine, nicardipine and nitrendipine), antifungals (ketoconazole, miconazole) and two anticancer drugs (paclitaxel, teniposide) caused more than 50% inhibition of clozapine metabolism in vitro. The extent of inhibition was increased in a concentration-dependant manner. Complementary clinical and pharmacokinetic studies should be performed to confirm these results.

Topics: Animals; Clozapine; Dogs; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Female; Guinea Pigs; Humans; Macaca fascicularis; Male; Mice; Mice, Inbred BALB C; Microsomes, Liver; NADP; Rats; Rats, Nude; Rats, Sprague-Dawley; Sex Factors; Species Specificity

...Arnold's article is very ambitious. He suggests rules that could be followed in order to decide whether health care should be rationed. He notes that explicit assessments of costs and benefits using the same monetary unit are rarely used. The main reason, it seems to me, is that the method of cost-benefit analysis is relatively difficult to apply in the context of health care. Arnold does not address the difficulties that are related to his approach. Thus, my impression is that the interest of his provocative article lies more in its ability to foster a useful debate than in the methodology itself. In this brief commentary, I will merely list some of the theoretical problems that occurred to me while reading this article....

Topics: Clozapine; Cost-Benefit Analysis; Decision Making; Decision Support Techniques; Delivery of Health Care; Drug-Related Side Effects and Adverse Reactions; Economics; Financial Support; Financing, Government; Health Care Rationing; Humans; Mentally Ill Persons; Patient Care; Psychotropic Drugs; Public Policy; Resource Allocation; Risk; Risk Assessment; Schizophrenia; Social Values; United States; Value of Life