clozapine and Agranulocytosis

Although clozapine is the most effective pharmacotherapy for treatment-resistant schizophrenia, it is under-utilized, and initiation is often delayed. One reason is the occurrence of a potentially fatal adverse reaction, clozapine-induced agranulocytosis (CIA). Identifying genetic variations contributing to CIA would help predict patient risk of developing CIA and personalize treatment. Here, we (1) review existing pharmacogenomic studies of CIA, and (2) conduct meta-analyses to identify targets for clinical implementation. A systematic literature search identified studies that included individuals receiving clozapine who developed CIA and controls who did not. Results showed that individuals carrying the HLA-DRB1*04:02 allele had nearly sixfold (95% CI 2.20-15.80, p

Topics: Agranulocytosis; Alleles; Antipsychotic Agents; Clozapine; Humans; Pharmacogenetics; Pharmacogenomic Testing

Clozapine (CLZ) is the superior drug in treatment of schizophrenia. Serum concentration of CLZ is associated with clinical response and dose-dependents side effects, where generalized tonic-clonic seizures are most critical. Thus, therapeutic drug monitoring (TDM) of CLZ may guide individual dosing to reach target exposure and prevent dose-dependent side effects. However, current TDM methods are not capable of predicting the risk of agranulocytosis, which is a dose-. The article provides an overview of clinical, pharmacological, and toxicological aspects of CLZ, and the role of TDM as a tool for dose titration and follow-up in patients with TRS. Main focus is on current challenges and strategies in CLZ TDM, including future perspectives on potential identification/analysis of CLZ metabolite biomarkers reflecting the risk of granulocyte toxicity.. The association between CLZ serum concentration, clinical response and risk of seizures is indisputable. TDM should therefore always guide CLZ dose titration. Development of advanced TDM methods, including biomarkers predicting the risk of granulocyte toxicity might extend TDM to be a tool for deciding which patients that can be treated safely with CLZ, potentially increasing its utility beyond TRS.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Monitoring; Drug Resistance; Humans; Schizophrenia; Seizures

Clozapine (CLZ) is an approved antipsychotic agent for the medication of treatment-resistant schizophrenia but is also well known as one of the most toxic antipsychotics. Recently, the World Health Organization's (WHO) global database (VigiBase) reported the relative lethality of severe adverse reactions of CLZ. Agranulocytosis is the most famous adverse CLZ reaction but is of lesser lethality compared with the other adverse drug reactions of CLZ. Unexpectedly, VigiBase indicated that the prevalence and relative lethality of pneumonia, cardiotoxicity, and seizures associated with CLZ were more serious than that of agranulocytosis. Therefore, haematological monitoring in CLZ patients monitoring system provided success in the prevention of lethal adverse events from CLZ-induced agranulocytosis. Hereafter, psychiatrists must amend the CLZ patients monitoring system to protect patients with treatment-resistant schizophrenia from severe adverse CLZ reactions, such as pneumonia, cardiotoxicity, and seizures, according to the clinical evidence and pathophysiology. In this review, we discuss the mechanisms of clinical efficacy and the adverse reactions of CLZ based on the accumulating pharmacodynamic findings of CLZ, including tripartite synaptic transmission, and we propose suggestions for amending the monitoring and medication of adverse CLZ reactions associated with pneumonia, cardiotoxicity, and seizures.

Topics: Agranulocytosis; Animals; Antipsychotic Agents; Cardiotoxicity; Clozapine; Connexin 43; Humans; Pneumonia; Schizophrenia; Seizures; Signal Transduction; Treatment Outcome

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

Clozapine is the only effective antipsychotic for treatment-resistant schizophrenia but remains widely under prescribed, at least in part due to its potential to cause agranulocytosis and neutropenia. In this article, we provide an overview of the current understanding of the genetics of clozapine-associated agranulocytosis and neutropenia. We now know that the genetic etiology of clozapine-associated neutropenia is complex and is likely to involve variants from several genes including HLA-DQB1, HLA-B and SLCO1B3/SLCO1B7. We describe recent findings relating to the Duffy-null genotype and its association with benign neutropenia in individuals with African ancestry. Further advances will come from sequencing studies, large, cross-population studies and in understanding the molecular mechanisms underlying these associations.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Genetic Association Studies; Genotype; HLA-B Antigens; HLA-DQ beta-Chains; Humans; Neutropenia; Schizophrenia; Solute Carrier Organic Anion Transporter Family Member 1B3

To identify the clinical determinants of fever in clozapine users and their impact on management of clozapine treatment.. Articles published in English or French identified with a MEDLINE, Web of Sciences, Cochrane Library and PsycINFO search, from inception through February 2019, using the term "clozapine" in combination with "fever" OR "hyperthermia" OR "body temperature" OR "pyrexia" OR "febrile" OR "heat" OR "thermoregulation". Information extracted for each medical condition were frequency, time to onset after initiation of clozapine treatment, characteristics of fever, associated symptoms, laboratory tests used for diagnosis, course, lethality, discontinuation of clozapine. Data were synthesized narratively.. Our search yielded 394 unique hits published from 1993 to 2018. We included 73 articles in the review: two meta-analyses, 14 reviews, six epidemiological studies, 11 clinical studies and 40 case reports. During clozapine initiation, fever is most frequently benign and transient but should be closely monitored as it may be the first stage of potentially life-threatening adverse drug reactions (ADR) (agranulocytosis, neuroleptic malignant syndrome myocarditis, hepatitis, pancreatitis, nephritis, colitis, etc.). Other ADR associated with fever are independent of duration of exposure to clozapine (heat stroke, pneumonia, pulmonary embolism, necrotizing colitis). If fever is due to intercurrent infection, therapeutic drug monitoring is recommended to adjust clozapine daily dosage.. Benign causes of fever are much more frequent than life-threatening ADR during clozapine treatment. Discontinuation should not be considered as automatic in the event of fever, especially during the early phase of clozapine initiation.

Topics: Agranulocytosis; Antipsychotic Agents; Chemical and Drug Induced Liver Injury; Clozapine; Colitis; Dose-Response Relationship, Drug; Drug Monitoring; Fever; Hepatitis; Humans; Infections; Lupus Erythematosus, Systemic; Myocarditis; Nephritis; Neuroleptic Malignant Syndrome; Pancreatitis; Pneumonia; Pulmonary Embolism; Schizophrenia; Serositis

Clozapine-induced agranulocytosis/granulocytopenia (CIAG) is an uncommon condition, but potentially fatal in consequences. The pathogenesis, despite multiple experiments, is not fully elucidated. The current theory suggests reactive oxygen species - nitrenium ion as the most important factor of CIAG. In this review, mechanism and monitoring of CIAG will be discussed.. The mechanism of CIAG seems to have an autoimmune background, rather than toxic. Clozapine has a high potential to undergo biochemical activation to nitrenium ion. The role of the primary metabolite of clozapine - N-desmethylclozapine - is in decline. Nitrenium ion is mainly synthesized by CYP3A4, CYP2D6, and myeloperoxidase system in leukocytes. An important component of CIAG pathogenesis is genetic aberration in human leukocyte antigen genes, and also genes associated with apoptosis and ubiquitination. Clozapine monitoring regimes differ between countries. US-derived clozapine Risk Evaluation and Mitigation Strategy is the most tolerant in the aspect of blood parameter thresholds. Therefore, it provides the opportunities for physician to continue the treatment and also to rechallenge the drug after the episode of CIAG.. Each patient with the episode of CIAG should be assessed individually, with special attention to risk factors and drug-drug interactions. Upon that, the decision about clozapine rechallenge or withdrawal should be made.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Humans

Clozapine is the first second generation antipsychotic with different receptor profile of action. Clozapine is the most efficacious drug for the treatment of psychotic disorder and is the drug of choice in treatment resistant schizophrenia. Clozapine is used in elderly patients infrequently owing to its adverse effects profile and tolerability. There is paucity of literature with respect to clozapine use in late life. In this narrative review, we discuss clozapine use in elderly and challenges associated with its use.

Topics: Aged; Aging; Agranulocytosis; Antipsychotic Agents; Cardiovascular Diseases; Clozapine; Cognitive Dysfunction; Humans; Metabolic Diseases; Schizophrenia; Seizures

To examine recent literature regarding the pharmacogenomics of clozapine (CLZ) efficacy, pharmacokinetics, and agranulocytosis.. Several genetic loci (FKBP5, NR3C1, BDNF, NTRK2) along the hypothalamic pituitary adrenal axis have been investigated as targets for CLZ response. Homozygous FKBP5-rs1360780, homozygous NTRK2-rs1778929, and homozygous NTRK2-rs10465180 conferred significant risks for CLZ nonresponse - 2.11x risk [95% confidence interval (CI) 1.22-3.64], 1.7x risk (95% CI 1.13-2.59), and 2.15x risk (95% CI 1.3-3.55), respectively. BDNF and NR3C1 had no significant associations with CLZ response. Candidate genes within neurotransmitter pathways continue to be explored including dopaminergic (DRD1-4, COMT) and glutamatergic pathways (GRIN2B, SLC1A2, SLC6A9, GRIA1, GAD1). Despite promising trending data, no significant associations between CLZ response and glutamatergic system variants have been found. Synergistic effect of catecholamine O-methyltransferase (COMT) Met and dopamine receptor-4 (DRD4) single 120 bp duplicate associated with improved CLZ response odds ratio (OR) 0.15 (95% CI 0.03-0.62) while COMT Val/Val confer a risk of CLZ nonresponse OR 4.34 (95% CI 0.98-23.9). Diagnostic performance testing continues through human leukocyte antigen (HLA) and other genetic loci but have yet to find statistically or clinically meaningful results.. Current landscape of pharmacogenomic research in CLZ continues to be limited by small sample sizes and low power. However, many promising candidate genes have been discovered and should be further investigated with larger cohorts.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Glycine Plasma Membrane Transport Proteins; Humans; Hypothalamo-Hypophyseal System; Membrane Glycoproteins; Pharmacogenetics; Pituitary-Adrenal System; Receptor, trkB; Receptors, Glucocorticoid; Schizophrenia; Tacrolimus Binding Proteins

Topics: Agranulocytosis; Clozapine; Drug Therapy, Combination; Humans; Lithium Compounds; Neutropenia; Psychotropic Drugs

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 associated with hematological abnormalities, notably neutropenia, which may progress to agranulocytosis. Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been used to reduce the frequency and duration of clozapine-associated neutropenia. This review aims to explore the use, efficacy, and tolerability of these cytokines in the treatment of clozapine-associated agranulocytosis.. We conducted a systematic review of published interventional and observational studies, case series, and case reports where G-CSF/GM-CSF was used to treat clozapine-associated agranulocytosis.. We identified 29 reports (40 patients). The median duration of neutrophil recovery time after stopping clozapine and starting cytokine treatment was 7 days (range, 2-13 days) for those with agranulocytosis (absolute neutrophil count < 0.5 × 10 cells/L). Ninety-four percent (n = 29) had no serious adverse reactions, and no deaths occurred.. Our findings indicate that G-CSF/GM-CSF use is well tolerated and suggest that G-CSF can sometimes be safely used to reduce the duration of neutropenia associated with clozapine use. However, the interpretation of this outcome is difficult, given the likely publication bias for positive outcomes in case reports.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Observational Studies as Topic

Schizophrenia and related disorders such as schizophreniform and schizoaffective disorder are serious mental illnesses characterised by profound disruptions in thinking and speech, emotional processes, behaviour and sense of self. Clozapine is useful in the treatment of schizophrenia and related disorders, particularly when other antipsychotic medications have failed. It improves positive symptoms (such as delusions and hallucinations) and negative symptoms (such as withdrawal and poverty of speech). However, it is unclear what dose of clozapine is most effective with the least side effects.. To compare the efficacy and tolerability of clozapine at different doses and to identify the optimal dose of clozapine in the treatment of schizophrenia, schizophreniform and schizoaffective disorders.. We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (August 2011 and 8 December 2016).. All relevant randomised controlled trials (RCTs), irrespective of blinding status or language, that compared the effects of clozapine at different doses in people with schizophrenia and related disorders, diagnosed by any criteria.. We independently inspected citations from the searches, identified relevant abstracts, obtained full articles of relevant abstracts, and classified trials as included or excluded. We included trials that met our inclusion criteria and reported useable data. For dichotomous data, we calculated the relative risk (RR) and the 95% confidence interval (CI) on an intention-to-treat basis based on a random-effects model. For continuous data, we calculated mean differences (MD) again based on a random-effects model. We assessed risk of bias for included studies and created 'Summary of findings' tables using GRADE.. We identified five studies that could be included. Each compared the effects of clozapine at very low dose (up to 149 mg/day), low dose (150 mg/day to 300 mg/day) and standard dose (301 mg/day to 600 mg/day). Four of the five included studies were based on a small number of participants. We rated all the evidence reported for the main outcomes of interest as low or very low quality. No data were available for the main outcomes of global state, service use or quality of life. Very low dose compared to low doseWe found no evidence of effect on mental state between low and very low doses of clozapine in terms of average Brief Psychiatric Rating Scale-Anchored (BPRS-A) endpoint score (1 RCT, n = 31, MD 3.55, 95% CI -4.50 to 11.60, very low quality evidence). One study found no difference between groups in body mass index (BMI) in the short term (1 RCT, n = 59, MD -0.10, 95% CI -0.95 to 0.75, low-quality evidence). Very low dose compared to standard doseWe found no evidence of effect on mental state between very low doses and standard doses of clozapine in terms of average BPRS-A endpoint score (1 RCT, n = 31, MD 6.67, 95% CI -2.09 to 15.43, very low quality evidence). One study found no difference between groups in BMI in the short term (1 RCT, n = 58, MD 0.10, 95% CI -0.76 to 0.96, low-quality evidence) Low dose compared to standard doseWe found no evidence of effect on mental state between low doses and standard doses of clozapine in terms of both clinician-assessed clinical improvement (2 RCTs, n = 141, RR 0.76, 95% CI 0.36 to 1.61, medium-quality evidence) and clinically important response as more than 30% change in BPRS score (1 RCT, n = 176, RR 0.93, 95% CI 0.78 to 1.10, medium-quality evidence). One study found no difference between groups in BMI in the short term (1 RCT, n = 57, MD 0.20, 95% CI -0.84 to 1.24, low-quality evidence).We found some evidence of effect for other adverse effect outcomes; however, the data were again limited. Very low dose compared to low doseThere was limited evidence that serum triglycerides were lower at low-dose clozapine compared to very low dose in the short term (1 RCT, n = 59, MD 1.00, 95% CI 0.51 to 1.49). Low dose compared to standard doseWeight gain was lower at very low dose compared to standard dose (1 RCT, n = 27, MD -2.70, 95% CI -5.38 to -0.02). Glucose level one hour after meal was also lower at very lose dose (1 RCT, n = 58, MD -1.60, 95% CI -2.90 to -0.30). Total cholesterol levels were higher at very low c. We found no evidence of effect on mental state between standard, low and very low dose regimes, but we did not identify any trials on high or very high doses of clozapine. BMI measurements were similar between groups in the short term, although weight gain was less at very low dose compared to standard dose in one study. There was limited evidence that the incidence of some adverse effects was greater at standard dose compared to lower dose regimes. We found very little useful data and the evidence available is generally of low or very low quality. More studies are needed to validate our findings and report on outcomes such as relapse, remission, social functioning, service utilisation, cost-effectiveness, satisfaction with care, and quality of life. There is a particular lack of medium- or long-term outcome data, and on dose regimes above the standard rate.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Humans; Psychotic Disorders; Schizophrenia

Topics: Agranulocytosis; Antipsychotic Agents; Asian People; Case-Control Studies; Chromosomes, Human, Pair 12; Clozapine; Genetic Predisposition to Disease; Humans; Japan; Polymorphism, Single Nucleotide

Clozapine was first introduced as an antipsychotic in the 1970's but a cluster of deaths, later linked to the drug's risk of agranulocytosis, led to its withdrawal in most countries. However, work in the 1980's established its unique efficacy in treatment resistant schizophrenia (TRS), which constitutes as many as 30% of those with the illness. Clozapine was reintroduced with this indication shortly thereafter, but because of this risk its use requires routine hematologic monitoring.. An update is provided regarding clozapine's risk of neutropenia, agranulocytosis, and associated mortality. In addition, updates are provided on other side effects, specifically myocarditis and bowel obstruction, as evidence suggests these are more common than agranulocytosis and associated with higher mortality rates.. Clozapine remains the only treatment indicated in TRS, but it is dramatically underutilized. Clearly there are serious side effects associated with its use, and while the focus has historically been on hematologic concerns, we highlight other side effects that also demand systematic monitoring. Because it is the only effective treatment option we have for TRS, though, efforts must be implemented that ensure its use in this population while maximizing safety.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Drug Monitoring; Drug Resistance; Humans; Neutropenia; Schizophrenia

To evaluate the epidemiology, pathobiology, and management of benign ethnic neutropenia and determine the extent to which these factors should influence measures designed to avoid clozapine-induced agranulocytosis.. A structured MEDLINE search with no language limitation was performed from database inception until March 31, 2015, using the terms clozapine and benign ethnic neutropenia. Retrieved articles were cross-checked for additional relevant studies.. Included in the study were articles that reported on the prevalence, etiology, and complications of benign ethnic neutropenia and the hematologic outcome of clozapine treatment in patients with this condition.. Study results that documented the epidemiology, pathobiology, and clozapine utilization in persons of African, Arabian, and Mediterranean descent with a neutrophil count in the 1,000-1,800/mm³ range.. The search identified 342 publications. Forty-two articles described the epidemiology, pathobiology, and management of benign ethnic neutropenia. Of these, 12 articles described patients with benign ethnic neutropenia whose neutrophil count decreased during treatment with clozapine. Persons with benign ethnic neutropenia do not have signs of impaired phagocytosis, and the frequency, severity, and outcome of their infections are similar to those observed in the general population. These features suggest that a neutrophil count > 1,000/mm³ is safe for initiating and/or resuming clozapine therapy.. The presence of benign ethnic neutropenia should not prevent treatment with clozapine. Patients with benign ethnic neutropenia who develop a clozapine-induced decrease in the neutrophil count, but have no evidence of infection or impaired phagocytosis, may resume clozapine as soon as they have > 1,000 neutrophils/mm³.

Topics: Agranulocytosis; Clozapine; Contraindications; Ethnicity; Humans; Leukocyte Count; Neutropenia; Neutrophils

Clozapine is effective for treatment-refractory schizophrenia, but it shows several severe and potentially life-threatening side effects such as agranulocytosis, myocarditis, and cardiomyopathy. Therefore, it is necessary to minimize the risk of clozapine and maximize its effectiveness by monitoring of safety. White blood cell monitoring is mandatory in many countries, but the clozaril patient monitoring service (CPMS) in Japan additionally requires blood sugar monitoring for adverse metabolic events. Aside from the side effects described above, clozapine can cause various adverse events including constipation, paralytic ileus, seizure, orthostatic hypotension, syncope, hypersalivation, aspiration pneumonia, and oversedation. Consequently, it is important to conduct safety monitoring other than CPMS-based in routine clinical settings. Regarding CPMS as one model for safety monitoring, herein we discuss how to monitor the side effects induced by psychotropic agents. Although the choice of monitoring method depends on which drug is used, routine monitoring of parameters such as serum drug concentration, full blood count, biochemistry test, ECG, EEG, chest and abdominal X-P, body weight, body temperature, pulse, and blood pressure is necessary for early detection and prevention of severe adverse events. Further examinations are necessary to reach consensus on how often monitoring is required. Psychiatrists must devote more attention not only to multidimensional psychiatric symptoms but also to physical conditions. Psychiatrists can show themselves at their best in holistic medical care only by administering balanced psychiatric and physical examinations.

Topics: Agranulocytosis; Clozapine; Drug Monitoring; Humans; Japan; Psychotropic Drugs; Schizophrenia

Clozapine is a drug used in the management of treatment-resistant schizophrenia. Numerous clinical trials, including randomized double-blind clinical trials and large cohort studies, have revealed that clozapine is more effective than any other antipsychotic drugs. However, the same studies have also shown that this drug has several adverse effects such as an agranulocytosis. Therefore, in Japan, clozapine is approved for administration to only patients with treatment-resistant schizophrenia in whom treatment with other antipsychotic drugs was ineffective. Clozapine is prescribed only at approved institutes that are under the registration called Clozaril Patient Monitoring Service (CPMS), and white blood cell counts and prescription dosage of clozapine are strictly monitored under this service.

Topics: Agranulocytosis; Antipsychotic Agents; Brain Waves; Clozapine; Humans; Japan; Leukocyte Count; Schizophrenia

Clozapine is often referred to as the gold standard for the treatment of schizophrenia and yet has also been described as the most underutilized treatment for schizophrenia supported by solid evidence-based medicine. In 2008, it was used to treat only 4.4% of patients with schizophrenia in the U.S., which is ~10-20% of those with approved indications for clozapine for which there is no alternative of equal efficacy. Its use is much higher in Scandinavian countries and China. The primary indications for clozapine are: 1) treatment-resistant schizophrenia or schizoaffective disorder, defined as persistent moderate to severe delusions or hallucinations despite two or more clinical trials with other antipsychotic drugs; and, 2) patients with schizophrenia or schizoaffective disorder who are at high risk for suicide. Concerns over a number of safety considerations are responsible for much of the underutilization of clozapine: 1) agranulocytosis; 2) metabolic side effects; and, 3) myocarditis. These side effects can be detected, prevented, minimized and treated, but there will be a very small number of fatalities. Nevertheless, clozapine has been found in two large epidemiologic studies to have the lowest mortality of any antipsychotic drug, mainly due to its very large effect to reduce the risk for suicide. Other reasons for limited use of clozapine include the extra effort entailed in monitoring white blood cell counts to detect granulocytopenia or agranulocytosis and, possibly, minimal efforts to market it now that it is largely generic. Awareness of the benefits and risks of clozapine is essential for increasing the use of this lifesaving agent.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Humans; Metabolic Diseases; Myocarditis; Risk Factors; Schizophrenia

Clozapine is the preferred option for treatment-resistant schizophrenia. However, since 1975, clozapine has been known to cause agranulocytosis. In the clozapine screening guidelines, white blood cell count is mandatory. In the past 20 years, after its reintroduction, 3 other serious side effects, namely, diabetic ketoacidosis, gastrointestinal hypomotility, and myocarditis have been documented but have so far failed to be incorporated in the screening guidelines. The objective of this review is to determine whether an update of the screening guidelines for serious side effects with clozapine is evidence based.. The English-language literature, available via MEDLINE or PubMed, on the incidence of 4 clozapine-related side effects, using clozapine, agranulocytosis, diabetic ketoacidosis, and gastrointestinal hypomotility as keywords, that have been published over the period 1976-2010, was collected.. 16 studies that provided incidence rates or data from which these rates could be calculated were included.. We compared 1-year incidence rates, mortality rates in the whole study population and in the affected cases. When rates reflected longer periods of observation, the given rate was recalculated to obtain a 1-year incidence rate.. The incidence of clozapine-induced agranulocytosis varies between 3.8‰-8.0‰. The mortality rate is 0.1‰-0.3‰, and the case-fatality rate is 2.2‰-4.2‰. In diabetic ketoacidosis, the incidence was calculated at 1.2‰-3.1‰, and the case-fatality rate was 20%-31%. In gastrointestinal hypomotility, the incidence was 4‰-8‰, and the case-fatality rate was 15%-27.5%. The discrepancy in incidence rates between Australia (7‰-34‰) and the rest of the world (0.07‰-0.6‰) impairs a general approach of this side effect.. In 2 of the 3 studied side effects, diabetic ketoacidosis and gastrointestinal hypomotility, reduction of mortality to the level of agranulocytosis is both necessary and feasible. In order to obtain this outcome, the screening guidelines need to be modified; early detection of treatment-emergent hyperglycemia, that might-via diabetes mellitus-develop into diabetic ketoacidosis, requires obligatory monthly measurement of fasting plasma glucose. To prevent gastrohypomotility, and complications therefrom, the clinician should be required to choose between either weekly monitoring or standard coprescription of laxatives for prevention. The reported incidence of myocarditis (high in Australia, low in the rest of the world) is too divergent to allow for an overall recommendation outside Australia.

Topics: Agranulocytosis; Clozapine; Constipation; Diabetic Ketoacidosis; Humans; Incidence; Leukocyte Count; Mass Screening; Myocarditis; Practice Guidelines as Topic

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

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

Clozapine is associated with various haematological adverse effects, including leukopenia, neutropenia, agarnulocytosis, leukocytosis, anaemia, eosinophilia, thrombocytopenia and thrombocythaemia. Recognition and treatment of clozapine-related seizures also will become increasingly important as clozapine use grows in the 1990s. The decision to stop clozapine as a result of haematological adverse effects or seizures is a frustrating one for the clinician, and frequently disastrous for the patient. Cessation of treatment results in relapse. In case that patient is unresponsive to other antipsychotic, restarting clozapine should be consider, despite the risk involved. As the risk of a second agranulocytosis is much higher in those patients, various methods of militating against repeat blood dyscrasias have been treated, including granulocyte colony-stimulating factor and lithium. The decision to restart clozapine should be taken on case-by-case basis and should take into account the likely risks and benefits of restarting. Prior response to clozapine and magnitude of patient deterioration on stopping treatment are important factors to take into this consideration. Clozapine-related seizures did not preclude successful treatment with clozapine. A strategy that has been proposed to reduce the occurrence of seizures is the addition of an anticonvulsant agent. However, clozapine does induce a variety of adverse effects, most of which are of limited duration and either preventable or manageable if a number of simple clinical procedures are followed. With careful haematologyc control, the risk of agranulocytosis can be minimized and in case of clozapine related seizures recommendations include dose reduction, electroencephalogram (EEG), plasma-level monitoring and prophylactic antiepileptic treatment. Re-exposure to clozapine may rarely be attempted where there are facilities for very close and frequent monitoring.

Topics: Adult; Agranulocytosis; Anticonvulsants; Antimanic Agents; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epilepsy; Female; Humans; Leukopenia; Lithium Carbonate; Psychotic Disorders; Recurrence; Risk Factors; Schizophrenia; Substance Withdrawal Syndrome; Thrombocytopenia

To review clozapine's position in treatment algorithms for schizophrenia.. Clozapine's status is reviewed in the context of its initial discovery and unique clinical and (or) pharmacological profile, withdrawal and link with hematologic concerns, reintroduction with monitoring guidelines, prototype for atypicality, positioning in treatment algorithms, and current evidence regarding efficacy, effectiveness, and side effects.. The hematologic monitoring implemented with clozapine's reintroduction here in North America has proven successful in preventing clozapine-related deaths secondary to agranulocytosis. While its other side effects are not without concern, present evidence does not link clozapine to increased mortality rates; indeed, it appears better than other antipsychotics in this regard. Moreover, its clinical superiority compared with all other antipsychotics has been confirmed both in efficacy and in effectiveness trials.. Schizophrenia continues to represent a treatment challenge, with many people demonstrating suboptimal response and poor functional outcome. Clozapine is routinely positioned as a third-line treatment in schizophrenia, but in light of existing evidence this warrants re-examination.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Cost-Benefit Analysis; Drug Monitoring; Humans; North America; Schizophrenia; Treatment Outcome

Clozapine-induced agranulocytosis (CiA) is a potentially life-threatening pharmacological adverse drug reaction, which limits a broader application of this highly effective atypical antipsychotic in schizophrenic patients. Although this adverse reaction has been well known for almost 30 years, only few genetically based determinants can be identified to date. Furthermore, owing to rare occurrence, specific clinical course and complexity of pathomechanisms of antipsychotic-induced agranulocytosis, only a few of the findings met the criteria of replication. The most promising susceptibility genes for CiA include genes involved in the human leukocyte antigen system and in specific metabolizing enzyme systems. However, complex idiosyncratic drug reactions such as CiA are considered to be determined by multiple, possibly interacting genetic variations, rather than by a single causative variant.

Topics: Agranulocytosis; Animals; Clozapine; Genetic Linkage; Genetic Variation; Humans; Psychotic Disorders

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

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

Clozapine is an atypical antipsychotic with superior efficacy in the treatment of refractory schizophrenia. But it can cause agranulocytosis, which occurs in one to two percent of patients. This paper was prepared to discuss the condoned and controversial issues of therapy with this drug, but only within a haematological context. The feasibility of attempting therapeutically controversial blood monitoring regimes, as opposed to following standardised Western guidelines, given the differences in terms of accessibility, convenience and financial considerations between the public and private sector medical care will also be discussed. The proposal of adopting a structured pro forma, with a risk-benefit assessment, in the event of unavoidable veering from the guidelines may allay medicolegal implications, especially in countries where blood monitoring is not mandatory. It is hoped that this article will stimulate further research in our region, bearing in mind the increasing awareness and focus on genetic polymorphism, and the possibility of drawing up our own monitoring guidelines in the near future.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Developing Countries; Drug Monitoring; Humans; Liability, Legal; Patient Education as Topic; Practice Guidelines as Topic; Schizophrenia

Clozapine remains the antipsychotic of choice for refractory schizophrenia despite its propensity for serious blood disorders. When neutropenia or agranulocytosis occur in people taking clozapine, cessation of treatment is mandated and relapse often results. Because such patients are usually unresponsive to other antipsychotics, many clinicians consider restarting clozapine, despite the risks involved. However, the risks of clozapine rechallenge vary according to the cause and nature of the blood dyscrasia. Neutropenia can arise because of factors unrelated or indirectly related to clozapine treatment. These include benign ethnic neutropenia, concomitant drug therapy, co-existing medical conditions and drug interactions. In such cases, clozapine may be restarted if non-clozapine causes of neutropenia are identified and eliminated, although concurrent treatment with lithium (to induce leukocytosis) is sometimes necessary. Close monitoring of the patient is essential because it is rarely possible to completely rule out the contribution of clozapine to the blood dyscrasia and because lithium does not protect against clozapine-related agranulocytosis. In cases of clozapine-induced neutropenia (as distinct from agranulocytosis, which may have a different pathology) rechallenge may also be considered and, again, lithium co-therapy may be required. Where clozapine is clearly the cause of agranulocytosis, rechallenge should not be considered or undertaken unless there are very exceptional circumstances (severe and prolonged relapse following clozapine discontinuation). In these cases, re-exposure to clozapine may rarely be attempted where there are facilities for very close and frequent monitoring. Granulocyte colony-stimulating factor is likely to be required as co-therapy, given the very high likelihood of recurrence. Uncertainty over the likely cause of blood dyscrasia in people taking clozapine, coupled with uncertainty over the mechanism by which clozapine causes both neutropenia and agranulocytosis, makes any attempt to restart clozapine a high-risk venture requiring the utmost caution.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Cytokines; Drug Administration Schedule; Humans; Neutropenia; Schisandra

Clozapine is an important antipsychotic agent that has a unique profile of clinical benefits, but that has also been associated with several serious and potentially life-threatening safety concerns. In order to minimise the impact of haematological adverse events, health professionals treating patients with clozapine are currently required to register their patients on a centrally administered data network and to conform to strict protocols. The consensus statement documented in this article extends existing protocols by recommending monitoring of patients treated with clozapine for additional adverse effects during treatment. This consensus statement reflects the current practice at five major public psychiatric hospitals in Victoria, Australia, for the monitoring and management of clozapine-related adverse events, and has been implemented at these sites because of emerging safety concerns associating clozapine with cardiovascular and metabolic adverse effects.

Topics: Agranulocytosis; Antipsychotic Agents; Australia; Clozapine; Consensus; Diabetes Mellitus; Humans; Hyperlipidemias; Neutropenia; Population Surveillance; Psychotic Disorders; Weight Gain

Clozapine, an atypical antipsychotic used in the treatment of refractory schizophrenia, causes agranulocytosis in 0.8% of patients. The risk factors for clozapine-induced agranulocytosis (CIA) and the underlying mechanisms are unclear.. To ascertain the genetic and immunological risk factors for CIA, and on the basis of these findings to construct an explanatory model for CIA.. We reviewed the literature via Medline (from 1966 to May 2004) and EMBASE (from 1980 to May 2004) using the search terms 'clozapine' and 'agranulocytosis'.. We found 8 case-control studies that fulfilled our selection criteria. In schizophrenia patients, CIA appeared to be significantly associated with certain haplotypes of HLA (human leukocyte antigens) genes, with the 4b,3d microsatellite alleles of TNF (tumor necrosis factor), with variant genes of HSP 70 (heat-shock protein), and with NQO2 (dihydronicotinamide riboside quinone oxidoreductase) gene polymorphism. Most of these genetic findings are interrelated. Gene abnormalities of this kind probably play an important aetiological role in CIA and may provide a basis for the construction of an immuno-toxic explanatory model for CIA.. It seems likely that CIA can be explained on the basis of genetic and immunotoxic factors. The model should help us to understand how agranulocytosis can be caused by various antipsychotics and how it can be treated. However, it is not yet possible to identify patients who are particularly at risk for CIA.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Genetic Predisposition to Disease; HLA Antigens; Humans; Major Histocompatibility Complex; Risk Factors; Schizophrenia

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Drug Monitoring; Drug Utilization; Evidence-Based Medicine; Humans; Practice Patterns, Physicians'; Risk Factors; Schizophrenia; Schizophrenic Psychology; Suicide; Suicide Prevention; United States

Haematological abnormalities are frequently encountered during treatment with antipsychotic drugs. Most of these are mild and of no clinical significance. In the case of many, there is often difficulty in establishing a cause-and-effect relationship between the drug and the abnormality. However, in a small minority of patients, hazardous, potentially life-threatening haematological effects can occur due to a combination of pharmacological and host factors. These include leucopenia and agranulocytosis. Although such effects are rare, it is essential that they are diagnosed and managed promptly. In this paper, the authors review the haematological adverse effects and safety of antipsychotic drugs and present a strategy for prevention.

Topics: Agranulocytosis; Anemia, Aplastic; Antipsychotic Agents; Clozapine; Hematologic Diseases; Humans; Leukopenia

Antidepressants and antipsychotics are frequently used as mood stabilizers in the treatment of bipolar disorder. As common as these agents appear to be in bipolar treatment, the literature contains little research on their efficacy and safety in the long term. Most of the available literature on long-term antidepressant treatment focuses on tricyclic antidepressants, which have been shown to induce mania or hypomania. Rapid cycling is another side effect that is associated with antidepressant treatment in bipolar disorder. Antidepressants do not appear to be any more effective than mood stabilizers in treating bipolar depression. Conventional antipsychotics in depot formulations have been shown to be an effective treatment, but conventional antipsychotics may cause tardive dyskinesia. The novel antipsychotics clozapine, risperidone, and olanzapine appear to be efficacious; however, their side effect profiles include agranulocytosis and weight gain. Given the frequency with which antidepressants and antipsychotics are used in bipolar disorder and that bipolar disorder is a chronic disease requiring maintenance treatment, more research on the use of these types of agents in long-term treatment is needed. Until more evidence is available on the long-term treatment outcomes, clinicians should be aware that the adverse events associated with antidepressants and antipsychotics may outweigh the benefit, if any, of the use of these agents in bipolar disorder.

Topics: Agranulocytosis; Antidepressive Agents; Antipsychotic Agents; Bipolar Disorder; Clinical Trials as Topic; Clozapine; Delayed-Action Preparations; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Humans; Long-Term Care; Treatment Outcome; Weight Gain

Clozapine is a dibenzodiazepine derivative and a truly atypical anti-psychotic. Its therapeutic effects are probably mediated by dopaminergic and serotonergic activity. Although it appears to be the most effective antipsychotic drug for treatment-resistant schizophrenia, its general use is limited because of the risk of agranulocytosis.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Drug Interactions; Humans; Schizophrenia

Four new antipsychotic medications--clozapine, risperidone, olanzapine, and quetiapine--have been introduced in the United States during the past decade. These new medications now account for the majority of antipsychotic prescriptions. The author reviews specific issues related to the use of traditional antipsychotic medications and then highlights the emerging clinical research data regarding the new medications, which have all been shown to be efficacious in the treatment of schizophrenia. Clinical research data indicate that they are also more useful for a broader array of symptoms associated with schizophrenia than traditional compounds. Furthermore, movement disorder side effects are substantially decreased--a property that leads to higher acceptability. Surprisingly, there has been little relationship between the pivotal trials designed for FDA approval and current dosing strategies in broader clinical settings. These dosing issues are described. New uses, including treatment of mood disorders and conduct disorder, are also discussed. These medicines offer substantial hope for improved treatment of schizophrenia.

Topics: Agranulocytosis; Akathisia, Drug-Induced; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Humans; Olanzapine; Pirenzepine; Prolactin; Quetiapine Fumarate; Risperidone; Schizophrenia

Clozapine has demonstrated superior efficacy in relieving positive and negative symptoms in treatment-resistant schizophrenic patients; unlike other antipsychotics, it causes minimal extrapyramidal side effects (EPS) and has little effect on serum prolactin. Despite these benefits, the use of clozapine has been limited because of infrequent but serious side effects, the most notable being agranulocytosis. In recent years, however, mandatory blood monitoring has significantly reduced both the incidence of agranulocytosis and its associated mortality. The occurrence of seizures appears to be dose-related and can generally be managed by reduction in clozapine dosage. Less serious and more common side effects of clozapine including sedation, hypersalivation, tachycardia, hypotension, hypertension, weight gain, constipation, urinary incontinence, and fever can often be managed medically and are generally tolerated by the patient. Appropriate management of clozapine side effects facilitates a maximization of the benefits of clozapine treatment, and physicians and patients alike should be aware that there is a range of benefits to clozapine use that is wider than its risks.

Topics: Agranulocytosis; Antipsychotic Agents; Cardiovascular Diseases; Clozapine; Drug Monitoring; Humans; Respiration Disorders; Seizures; Sialorrhea; Weight Gain

Topics: Agranulocytosis; Clozapine; Female; Humans; Incidence; Israel; Male; Risk Assessment; Sampling Studies; Schizophrenia

Compliance with conventional antipsychotic medication is often poor, with many patients discontinuing treatment only a few months after commencing therapy. The side effects of treatment, which are not necessarily restricted solely to motor symptoms, are often considered to be responsible for this noncompliance. In contrast to conventional antipsychotics, clozapine is associated with only minimal extrapyramidal symptoms, and in most patients, its use results in significant improvements in compliance. However, clozapine does induce a variety of adverse effects, most of which are of limited duration and either preventable or manageable if a number of simple clinical procedures are followed. Clozapine therapy is associated with a beneficial risk/benefit ratio in the majority of treatment-resistant schizophrenic patients. With careful hematologic control, the risk of agranulocytosis can be minimized. The marked increase in the well-being of patients receiving clozapine should stimulate psychiatrists to broaden its use and not limit it to severely treatment-resistant individuals.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Drug Administration Schedule; Drug Resistance; Drug Therapy, Combination; Electroencephalography; Fatigue; Humans; Patient Compliance; Risk Assessment; Schizophrenia; Schizophrenic Psychology; Seizures; Sialorrhea; Tachycardia; Treatment Outcome

Clozapine represents the "gold standard" therapy for treatment-resistant schizophrenia including use for symptom reduction and use in patients intolerant of extrapyramidal side effects associated with other antipsychotics. Despite its clear benefit in these areas, its use has been associated with a serious, and sometimes life-threatening, risk for agranulocytosis. Effective white blood cell monitoring systems have been developed by Novartis affiliates across the world to ensure its safe use and to meet local health standards. The goals of the monitoring programs include: (1) weekly white blood cell monitoring during the initial months of therapy for early detection of severe leukopenia; (2) immediate discontinuation of clozapine if severe leukopenia is observed; (3) exclusion from reexposure to clozapine if a patient experiences clozapine-induced agranulocytosis; and (4) early cessation of treatment if hematologic guidelines are not followed ("no blood, no drug" policy). Together, these systems have demonstrated a worldwide reduction in the observed rate of agranulocytosis and in fatalities related to the emergence of agranulocytosis when rigorous monitoring systems are in place.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Drug Monitoring; Drug Resistance; Humans; Leukocyte Count; Leukopenia; Risk Factors; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

The Clozaril National Registry (CNR) was created to help protect patients from developing potentially fatal agranulocytosis secondary to treatment with the antipsychotic medicine clozapine. The CNR, designed and maintained by the manufacturer of the branded Clozaril (clozapine), has the principal goals of (1) prophylaxis-preventing inappropriate retreatment, and (2) quality assurance-overseeing adherence to a "no blood, no drug" policy. This article reviews the estimated impact of the CNR on clozapine-related morbidity and mortality over the first 5 years of commercial experience in the United States.. Complete data on leukopenia and agranulocytosis, gathered from the CNR database for the period of 1990-1994, were reviewed and compared with data from the pre-CNR period.. Use of clozapine in 99,502 patients according to package labeling requirements (distribution of the medicine linked to mandated white blood cell count testing) was associated with a total of 382 cases of agranulocytosis (0.38%) versus an expected cumulative total of 995 cases (based on the pre-CNR rate of 1% to 2%). Based on the expected agranulocytosis rate, up to 149 deaths might have been anticipated. Instead, there were only 12 deaths attributed to complications of agranulocytosis.. The CNR provides for universal rechallenge protection as well as controlled dispensing of clozapine. It also serves as an early warning system to promote the safe and effective use of clozapine. The CNR includes quality assurance mechanisms designed to enhance compliance. Despite the added logistic requirements this system places upon physician, pharmacist, and manufacturer, the CNR has helped to reduce substantially potential fatal outcomes. The CNR reinforces both patient and treatment system compliance. Based on this favorable experience concerning agranulocytosis and associated fatalities, the Neuropsychopharmacology Advisory Committee to the U.S. Food and Drug Administration has unanimously recommended a reduction in frequency of the white blood cell count testing requirement after 6 months to every 14 days, instead of weekly. Finally, the CNR database containing white blood cell count and demographic data on every patient in the United States who has received the medicine has served as a unique epidemiologic database.

Topics: Adverse Drug Reaction Reporting Systems; Agranulocytosis; Clozapine; Databases, Factual; Drug Approval; Drug Information Services; Humans; Leukocyte Count; Leukopenia; Registries; Schizophrenia; United States

Suicide is the major cause of premature death in patients with schizophrenia. Among these patients, 40% report suicidal thoughts, 20% to 40% make unsuccessful suicide attempts, and 9% to 13% end their lives by suicide. Traditional antipsychotic drugs undertreat many schizophrenic patients and can produce serious side effects, such as tardive dyskinesia. Clozapine is the only antipsychotic drug that has been shown in controlled clinical trials to be effective in reducing both positive and negative symptoms in schizophrenic patients who fail to respond to typical neuroleptic drugs. The potential decrease in suicide among schizophrenic patients treated with clozapine is estimated to be as high as 85%. Treatment with clozapine is cost-effective, and the significant decrease in the risk of suicide far outweighs the very low risk of mortality from agranulocytosis. Clozapine should be considered for treatment of both neuroleptic-resistant and neuroleptic-responsive schizophrenic patients who have persistent suicidal thoughts or behavior.

Topics: Adult; Aged; Agranulocytosis; Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Cost-Benefit Analysis; Dyskinesia, Drug-Induced; Female; Humans; Infant, Newborn; Male; Middle Aged; Risk Assessment; Risk Factors; Schizophrenia; Schizophrenic Psychology; Suicide; Suicide Prevention

Since its introduction to the United States in 1990, the benefits of clozapine use have been repeatedly validated. Clozapine remains the only antipsychotic with proven efficacy in treatment-resistant schizophrenia. Because clozapine has been part of the psychiatric pharmacopeia for considerably less time than neuroleptics, which have dominated the field for over 4 decades, its underutilization may be partly attributed to a lack of experience in managing associated side effects. Most side effects associated with clozapine are typical of antipsychotics in general, and with clozapine, these side effects are typically benign, tolerable, and manageable. It is conceivable that there remains a concern over the risk of agranulocytosis. However, the mandatory blood monitoring carried out through the Clozaril National Registry has considerably reduced the incidence of fully developed cases of agranulocytosis from premarketing values of approximately 1% to 2% to current values of 0.38% and virtually prevented mortalities. These values are likely to decrease further with the application of cytokine augmentation therapy among patients developing blood dyscrasias. Many side effects of clozapine are observed early after treatment onset and are greatly reduced by dose adjustments. Appropriate management of side effects will facilitate a maximization of the benefits of clozapine treatment. Clearly, the benefits of clozapine therapy far outweigh its risks.

Topics: Agranulocytosis; Antipsychotic Agents; Basal Ganglia Diseases; Chemical and Drug Induced Liver Injury; Clozapine; Drug Administration Schedule; Drug Monitoring; Humans; Incidence; Risk Factors; Schizophrenia; Sleep Wake Disorders; Tachycardia; Urinary Incontinence; Weight Gain

Clozapine has been found to be superior to traditional neuroleptics in the treatment of refractory schizophrenia and is increasingly being used to treat schizophrenia, affective disorders, some neurological disorders, and aggression. For many patients, clozapine offers new hope for the successful pharmacological management of a disabling mental disorder. However, up to 17 percent of patients must discontinue treatment with clozapine because of adverse effects, which also limit the rate at which the dose can be increased and the maximum dose that can be tolerated. This article reviews strategies for minimizing and managing the adverse effects of clozapine, including agranulocytosis, seizures, sedation, delirium, obsessive-compulsive symptoms, hypotension, tachycardia, weight gain, sialorrhea, elevated liver enzymes, constipation, nausea, enuresis, fever, and neuromuscular effects. Incidence and morbidity are presented first. Then, the known or hypothesized pathophysiology of the adverse effects are described. Finally, nonpharmacological and pharmacological interventions are reviewed. Under-standing the incidence, pathophysiology, and treatments of adverse effects is essential for a positive therapeutic outcome when prescribing clozapine.

Topics: Agranulocytosis; Antipsychotic Agents; Cardiovascular Diseases; Central Nervous System Diseases; Clozapine; Drug Administration Schedule; Dyskinesia, Drug-Induced; Gastrointestinal Diseases; Humans; Schizophrenia

Adverse effects of antipsychotics often lead to noncompliance. Thus, clinicians should address patients' concerns about adverse effects and attempt to choose medications that will improve their patients' quality of life as well as overall health. The side effect profiles of the atypical antipsychotics are more advantageous than those of the conventional neuroleptics. Conventional agents are associated with unwanted central nervous system effects, including extrapyramidal symptoms (EPS), tardive dyskinesia, sedation, and possible impairment of some cognitive measures, as well as cardiac effects, orthostatic hypotension, hepatic changes, anticholinergic side effects, sexual dysfunction, and weight gain. The newer atypical agents have a lower risk of EPS, but are associated in varying degrees with sedation, cardiovascular effects, anticholinergic effects, weight gain, sexual dysfunction, hepatic effects, lowered seizure threshold (primarily clozapine), and agranulocytosis (clozapine only). Since the incidence and severity of specific adverse effects differ among the various atypicals, the clinician should carefully consider which side effects are most likely to lead to the individual's dissatisfaction and noncompliance before choosing an antipsychotic for a particular patient.

Topics: Agranulocytosis; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Central Nervous System Diseases; Clozapine; Dibenzothiazepines; Drug Interactions; Dyskinesia, Drug-Induced; Health Status; Humans; Hypotension, Orthostatic; Olanzapine; Pirenzepine; Quality of Life; Quetiapine Fumarate; Receptors, Cholinergic; Risperidone; Schizophrenia; Sexual Dysfunctions, Psychological; Sleep Wake Disorders; Treatment Refusal; Weight Gain

To report and review the use of cytokines for the treatment of clozapine-induced neutropenia.. Case report and review of literature.. Cytokines, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), appear to shorten the duration of clozapine-induced neutropenia.. G-CSF or GM-CSF therapy should be considered in patients with profound neutropenia of prolonged duration (high-risk neutropenia).

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Granulocyte Colony-Stimulating Factor; Granulocytes; Humans; Injections, Subcutaneous; Leukocyte Count; Male; Neutropenia; Schizophrenia; Schizophrenic Psychology

Central to most hypotheses of the mechanism of idiosyncratic drug-induced blood dyscrasias is the involvement of reactive metabolites. In view of the reactive nature of the majority of such metabolites, it is likely that they are formed by, or in close proximity to the blood cells affected. The major oxidative system of neutrophils generates hypochlorous acid. We have demonstrated that the drugs associated with the highest incidence of agranulocytosis are oxidized to reactive metabolites by hypochlorous acid and/or activated neutrophils. There are many mechanisms by which such reactive metabolites could induce agranulocytosis. In the case of aminopyrine-induced agranulocytosis, most cases appear to involve drug-dependent anti-neutrophil antibodies, and these are likely to be induced by cell membrane antigens modified by the reactive metabolite of aminopyrine. The target of agranulocytosis associated with many other drugs is usually neutrophil precursors and may involve cytotoxicity or a cell-mediated immune reaction induced by a reactive metabolite. In the case of aplastic anaemia, there is evidence in some cases for involvement of cytotoxic T cells, which could either be induced by metabolites generated by neutrophils, or more likely, by reactive metabolites generated by stem cells.

Topics: Agranulocytosis; Aminopyrine; Clozapine; Humans; Hypochlorous Acid; Neutrophil Activation

Clozapine, an atypical antipsychotic medication, is the most significant pharmacological advancement in the treatment of chronic schizophrenia in years. Effective in treating the nearly 30 percent of people with schizophrenia who do not respond to conventional pharmacological and psychosocial therapies, clozapine offers new hope to many. However, high cost, a potentially lethal side effect, and a weekly mandatory monitoring system have hampered access to clozapine treatment. This article reviews a brief history of clozapine use in the United States and also the unique features of the medication. Economic, ethical, and personnel resource issues of clozapine use are summarized. The author describes her clinical experiences with the psychosocial issues faced by those who respond to clozapine treatment, case highlights, and social work interventions. Social work advocacy for increased access to clozapine, the potential contributions of social workers in the selection of patients for treatment, and the logistical management issues confronting social workers in inpatient and outpatient mental health settings are addressed.

Topics: Agranulocytosis; Clozapine; Drug Monitoring; Health Care Rationing; Humans; Patient Advocacy; Schizophrenia; United States

In four patients, a woman aged 85 and three men aged 33, 42 and 70 years, clozapine-induced agranulocytosis was diagnosed. In three patients the white cell counts were not performed as they should have been. Two patients were treated for their agranulocytosis with granulocyte colony-stimulating factor (G-CSF; filgrastim). Two patients were not treated. The literature concerning clozapine-induced agranulocytosis and its treatment with growth factors consists of only a few case reports. Therefore a definite conclusion about the efficacy of the treatment for this particular indication is not yet possible.

Topics: Adult; Aged; Aged, 80 and over; Agranulocytosis; Antipsychotic Agents; Clozapine; Female; Granulocyte Colony-Stimulating Factor; Humans; Male; Time Factors

Topics: Agranulocytosis; Clozapine; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans

The agranulocytosis associated with clozapine is, indeed, a serious medical disorder. Patients experience prolonged and profound severe granulocytopenia--often with absolute neutrophil counts of less than 100/cu mm. Patients suffer neutropenic sepsis and often are as sick as patients undergoing induction chemotherapy for lymphoma or leukemia. Thus, it is important to evaluate the state-of-the-art management of such patients and to define the role of growth factors such as granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Early use of G-CSF or GM-CSF can shorten the duration of granulocytopenia from a mean of 16 to 8 days and reduce the morbidity of the disorder. Such intervention can potentially decrease the total cost of agranulocytosis. Further issues under consideration are the early use of hematopoietic growth factors prior to the onset of agranulocytosis and the use of these factors for the outpatient management of this disorder.

Topics: Agranulocytosis; Ambulatory Care; Clozapine; Costs and Cost Analysis; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Hospitalization; Humans; Leukocyte Count; Neutrophils; Treatment Outcome

The development of antipsychotic drugs has followed two complementary approaches, either towards highly specific actions (e.g. on the dopamine receptor) or targeting a broad range of receptors. The properties of 'atypical' agents challenge the original dopamine hypothesis and suggest roles for a variety of dopamine receptors and for other pathways, such as serotonin. Older drugs, despite their proven efficacy in relieving many schizophrenic symptoms, have several drawbacks, being ineffective in some patients, relatively ineffective against negative symptoms, and causing adverse neurological effects which may, in turn, be associated with poor compliance. Among newer agents, currently available ones, such as clozapine and risperidone, offer the possibility of more effective control of negative symptoms and an improved side-effect profile, while others are in earlier stages of development. However, much still remains to be understood about their mechanisms of action.

Topics: Agranulocytosis; Anemia, Aplastic; Antipsychotic Agents; Brain; Clozapine; Humans; Neurologic Examination; Receptors, Dopamine; Receptors, Serotonin; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

In order to extend the analysis of the association between class I and class II HLA markers and HSP-70 alleles, we studied the genetic polymorphism of HSP70-2 genes by restriction fragment length polymorphism analysis in a panel of HLA-homozygous cell lines carrying the HLA-B alleles known to be associated with clozapine-induced agranulocytosis. We have found a linkage disequilibrium between the 9.0 kb variant of HSP70-2 with the class I antigens HLA-B7, B38, and B44 and with the class II antigens HLA-DR2 and DR4. We discuss the importance of analyzing the variants of HSP70-2 in patients with agranulocytosis to confirm that the 9.0 kb allele is a genetic marker for the disease. If that is the case, HSP-70 variants could explain the different associations of HLA alleles in individuals of Jewish and non-Jewish ancestry because the HLA alleles are in linkage disequilibrium with the 9.0 kb band. We postulate that HSP-70 molecules could also play a significant role in determining the molecular mechanisms that induce agranulocytosis by clozapine.

Topics: Agranulocytosis; Clozapine; Genetic Variation; HLA-B Antigens; HLA-DR2 Antigen; HLA-DR4 Antigen; HSP70 Heat-Shock Proteins; Humans; Linkage Disequilibrium; Polymorphism, Genetic

This paper reviews the epidemiology and pathogenesis of clozapine-associated agranulocytosis. According to present clinical experience, granulocytopenia can be expected in approximately 3% of patients during clozapine treatment. The risk of serious sequelae of granulocytopenia can be minimised by regular white blood cell count monitoring. Although research suggests that some patient groups may be at higher risk of developing this serious adverse reaction, we cannot yet predict the susceptible patients, so all patients exposed to clozapine should receive regular blood monitoring throughout treatment. Because of the risk of agranulocytosis, clozapine should only be used in schizophrenic patients who are resistant to, or intolerant of, conventional antipsychotic medications. Unless compliance with blood monitoring is assured, clozapine treatment should not be recommended.

Topics: Agranulocytosis; Clozapine; Drug Monitoring; Female; Humans; Leukocyte Count; Male; Schizophrenia

The treatment of patients with schizophrenia who fail to respond to antipsychotic medications remains a challenge. Despite numerous attempts to establish effective somatic treatment approaches for this population, clozapine appears to be the only well established alternative. Depending upon trial duration and response criteria, between 30% and 60% of previously unresponsive patients appear to derive clinically significant benefit from clozapine. Clozapine also has important advantages in terms of its reduced propensity to produce extrapyramidal side-effects. Agranulocytosis remains an important risk, so strategies to improve the benefit-to-risk ratio should be explored. Issues such as trial duration, dosage, blood levels and predictors of response require additional study.

Topics: Agranulocytosis; Basal Ganglia Diseases; Clozapine; Female; Humans; Male; Schizophrenia; Schizophrenic Psychology

The arrival of clozapine has been one of the most significant developments in antipsychotic drug treatment since the advent of chlorpromazine ushered in the psychopharmacologic era. However, its utilization has been significantly limited and complicated by its potential to cause adverse effects and agranulocytosis in particular. It must be emphasized that clozapine has a side effect profile that is in many ways distinct from standard typical antipsychotic drugs. Side effects with clozapine are common and range from the benign to the potentially lethal. The most common side effects include sedation, dizziness, and sialorrhea during sleep; the most serious are agranulocytosis, seizures and respiratory depression. Although side effects from clozapine are not necessarily preventable, they are for the most part manageable. Even with the most serious adverse effects, proper knowledge of the medication's actions, clinical vigilance, and prompt intervention can prevent the occurrence of significant morbidity and mortality as a consequence of clozapine treatment.

Topics: Adult; Aged; Agranulocytosis; Blood Chemical Analysis; Central Nervous System Diseases; Clozapine; Female; Humans; Male; Middle Aged; Neuroleptic Malignant Syndrome; Psychotic Disorders; Seizures

The aetiology of clozapine-induced agranulocytosis remains unknown. Leading candidates include an immune mechanism that is possibly complement- or drug-dependent and a toxic mechanism. We analysed these mechanisms by culturing the granulocyte precursor stem cell from the bone marrow in the presence of patients' serum, clozapine or clozapine metabolites. Studies with patients' serum failed to identify an immune mechanism. On the basis of our preliminary data, it appears that a toxic mechanism may be responsible, and this is more likely to be due to a metabolite than to clozapine itself. Further studies are required to determine the sensitivity of bone marrow precursors to these clozapine derivatives. For instance, prospective collection of serum will make it possible to evaluate whether high metabolite concentrations develop in sensitive individuals and whether they are responsible for agranulocytosis. If such elevated levels occur, further studies will be required to determine whether prospective monitoring will effectively identify patients at risk and ultimately prevent the onset of agranulocytosis by early discontinuation of the drug.

Topics: Agranulocytosis; Clozapine; Drug Therapy, Combination; Hematopoiesis; Humans; Risk Factors

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

Studies were conducted on serum removed from 15 patients before, during, and after, clozapine-induced agranulocytosis. Cytotoxic studies were compared with samples taken from patients during treatment with clozapine who did not develop agranulocytosis or treatment controls (TC); additional controls consisted of allogeneic (NC) and autogeneic serum from apparently normal people. The effect of serum on measurable functions of polymorphonuclear neutrophils (PMNs) taken from normal people was tested. Procedures under study included suppression of post-phagocytosis-induced 14CO2-indicated respiratory burst, as well as ejection of trypan blue by test PMNs. PMNs exposed to active agranulocytosis serum plus complement displayed diminished 14CO2 emission during phagocytosis or failed to eject trypan blue. PMNs exposed to serum of TC and NC continued to function normally as regards 14CO2 emission and trypan blue ejection. Five patients studied before the development of agranulocytosis showed suppressed PMN function, which increased to peak value during agranulocytosis and then disappeared within 40 days of recovery. Similar suppression of colony forming units of granulocytes and macrophages (CFU-GM) was found whenever agranulocytosis serum was included in the marrow culture. The cytotoxic material required complement for its full expression, was not dialysable, was neutralised by anti-IgM serum, and was absorbed by test PMNs. Furthermore, solutions of clozapine or 5 of its metabolites offered no similar suppression of PMN function in vitro after incubation in an aqueous medium or with normal serum. These observations favour development of an immunogenic clone in sensitive people during active treatment with clozapine, which eventually leads to precipitous depletion of PMNs and their precursors. The early appearance of this suppressive substance may offer an early warning for development of agranulocytosis.

Topics: Agranulocytosis; Clozapine; Colony-Forming Units Assay; Cytotoxicity Tests, Immunologic; Erythropoiesis; Granulocytes; Humans; Macrophages; Predictive Value of Tests

Many types of adverse drug reactions appear to involve reactive metabolites which, by their very nature, usually have short biological half-lives. Therefore, reactive metabolites formed by neutrophils, or neutrophil precursors in the bone marrow, would seem more likely to be responsible for drug-induced agranulocytosis than metabolites formed in the liver. We have found that several drugs associated with a relatively high incidence of drug-induced agranulocytosis are metabolised by activated neutrophils to chemically reactive metabolites. In preliminary experiments with clozapine, we found that clozapine was metabolised by neutrophils. It also reacted with hypochlorous acid, the principal oxidant generated by neutrophils, to form a reactive intermediate. This intermediate has a half-life of 1 minute in buffer, but reacts very rapidly with glutathione. We believe that this intermediate is a nitrenium ion. Such a metabolite could be responsible for clozapine-induced agranulocytosis, either by direct toxicity or through an immune-mediated mechanism.

Topics: Agranulocytosis; Clozapine; Humans; Neutrophils

Clozapine is the first truly new antipsychotic drug introduced in the last 40 years. Compared to traditional neuroleptic agents, clozapine appears to have a stronger effect on most schizophrenic symptoms. Thus, it seems to be more effective than other agents in severely ill, treatment-resistant patients. Clozapine rarely causes extrapyramidal symptoms such as pseudoparkinsonism or akathisia. To date, no confirmed cases of tardive dyskinesia have been attributed to the drug. Despite these advantages, the usefulness of clozapine is limited by its potentially life-threatening side effects, which include agranulocytosis and respiratory depression.

Topics: Agranulocytosis; Clozapine; Humans; Psychotic Disorders

Clozapine (CLOZ) is an atypical antipsychotic drug being used with increasing frequency throughout the world and has recently been commercially marketed in the United States. Its unique properties make it a promising but challenging drug to use in the treatment of schizophrenia. In order to use CLOZ most effectively and efficiently, clinicians must be aware of its potential benefits and risks. This report is a review and critical evaluation of current knowledge regarding the clinical efficacy and side effects of CLOZ. Although CLOZ has proven to be effective in some treatment-refractory schizophrenic patients and to produce relatively few extrapyramidal side effects compared to classical neuroleptic drugs, several issues require further investigation including what defines neuroleptic intolerance, the optimal dose range, and the appropriate duration of a CLOZ treatment trial. Similarly, studies are needed to determine what role CLOZ should have in the treatment of patients with predominantly negative symptoms and those patients who are only partially responsive to standard neuroleptics. In addition, important questions remain as to what other conditions might be indications for CLOZ, for example, schizoaffective disorder, affective psychoses, and idiopathic Parkinson's disease.

Topics: Agranulocytosis; Basal Ganglia Diseases; Clozapine; Humans; Nervous System; Schizophrenia

Topics: Agranulocytosis; Clozapine; Humans; Psychotic Disorders

Drug-induced agranulocytosis is a highly individualized and unexpected reaction to specific drugs. It may be due to immunogenic or cytotoxic factors. Most instances are produced by a poorly understood immune response to immunogenic drugs. Others are associated with direct suppression of marrow committed stem cells by the direct action of the offending drug or its toxic metabolic end products. The early appearance of polymorphonuclear neutrophil (PMN) antibodies may offer an early warning to sensitized patients. Antibodies, if present, disappear shortly after the drug is discontinued. Agranulocytosis, due to direct action of the drug, is characterized by morphologic aplasia of marrow and is more likely to occur if the affected host has a concomitant defect in marrow cellular proliferation. Accumulation of toxic metabolic end products such as arene oxides may occur if the host is deficient in a microsomal system required to dispose of this material.

Topics: Agranulocytosis; Aminopyrine; Anemia, Aplastic; Bone Marrow; Clozapine; Female; Hematopoiesis; Hematopoietic Stem Cells; Humans; Male; Neutrophils; Phenothiazines

Clozapine holds great clinical promise for some chronic schizophrenic patients. However, limitations on access to the drug by the largest subgroup who need it, the indigent, are causing frustration for patients, their families, physicians, and public-sector mental health systems. The drug is available only through the manufacturer's proprietary monitoring system; many public-sector professionals and agencies feel that the system is overpriced, is unfairly exclusive, and has thus far kept the drug out of reach of most patients who need it. Arguments that patient improvement will lead to dollar savings in the long run seem overly optimistic. The ethical issue of access to treatment remains. The author discusses these and related issues and reports early experience from several public mental health systems.

Topics: Agranulocytosis; Chronic Disease; Clozapine; Cost-Benefit Analysis; Dibenzazepines; Health Services Accessibility; Humans; Medicaid; Medical Indigency; Risk Factors; Schizophrenia; Schizophrenic Psychology; United States

Topics: Agranulocytosis; Clozapine; Dibenzazepines; Humans; Schizophrenia; Time Factors

Although toxicity and inborn errors of metabolism may also be involved, immunological reactions play an important role in the induction of drug-induced agranulocytosis. Drug-induced antibodies may lead to agranulocytosis by at least three different immunological mechanisms. Immune complexes may selectively adhere to granulocytes or their immature precursor cells, the drug may bind to the granulocytes as carriers of the immunogenic drug and finally the drug may induce antibodies directed to granulocyte-specific structures. The use and the interpretation of in vitro assays to detect drug-dependent antibodies against granulocytes or myeloid precursor cells are discussed. These assays will be used to detect a possible immunological mechanism involved in clozapine-induced agranulocytosis. Further studies will concern the identification of possible genetic risk factors associated with clozapine-induced agranulocytosis.

Topics: Agranulocytosis; Clozapine; Dibenzazepines; Humans

Topics: Agranulocytosis; Clozapine; Dibenzazepines; Humans

Topics: Agranulocytosis; Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Dibenzazepines; Humans; Schizophrenia; United States

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Eosinophils; Female; Humans; Leukocyte Count; Male; Middle Aged; Schizophrenia; Sex Characteristics; Sex Factors

When a schizophrenia patient has an inadequate response to treatment with an antipsychotic drug, it is unclear what other antipsychotic to switch to and when to use clozapine. In this study, the authors compared switching to clozapine with switching to another atypical antipsychotic in patients who had discontinued treatment with a newer atypical antipsychotic in the context of the Clinical Antipsychotic Trials for Interventions Effectiveness (CATIE) investigation.. Ninety-nine patients who discontinued treatment with olanzapine, quetiapine, risperidone, or ziprasidone in phase 1 or 1B of the trials, primarily because of inadequate efficacy, were randomly assigned to open-label treatment with clozapine (N=49) or blinded treatment with another newer atypical antipsychotic not previously received in the trial (olanzapine [N=19], quetiapine [N=15], or risperidone [N=16]).. Time until treatment discontinuation for any reason was significantly longer for clozapine (median=10.5 months) than for quetiapine (median=3.3), or risperidone (median=2.8), but not for olanzapine (median=2.7). Time to discontinuation because of inadequate therapeutic effect was significantly longer for clozapine than for olanzapine, quetiapine, or risperidone. At 3-month assessments, Positive and Negative Syndrome Scale total scores had decreased more in patients treated with clozapine than in patients treated with quetiapine or risperidone but not olanzapine. One patient treated with clozapine developed agranulocytosis, and another developed eosinophilia; both required treatment discontinuation.. For these patients with schizophrenia who prospectively failed to improve with an atypical antipsychotic, clozapine was more effective than switching to another newer atypical antipsychotic. Safety monitoring is necessary to detect and manage clozapine's serious side effects.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Chronic Disease; Clozapine; Cross-Over Studies; Dibenzothiazepines; Drug Monitoring; Drug Resistance; Eosinophilia; Female; Follow-Up Studies; Humans; Male; Olanzapine; Piperazines; Prospective Studies; Psychiatric Status Rating Scales; Quetiapine Fumarate; Risperidone; Schizophrenia; Schizophrenic Psychology; Thiazoles; Treatment Outcome

The pathomechanisms of most drug-induced agranulocytoses are unclear; however, there are some studies pointing to genetic determinants. Some drug-induced agranulocytoses such as clozapine-induced agranulocytosis (CA) may be regarded as an idiosyncratic drug reaction because of its preclinical and clinical characteristics. To study some aspects of the genetic background of CA further, polymorphisms of specific metabolizing enzyme systems of clozapine were examined. Thirty-one schizophrenic patients with CA and 77 schizophrenic comparison subjects without this adverse effect underwent genotyping of a recently discovered G(-463)A polymorphism of myeloperoxidase (MPO) gene and cytochrome P4502D6. Neither the MPO mutation nor specific genotypes of cytochrome P4502D6 were associated with CA. Both were equally distributed among CA patients and controls. Thus, our data suggest lack of evidence of an association of CA and genetically variable activity of these specific drug metabolizing enzymes; however, this may be due to statistical reasons only. Thus, further studies with greater CA samples are necessary to draw final conclusions about these genetically based hypotheses.

Topics: Adult; Aged; Aged, 80 and over; Agranulocytosis; Antipsychotic Agents; Clozapine; Cytochrome P-450 CYP2D6; Female; Genotype; Humans; Male; Middle Aged; Peroxidase; Polymorphism, Genetic; Schizophrenia

There has been an absence of controlled studies focusing specifically on neuroleptic treatment in the elderly schizophrenic population. Therefore, we conducted a 12-week double-blind comparison study to assess the efficacy and tolerability of clozapine and chlorpromazine in a group of elderly inpatients with chronic schizophrenia.. Forty-two elderly DSM-IV schizophrenic veterans were randomly assigned to clozapine or chlorpromazine and assessed for efficacy at baseline and at termination with the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impressions scale (CGI). Side effects were also monitored. Medications were titrated, on the basis of clinical response and side effects, to a maximum dose of 300 mg/day of clozapine or 600 mg/day of chlorpromazine.. The results suggest that both the chlorpromazine and clozapine groups improved their PANSS scores at termination compared with baseline, but the difference between the 2 groups was not statistically significant. The mean CGI scores reflecting severity of illness also demonstrated improvement in both groups over time. Both groups had similar incidences of side effects. One patient in each group had a life-threatening side effect. More patients taking clozapine had tachycardia and weight gain, while more chlorpromazine patients noted sedation.. We concluded that both clozapine and chlorpromazine are effective treatments for psychosis and behavioral disturbances in geriatric schizophrenia. Both agents had similar incidences of side effects. With careful monitoring and titration of dosage, both clozapine and chlorpromazine were fairly well tolerated in this population.

Topics: Age Factors; Aged; Agranulocytosis; Antipsychotic Agents; Chlorpromazine; Clozapine; Double-Blind Method; Humans; Intestinal Pseudo-Obstruction; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Weight Gain

A possible relationship between haematological adverse reactions and clozapine (CLZ) metabolism rate was studied. Sixteen chronic schizophrenic outpatients (mean age 34.62 years +/- 7.56 SD) were treated with CLZ, 75-600 mg/daily for 9 weeks. CLZ and norclozapine (NCLZ) plasma levels were determined weekly, contemporarily with blood cell counts. CLZ plasma levels ranged from 25 to 1270 ng/ml (mean 266.27 ng/ml +/- 197.44 SD), while NCLZ plasma levels ranged from 25 to 1280 ng/ml (mean 169.0 ng/ml +/- 127.94 SD). NCLZ/CLZ ratio ranged from 0.13 to 1.72 (mean 0.72 +/- 0.28 SD). Leukocyte count ranged from 5.2 to 18.8 10(9)/l (mean 9.37 10(9)/l +/- 2.94 SD) and neutrophil count ranged from 1.8 to 13.4 10(9)/l (mean 5.73 +/- 2.57 SD). No correlation was found between CLZ dosage and NCLZ plasma levels. Both CLZ and NCLZ plasma levels correlated positively with neutrophil count (CLZ: P = 0.001, r = 0.26; NCLZ: P = 0.01, r = 0.20). The correlation between NCLZ/CLZ plasma level ratio and neutrophil count was significantly negative (P = 0.002, r = 0.25). These preliminary data suggest that the NCLZ/CLZ ratio, as an index of CLZ metabolism, might be a possible risk factor associated with CLZ treatment.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Female; Humans; Leukocyte Count; Leukocytosis; Male; Middle Aged; Risk Factors; Schizophrenia

Topics: Adult; Agranulocytosis; Clozapine; Female; Haloperidol; Humans; Male; Prospective Studies; Receptors, Interleukin-2; Risk Factors; Schizophrenia

The authors provide the data on the dynamics of the hematological parameters during continuous leponex (clozapin) treatment of two group of patients treated in 1973-1989 at the All-Union Mental Health Research Center, USSR AMS (107 patients) and at 12 Research Centers of the USSR, CSFR, Bulgaria and Poland (642 patients). The mean duration of the treatment was 4.8 and 12.4 months respectively. Moderate leukopenia (3000-4000/ml) developed in 0.5 and 1.2% of all the analyses, the neutrophil/leukocyte ratio always remained within normal (50% and higher), whereas the neutrophil count did not drop below 1600/ml, i. e. it was not pathological. Despite the relatively long treatment no cases of granulocytopenia (or agranulocytosis) were recorded. It is shown that the side hematological effect is not related to the magnitude of the diurnal dose of leponex. Recommendations are given for wide use of leponex in medical practice under constant control of the blood status, with the use of the method of a slow and progressive augmentation of the daily dose.

Topics: Adult; Agranulocytosis; Clozapine; Drug Monitoring; Europe, Eastern; Female; Granulocytes; Humans; International Cooperation; Leukocyte Count; Lymphocytes; Lymphopenia; Male; Middle Aged; Schizophrenia, Catatonic; USSR

Clozapine (CLOZ) is an atypical antipsychotic drug being used with increasing frequency throughout the world and has recently been commercially marketed in the United States. Its unique properties make it a promising but challenging drug to use in the treatment of schizophrenia. In order to use CLOZ most effectively and efficiently, clinicians must be aware of its potential benefits and risks. This report is a review and critical evaluation of current knowledge regarding the clinical efficacy and side effects of CLOZ. Although CLOZ has proven to be effective in some treatment-refractory schizophrenic patients and to produce relatively few extrapyramidal side effects compared to classical neuroleptic drugs, several issues require further investigation including what defines neuroleptic intolerance, the optimal dose range, and the appropriate duration of a CLOZ treatment trial. Similarly, studies are needed to determine what role CLOZ should have in the treatment of patients with predominantly negative symptoms and those patients who are only partially responsive to standard neuroleptics. In addition, important questions remain as to what other conditions might be indications for CLOZ, for example, schizoaffective disorder, affective psychoses, and idiopathic Parkinson's disease.

Topics: Agranulocytosis; Basal Ganglia Diseases; Clozapine; Humans; Nervous System; Schizophrenia

Topics: Agranulocytosis; Clinical Trials as Topic; Clozapine; Dibenzazepines; Home Care Services; Humans; Schizophrenia; Seizures

Clozapine, a new drug for schizophrenia, was recently released for use. We have described the drug and nursing care involved for patients who are on acute inpatient unit for a trial of the drug. From our early observations, clozapine appears to be a promising drug for patients who have not responded to standard neuroleptics.

Topics: Adolescent; Adult; Agranulocytosis; Clinical Trials as Topic; Clozapine; Dibenzazepines; Female; Humans; Male; Patient Compliance; Patient Education as Topic; Professional-Family Relations; Schizophrenia; Seizures

Clozapine is a novel antipsychotic agent that selectively blocks mesolimbic--rather than nigrostriatal--dopamine receptors, causes fewer extrapyramidal symptoms than do other neuroleptics, and has superior antipsychotic efficacy in some patients. However, clozapine also causes agranulocytosis more frequently than do other neuroleptics. The evidence documenting the superior benefits obtained with clozapine has primarily involved short-term (4-6 weeks) trials, and the systematic evaluation of long-term clozapine use has been limited. In this study, 14 patients with refractory chronic schizophrenia were treated openly with clozapine up to 2 years; 8 did substantially better when given clozapine than they had when given other neuroleptics. That finding suggests that clozapine may provide a useful addition to the therapeutic armamentarium for the long-term treatment of schizophrenia, despite the increased risks and the need for frequent blood tests.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Chronic Disease; Clinical Trials as Topic; Clozapine; Dibenzazepines; Female; Humans; Male; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Topics: Agranulocytosis; Antipsychotic Agents; B-Lymphocytes; Clinical Trials as Topic; Clozapine; Humans; Leukocyte Count; Lymphocytes; Schizophrenia; T-Lymphocytes

Topics: Agranulocytosis; Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Dibenzazepines; Humans; Schizophrenia; United States

Clozapine is considered the most effective antipsychotic for schizophrenia, but it can cause neutropenia and even agranulocytosis. We describe the first case in Hong Kong involving the use of filgrastim, a recombinant form of human granulocyte colony-stimulating factor, to enable clozapine continuation therapy for a severely ill patient with treatment-resistant schizoaffective disorder who developed recurrent neutropenia after almost 20 years of continuous clozapine therapy. Therefore, clinical vigilance is important, regardless of clozapine treatment duration. Filgrastim can facilitate long-term clozapine therapy in patients with clozapine-induced neutropenia.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Neutropenia

The outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic had multiple consequences for the health care system, especially for patients with mental illnesses. Schizophrenia patients particularly appear to have a higher risk of complications due to coronavirus-19 (COVID-19). Clozapine remains the gold standard for treatment-resistant schizophrenia (TRS). However, the COVID-19 pandemic had an important negative impact on clozapine treatment, mainly because of its administration protocol, which was very difficult to follow during the restrictions imposed in the pandemic, and its side effects in patients with COVID-19 infection. Vaccination is an effective method of avoiding SARS-CoV-2 infection or its severe complications, especially in susceptible populations. Data on adverse events after vaccination against COVID-19 are limited, both in the general population and in schizophrenia patients.. The study aimed to investigate the safety of COVID-19 vaccination in patients treated with clozapine for hematological parameters.. We conducted an analytical cross-sectional study between July 1, 2021, and June 30, 2022. We compared 2 groups of COVID-19 vaccinated patients who had previously experienced SARS-CoV-2 infection: The first group was treated with clozapine, whereas the second group was treated with other antipsychotics.. The primary objective was to identify granulocytopenia, leukocytopenia, and lymphocytopenia. The results were measured after the second dose of the Pfizer-BioNTech vaccine.. This study included 100 patients. White blood cell count changes were limited to a few cases of mild granulocytopenia (8.16% in the clozapine group and 3.92% in the nonclozapine group, P = 0.37) with no cases of severe granulocytopenia or agranulocytosis.. As far as leukocyte counts are concerned, mRNA COVID-19 vaccination seems to be safe in patients treated with clozapine who previously had SARS-CoV-2 infection. Leukocyte changes had no clinical implications.

Topics: Agranulocytosis; Clozapine; COVID-19; COVID-19 Vaccines; Cross-Sectional Studies; Humans; Leukopenia; Pandemics; SARS-CoV-2; Vaccination; World Health Organization

Although clozapine is a highly efficacious schizophrenia treatment, it is under-prescribed due to the risk of idiosyncratic drug-induced agranulocytosis (IDIAG). Clinical data indicate that most patients starting clozapine experience a transient immune response early in treatment and a similar response has been observed in clozapine-treated rats, but the mechanism by which clozapine triggers this transient inflammation remains unclear. Therefore, the aim of this study was to characterize the role of inflammasome activation during the early immune response to clozapine using in vitro and in vivo models. In both differentiated and nondifferentiated human monocytic THP-1 cells, clozapine, but not its structural analogues fluperlapine and olanzapine, caused inflammasome-dependent caspase-1 activation and IL-1β release that was inhibited using the caspase-1 inhibitor yVAD-cmk. In Sprague Dawley rats, a single dose of clozapine caused an increase in circulating neutrophils and a decrease in lymphocytes within hours of drug administration along with transient spikes in the proinflammatory mediators IL-1β, CXCL1, and TNF-α in the blood, spleen, and bone marrow. Blockade of inflammasome signaling using the caspase-1 inhibitor VX-765 or the IL-1 receptor antagonist anakinra attenuated this inflammatory response. These data indicate that caspase-1-dependent IL-1β production is fundamental for the induction of the early immune response to clozapine and, furthermore, support the general hypothesis that inflammasome activation is a common mechanism by which drugs associated with the risk of idiosyncratic reactions trigger early immune system activation. Ultimately, inhibition of inflammasome signaling may reduce the risk of IDIAG, enabling safer, more frequent use of clozapine in patients.

Topics: Agranulocytosis; Animals; Caspase 1; Clozapine; Humans; Inflammasomes; Interleukin-1beta; NLR Family, Pyrin Domain-Containing 3 Protein; Rats; Rats, Sprague-Dawley

To investigate the safety of COVID-19 vaccination in patients on clozapine as regards plasma clozapine concentration and haematological parameters.. We conducted a multicentre observational cohort study from 22 February 2021 to 2 September 2021. Primary outcomes were clinically relevant increase in clozapine blood levels (>100 μg/L increase compared to baseline) and clozapine alert levels (>1000 μg/L). Secondary outcomes were granulocytopenia, leukocytopenia and lymphocytopenia. Outcomes were measured approximately 5 days after the first and (where applicable) second dose of COVID-19 vaccine.. This study included 139 patients. Compared to baseline, clozapine blood levels increased significantly (ES = 0.28, p = 0.003) after the second vaccination. Clinically relevant increases in clozapine blood levels occurred in 20/92 patients (22%) and in 16/56 patients (29%) during the first and second phases, respectively. Clozapine alert levels developed in one patient (1%) following the first dose and in three patients (5%) after the second dose. In both phases, changes in white blood cells (WBC) were limited to mild granulocytopenia (3% and 5%), moderate granulocytopenia (1% and 0%) and leukocytopenia (2% and 3%) without cause for extra monitoring according to the guideline.. In general, as regards WBC counts COVID-19 vaccination seems to be safe in patients with SMI. Changes in WBC had no clinical implications. Psychoeducation on the symptoms of clozapine intoxication is recommended, especially in patients with clozapine blood levels approaching the upper limit of the therapeutic range. Increase in the C-reactive protein (CRP) level can signal inflammation rapidly and help to prevent clozapine intoxication following vaccination.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Cohort Studies; COVID-19; COVID-19 Vaccines; Humans; Leukocytes; Leukopenia; Vaccination

Clozapine is the most efficacious treatment for schizophrenia and is associated with lower overall mortality than are other antipsychotic drugs, despite the risk of agranulocytosis. Preliminary reports over the past 10 years suggest a possible risk of haematological malignancies, but the issue has remained unsettled. We aimed to study the risk of haematological malignancies associated with use of clozapine and other antipsychotics.. We did a nationwide case-control (and cohort) study of people with schizophrenia, using prospectively gathered data from Finnish national registers. A nested case-control study was constructed by individually matching cases of lymphoid and haematopoietic tissue malignancy with up to ten controls without cancer by age, sex, and time since first schizophrenia diagnosis. For the case-control study, we restricted inclusion criteria to malignancies diagnosed on a histological basis, and excluded individuals outside of the age range 18-85 years, and any patients that had a previous malignancy. Analyses were done using conditional logistic regression adjusting for comorbid conditions.. For the case-control study 516 patients with a first-time diagnosis of lymphoid and haematopoietic tissue malignancy during years 2000-17 and diagnosed after their first diagnosis of schizophrenia were identified. 102 patients were excluded due to diagnosis that was without a histological basis, five patients were excluded because of their age, and 34 were excluded for a previous malignancy, resulting in 375 patients being matched to controls. We selected up to ten controls without cancer (3734 in total) for each case from the base cohort of people with schizophrenia. For the cohort study, data for 55 949 people were included for analysis. Cumulative incidence of haematological malignancies during the mean follow-up of 12·3 years (SD 6·5) was 102 (0·7%) cases among 13 712 patients who had used clozapine (corresponding to event rate of 61 cases per 100 000 person-years), and during mean follow-up of 12·9 years (SD 7·2) was 235 (0·5%) malignancies among 44 171 patients having used other antipsychotic medication than clozapine (corresponding to 41 cases per 100 000 person-years). Of the 375 individuals with haematological malignancies (305 lymphomas, 42 leukaemia, 22 myelomas, 6 unspecified) observed from 2000-17, 208 (55%) were males and 167 (45%) were female. Ethnicity data were not available. Compared with non-use of clozapine (most had used other antipsychotics and a few had used no antipsychotics), clozapine use was associated with increased odds of haematological malignancies in a dose-response manner (adjusted odds ratio 3·35, [95% CI 2·22-5·05] for ≥5000 defined daily dose cumulative exposure, p<0·0001). Exposure to other antipsychotic drugs was not associated with increased odds. A complementary analysis showed that the clozapine-related risk increase was specific for haematological malignancies, because no such finding was observed for other malignancies. Over 17 years of follow-up of the base cohort, 37 deaths occurred due to haematological malignancy among patients exposed to clozapine (26 with ongoing use at time of haematological malignancy diagnosis, and 11 in patients who did not use clozapine at the exact time of their cancer diagnosis), whereas only three deaths occurred due to agranulocytosis.. Unlike other antipsychotics, long-term clozapine use is associated with increased odds of haematological malignancies. Long-term clozapine use has a higher effect on mortality due to lymphoma and leukaemia than due to agranulocytosis. However, acknowledging that the absolute risk is small compared with the previously observed absolute risk reduction in all-cause mortality is important. Our results suggest that patients and caregivers should be informed about warning signs of haematological malignancies, and mental health clinicians should be vigilant for signs and symptoms of haematological malignancy in patients treated with clozapine.. The Finnish Ministry of Social Affairs and Health and Academy of Finland.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Agranulocytosis; Antipsychotic Agents; Case-Control Studies; Clozapine; Cohort Studies; Female; Finland; Hematologic Neoplasms; Humans; Leukemia; Male; Middle Aged; Schizophrenia; Young Adult

Although clozapine-induced granulocytopenia (CIG) is less severe than clozapine-induced agranulocytosis (CIA), and some patients with CIG may not go on to develop serious complications, clozapine is discontinued in cases of both CIA and CIG. Understanding the pathogenic mechanisms of CIA/CIG could provide better management of clozapine therapy. Recently, as a mechanistic insight into adaptive immune systems, European groups reported clozapine-specific proliferative responses and clozapine-specific T cells using blood taken from patients with CIA and/or CIG.. The aims of our study are to support this mechanistic evidence and to investigate the difference in the lymphocyte response to clozapine between patients with CIG and those with CIA.. Lymphocyte stimulation tests (LSTs) were conducted using CD25-positive cell-depleted peripheral blood-derived mononuclear cells (PBMCs) isolated from blood of four Japanese patients with CIA, four patients with CIG, and nine clozapine-tolerant subjects.. Three of four patients with CIA and one of four patients with CIG showed proliferative responses to clozapine with a stimulation index of greater than 2. In contrast, none of the nine clozapine-tolerant subjects showed any response to clozapine. Olanzapine did not stimulate PBMCs of patients with CIA, patients with CIG, or clozapine-tolerant subjects.. Clozapine- and CIA-specific lymphocyte reactions in a Japanese population provided supportive evidence that the pathogenesis of CIA is based on adaptive immune reactions. In addition, patients with CIG who show a positive response to an LST may at the very least not be chosen for clozapine-rechallenge and further prospective studies are desirable to verify this hypothesis.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Humans; Japan; Olanzapine; Prospective Studies

Clozapine is an atypical antipsychotic with several advantages over conventional antipsychotics, in addition to its well-known efficacy in treatment-resistant schizophrenia. However, the high risk of agranulocytosis associated with clozapine therapy limits its clinical application. Clozapine bioactivation to an unstable protein-reactive metabolite, identified as a nitrenium intermediate, has been implicated in cytotoxicity toward neutrophils. Clozapine affects myeloid precursor cells rather than neutrophils; however, the impact of its reactive metabolite on myeloid precursor cells undergoing granulocytic differentiation remains unclear. Herein, we used hydrogen peroxide (H

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Glutathione; HL-60 Cells; Humans; Hydrogen Peroxide

Schizophrenia is one of the major neuropsychiatric disorders affecting people worldwide. Unfortunately, currently available antipsychotic medications possess several side effects. Among them, clozapine is one of the atypical antipsychotics prescribed in schizophrenia wing to its blocking effect on dopamine (D2) and serotonin (5-HT

Topics: Agranulocytosis; Animals; Antipsychotic Agents; Clozapine; Flavanones; Humans; Rats; Weight Gain

This survey was conducted to identify the actual usage of clozapine and changes required to increase the number of patients with schizophrenia who would benefit from clozapine. We obtained Clozaril® Patient Monitoring Service (CPMS) data for 8,263 patients that received clozapine between July 2009 and January 2020. Patients were divided into the early (n=3,696 cases, which have been analyzed previously) and late groups (n=4,567 cases) according to the date of the treatment initiation. In total, 417 facilities offered the drug, with a surge in cases in the late group (40.0 hospitals/year, 568.6 cases/year vs. 39.3 hospitals/year, 1,141.8 cases/year). We found a significant between-group difference in the mean dosage during treatment (early group: 309.1 mg/day; late group: 247.9 mg/day). The treatment continuation rates at 1 and 4 years in all study participants were 77.2% and 65.1%, respectively. The incidences of granulocytopenia and agranulocytosis were 5.5% and 1.0%, respectively. The discontinuation rate because of granulocytopenia was significantly lower in the late group. There were no differences in the discontinuation rate because of glucose intolerance between the groups. An assessment of the current CPMS regulations may be required to further examine the clozapine use effectiveness.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Humans; Japan; Schizophrenia

As an emergency measure during the coronavirus disease pandemic, the monitoring interval for clozapine use was temporarily extended beyond the regulatory requirement in Japan, which is the safest monitoring interval worldwide. In this study, we aimed to explore the effect of this measure on patients undergoing clozapine treatment.. This retrospective chart review study included patients with treatment-resistant schizophrenia (TRS) who were undergoing clozapine treatment at four psychiatric institutions in Japan. Demographic characteristics and clinical information of these patients were collected on April 27, 2020, when Japanese psychiatrists were virtually allowed to prescribe clozapine beyond the regulatory requirement. Furthermore, information of adverse events related to the emergency measure was collected and analyzed.. Of the 41 patients with TRS included in this study, 19 patients underwent extended hematological monitoring during clozapine treatment. No psychiatric or hematological adverse events were observed in the patients during the extended monitoring interval.. This study suggested that there were few adverse events of clozapine-treated patients related to emergency measures in Japan. However, hematological monitoring intervals during clozapine treatment have been emergently extended worldwide; hence, it is necessary to verify the results of these measures.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; COVID-19; Drug Monitoring; Female; Humans; Japan; Male; Retrospective Studies; SARS-CoV-2; Schizophrenia

The risk of neutropenia decreases significantly after the first year of clozapine initiation, and indefinite hematological monitoring is increasingly questioned. Despite comparable risks of neutropenia, the guidelines for antithyroid drugs - carbimazole and propylthiouracil do not recommend routine hematological monitoring. Assuming a similar pathogenic mechanism, data from antithyroid drugs indicate that neutropenia develops rapidly, and indefinite hematological monitoring misses a large majority of cases in the pre-symptomatic phase. Hence, a more pragmatic strategy of intensive hematological monitoring in the first year of clozapine initiation followed by selective haematological monitoring in case of febrile illnesses or pharyngitis needs to be explored.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Cognition; Humans; Neutropenia

The inherent risk of agranulocytosis associated with clozapine requires the realization of weekly white blood cell monitoring (WBCM) during the 18 first weeks of treatment. The aim of this study was to assess the compliance with WBCM during clozapine initiation for schizophrenia and Parkinson's disease (PD) subjects.. The analysis was conducted using SNDS data on a cohort of new users of clozapine in 2018. We analyzed all reimbursements for WBCM from 2 weeks before the index date to 18 weeks after (optimal monitoring during hospitalization was assumed). The primary outcome was the proportion of good realization of WBCM according to different thresholds of completion (70%; 80%; 90%). Descriptive and comparative analyses with chi-squared test or Student's t-test were performed.. Two hundred and ninety-six subjects were included. Rates of patients with WBCM realization over 70%, 80%, and 90% of WBCM expected were, respectively, 78.1%, 70.0%, and 56.9% for subjects with schizophrenia and 71.3%, 63.2%, and 47.8% for PD subjects. Only hospitalization during the follow-up period for schizophrenia subjects was significantly associated with good WBCM realization.. We observed rather good results for compliance with clozapine initial monitoring. Other studies are needed to confirm our results.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Databases, Factual; Drug Monitoring; Female; France; Guideline Adherence; Hospitalization; Humans; Insurance, Health; Leukocyte Count; Male; Middle Aged; Schizophrenia

Topics: Agranulocytosis; Clozapine; Humans

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

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Drug Monitoring; Humans

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; COVID-19; Humans; SARS-CoV-2

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; HLA Antigens; Humans; Japan; Leukocyte Count; Schizophrenia

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; HLA Antigens; Humans; Leukocyte Count

Clozapine is the most effective antipsychotic drug for schizophrenia, yet it can cause life-threatening adverse drug reactions, including myocarditis. The aim of this study was to determine whether schizophrenia patients with clozapine-induced myocarditis have a genetic predisposition compared with clozapine-tolerant controls. We measured different types of genetic variation, including genome-wide single-nucleotide polymorphisms (SNPs), coding variants that alter protein expression, and variable forms of human leucocyte antigen (HLA) genes, alongside traditional clinical risk factors in 42 cases and 67 controls. We calculated a polygenic risk score (PRS) based on variation at 96 different genetic sites, to estimate the genetic liability to clozapine-induced myocarditis. Our genome-wide association analysis identified four SNPs suggestive of increased myocarditis risk (P < 1 × 10

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Genome-Wide Association Study; Humans; Myocarditis; Schizophrenia

Topics: Agranulocytosis; Amisulpride; Antipsychotic Agents; Clozapine; Granulocyte Colony-Stimulating Factor; Humans; Male; Middle Aged; Schizophrenia

Clozapine remains the only medication licensed for treating refractory schizophrenia. However, it remains underutilized in part due to concerns regarding adverse events.. Published literature.. Common adverse events during clozapine treatment include sedation, hypersalivation, postural hypotension, dysphagia, gastrointestinal hypomotility, weight gain, diabetes mellitus and dyslipidaemia. Rare but serious events include agranulocytosis, cardiomyopathy, myocarditis, pneumonia, paralytic ileus and seizure.. It remains unclear how best to minimize clozapine-induced morbidity/mortality (i) during dose titration, (ii) from hypersalivation and (iii) from gastrointestinal hypomotility. It is also unclear how clozapine pharmacokinetics are affected by (i) gastrointestinal hypomotility, (ii) systemic infection and (iii) passive exposure to cigarette smoke. Whether monthly haematological monitoring needs to continue after 12 months of uninterrupted therapy is also a subject of debate.. There is a need for better management of serious clozapine-related adverse events in addition to agranulocytosis. There is also a need for better education of patients and carers, general practitioners, A&E and ITU staff and others of the problems posed in using clozapine safely.. There is a need for more research on assessing clozapine dosage (i) as patients get older, (ii) with respect to exposure to cigarette smoke and (iii) optimizing response if adverse events or other factors limit dosage.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Delivery of Health Care; Humans; Schizophrenia

Less than 1% of adult patients with schizophrenia taking clozapine develop agranulocytosis, and most of these cases occur within the first weeks of treatment. The human leukocyte antigen (HLA) region has been associated with genetic susceptibility to clozapine-induced agranulocytosis (single amino acid changes in HLA-DQB1 (126Q) and HLA-B (158T)). The current study aimed to evaluate the cost-effectiveness, from a healthcare provider's perspective, of an HLA genotype-guided approach in patients with treatment-resistant schizophrenia who were taking clozapine and to compare the results with the current absolute neutrophil count monitoring (ANCM) schemes used in the USA. A semi-Markovian model was developed to simulate the progress of a cohort of adult men and women who received clozapine as a third-line antipsychotic medication. We compared current practices using two genotype-guided strategies: (1) HLA genotyping followed by clozapine, with ANCM only for patients who tested positive for one or both alleles (genotype-guided blood sampling); (2) HLA genotyping followed by clozapine for low-risk patients and alternative antipsychotics for patients who tested positive (clozapine substitution scheme). Up to a decision threshold of $3.9 million per quality-adjusted life-year (90-fold the US gross domestic product per capita), the base-case results indicate that compared with current ANCM, genotype-guided blood sampling prior to clozapine initiation appeared cost-effective for targeted blood monitoring only in patients with HLA susceptibility alleles. Sensitivity analysis demonstrated that at a cost of genotype testing of up to USD700, HLA genotype-guided blood monitoring remained a cost-effective strategy compared with either current ANCM or clozapine substitution.

Topics: Adult; Agranulocytosis; Alleles; Clozapine; Cohort Studies; Cost-Benefit Analysis; Female; Genetic Predisposition to Disease; Genotype; HLA-B Antigens; HLA-DQ beta-Chains; Humans; Male; Middle Aged; Pharmacogenomic Testing; Schizophrenia

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Colitis; Critical Illness; Cytomegalovirus; Cytomegalovirus Infections; Female; Humans; Middle Aged; Neutropenia; Schizophrenia

A 26-year-old man with history of schizophrenia was admitted for neutropaenia. He was started on clozapine 3 months prior to admission. As a result he had weekly monitoring of his blood counts and on day of admission was noted to have an absolute neutrophil count (ANC) of 450 cells/μL. He was admitted for clozapine-induced agranulocytosis. Clozapine was held and the patient was started on granulocyte colony-stimulating factor (G-CSF) filgrastim and received two doses without any signs of ANC recovery. On further review, it was noted that the absolute monocyte count (AMC) was also low and tracked with the trend of ANC. We then theorised that the impact of clozapine was on a haematopoietic precursor (colony-forming unit granulocyte-macrophage, CFU-GM) which gives rise to both monocytic and myeloid lineages. Therefore, sargramostim GM-CSF was started. After two doses, the ANC and AMC started trending up and by the third dose, both counts had fully recovered. He was discharged from the hospital and there are no plans to rechallenge with clozapine. Thus, we demonstrate a case of monocytopenia accompanying clozapine-induced agranulocytosis with successful use of GM-CSF. At least in this case, the target of the clozapine injury appears to be the CFU-GM, explaining the rapid and full response to GM-CSF after lack of response to G-CSF.

Topics: Adult; Agranulocytosis; Clozapine; Filgrastim; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Male; Monocytes; Neutropenia; Recombinant Proteins; Schizophrenia; Treatment Outcome

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

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clopenthixol; Clozapine; Drug Resistance; Drug Substitution; Drug Synergism; Drug Therapy, Combination; Humans; Male; Olanzapine; Schizophrenia, Paranoid; Valproic Acid

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Female; Humans; Middle Aged; Schizophrenia, Paranoid

Topics: Agranulocytosis; Antimanic Agents; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Humans; Lithium Compounds; Male; Middle Aged; Schizophrenia

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Eosinophils; Humans; Leukocyte Count; Male; Middle Aged; Predictive Value of Tests

Blood dyscrasias excluding agranulocytosis received limited attention in antipsychotic-treated patients during the first 18 weeks of therapy, although severe clinical conditions have been reported in a few cases. We extracted data records of 285 Caucasian patients after 18 weeks of antipsychotic treatments to investigate risk factors of blood dyscrasias. We observed a higher risk to develop both transient and persistent anemia, neutrophilia and eosinophilia in clozapine-treated patients, whereas in those treated with other atypical antipsychotics when compared to a reference group under typical antipsychotics, emerged an increased risk for transient neutrophilia and eosinophilia. Male patients revealed a higher risk of persistent eosinophilia, neutrophilia, and leukocytosis. Concomitant treatments with mood stabilizers or benzodiazepines proved to be risk factors for transient anemia, antidepressants for transient eosinophilia. Severe complications emerged in 3 cases of agranulocytosis. Cross-tabulation analysis showed a higher probability of a poor response in clozapine-treated patients with persistent anemia and a positive with persistent neutrophilia and eosinophilia. Our data evidenced that emerging blood dyscrasias were not associated with critical adverse effects, and only agranulocytosis required a treatment interruption. Other atypical antipsychotics might represent a viable alternative to potentially harmful clozapine and typical antipsychotics at the onset of life-threatening haematological alterations.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Clozapine; Female; Humans; Male; Middle Aged; Paraproteinemias; Retrospective Studies; Risk Factors; Time Factors

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Humans; Neutropenia

Clozapine-induced agranulocytosis, a potentially serious adverse effect, is a limiting factor for its therapeutic use, leading to the suspension of the drug. Its annual incidence in Argentina is 0.05%. In 2000, under provision number 935, the ANMAT approved the Monitoring Program for Ambulatory and Inpatient Patients Treated with Clozapine. In this provision arises the obligation to sign the informed consent where the patient is informed of the risks and benefts of the treatment. In psychiatric care practice patients may not possess, because of their altered psychic state, the level of competence necessary to sign informed consent for their treatment with clozapine. The objective of the present work is to analyze the doctrine of Informed Consent by Representation for the users of clozapine, as well as to propose a decision algorithm for its application in clinical practice.

Topics: Agranulocytosis; Algorithms; Antipsychotic Agents; Argentina; Clozapine; Humans; Third-Party Consent

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

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

Use of the atypical antipsychotic clozapine (CZP) is compromised by the risk of potentially fatal agranulocytosis/granulocytopenia (CIAG). To address this, we have established a simple, personalized cell culture-based strategy to identify CIAG-susceptible patients, hypothesizing that an immunogenic and possibly haptene-based mechanism underlies CIAG pathophysiology. To detect a putative haptene-induced response to CZP in vitro exposure, a traditional lymphocyte stimulation assay was adapted and applied to patient-specific peripheral blood-derived mononuclear cells (PBMC). 6 patients with a history of CIAG, 6 patients under CZP treatment (without CIAG) and 12 matched healthy controls were studied. In vitro CZP exposure, even at strikingly low levels, resulted in significantly increased proliferation rates only in CIAG patients' PBMC. Other parameters including cell viability and mitogen-induced proliferation were also affected by in vitro CZP exposure, yet there was no significant difference between the groups. This personalized approach is a starting point for further investigations into a putative haptene-based mechanism underlying CIAG development, and may facilitate the future development of predictive testing.

Topics: Agranulocytosis; Antipsychotic Agents; Cell Proliferation; Cell Survival; Cells, Cultured; Clozapine; Dose-Response Relationship, Drug; Humans; Immunity, Cellular; Leukocytes, Mononuclear; Schizophrenia

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Granulocyte Colony-Stimulating Factor; Humans; Male; Schizophrenia, Paranoid; Treatment Outcome

Clozapine-induced agranulocytosis (CIA)/clozapine-induced granulocytopenia (CIG) (CIAG) is a life-threatening event for schizophrenic subjects treated with clozapine.. To examine the genetic factor for CIAG, a genome-wide pharmacogenomic analysis was conducted using 50 subjects with CIAG and 2905 control subjects.. We identified a significant association in the human leukocyte antigen (HLA) region (rs1800625, p = 3.46 × 10(-9), odds ratio [OR] = 3.8); therefore, subsequent HLA typing was performed. We detected a significant association of HLA-B*59:01 with CIAG (p = 3.81 × 10(-8), OR = 10.7) and confirmed this association by comparing with an independent clozapine-tolerant control group (n = 380, p = 2.97 × 10(-5), OR = 6.3). As we observed that the OR of CIA (OR: 9.3~15.8) was approximately double that in CIG (OR: 4.4~7.4), we hypothesized that the CIG subjects were a mixed population of those who potentially would develop CIA and those who would not develop CIA (non-CIA). This hypothesis allowed the proportion of the CIG who were non-CIA to be calculated, enabling us to estimate the positive predictive value of the nonrisk allele on non-CIA in CIG subjects. Assuming this model, we estimated that 1) ~50% of CIG subjects would be non-CIA; and 2) ~60% of the CIG subjects without the risk allele would be non-CIA and therefore not expected to develop CIA.. Our results suggest that HLA-B*59:01 is a risk factor for CIAG in the Japanese population. Furthermore, if our model is true, the results suggest that rechallenging certain CIG subjects with clozapine may not be always contraindicated.

Topics: Adult; Agranulocytosis; Alleles; Asian People; Case-Control Studies; Clozapine; Female; Genetic Predisposition to Disease; Genotype; Histocompatibility Testing; HLA-B Antigens; Humans; Male; Pharmacogenomic Testing; Risk Factors; Sensitivity and Specificity; Young Adult

Clozapine use is associated with leukopenia and more rarely agranulocytosis, which may be lethal. The drug and its metabolites are proposed to interact with the multidrug resistance transporter (ABCB1/MDR1) gene product, P-glycoprotein (P-gp). Among various P-glycoprotein genetic polymorphisms, nucleotide changes in exons 26 (C3435T), 21 (G2677T), and 12 (C1236T) have been implicated for changes in pharmacokinetics and pharmacodynamics of many substrate drugs. In this study, we aimed to investigate the association between these specific ABCB1 polymorphisms and clozapine-associated agranulocytosis (CAA). Ten patients with a history of CAA and 91 control patients without a history of CAA, despite 10 years of continuous clozapine use, were included. Patient recruitment and blood sample collection were conducted at the Hacettepe University Faculty of Medicine, Department of Psychiatry, in collaboration with the members of the Schizophrenia and Other Psychotic Disorders Section of the Psychiatric Association of Turkey, working in various psychiatry clinics. After DNA extraction from peripheral blood lymphocytes, genotyping was performed using polymerase chain reaction and endonuclease digestion. Patients with CAA had shorter duration of clozapine use but did not show any significant difference in other clinical, sociodemographic characteristics and in genotypic or allelic distributions of ABCB1 variants and haplotypes compared with control patients. Among the 10 patients with CAA, none carried the ABCB1 all-variant haplotype (TT-TT-TT), whereas the frequency of this haplotype was approximately 12% among the controls. Larger sample size studies and thorough genetic analyses may reveal both genetic risk and protective factors for this serious adverse event.

Topics: Adolescent; Adult; Aged; Agranulocytosis; Alleles; Antipsychotic Agents; ATP Binding Cassette Transporter, Subfamily B; Clozapine; Humans; Middle Aged; Pharmacogenomic Variants; Schizophrenia; Turkey; Young Adult

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Drug Monitoring; Humans; Schizophrenia; United States

US FDA decision to change their clozapine monitoring guidelines in 2015 for the first time. The changes proposed are as follows: lowering the neutrophil count before ceasing clozapine from 1.5 to 1.0×10(9)/l, allowing the potential for re-challenge following severe neutropenia (<1.0×10(9)/l) and allowing those with benign ethnic neutropenia the opportunity to be commenced on clozapine. These changes will allow a greater number of patients with schizophrenia in USA to be continued on clozapine. In our correspondence we summarize the evidence that support these changes. The FDA changes will likely have impact on clozapine monitoring protocols in other countries.

Topics: Agranulocytosis; Clozapine; Drug Monitoring; Guidelines as Topic; Humans; Neutropenia; United States; United States Food and Drug Administration

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Granulocyte Colony-Stimulating Factor; Humans; Male; Psychotic Disorders; Recurrence; Young Adult

The risks of severe leukopenia and agranulocytosis have varied over time and among geographical regions and cultures, with little information available on South American populations. Accordingly, we reviewed and analyzed data from a 6-year experience monitored by an Argentine national registry to which reporting of adverse events reports is required. We analyzed data for 2007-2012 from the pharmacovigilance program of the Argentine drug-regulatory agency (ANMAT) using standard bivariate and multivariate statistical methods and survival analysis. We identified 378 cases of adverse hematological events over 6 years among an average of 12 305 individuals/year treated with clozapine (308±133 mg/day) to estimate the mean annualized rates of leukopenia [0.19 (95% confidence interval [CI] 0.11-0.27)], neutropenia [0.38 (95% CI 0.34-0.43)], and agranulocytosis [0.05 (95% CI 0.02-0.08)] % per year [median latency 2 (95% CI 1.3-2.1) months]; fatalities related to agranulocytosis averaged 4.2 (95% CI 0.0-9.2) per 100 000 treated individuals/year. Factors associated significantly and independently with agranulocytosis were female sex, older age, and use of other drugs in addition to clozapine. With monitoring by international standards, recent risks of clozapine-associated agranulocytosis in Argentina were lower, but fatality rates were higher than that in other regions of the world. Risk factors include the use of multiple psychotropic drugs, female sex, and older age.

Topics: Adult; Age Distribution; Agranulocytosis; Antipsychotic Agents; Argentina; Clozapine; Female; Humans; Leukopenia; Male; Middle Aged; Neutropenia; Registries; Risk Factors

Clozapine is the only evidence-based therapy for treatment-resistant schizophrenia, but it induces agranulocytosis, a rare but potentially fatal haematological adverse reaction, in less than 1% of users. To improve safety, the drug is subject to mandatory haematological monitoring throughout the course of treatment, which is burdensome for the patient and one of the main reasons clozapine is underused. Therefore, a pharmacogenetic test is clinically useful if it identifies a group of patients for whom the agranulocytosis risk is low enough to alleviate monitoring requirements. Assuming a genotypic marker stratifies patients into a high-risk and a low-risk group, we explore the relationship between test sensitivity, group size and agranulocytosis risk. High sensitivity minimizes the agranulocytosis risk in the low-risk group and is essential for clinical utility, in particular in combination with a small high-risk group.

Topics: Agranulocytosis; Clozapine; Drug Hypersensitivity; Female; HLA-DQ beta-Chains; Humans; Pharmacogenetics; Polymorphism, Single Nucleotide; Risk Factors; Schizophrenia

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Genetic Testing; HLA Antigens; Humans; Pharmacogenetics

Clozapine is the treatment of choice in drug-resistant schizophrenia. Lamotrigine is a mood stabiliser recommended as combined treatment strategy in clozapine-resistant patients. There are cases of late-onset agranulocytosis reported in literature. Some are associated with clozapine or lamotrigine, others with the combination of both.. The article presents a case of rapid-onset agranulocytosis in a 60-year old clozapine-resistant patient, in whom lamotrigine was introduced as potentiation strategy. Discontinuation of both substances and GCSF treatment resulted in normalization of the absolute neutrophil count.. The case suggests a possibility of developing rapid-onset agranulocytosis in clozapine-resistant patients who require lamotrigine as augmentation strategy. This emphasises the significance of monitoring a patient's blood count and early management of any dyscrasias noticed.

Topics: Agranulocytosis; Clozapine; Drug Therapy, Combination; Female; Humans; Lamotrigine; Leukocyte Count; Middle Aged; Neutrophils; Schizophrenia, Paranoid; Time Factors; Triazines

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Humans; Leukocyte Count; Neutrophils; Schizophrenia

To examine the rate of neutropenia and agranulocytosis, and the pattern of development of these 2 disorders among Chinese patients prescribed clozapine treatment in a local psychiatric unit.. Patients who were receiving clozapine when they were under the care of Pamela Youde Nethersole Eastern Hospital Psychiatric Unit, Hong Kong, from 1 January 1997 to 31 December 2012 and who developed neutropenia and agranulocytosis from 1 January 1997 to 30 June 2013 were retrospectively reviewed.. A total of 13 patients out of 980 clozapine recipients developed neutropenia and 3 developed agranulocytosis during treatment. Half of them were aged > 50 years and three quarters were female. The majority of patients who developed neutropenia and agranulocytosis were prescribed > 1 psychotropic medication in addition to clozapine. Half of the incidents occurred in the first 18 weeks of clozapine treatment.. Long-term monitoring of white cell count is necessary during clozapine treatment. The concurrent use of clozapine with other potentially leukopenic psychotropic drugs should be limited.

Topics: Adult; Aged; Agranulocytosis; Antipsychotic Agents; Clozapine; Female; Hong Kong; Humans; Leukocyte Count; Male; Middle Aged; Neutropenia; Retrospective Studies; Schizophrenia

Topics: Agranulocytosis; Antipsychotic Agents; Case-Control Studies; Clozapine; Exome; Female; Finland; Gene Frequency; Genetic Variation; Genotype; HLA-DQ beta-Chains; Humans; Male; Psychotic Disorders; Schizophrenia

Amodiaquine (AQ) and clozapine (CLZ) are associated with a relatively high incidence of idiosyncratic agranulocytosis, a reaction that is suspected to involve covalent binding of reactive metabolites to neutrophils. Previous studies have shown that both AQ and CLZ are oxidized to reactive intermediates in vitro by activated neutrophils or by the combination of hydrogen peroxide and myeloperoxidase (MPO). Neutrophil activation leads to an oxidative burst with activation of NADPH oxidase and the production of hydrogen peroxide. However, the importance of this pathway in covalent binding in vivo has not been examined. In this study, we found that the binding of both AQ and CLZ to neutrophils from MPO knockout mice ex vivo decreased approximately 2-fold compared to neutrophils from wild-type mice, whereas binding to activated neutrophils from gp91 knockout (NADPH oxidase null) mice decreased 6-7-fold. When the AQ studies were performed in vivo, again the binding was decreased in MPO knockout mice to about 50% of the binding in wild-type mice; however, covalent binding was significant in the absence of MPO. Surprisingly, there was no significant decrease in covalent binding of AQ to neutrophils in vivo in gp91 knockout mice. In addition, there was extensive binding of AQ to many types of bone marrow cells and to peripheral lymphocytes. These results indicate that MPO is not the only neutrophil enzyme involved in the oxidation of AQ and that NADPH oxidase is not the major source of peroxide. There was also no decrease in AQ binding to neutrophils in COX-1 or COX-2 knockout mice. We were not able to readily reproduce the AQ in vivo studies with CLZ because of its acute toxicity in mice. These are the first studies to examine the enzymes involved in the bioactivation of AQ by neutrophils in vivo.

Topics: Agranulocytosis; Amodiaquine; Animals; Clozapine; Electrophoresis, Polyacrylamide Gel; Enzyme-Linked Immunosorbent Assay; Female; Mice; Mice, Knockout; NADPH Oxidases; Neutrophils; Peroxidase; Protein Binding; Rats; Rats, Sprague-Dawley

Clozapine is effective in the treatment of schizophrenia; however, its use is limited by a relatively high incidence of idiosyncratic agranulocytosis. The mechanism of clozapine-induced idiosyncratic agranulocytosis is unknown. Although most patients treated with clozapine do not develop agranulocytosis, most do have an immune response with an increase in inflammatory cytokines such as IL-6 and a release of immature neutrophils with neutrophilia rather than agranulocytosis. We have previously shown that treatment of rabbits with clozapine also causes an early release of neutrophils. Clozapine is oxidized to a reactive nitrenium ion that covalently binds to neutrophils, and this reactive metabolite may be responsible for the observed effects. Olanzapine and clozapine have very similar structures, and olanzapine is also oxidized to a reactive nitrenium ion; however, if it ever causes agranulocytosis, the incidence is much lower than that of clozapine. One possible basis for the difference in incidence of agranulocytosis between clozapine and olanzapine is that the therapeutic dose of olanzapine is much lower than that of clozapine. In this study, we compared the effects of clozapine and olanzapine in Sprague-Dawley rats at an equimolar dose and found that only clozapine had a significant effect on neutrophil kinetics. This suggests that the immune response and effects on neutrophil kinetics induced by clozapine are related to its ability to cause agranulocytosis.

Topics: Agranulocytosis; Animals; Antipsychotic Agents; Benzodiazepines; Bone Marrow; Clozapine; Female; Femur; Kinetics; Leukocyte Count; Neutrophils; Olanzapine; Rats, Sprague-Dawley; Tibia

Clozapine is a particularly effective antipsychotic medication but its use is curtailed by the risk of clozapine-induced agranulocytosis/granulocytopenia (CIAG), a severe adverse drug reaction occurring in up to 1% of treated individuals. Identifying genetic risk factors for CIAG could enable safer and more widespread use of clozapine. Here we perform the largest and most comprehensive genetic study of CIAG to date by interrogating 163 cases using genome-wide genotyping and whole-exome sequencing. We find that two loci in the major histocompatibility complex are independently associated with CIAG: a single amino acid in HLA-DQB1 (126Q) (P=4.7 × 10(-14), odds ratio (OR)=0.19, 95% confidence interval (CI)=0.12-0.29) and an amino acid change in the extracellular binding pocket of HLA-B (158T) (P=6.4 × 10(-10), OR=3.3, 95% CI=2.3-4.9). These associations dovetail with the roles of these genes in immunogenetic phenotypes and adverse drug responses for other medications, and provide insight into the pathophysiology of CIAG.

Topics: Agranulocytosis; Alleles; Amino Acid Substitution; Antipsychotic Agents; Case-Control Studies; Clozapine; Exome; Gene Frequency; Genetic Predisposition to Disease; Genome-Wide Association Study; Heterozygote; HLA-B Antigens; HLA-DQ beta-Chains; Humans; Odds Ratio; Psychotic Disorders; Severity of Illness Index

Although many patients with schizophrenia fail to respond adequately to trials of 2 or more antipsychotics, utilization of clozapine for these patients remains low, despite recommendations for its use by accepted treatment guidelines. Some experts estimate that 5-10 times more patients could benefit from clozapine than who are now receiving it. Learning how to manage the unique side effect profile of clozapine can potentially remove barriers to prescribing this agent and thus unlock its unique therapeutic efficacy for more patients.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Constipation; Diabetes Mellitus; Eosinophilia; Humans; Myocarditis; Neuroleptic Malignant Syndrome; Neutropenia; Practice Guidelines as Topic; Practice Patterns, Physicians'; Schizophrenia; Sialorrhea; Tachycardia; Weight Gain

Late-onset agranulocytosis is rare during treatment with clozapine, especially in monotherapy. The authors describe a case of agranulocytosis that emerged after 19 years of continuous clozapine monotherapy. The discovery of the agranulocytosis was due to the lifelong white blood cell counts that are now required for clozapine treatment. Despite the fact that this requirement probably saved the life of this patient, this monitoring is not evidence-based because the incidence of agranulocytosis does not exceed that of conventional antipsychotic drugs, for which no such requirement exists. For mentally competent and adequately informed patients, the Netherlands Clozapine Collaboration Group now permits quarterly monitoring after the first 6 months of clozapine treatment.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Basophils; Clozapine; Humans; Leukocyte Count; Male; Neutrophils

The aim of the study was to estimate the maximum incidence of agranulocytosis which clozapine would have caused between 2006 and 2010 had there been no blood monitoring system; and to determine the number of clozapine-associated cases of agranulocytosis and related deaths recorded between 1993 and 2011.. Records associating clozapine use with white blood cell deficiency (WBCD), in the Therapeutic Goods Administration's Case Line Listing of adverse drug reactions, were examined. The figure of 11,000 was used as the population on clozapine each year from 2006-2010.. Between 2006 and 2010 there were 209 cases of clozapine-associated WBCD recorded, probably caused by clozapine in 141 cases. WBCD caused by clozapine could have progressed to agranulocytosis if clozapine had not been withdrawn. The risk of WBCD/agranulocytosis decreased with increasing duration of clozapine use. Between 1993 and 2011 there were 141 recorded cases of agranulocytosis, and four deaths, from clozapine-associated WBDC.. During 2006-2010, without any monitoring system, the maximum annual incidence of agranulocytosis caused by clozapine would have been 0.26%. The risks of agranulocytosis, and related deaths, decreased with length of time on clozapine. During 1993-2011 141 cases of agranulocytosis, with four deaths, were recorded in association with clozapine use. The monitoring system could have successfully prevented relatively few deaths.

Topics: Agranulocytosis; Australia; Clozapine; Drug Monitoring; Humans; Incidence; Risk Factors

Topics: Agranulocytosis; Antipsychotic Agents; Chronic Disease; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Substitution; Follow-Up Studies; Humans; Injections, Intramuscular; Leukocyte Count; Male; Medication Adherence; Middle Aged; Neutropenia; Neutrophils; Schizophrenia, Paranoid

Clozapine is reserved for overcoming treatment resistance in schizophrenia. Malignancy is common in schizophrenia; however, there is limited evidence available on continuing clozapine with chemotherapy, with both having hematological adverse effects.. To report a case on the use of granulocyte colony-stimulating factor (G-CSF) in conjunction with clozapine and chemotherapy.. We searched PubMed for any available information on the use of granulocyte G-CSF with clozapine and chemotherapy. We report the case of a patient with schizophrenia who developed B-cell lymphoma and was treated with chemotherapy consisting of CHOP regimen, rituximab, and methotrexate. He was continued on clozapine and G-CSF.. We did not find any reports on G-CSF use in conjunction with clozapine and chemotherapy. We found case reports and a case series on the use of G-CSF in clozapine rechallenge with clozapine-induced agranulocytosis with mixed results. In our patient on clozapine, the white blood cell counts reduced by chemotherapy, were successfully replenished with the use of filgrastim, a G-CSF.. With risks of psychosis relapse and exacerbation with discontinuing clozapine, the addition of G-CSF could be a useful aid in replenishing white cell counts lost to chemotherapy whilst continuing clozapine. However, further study is needed on this combination.

Topics: Agranulocytosis; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antipsychotic Agents; Clozapine; Cyclophosphamide; Doxorubicin; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Lymphoma, B-Cell; Male; Methotrexate; Middle Aged; Prednisone; Recombinant Proteins; Rituximab; Schizophrenia; Treatment Outcome; Vincristine

Early and effective treatment in first-episode schizophrenia is associated with better outcomes. Evidence suggests that response is generally robust in a first antipsychotic trial, but a marked reduction in response rate is observed among patients for whom a second trial is warranted, and even further reductions are seen in subsequent trials. Clozapine, the treatment of choice in refractory schizophrenia, is routinely employed only as a third-line treatment, and it has been shown to markedly enhance the rate of response, even when compared with other atypical antipsychotics. This raises the question of whether clozapine would be more effectively positioned as a first-line treatment. Current evidence addressing this question does not support this position, although the limited data available and methodological issues preclude a firm conclusion. Practical issues related to clozapine use, in combination with the robust response reported for other agents when used as first-line treatment, certainly call into question the likelihood that clozapine would be chosen if it were an option at this stage. In contrast, the notable reduction in response rate to second-line treatments, coupled with clozapine's substantial response rate in refractory schizophrenia and evidence indicating better outcomes with early, effective treatment, makes a compelling argument for research examining clinical and functional outcomes with clozapine positioned as a second-line treatment.

Topics: Age of Onset; Agranulocytosis; Algorithms; Antipsychotic Agents; Clozapine; Drug Monitoring; Drug Resistance; Drug Tolerance; Episode of Care; Humans; Medication Therapy Management; Outcome and Process Assessment, Health Care; Pharmacovigilance; Schizophrenia; Treatment Outcome; Weight Gain

Recent studies suggest that restrictions on the use of clozapine should be reassessed considering the risk-benefit ratio. We analyzed all cases of clozapine-induced agranulocytosis reported to the Finnish National Agency for Medicines between 1982 and 2007.. In this retrospective longitudinal study, we defined agranulocytosis as a neutrophil count below 0.5 × 10⁹/L and, accordingly, identified a total of 163 patients with clozapine-induced agranulocytosis. We collected all available information on patient demography, as well as on daily clozapine doses, treatment duration, concomitant medication prior to the onset of agranulocytosis, and infections during the adverse event. The amount of clozapine used annually in Finland was estimated on the basis of the defined daily dose, and the frequency of agranulocytosis was calculated from the absolute number of cases in relation to the defined daily dose each year, as reported by the Finnish National Agency for Medicines.. In 10.3% of cases, agranulocytosis occurred after the second treatment year, and, in some patients, agranulocytosis occurred even after 13, 14, and 22 years of clozapine treatment. Strikingly, a total of 40% of all patients and 80% of those with fatal agranulocytosis had received, concomitantly with clozapine, other medication associated with agranulocytosis.. Some restrictions and long-term blood monitoring during the use of clozapine are still needed. In addition, we raise the question of whether guidelines for concomitant use of drugs associated with agranulocytosis during clozapine therapy are warranted.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Agranulocytosis; Antipsychotic Agents; Clozapine; Female; Finland; Humans; Longitudinal Studies; Male; Middle Aged; Retrospective Studies; Risk Factors; Time Factors

Clozapine was the first of the atypical antipsychotics to be developed, but its use has been restricted because of toxicity issues, particularly the risk of potentially life-threatening drug-induced neutropenia and agranulocytosis, which occurs in about 1% of patients. Bioactivation of clozapine by peroxidases forms a reactive nitrenium ion, which covalently adducts to protein and leads to neutrophil toxicity. The current generation of clozapine-inspired atypical antipsychotics has reduced toxicity through improved potency/decreased dose or through structural modification to prevent peroxidase-catalyzed nitrenium ion formation. Through the substitution of sulfur for the bridging nitrogen found in clozapine, quetiapine does not directly form a nitrenium ion when incubated with myeloperoxidase/H(2)O(2). We present evidence that cytochrome P450 2D6 catalyzes the formation of 7-hydroxyquetiapine, which can be oxidized by human myeloperoxidase to form a reactive quinone-imine and a reactive radical, which may account for the continued, although reduced, neutrophil toxicity. In the presence of myeloperoxidase/H(2)O(2) and glutathione, covalent 7-hydroxyquetiapine-glutathione adducts were formed. Bioactivation of quetiapine was verified in vivo in rat where three 7-hydroxyquetiapine-mercaptate adducts and a 7-hydroxyquetiapine-glutathione adduct were detected from bile after oral dosing. The decreased incidence of agranulocytosis with quetiapine over clozapine is postulated to be due to the lower exposure of the toxic precursor, 7-hydroxyquetiapine versus clozapine, respectively.

Topics: Agranulocytosis; Animals; Antipsychotic Agents; Clozapine; Cyanides; Cytochrome P-450 CYP2D6; Dibenzothiazepines; Female; Glutathione; Horseradish Peroxidase; Humans; Male; Neutropenia; Peroxidase; Quetiapine Fumarate; Rats; Rats, Sprague-Dawley

Agranulocytosis is a very serious side-effect of treatment with clozapine. For this reason, the Dutch guidelines state the specific values of leukocyte and neutrophil counts at which treatment with clozapine should be discontinued. We focus on a patient with a benign ethnic neutropenia who, despite a low neutrophil count, was allowed to continue taking clozapine. We discuss a number of important practical considerations that can affect the way in which leukocyte and neutrophil counts are interpreted in relation to the use of clozapine.

Topics: Agranulocytosis; Antipsychotic Agents; Blood Cell Count; Clozapine; Humans; Leukocyte Count; Male; Neutropenia; Neutrophils; Schizophrenia; Young Adult

Clozapine is considered to be the most efficacious drug to treat schizophrenia, although it is underutilized, partially due to a side effect of agranulocytosis. This analysis of 74 candidate genes was designed to identify an association between sequence variants and clozapine-induced agranulocytosis (CIA).. Blood and medical history were collected for 33 CIA cases and 54 clozapine-treated controls enrolled between April 2002 and December 2003. Significant markers from 4 genes were then assessed in an independently collected case-control cohort (49 CIA cases, 78 controls).. Sequence variants in 5 genes were found to be associated with CIA in the first cohort: HLA-DQB1, HLA-C, DRD1, NTSR1, and CSF2RB. Sequence variants in HLA-DQB1 were also found to be associated with CIA in the second cohort. After refinement analyses of sequence variants in HLA-DQB1, a single SNP (single nucleotide polymorphism), 6672G>C, was found to be associated with risk for CIA; the odds of CIA are 16.9 times greater in patients who carry this marker compared to those who do not.. A sequence variant (6672G>C) in HLA-DQB1 is associated with increased risk for CIA. This marker identifies a subset of patients with an exceptionally high risk of CIA, 1,175% higher than the overall clozapine-treated population under the current blood-monitoring system. Assessing risk for CIA by testing for this and other genetic variants yet to be determined may be clinically useful when deciding whether to begin or continue treatment with clozapine.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Case-Control Studies; Clozapine; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; HLA-DQ Antigens; HLA-DQ beta-Chains; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Young Adult

Clozapine is a well-known drug that is used in treatment-resistant schizophrenia, but granulocytopenia, which may lead to a potentially fatal condition such as agranulocytosis, limit its use. The question about which antipsychotic should be used after a diagnosis of clozapine-associated granulocytopenia is difficult to answer, because antipsychotics other than clozapine may also have hematologic toxicity, or they may prolong clozapine-associated granulocytopenia. In this study, we aimed to find out the incidence of clozapine-associated granulocytopenia in our treatment sample and discuss suitable antipsychotic drug options in terms of hematologic toxicity, for management of clozapine-associated granulocytopenia.. One thousand five hundred twenty-four schizophrenia patients, treated with clozapine, were included in the study.. Patients' white blood cell counts were monitored closely. Should granulocytopenia related to clozapine be diagnosed, clozapine was stopped immediately, and a new antipsychotic that the patient did not have a history of use was begun, according to the clinical profile of the patient. Persistent low white blood cell count after the 10th day of cessation of clozapine was accepted as prolongation effect.. Of the 1524 schizophrenia patients, 18 were diagnosed to have granulocytopenia, which means that 1.18% of the clozapine users developed granulocytopenia related to clozapine. Six of the patients were treated with olanzapine, 5 patients were treated with quetiapine, 1 patient was treated with risperidone, and 6 patients were treated with amisulpride after clozapine is stopped. None of the patients treated with risperidone or amisulpride showed prolonged low white blood cell count. Two of the patients treated with olanzapine (33.3%) and 2 of the patients treated with quetiapine (40.0%) showed prolonged leukopenia.. It is noteworthy that 33.3% of the patients treated with olanzapine and 40.0% of the patients treated with quetiapine showed prolonged leukopenia. This finding is also consistent with the literature that declares higher numbers of cases about prolongation of clozapine-associated granulocytopenia for olanzapine and quetiapine than risperidone and amisulpride. After switching to another antipsychotic drug, close monitoring of white blood cell count on a daily basis for the first 2 weeks should be continued until white blood cell counts are stabilized. Quetiapine and olanzapine especially need attention after clozapine-associated granulocytopenia. Further studies with larger series and longer follow-up should be carried out.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Drug Substitution; Female; Follow-Up Studies; Humans; Male; Middle Aged; Schizophrenia; Young Adult

Topics: Adult; Agranulocytosis; Alleles; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Clozapine; Genetic Variation; Humans; Male; Schizophrenia, Paranoid; Twins, Monozygotic

Despite its superior efficacy, clozapine is typically reserved for treatment-refractory schizophrenia due to the risk of agranulocytosis with an occurrence of up to 1% in recipients. The FDA has rigid treatment guidelines for hematologic monitoring for clozapine patients. If the white blood cell (WBC) count or absolute neutrophil count (ANC) falls below predetermined values, clozapine treatment must be held or discontinued. Diurnal and ethnic variations in complete blood count (CBC) values, somewhat dependent upon blood sampling time have been reported, and called pseudoneutropenia, which appears independent of clozapine therapy. Unnecessary treatment interruption or discontinuation is costly and may lead to disease relapse. The purpose of this study was to evaluate the effect of a time change in CBC sampling on WBC and ANC values in a group of clozapine patients in a regional public inpatient psychiatric facility.. Facility CBC sampling for clozapine patients was switched from 0630 to on or after 0830. A retrospective record review was conducted for all patients who were receiving clozapine before and after the time switch, with a minimum of six values pre- and post-change. CBC values sampled on or after 0830 were accepted as applicable post data, as patients are awakened daily at 0630, and a minimum of two hours of wakefulness/mobility had occurred. Patient medical records, automated lab information system, and the Clozapine National Registry were data sources. Data extracted included WBC/ANC values (with date/time of sampling) and demographic information (DOB, sex, weight, height, BMI, and ethnicity). The data were analyzed using repeated measures ANOVA.. Ten patients (80% male, 90% Caucasian, mean age=55.7 years) met study criteria. The difference in the pre/post time change WBC values was marginally significant (mean increase=667/mm3, p=.07), with a significant difference (mean increase=1,130/mm3, p=.003) between the pre/post time change ANC values. ANC values were more positively impacted by the sampling time change than WBC values in this sample. The mean sampling time change across all subjects pre/post was 5 hours 24 minutes.. All reasonable steps should be considered to safely continue an effective therapy in treatment-refractory schizophrenia. A larger, more ethnically diverse sample is needed to validate the present work; however, changing the timing of CBC sampling for clozapine patients from early morning to after a minimum two-hour period of wakefulness/movement may have potential to improve WBC and ANC values. Marginal improvements in resultant WBC/ANC values could potentially allow clozapine therapy to continue uninterrupted per FDA monitoring guidelines.

Topics: Adult; Aged; Agranulocytosis; Antipsychotic Agents; Blood Cell Count; Blood Specimen Collection; Circadian Rhythm; Clozapine; Drug Monitoring; Drug Resistance; Female; Hospitalization; Humans; Leukocyte Count; Male; Middle Aged; Neutropenia; Neutrophils; Predictive Value of Tests; Reference Values; Retrospective Studies; Schizophrenia; United States; United States Food and Drug Administration

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: Agranulocytosis; Antipsychotic Agents; Clinical Protocols; Clozapine; Female; Humans; Middle Aged; Schizophrenia

Topics: Adult; Agranulocytosis; Anticonvulsants; Antipsychotic Agents; Clozapine; Female; Humans; Lamotrigine; Schizophrenia, Paranoid; Time Factors; Triazines

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Female; Genotype; HLA-DQ beta-Chains; Humans; Polymorphism, Single Nucleotide; Psychotic Disorders

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Granulocyte Colony-Stimulating Factor; Humans; Male; Middle Aged; Neutropenia; Paraproteinemias; Schizophrenia; Severity of Illness Index

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Drug Monitoring; Humans; Paraproteinemias; Risk Factors

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Humans; Schizophrenia

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

Clozapine is an atypical antipsychotic drug effective in the treatment of refractory schizophrenia; however, its use is limited due to its propensity to cause agranulocytosis in some patients. Little is known about the mechanism of idiosyncratic drug-induced agranulocytosis, in part because of the lack of a valid animal model. Clozapine is oxidized by activated human neutrophils and bone marrow cells to a reactive nitrenium ion by the myeloperoxidase-hydrogen peroxide system of neutrophils. This reactive metabolite has been shown in vitro to induce the apoptosis of neutrophils and bone marrow cells. While in vitro studies demonstrated the toxic potential of clozapine upon oxidation, it is not clear if similar conditions occur in vivo. In response to the difficulties encountered with detecting apoptotic neutrophils in vivo, we conducted a series of studies in rabbits using two fluorescent cell-labeling techniques to study the effect of clozapine treatment on neutrophil kinetics, that is, their rates of production and removal from circulation. The fluorescein dye, 5-(and-6)-carboxyfluorescein diacetate succinimidyl ester (CFSE), was used as a general cell label to measure the half-life of neutrophils in blood. In addition, the thymidine analogue, 5-bromo-2-deoxyuridine (BrdU), was used to label dividing cells, thus enabling the measurement of the efflux of neutrophils from the bone marrow. Clozapine, indeed, increased the rate of both the release of neutrophils from the bone marrow and their subsequent disappearance from circulation. Failure of the bone marrow to compensate for a shorter neutrophil half-life could lead to agranulocytosis. Alternatively, the damage to neutrophils caused by clozapine could, in some patients, lead to an immune-mediated response against neutrophils resulting in agranulocytosis.

Topics: Agranulocytosis; Animals; Antipsychotic Agents; Apoptosis; Clozapine; Deoxyuridine; Female; Fluoresceins; Fluorescent Dyes; Half-Life; Humans; Neutrophils; Rabbits; Reactive Nitrogen Species; Succinimides

Topics: Adult; Aged; Agranulocytosis; Antipsychotic Agents; Bone Marrow Cells; Cells, Cultured; Clozapine; Fibroblasts; Humans; Male; Mesenchymal Stem Cells; Young Adult

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Humans; Leukocyte Count; Netherlands; Practice Guidelines as Topic; Schizophrenia

Clozapine is an effective antipsychotic drug for the treatment of therapy-resistant schizophrenia. Mandatory screening of white blood cells is a safety measure for the early detection of agranulocytosis caused by treatment with clozapine. However, so far, there is no standard screening for two other potentially lethal side-effects, namely diabetic ketoacidosis and gastro-intestinal hypomotility. The current situation is weighed up on the basis of a comparison of the chances that these side-effects can occur and cause death. The conclusion is that weekly or monthly screening should be carried out for all these side-effects.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Diabetic Ketoacidosis; Gastrointestinal Motility; Humans; Leukocyte Count; Schizophrenia

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Resistance; Drug Therapy, Combination; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Recombinant Proteins; Schizophrenia

Clozapine has the potential to cause agranulocytosis and an association to an increased risk of infections has been suggested. Patients with an ICD-10 F20.x were identified from the Danish Central Psychiatric Research Registry and were linked to the national prescription database to identify schizophrenia patients treated with clozapine from 1996 to 2005(N=3374). Binomial regression and Cox proportional hazards models were used. An increased use of antibiotics was found RR=1.43, CI: 1.26-1.61, P<0.0001 and HR 1.14, 95% CI: 1.05-1.24, P=0.0025 with binomial regression and Cox proportional hazard model, respectively. The exact mechanism for the increased risk remains unknown, but the increased risk might be due to aspiration pneumonia caused by hypersalivation and the sedating properties of clozapine. The findings reported here should alert clinicians to be mindful of infectious processes as yet another possible somatic manifestation of clozapine treatment.

Topics: Agranulocytosis; Anti-Bacterial Agents; Antipsychotic Agents; Clozapine; Databases, Bibliographic; Drug Monitoring; Humans; International Classification of Diseases; Prescriptions; Proportional Hazards Models; Retrospective Studies; Schizophrenia

In a 37-year-old female, a combined treatment consisting of chemotherapy and radiation was considered for cervical cancer. However, she was using clozapine for the treatment of schizophrenia. As both clozapine and chemotherapy can induce decrease of white blood cell counts, we had to decide if clozapine and chemotherapy could be safely co-prescribed. Hypotheses concerning the mechanisms underlying clozapine-induced decrease of white blood cell counts and case reports on combining chemotherapy and clozapine are discussed. After cessation of clozapine the psychosis recurred despite treatment with risperidone. The decision was made to administer radiotherapy only and to reinstate the treatment with clozapine. The radiotherapy treatment went according to plan and the psychosis receded.

Topics: Adult; Agranulocytosis; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antipsychotic Agents; Clozapine; Drug Interactions; Female; Humans; Schizophrenia; Uterine Cervical Neoplasms

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Disease Progression; Dose-Response Relationship, Drug; Haloperidol; Humans; Male; Schizophrenia; Tourette Syndrome; Young Adult

Despite the frequent use of the antipsychotic medication, clozapine, in chronic treatments of psychiatric patients, there is limited clinical evidence available to guide clinicians in the problematic situation of a chemotherapy-induced blood dyscrasia.. To perform a literature review and add a case report to the available clinical evidence.. We gathered evidence through literature searches on Medline and with the assistance of a medical information specialist from Novartis who searched their internal database. We also report the case of a patient maintained on clozapine treatment despite full-dose chemotherapy (cisplatin and etoposide) for an extensive lung cancer.. The searches returned seven clinically relevant references. These references do not establish a synergistic effect of clozapine and chemotherapy on blood counts. However, it has been shown that clozapine exposure activates common apoptotic pathways shared with anticancer drugs.. Although the meagre clinical evidence precludes drawing any general conclusion as to the safety of maintaining clozapine administration during chemotherapy, it does not point to an obvious worsening of the haematological outcomes.

Topics: Agranulocytosis; Antineoplastic Combined Chemotherapy Protocols; Antipsychotic Agents; Carcinoma, Small Cell; Cisplatin; Clozapine; Comorbidity; Cooperative Behavior; Drug Interactions; Etoposide; Humans; Leukocyte Count; Lung Neoplasms; Neoplasm Staging; Palliative Care; Patient Care Team; Quality of Life; Referral and Consultation; Remission Induction; Schizophrenia, Paranoid

A 74-year-old psychotic female patient who was treated with clozapine developed Sweet's syndrome followed by agranulocytosis from which she later died. A link between these two conditions seems unlikely. Sweet's syndrome is characterised by an acute onset of fever, leukocytosis and erythematous plaques with dense neutrophilic infiltrates. Frequent counting of the numbers of neutrophiles is advisable when skin disorders appear during treatment with clozapine.

Topics: Aged; Agranulocytosis; Clozapine; Fatal Outcome; Female; Fever; Humans; Sweet Syndrome

Clozapine is an effective atypical antipsychotic associated with a relatively high incidence of drug-induced agranulocytosis. It forms a reactive nitrenium ion metabolite upon oxidation by peripheral neutrophils and their precursors in the bone marrow. Although the mechanism of this idiosyncratic drug reaction is still unknown, the observation that it does not occur rapidly on rechallenge of patients with a history of clozapine-induced agranulocytosis suggests that it is not immune-mediated. Previous studies by other research groups had found that patients on clozapine had lower plasma and red blood cell levels of selenium. The reactive metabolite of clozapine reacts with glutathione, and therefore, it is likely that it also binds to selenocysteine-containing proteins, such as glutathione peroxidase, thioredoxin reductase, and protein disulfide isomerase. We set out to test the hypothesis that clozapine-induced agranulocytosis is associated with selenium deficiency with rats on a selenium-deficient diet. We studied the effects of clozapine on selenium levels and the effect of selenium deficiency on leukocyte and neutrophil counts and clozapine covalent binding. We did not observe any significant difference between clozapine-treated rats given a selenium-adequate or deficient diet. Therefore, it is unlikely that selenium deficiency is a major risk factor for clozapine-induced agranulocytosis.

Topics: Agranulocytosis; Animals; Antipsychotic Agents; Bone Marrow; Clozapine; Female; Glutathione Peroxidase; Leukocyte Count; Liver; Proteins; Rats; Rats, Sprague-Dawley; Risk Factors; Selenium

The use of clozapine is limited by a relatively high incidence of drug-induced agranulocytosis. Clozapine is oxidized by bone marrow cells to a reactive nitrenium ion. Although many idiosyncratic drug reactions are immune-mediated, the fact that patients with a history of clozapine-induced agranulocytosis do not immediately develop agranulocytosis on rechallenge suggests that some other factor may be responsible for the idiosyncratic nature of this reaction. The reactive nitrenium ion is very rapidly reduced back to clozapine by vitamin C, and many schizophrenic patients are vitamin C deficient. We set out to test the hypothesis that vitamin C deficiency is a major risk factor for clozapine-induced agranulocytosis using a vitamin C deficient guinea pig model. Although the vitamin C deficient guinea pigs did not develop agranulocytosis, the amount of clozapine covalent binding in these animals was less than we had previously observed in samples from rats and humans. Therefore, we studied ODS rats that also cannot synthesize vitamin C. Vitamin C deficient ODS rats also did not develop agranulocytosis, and furthermore, although covalent binding in the bone marrow was greater than that in the guinea pig, it was not increased in the vitamin C deficient ODS rats relative to ODS rats that had adequate vitamin C in their diet. Therefore, it is very unlikely that vitamin C deficiency is a major risk factor for clozapine-induced agranulocytosis.

Topics: Agranulocytosis; Animals; Antipsychotic Agents; Ascorbic Acid; Ascorbic Acid Deficiency; Clozapine; Female; Guinea Pigs; Leukocyte Count; Rats; Risk Factors

Although a highly effective medication, the usage of clozapine is limited mostly by its 2.7% incidence of neutropenia. It is often a treatment of last resort for patients with severe psychiatric illnesses, and therefore often the only medication to which a patient has responded. There has thus been a great deal of interest in ways to continue the medication in spite of emergent blood dyscrasias. There have been several reports documenting the successful continuation of clozapine in spite of neutropenia by adding granulocyte colony-stimulating factors such as filgrastim. This strategy was unsuccessful for a 63-year-old man, resulting in severe, prolonged agranulocytosis. Although a promising strategy for such refractory patients, its inherent dangers should not be underestimated.

Topics: Agranulocytosis; Antipsychotic Agents; Bipolar Disorder; Clozapine; Drug Administration Schedule; Drug Resistance; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Injections, Subcutaneous; Male; Middle Aged; Recombinant Proteins; Recurrence; Retreatment

Topics: Agranulocytosis; Antimanic Agents; Antipsychotic Agents; Bipolar Disorder; Clozapine; Drug Approval; Drug Resistance; Drug Therapy, Combination; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Informed Consent; Legal Guardians; Recombinant Proteins

Clozapine-induced agranulocytosis (CA) is still among the least understood adverse drug reactions in psychopharmacology. In particular, its genetic background is far from being clarified. Within the framework of a case-control study, we performed human leukocyte antigen (HLA) genotyping and haplotype analyses in 42 non-Jewish Caucasian schizophrenic patients (N=42) suffering from CA and 75 non-Jewish Caucasian schizophrenic patients treated with clozapine without developing CA. While controlling for age (P<0.0001) and sex (P=0.835), testing of the alleles from both HLA-loci resulted in borderline results for Cw2 (P=0.085, odds ratio (OR)=0.36, 95% confidence interval (CI): 0.08-1.23), Cw7 (P=0.058, OR=2.0, 95% CI: 0.87-4.63) and DRB5*0201 (P=0.005, adjusted OR=22.15). For haplotype analysis, we obtained significant association results with CA for the two-locus haplotypes HLA-Cw-B (P=0.022) and HLA-DRB5-DRB4 (P=0.050), and for the three-locus haplotype HLA-Cw-B-DRB5 (P=0.030). The complex nature of CA implies that many genes might play a role, but currently, only HLA associations with CA are identified as clinically relevant.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Case-Control Studies; Clozapine; Female; Gene Frequency; Genetic Predisposition to Disease; Haplotypes; Histocompatibility Antigens Class I; Histocompatibility Antigens Class II; Humans; Male; Middle Aged; Odds Ratio; Risk Assessment; Risk Factors; Schizophrenia; Treatment Outcome; White People

Clozapine use has been notably lower in African American patients than in Caucasians. It has been suggested that lower normal ranges for white blood cell (WBC) counts in African Americans, known as benign ethnic neutropenia, may account partially for the disparity. We examined the rates of leucopenia and agranulocytosis as reasons for discontinuation of clozapine in a sample of 1875 patients with schizophrenia treated in the State of Maryland. Between 1989 and 1999, 5.3% (31/588) of African Americans and 2.4% (31/1287) of Caucasians discontinued clozapine treatment due to leucopenia (chi square = 10.35, df = 1, P = 0.001). No African American patients developed agranulocytosis while 8 Caucasian patients (0.62%) developed this blood dyscrasia. Discontinuations due to leucopenia occurred throughout treatment. Discontinuations due to agranulocytosis occurred primarily in the first 18 weeks (7/8; 87.5% patients with agranulocytosis). It is likely that African Americans had clozapine discontinued unnecessarily due to benign ethnic neutropenia. We concur with recent recommendations to acknowledge differences in WBC values in African Americans and to modify prescribing guidelines or formally acknowledge benign ethnic leucopenia like in other countries in order to facilitate greater use of clozapine in these patients.

Topics: Agranulocytosis; Antipsychotic Agents; Black or African American; Clozapine; Drug Utilization; Female; Humans; Leukocyte Count; Leukocytes; Leukopenia; Male; Maryland; Middle Aged; Pharmacogenetics; Schizophrenia; Treatment Outcome; White People

While clozapine is an effective treatment for refractory schizophrenia, its use is limited by haematological side effects. Treatment options that allow continued prescription of clozapine by tackling these side effects will greatly aid patients for whom this medication is all too often their only hope of recovery.. In this case report, we describe what we believe are two 'firsts' in the clozapine literature: the use of granulocyte-colony stimulating factor on a prophylactic basis in an intellectually disabled patient receiving clozapine for refractory schizophrenia.. Treatment with granulocyte-colony stimulating factor prevented discontinuation of clozapine, enabling our intellectually disabled patient's recovery from a schizophrenic illness.

Topics: Adult; Agranulocytosis; Clozapine; Comorbidity; Drug Therapy, Combination; Granulocyte Colony-Stimulating Factor; Humans; Injections, Subcutaneous; Intellectual Disability; Leukocyte Count; Leukopoiesis; Lithium Carbonate; Male; Schizophrenia, Paranoid

Up to now direct toxic effects or immunological processes have been said to explain clozapine-induced agranulocytosis. However, more recent studies may suggest that not yet metabolized clozapine is taken up by leukocytes and transformed by oxidative processes to apoptosis-inducing metabolites. To verify this hypothesis the concentrations of clozapine were measured in the plasma and the leukocytes of a patient receiving clozapine who developed clozapine-induced leukocytopenia and in 10 patients receiving clozapine who did not show any serious adverse side effects. The patient who developed leukocytopenia showed clozapine concentrations in the leukocytes that were about 8 times higher than the mean clozapine concentrations in the leukocytes in the group of 10 patients receiving clozapine with no changes in the leukocyte count in the history. However, no major difference was found in the clozapine plasma concentrations. The results may suggest that patients at risk of developing clozapine-induced leukocytopenia show increased clozapine concentrations in the leukocytes although the clozapine plasma concentration is in the therapeutic range. It is assumed that changes or abnormalities of clozapine uptake at the cell membrane might play a role in the development of clozapine-induced leukocytopenia and/or agranulocytosis.

Topics: Adolescent; Adult; Aged; Agranulocytosis; Antipsychotic Agents; Clozapine; Female; Humans; Leukocyte Count; Leukocytes; Leukopenia; Male; Middle Aged; Psychotic Disorders

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Humans; Lithium Compounds; Neutropenia

This article describes four patients using clozapine, with neutropenia. Clozapine-induced neutropenia can be one of three types: pseudo, benign or malignant. The malignant type can give cause for serious concern; in that case treatment with clozapine must be stopped. Pseudo-neutropenia and benign neutropenia, however, occur frequently. In these cases it is probably unnecessary to stop clozapine medication, particularly if clozapine is clearly indicated.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Female; Humans; Male; Middle Aged; Neutropenia

An exemplary case report of a patient who developed an unpredictable sudden, late-onset clozapine-related life-threatening agranulocytosis expressed by a nadir of 14 polymorphonuclear cells/microL, and subsequently underwent protective hospitalisation and broad spectrum, empiric antimicrobial therapy and also experienced serious intolerance to a number of administered antibiotic and antifungal agents, is reported and discussed on the grounds of the available evidence from the literature.

Topics: Adult; Agranulocytosis; Anti-Infective Agents; Antipsychotic Agents; Clozapine; Fever of Unknown Origin; Hospitalization; Humans; Leukocyte Count; Male

Define the incidence of clozapine-induced leukopenia, neutropenia, and agranulocytosis in patients with schizophrenia at Srinagarind Hospital.. A descriptive study was done by retrospective reviews of the medical records of schizophrenic outpatients at psychiatric clinic in Srinagarind Hospital who had received clozapine from January 1st, 2003 to December 31st, 2005. The demographic data, incidence rate, and incidence density of leukopenia, neutropenia, and agranulocytosis were collected.. One hundred and seventeen medical records were reviewed, 65 patients met the inclusion criteria. One patient developed neutropenia. The incidence rate of neutropenia was 1.5% and the incidence density of neutropenia was 0.01/year. No leukopenia or agranulocytosis was found in the present study. The complete blood counts were not obtained regularly due to the problems of patient's adherence and variations in practice among the physicians.. Neutropenia is uncommon. No leukopenia and agranulocytosis were found. According to variations of incidence reports among different studies, the monitoring of white blood count should be continued.

Topics: Adolescent; Adult; Aged; Agranulocytosis; Antipsychotic Agents; Clozapine; Female; Humans; Incidence; Leukopenia; Male; Middle Aged; Neutropenia; Retrospective Studies; Risk Factors; Schizophrenia; Thailand

Topics: Aggression; Agranulocytosis; Antipsychotic Agents; Clozapine; Fatal Outcome; Humans; Intellectual Disability; Male; Middle Aged; Myelodysplastic Syndromes; Substance Withdrawal Syndrome; Time Factors

Topics: Agranulocytosis; Antipsychotic Agents; Black People; Canada; Clozapine; Drug Monitoring; Drug Utilization; Humans; Practice Guidelines as Topic; Schizophrenia; United Kingdom; United States

To provide information for physicians and patients on which to base a decision as to whether to stop mandatory blood testing.. Articles on drug-induced blood dyscrasias were identified by searches of MEDLINE (1966-September 2005) and review of their bibliographies. Novartis was asked to provide additional data on clozapine, leukopenia, agranulocytosis, and suicidality.. Data on the chance of clozapine-induced leukopenia and agranulocytosis were combined with data about possible fatality and compared with the risks associated with other medications and with life in general.. The chance of clozapine-induced leukopenia or agranulocytosis decreases exponentially over time. In the US, the chance in the second 6 months of treatment is 0.70/1000 patient-years and, after the first year, 0.39/1000 patient-years. The case fatality rate of clozapine-induced agranulocytosis is estimated as 4.2-16%, depending on whether a granulocyte colony-stimulating factor is used. Nevertheless, treatment with clozapine reduces overall mortality, probably because it reduces suicidality.. After at least 6 months' treatment with clozapine, the mortality involved in stopping white blood cell monitoring is about the same as the mortality associated with other medications, such as mianserin or phenylbutazone, and with life in general (traffic or occupational accident). If the patient has been well informed and wishes to stop the monitoring, it is a medically justifiable option to do so and is preferable to stopping treatment with clozapine since this drug reduces overall mortality.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Humans; Leukocyte Count; Leukocytes; Leukopenia; MEDLINE; Monitoring, Physiologic; Risk

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Humans; Interferon-alpha; Male; Middle Aged; Ribavirin; Schizophrenia

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Humans; Leukocyte Count; Schizophrenia

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Drug Monitoring; Female; Health Knowledge, Attitudes, Practice; Humans; Leukocyte Count; Male; Mental Recall; Middle Aged; Patient Education as Topic; Psychotic Disorders; Risk; Schizophrenia; Schizophrenic Psychology

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Female; Humans; Middle Aged; Schizophrenia

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Clozapine; Drug Monitoring; Humans; Leukocyte Count; Male; Neutropenia; Neutrophils; Olanzapine; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Clozapine is a uniquely effective antipsychotic, although its use is limited by the risk of neutropenia. Lithium is occasionally prescribed during a clozapine rechallenge, with the hope that it will prevent a second neutropenia or agranulocytosis. There are concerns, however, that lithium use will mask the onset of a neutropenia, leading to a more severe dyscrasia. The objective of this analysis was to determine the utility and safety of lithium coprescription in clozapine rechallenge.. A retrospective case analysis was performed of all patients who had experienced a previous clozapine-induced blood dyscrasia and had a clozapine rechallenge with lithium coprescribed in a tertiary referral center between September 1998 and September 2003.. Twenty-five patients met the study criteria; 1 patient (4%) had a second episode of neutropenia or agranulocytosis while undergoing the rechallenge. This rate was significantly lower (p = .021) than the national (U.K.) rate (21.2%). Although recurrent dyscrasias were not more common, or more severe, than those seen with rechallenge in general, our single case did show some evidence that the patient's neutropenia was masked by lithium use.. This study provides support for the utility of lithium in preventing neutropenias in rechallenge; extra vigilance may be required, however, to detect masked blood dyscrasias.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Female; Humans; Lithium; Male; Neutropenia; Retrospective Studies; Secondary Prevention; Severity of Illness Index; United Kingdom

Clozapine, an atypical antipsychotic drug effective in treatment of refractory schizophrenia causes potentially life-threatening agranulocytosis. The drug undergoes bioactivation to a toxic, chemically reactive intermediate with capacity to target stromal cells, central components of the bone marrow microenvironment implicated in neutrophil development. To identify possible mechanisms underpinning disruption of stroma as a site of drug bioactivation, toxicity was induced in vitro. Therefore metabolite generation procedures utilizing HOCl or HRP-H(2)O(2) as primary components involved in clozapine metabolism were adapted for stromal culture and coupled with viability determinations. Drug oxidation by HOCl was less toxic to stromal cells than HRP-H(2)O(2) based methods. More specifically, clozapine bioactivation by HRP-H(2)O(2) caused dose-dependent inhibition of stromal viability at therapeutically relevant concentrations. Differences in susceptibility of HAS303 and LP101 cells to the clozapine nitrenium ion were also evident. Stromal cell death was attributed to clozapine in the presence of a complete metabolising system comprising HRP and H(2)O(2). In the absence of a complete metabolising system clozapine was not cytotoxic. For LP101 cells, drug plus HRP (minus H(2)O(2)) also induced toxicity. Importantly, other antipsychotic drugs including risperidone, olanzapine and haloperidol when bioactivated, were not cytotoxic, indicating system specificity for clozapine. Exogenous GSH, N-acetylcysteine, l-ascorbic acid, catalase, and sodium azide afforded protection to cells whereas S-methylGSH, GSSG, ketoprofen and proadifen did not. Thus functional data derived from the in vitro stromal system defined in these studies may enable further investigation of the mechanisms subserving stromal impairment in clozapine-induced agranulocytosis and direct attention to improved methods for its prevention.

Topics: Agranulocytosis; Antipsychotic Agents; Bone Marrow; Clozapine; Dose-Response Relationship, Drug; Humans; Stromal Cells

To report the findings of a switch from brand-name to generic clozapine in a Canadian outpatient population.. The medical records of 58 outpatients diagnosed with schizophrenia and other psychotic disorders and stabilized on brand-name clozapine therapy were reviewed retrospectively. Patients were switched from brand-name to generic clozapine on their next dispensing supply after September 29, 2003. Data regarding clozapine dose regimens, physicians' visits, hospitalizations, and adverse events were collected from the patients' charts for the 6 months preceding and the 6 months after the switch from brand-name to generic clozapine. Relevant measurement changes in those data associated with the switch are evaluated.. No significant changes in dose, number of physician's visits, or hospitalization rates were observed as a consequence of the switch from brand-name to generic clozapine. In addition, there were no reported increases in the frequency of the most common adverse events, including decreases in white blood cell counts. None of the patients received a "nonrechallengeable" status, and no discontinuation of clozapine therapy occurred for any reason (toxicity or treatment failure) in the 6 months after the formulation switch.. In the current outpatient population, retrospective evaluation of the conversion from brand-name clozapine to the first generic alternative available on the Canadian market did not reveal any significant treatment changes.

Topics: Adult; Aged; Agranulocytosis; Ambulatory Care; Canada; Clozapine; Drug Administration Schedule; Drugs, Generic; Evaluation Studies as Topic; Female; Follow-Up Studies; Hospitalization; Humans; Legislation, Drug; Male; Middle Aged; Psychotic Disorders; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

This study documents the incidences of agranulocytosis and neutropenia, and the patterns of incidence of the side effects of long-term clozapine treatment in order to determine an appropriate time to stop the Clozaril Patient Monitoring System (CPMS).. Hematological, demographic, and other data from the CPMS for 6782 patients who took clozapine for the past 11 years in the Republic of Korea has been analyzed.. Twenty-nine (53.7%) of fifty-four agranulocytosis cases occurred within the first 18 weeks. The cumulative incidence of agranulocytosis was 1.64% between 6 and 11 years and the crude incidence was 0.8%. Neutropenia occurred in 697 patients, and 365 (52.4%) of these cases occurred within the first 18 weeks. The cumulative incidence of neutropenia was 19.8% between 8 and 11 years, and the crude incidence was 10.3%. There were no cases of agranulocytosis or neutropenia after the 9th year of clozapine treatment.. The incidence of agranulocytosis in the Republic of Korea was similar to those in the rest of the world. While agranulocytosis began several years after clozapine treatment, long-term monitoring of white blood cells is necessary. We suggest that the CPMS should be stopped or less frequently after the 9th year of treatment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Agranulocytosis; Antipsychotic Agents; Clozapine; Drug Monitoring; Female; Follow-Up Studies; Humans; Incidence; Korea; Leukocyte Count; Male; Middle Aged; Neutropenia; Time Factors

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Humans; Neutropenia; Psychotic Disorders; Time Factors

Clozapine, synthesized in the sixties, is an atypical antipsychotic drug whose history has been marked by its haematological toxicity. The purpose of this study was, ten years after it had been replaced at French psychiatrists' disposal, to gather data on the prescription modalities of clozapine, assess whether some factors could affect its efficacy, and describe the population of schizophrenic patients concerned.. Psychiatrists in the Paris region were asked to answer a questionnaire about their patients treated with clozapine. The information collected was about socio-demographic data, history of psychiatric disorder and the way clozapine was used. It was a retrospective study concerning 98 patients.. Subjects were 57 men and 41 women, with a mean age of 38 years. The majority of patients came from metropolitan France. Patients suffered from various clinical subtypes of schizophrenia, as assessed according to DSM IV criteria. Predominant symptomatology during lifetime was most often auditory hallucinations (41%). Mean duration of lifetime neuroleptic treatment was 10.3 years and breaks in follow-up were rare. Mean number of hospitalisations was 6.9 and a little less than half of the patients had been committed involuntarily. Lastly, 38% of patients had attempted suicide at least once and 35% had expressed hetero-agressive behavior. Main indication of clozapine was resistant schizophrenia (88.5% of patients) and mean duration of treatment was 2 years and 4 months. Treatment efficacy was assessed as good or medium in 77.9% of patients, at mean doses (322 mg per day) in keeping with data from the literature. Tolerance was considered on the whole as satisfactory by half of the clinicians. Among the 98 patients of the study, 21.6% had stopped taking clozapine. The reasons for withdrawal were: inefficacy (6.2%), granulopenia (5.2%), epilepsy (1%) and 8.2% for various reasons (half of these cases being non-compliance with treatment). The study of the 5 cases of granulopenia showed that 3 patients had another associated psychotropic medication: 1 patient received only clozapine as monotherapy, 1 data was missing. Two thirds of all patients were receiving another psychotropic drug in association with clozapine, mainly benzodiazepines (18.4%), antidepressants (15.3%) or mood stabilizers (7.1%). The "therapeutic efficacy" variable was compared with some variables in order to isolate factors possibly associated with a better efficacy of clozapine or, on the contrary, with a population of patients poorly responding to treatment. However, no statistically significant difference appeared according to the variables studied, such as gender or lifetime duration of neuroleptic treatment. Moreover, there was no statistically significant difference in efficacy according to schizophrenia subtype, main symptomatology during the course of illness or substance abuse. We studied whether any factor could affect the occurrence of granulopenia. No statistically significant difference was found. The mean age of patients having stopped the treatment because of granulopenia was higher than in the group with other reasons for interruption, but did not reach statistical significance. A. As expected, the main indication for prescribing clozapine was resistant schizophrenia, but contrary to data from the international literature, the efficacy profile was the same whatever the clinical subtype of schizophrenia. The tolerance to clozapine was considered on the whole as satisfactory, but the high proportion of granulopenias leading to treatment withdrawal (5.2% of patients) confirms the need to remain cautious and stresses the importance of regular haematological monitoring. Furthermore, the study of the prescription modalities of clozapine shows that contrary to the guidelines, clozapine is often associated with other psychotropic drugs. In this study, it is striking to note that 75% of granulopenias occurred in a coprescription situation.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Drug Resistance; Drug Therapy, Combination; Female; France; Humans; Male; Middle Aged; Practice Patterns, Physicians'; Psychotropic Drugs; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Granulocyte Colony-Stimulating Factor; Histocompatibility Testing; Humans; Male; Middle Aged; Polymerase Chain Reaction; Risk Factors; Schizophrenia; Schizophrenic Psychology; Schizotypal Personality Disorder

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Drug Monitoring; Humans; Long-Term Care; Male; Middle Aged; Schizophrenia

The danger of severe haematological abnormalities limits the use of clozapine in the treatment of psychoses. The development of modern second generation antipsychotics such as olanzapine, risperidone, quetiapine, amisulpride, ziprasidone or aripiprazol, however, makes it possible to use the positive effects of this class of drugs without the risks of a clozapine treatment. Nevertheless, there are several case reports about severe haematological abnormalities even during treatment with these second generation antipsychotics. This review summarises recently published cases and discusses the consequences for the daily clinical work.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Female; Humans; Leukocyte Count; Leukopenia; Male; Psychotic Disorders; Risk Factors

Topics: Adult; Agranulocytosis; Clozapine; Female; Humans; Male; Middle Aged

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Humans; Neutropenia; Risk Factors; Schizophrenia

Drug-induced agranulocytosis is a rare but life-threatening side effect which is possibly based on immunogenetic mechanisms. Some studies regarding agranulocytosis induced by the atypical antipsychotic clozapine dealing with HLA subtyping and enzyme polymorphisms have been performed to elucidate its genetic background. To further screen possibly genetically based pathways of developing agranulocytosis, we assessed clinically relevant polymorphisms of immunoglobulin G or Fcgamma receptors in patients with clozapine-induced (n = 48), ticlopidine-induced (n = 11), thyroid inhibitors-induced agranulocytosis (n = 8), and controls (n = 75). We found significant age-related effects in each of the drug-induced agranulocytoses but no further associations that underline an effect of polymorphisms in FcgammaRIIa, FcgammaRIIIa, and FcgammaRIIIb genes on drug-induced agranulocytosis. Thus, Fcgamma receptors may not serve as a genetic marker to identify patients at risk for this life-threatening side effect.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Antithyroid Agents; Clozapine; DNA; Female; Fibrinolytic Agents; Genotype; Humans; Leukocyte Count; Male; Middle Aged; Receptors, IgG; Ticlopidine

To retrospectively examine rates of hematological adverse events (HAEs) in psychiatrically ill, hospitalized children treated with clozapine.. Clozapine treatment was administered in an open-label fashion using a flexible titration schedule, and data from weekly complete blood counts was obtained. The rate of neutropenia and agranulocytosis (HAEs) development was determined for 172 eligible patients (mean age at clozapine initiation, 15.03 +/- 2.13 years) with a median observation period of 8 months.. Neutropenia (absolute neutrophil count <1,500/mm) developed in 23 (13%) patients and agranulocytosis (absolute neutrophil count <500/mm) in one (0.6%) patient. The cumulative probability of developing an initial HAE at 1 year of clozapine treatment was 16.1% (95% confidence interval 9.7%-22.5%). Eleven (48%) of 24 patients who developed an HAE were successfully rechallenged on clozapine. Eight (5%) of 172 patients from this sample eventually discontinued clozapine because of an HAE (one agranulocytosis, seven neutropenia).. The occurrence of HAEs is a significant risk associated with the administration of clozapine. However, in this sample, few children actually discontinued therapy because of an HAE and the incidence of agranulocytosis does not appear higher than what has been reported in the adult literature.

Topics: Adolescent; Agranulocytosis; Antipsychotic Agents; Child; Clozapine; Cohort Studies; Female; Humans; Male; Neutropenia; Psychotic Disorders; Retrospective Studies

We report the case of a patient with schizophrenia, who experienced agranulocytosis during clozapine treatment, followed by bronchopulmonal infection and Guillain-Barré syndrome. The case was recorded within the German surveillance project "drug safety in psychiatry" (AMSP).

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Female; Guillain-Barre Syndrome; Humans; Middle Aged; Psychomotor Agitation; Respiratory Tract Infections; Schizophrenia; Sepsis

Topics: Agranulocytosis; Antipsychotic Agents; Bipolar Disorder; Clozapine; Dibenzothiazepines; Female; Humans; Leukopenia; Middle Aged; Quetiapine Fumarate

Topics: Agranulocytosis; Antibiotics, Antineoplastic; Antipsychotic Agents; Breast Neoplasms; Clozapine; Doxorubicin; Female; Humans; Middle Aged; Neutropenia; Schizophrenia

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Drug Monitoring; Humans; Schizophrenia

Topics: Agranulocytosis; Antineoplastic Agents; Apoptosis; Clozapine; Genistein; Granulocyte Colony-Stimulating Factor; Humans; Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Reactive Oxygen Species; Schizophrenia; Serotonin Antagonists

A case report describes an adolescent girl with a treatment-resistant bipolar disorder, who developed pericarditis and polyserositis while being treated with clozapine. The sparse literature about this rare, severe side effect of clozapine is discussed. Clinical recommendations with regard to monitoring are given. If myocarditis/polyserositis occurs, clozapine has to be discontinued immediately.

Topics: Adolescent; Agranulocytosis; Antipsychotic Agents; Bipolar Disorder; Clozapine; Female; Humans; Pericarditis; Psychiatric Status Rating Scales; Serositis

A 45-year-old female suffering from severe chronic schizophrenia of the paranoid type did not respond to typical antipsychotics. Five weeks after starting therapy with clozapine, she developed a clozapine-induced agranulocytosis (CA). Discontinuation of clozapine and treatment with granulocyte colony-stimulating factor (G-CSF) led to normalization of blood neutrophil counts within three weeks. This report suggests enhanced apoptosis of blood neutrophils during the acute phase of CA resulting from enhanced expression of the pro-apoptotic proteins Bax and Bik and from a decrease of the anti-apoptotic BCl-X(L) mRNA. The time course of decline and recovery of neutrophilic cells, as well as the release pattern of endogenous G-CSF, resembles those of chemotherapy-induced neutropenia. The kinetics of CD 34-positive cells mimics that of cytotoxic progenitor cell mobilization, e. g., after cytostatic drug administration. Our findings argue against the hypothesis that clozapine-mediated inhibition of G-CSF or granulocyte-macrophage colony-stimulating factor (GM-CSF) release is involved in CA development. Because clozapine-induced cell death mainly affects the neutrophil lineage, the elucidation of the exact mechanism of CA may open new perspectives for the treatment of psychiatric and possibly hematological disorders.

Topics: Agranulocytosis; Antipsychotic Agents; Apoptosis; Clozapine; Female; Humans; Middle Aged; Neutrophils; Schizophrenia, Paranoid

Short-term treatment with granulocyte colony-stimulating factor has been successful in reducing the duration of clozapine-induced agranulocytosis. Long-term combination treatment with filgrastim and clozapine in patients with clozapine-induced agranulocytosis has only been described in two previous cases. We describe three patients with schizophrenia who developed granulocytopenia or agranulocytosis during treatment with clozapine and who did not respond to other antipsychotics. The patients received long-term combination treatment with clozapine and filgrastim. Using a combination treatment with filgrastim and clozapine, the psychotic symptoms were successfully controlled and no haematological complications were observed during the follow-up periods of 11, 30 and 48 months, respectively. Our cases suggest that long-term treatment with filgrastim might be a useful, but exceptional, treatment approach in patients who have developed clozapine-induced granulocytopenia or agranulocytosis.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Female; Granulocyte Colony-Stimulating Factor; Humans; Middle Aged; Schizophrenia; Treatment Outcome

Topics: Agranulocytosis; Clozapine; Humans; Male; Middle Aged; Schizophrenia

Clozapine is a dibenzodiazepine neuroleptic with atypical pharmacological and clinical profiles. Treatment with this drug may be complicated with agranulocytosis (AGR). It is likely that defective oxidative mechanism may be the cause of AGR. A candidate gene, dihydronicotinamide riboside (NRH) quinone oxidoreductase 2 (NQO2), which is involved in detoxification of drugs, was selected. This gene has been mapped to the short arm of chromosome six. The gene was studied by single-strand conformation polymorphism analysis and direct sequencing in 98 schizophrenic patients that were treated with clozapine. Eighteen of these patients developed AGR. Ten polymorphisms in the coding regions, in intron 1, and in the promoter region were found, two of which were novel. Comparisons of the polymorphisms in the first intron in AGR patients and controls suggested that this site might be connected with AGR. Quantitative reverse transcriptase-polymerase chain reaction analysis showed that the level of NQO2 mRNA is low in AGR patients compared with the control group. Such a reduction in message suggests that the NQO2 gene may be involved in the development of clozapine-induced AGR.

Topics: Agranulocytosis; Clozapine; Densitometry; Gene Frequency; Genotype; Humans; Polymorphism, Single-Stranded Conformational; Promoter Regions, Genetic; Quinone Reductases

Topics: Agranulocytosis; Anticonvulsants; Chronic Disease; Clozapine; Drug Therapy, Combination; Humans; Male; Middle Aged; Schizophrenia, Paranoid; Serotonin Antagonists; Valproic Acid

DMP 406 is a clozapine analogue developed by Dupont-Pharma for the treatment of schizophrenia. Unfortunately it caused agranulocytosis in dogs during preclinical studies. Clozapine also causes agranulocytosis and this is believed to be due to a reactive nitrenium ion metabolite produced by neutrophils. We studied the oxidation of DMP 406 by activated neutrophils and found that the major reactive species that is produced is not a nitrenium ion but rather an imine. This metabolite is similar to the reactive metabolite that has been proposed to be responsible for mianserin-induced agranulocytosis. Therefore we also studied the oxidation of mianserin by activated neutrophils and found that, although the major species is an iminium ion, it also bears a lactam moiety in the piperazine ring resulting from further oxidation. We usually find that HOCl is a good model system for the production of reactive metabolites of drugs that are formed by activated neutrophils, but in the case of both DMP 406 and mianserin, the products produced were significantly different than those formed by activated neutrophils. In contrast, the combination of horseradish peroxidase and hydrogen peroxide (HRP/H(2)O(2)) formed a very similar pattern of products, and this system was used to produce sufficient quantities of metabolites to allow for identification. The reactive metabolites of both DMP 406 and mianserin reacted with a range of nucleophiles, but in many cases the reaction was reversible. The best nucleophile for trapping these reactive metabolites was cyanide. It has been demonstrated that the products of clozapine oxidation by HRP/H(2)O(2), presumably the nitrenium ion, induced apoptosis in neutrophils at therapeutic concentrations of clozapine. It has been suggested that this process is involved in the mechanism of clozapine-induced agranulocytosis. We tested DMP 406 and mianserin in this system to see if the ability of a reactive metabolite of a drug to cause apoptosis could predict the ability of that drug to cause agranulocytosis. We used clozapine as a positive control and we also tested olanzapine, a drug that forms a reactive metabolite similar to that of clozapine but is given at a lower dose and does not cause agranulocytosis. We found that DMP 406 did not increase apoptosis at concentrations below 50 microM, and although mianserin did increase apoptosis at 10 microM this is above the therapeutic concentration. Olanzapine caused an increase in apoptosis at the same c

Topics: Agranulocytosis; Antipsychotic Agents; Apoptosis; Benzodiazepines; Chromatography, High Pressure Liquid; Chromatography, Liquid; Clozapine; Cyanides; Horseradish Peroxidase; Humans; Hydrogen Peroxide; Hypochlorous Acid; Mass Spectrometry; Mianserin; Neutrophils; Nuclear Medicine; Olanzapine; Pirenzepine

Granulocytopenia and agranulocytosis are considered among the most dangerous adverse effects of clozapine. During the last 15-year period, this atypical antipsychotic agent has been administered to 750 patients managed at the Emergency Psychiatry Services and Clinical Pharmacology Unit of the National Institute of Psychiatry and Neurology (NIPandN; Budapest, Hungary). Granulocytopenia was ascertained in seven, whereas agranulocytosis was diagnosed in two patients of this population. The latter two comprised a 42-year-old female with schizoaffective psychosis and a 35-year-old male with paranoid schizophrenia. The female patient received clozapine in a daily dose of 400 mg, which induced agranulocytosis after 2 months. The male patient was treated with 225-mg/day clozapine and the time to the diagnosis of agranulocytosis was 6 weeks. These adverse reactions were recognized early and the appropriate treatment of agranulocytosis resulted in complete recovery in both cases.

Topics: Adult; Agranulocytosis; Clozapine; Female; Humans; Male; Schizophrenia

To report a patient who suddenly developed agranulocytosis after long-term clozapine therapy.. A 41-year-old white man suddenly developed agranulocytosis after 89 months of nearly continuous clozapine therapy. During this time, which included the addition of risperidone to the treatment regimen, his white blood cell (WBC) and granulocyte counts remained stable. One week after having stable hematologic counts, the patient suddenly developed agranulocytosis. WBC and granulocyte counts returned to baseline shortly after discontinuation of all medications and administration of sargramostim.. The main factor limiting the use of clozapine as a first-line agent in mentally ill patients is the risk of agranulocytosis. Although the greatest risk of developing this adverse reaction is during the initial 6-month exposure, clozapine-induced agranulocytosis continues to pose a risk after years of exposure. Current product labeling requires weekly WBC and granulocyte monitoring for the first 6 months of treatment with clozapine, which may be decreased to biweekly monitoring after 6 months. Based on the sudden and late onset of agranulocytosis in our patient, clinicians may consider opting for weekly monitoring of hematologic function for patients on long-term clozapine therapy. The likelihood that clozapine was the cause of the agranulocytosis was rated possible according to the Naranjo probability scale.. Clinicians must remain vigilant to trends in WBC and granulocyte counts and may wish to consider weekly hematologic monitoring regardless of duration of clozapine therapy. Patient and treatment system compliance with the registries' protocol regarding WBC monitoring is instrumental in reducing morbidity and mortality rates associated with clozapine use.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Drug Administration Schedule; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Male; Recombinant Proteins

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Cholinesterase Inhibitors; Clozapine; Drug Therapy, Combination; Galantamine; Humans; Male; Middle Aged; Parasympathomimetics; Risperidone; Schizophrenia

Topics: Adult; Agranulocytosis; Clozapine; Dose-Response Relationship, Drug; Female; Histocompatibility Testing; HLA-DQ Antigens; HLA-DQ beta-Chains; HLA-DR Antigens; HLA-DRB4 Chains; Humans; Jews; Male; Middle Aged; Pharmacogenetics; Schizophrenia; White People

Several studies indicate an association between human leukocyte antigens (HLA) and clozapine-induced agranulocytosis. The authors have previously reported a significantly increased frequency of HLA-A1 among patients with schizophrenia who do not respond to conventional drugs, but do respond to clozapine treatment. In this study, the authors addressed the question of whether the same association is found in patients developing granulocytopenia or agranulocytosis. The frequency of the HLA-A1 allele in patients with clozapine-induced agranulocytosis or granulocytopenia was low (11.5%), whereas HLA-A1 was associated with a good therapeutic response to clozapine at an allele frequency of 58%. The frequency of HLA-A1 is 20% in the Finnish population. These results suggest that HLA-A1 may predict a good therapeutic outcome and a low risk of agranulocytosis and, thus, enable defining a subgroup of patients with schizophrenia in whom clozapine treatment could be started early to stop the disease from progressing.

Topics: Adult; Aged; Agranulocytosis; Antipsychotic Agents; Clozapine; Female; Gene Frequency; Genetic Predisposition to Disease; HLA-A1 Antigen; Humans; Male; Middle Aged; Prognosis; Risk Factors; Schizophrenia

To further examine the human leukocyte antigen (HLA)-encoded genetic susceptibility to clozapine-induced agranulocytosis (CA) we performed HLA-genotyping in a sample of German schizophrenic patients, who suffered from this haematotoxic side-effect. Thirty-one schizophrenic patients with CA (17 women and 14 men) and 77 schizophrenic comparison subjects (40 women and 37 men) were included in the study. HLA-genotyping included identification of major histocompatibility complex (MHC) class I (HLA-A, B, Cw) and class II (HLA-DR, DQ) antigens. CA was significantly associated with HLA-Cw*7 (P<0.02), DQB*0502 (P<0.04), DRB1*0101 (P<0.03) and DRB3*0202 (P<0.02). These HLA-haplotypes are also partly linked to other diseases with a strong genetic background. All other antigens revealed no association to this haematotoxic reaction. In addition, we did not find gender-related effects, whereas age seemed to be a further major risk factor of CA (P<0.0003). Thus, HLA loci may serve as genetic marker to identify subjects of different ethnic subgroups prone to this severe idiosyncratic drug reaction of clozapine. Further studies are needed to investigate whether these associations with CA are due to causal involvement or linkage disequilibrium.

Topics: Adult; Aged; Aged, 80 and over; Agranulocytosis; Antipsychotic Agents; Case-Control Studies; Clozapine; Female; Genetic Predisposition to Disease; HLA Antigens; Humans; Male; Middle Aged; Schizophrenia

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Dibenzothiazepines; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Middle Aged; Quetiapine Fumarate; Schizophrenia

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Female; Humans; Lymphoma, B-Cell; Schizophrenia

The indication of clozapine therapy is governed by special guidelines due to a 1%-3% risk of clozapine-induced agranulocytosis. Up to now there has never been a report of such a case in a child with schizophrenia. The case report presented here is concerned with the clinical features and the treatment of clozapine-induced agranulocytosis in childhood schizophrenia.. It deals with the treatment of a 12-yearold boy with a schizophrenic psychosis. The psychotic symptoms before treatment and during inpatient treatment are described. The procedures for the diagnosis and treatment of the clozapine-induced agranulocytosis are presented.. Clozapine medication may induce agranulocytosis in the treatment of a child with a schizophrenic psychosis. The highly specific guidelines governing its use must be followed as well in the treatment of very early onset schizophrenia. An agranulocytosis may result following 15 weeks of clozapine medication. The treatment with granulocyte colony-stimulating factor seems to support normalization of the blood picture.

Topics: Agranulocytosis; Child; Clozapine; Granulocyte Colony-Stimulating Factor; Humans; Male; Schizophrenia, Childhood

Topics: Adult; Agranulocytosis; Anticonvulsants; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Female; Humans; Neutropenia; Risk Factors; Schizophrenia; Valproic Acid

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Clozapine; Female; Humans; Leukocyte Count; Neutropenia; Olanzapine; Perphenazine; Pirenzepine; Risperidone; Schizophrenia

1. Clozapine is a dibenzodiazepine neuroleptic which presents the advantage of not having undesirable neurological side-effects. Its efficacy for the treatment of the symptoms of schizophrenia is known, but the use of clozapine is limited to treatment-resistant schizophrenic patients as it induces agranulocytosis with a higher incidence than that of other neuroleptic drugs. 2. The present study was designed in order to evaluate the benefit/risk of chronic treatment. The analysis was performed using the files of schizophrenic patients. These patients were not stabilized by a classical neuroleptic treatment and/or presented individual secondary effects. 3. Clozapine induced neutropenia and 1 case of agranulocytosis in 3 females. Analysis of leukocyte expression highlighted some premonitory symptoms in patients who presented neutropenia. The observation of 2 to 3 early successive peaks in leukocyte expression (between the third and tenth week of treatment) could be predictive of neutropenia in the 3 to 4 months of treatment. 4. The patients who presented a lower leukocyte base-line following a peak had a higher risk, of developing neutropenia. This might explain some late accidents beyond the first six months of treatment. 5. The present study confirmed the advantages of clozapine treatment and demonstrated that the risk of neutropenia may be diminished by the detection of premonitory symptoms and the early monitoring of patients at risk i.e. female patients and subjects with a lower leukocyte base-line.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Drug Resistance; Female; Follow-Up Studies; Humans; Incidence; Leukocyte Count; Male; Neutropenia; Retrospective Studies; Risk Factors; Schizophrenia; Sex Factors; Treatment Outcome

Little is known about possibilities of chronic hepatitis C treatment with interferon-alpha (IFN-alpha) in psychiatric patients continuously taking antipsychotics. We report on a 28-year-old hepatitis C-positive man with paranoid psychosis. He was successfully treated with clozapine, an atypical antipsychotic drug which is known for the risk of granulocytopenia and agranulocytosis. With doses up to 200 mg/day over 3 years, he showed no remarkable changes in WBC. Because of the chronic hepatitis C with genotype 3a, additional treatment was started with IFN-alpha (s.c., 3 x 6 million IU/week). After 2 months of therapy he developed a severe agranulocytosis. Both clozapine and IFN-alpha were discontinued, and his WBC returned to normal. Results from bone marrow examination were compatible with a toxic reaction possibly caused by either or both medications. We discuss possible problems with IFN-alpha during the treatment of psychiatric patients, interactions with psychiatric medication, and hematotoxic side effects like those from clozapine. We recommend combining IFN-alpha with less "toxic" antipsychotics and weekly checks of WBC.

Topics: Adult; Agranulocytosis; Cannabinoids; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Follow-Up Studies; Hepatitis C; Heroin Dependence; Humans; Interferon alpha-2; Interferon-alpha; Lysergic Acid Diethylamide; Male; Psychoses, Substance-Induced; Recombinant Proteins; Substance Abuse, Intravenous

Clozapine remains the most effective agent for diminishing or eliminating psychotic symptoms in treatment-resistant patients. However, among such patients, a small percentage (<3.0%) develops clozapine-induced granulocytopenia (CIG). In spite of the fact that lithium and granulocyte colony stimulating factor (G-CSF) have been shown to reverse CIG, many such patients are consigned to treatment with antipsychotic agents that have failed in the past. Apparently, their physicians are not aware that these patients can be salvaged for ongoing clozapine treatment. We report the effectiveness of lithium in reversing CIG in a young man with preexisting mild granulocytopenia. The rapidity of onset of leukocyte depletion is discussed in light of previously hypothesized autoimmune mechanisms of CIG. This case dramatizes the importance of lithium (or G-CSF) augmentation in those patients to maintain clozapine treatment so that their neutropenia can be reversed, and they can continue to benefit from the unique antipsychotic qualities of clozapine.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Humans; Lithium; Male; Precipitating Factors

The use of fluperlapine and the structurally related clozapine has been associated with the induction of agranulocytosis in humans. Unlike clozapine, fluperlapine is relatively resistant to chemical and biochemical oxidations. In this study we demonstrated that 7-hydroxyfluperlapine, the major metabolite of fluperlapine in humans, is oxidized to a reactive intermediate by HOCl and by myeloperoxidase in the presence of H(2)O(2) and Cl(-). This reactive intermediate was identified as an iminoquinone species with a M + 1 ion at m/z 324 by mass spectrometry. The iminoquinone intermediate was trapped by N-acetyl-L-cysteine (NAC) as well as GSH. NMR spectra of the NAC adducts indicated that the NAC was bound to the 6 and 9 positions of the aromatic ring. This is the same orientation as the binding of nucleophiles to the reactive metabolite of clozapine. We were able to use an antibody against clozapine to demonstrate that 7-hydroxyfluperlapine, but not fluperlapine itself, covalently modifies human myeloperoxidase. Furthermore, we demonstrated that 7-hydroxyfluperlapine is metabolized by activated neutrophils to a reactive intermediate that covalently binds to neutrophils. In the presence of NAC or GSH, such covalent binding was inhibited and the NAC or GSH adducts were formed. Thus, the reactivity and even the orientation of the binding of the reactive metabolite of 7-hydroxyfluperlapine is very similar to that of clozapine. These results provide a mechanism for the formation of a reactive metabolite of fluperlapine similar to clozapine that may explain its ability to induce agranulocytosis.

Topics: Acetylcysteine; Agranulocytosis; Binding, Competitive; Clozapine; Dibenzazepines; Glutathione; Hemocyanins; Humans; Hypochlorous Acid; Immune Sera; Immunoblotting; Neutrophil Activation; Neutrophils; Oxidation-Reduction; Peroxidase; Protein Binding

Clozapine is a dibenzodiazepine derivative that is more effective than standard neuroleptic drugs in refractory schizophrenic patients, but its introduction in some countries was delayed by its propensity to cause blood dyscrasias. However, over the last ten years, different reports have clearly demonstrated that agranulocytosis and neutropenia can be easily prevented by means of strict hematologic surveillance. This article reviews the results of the first five years of the Italian Clozapine Monitoring System (ICLOS).. The hematologic parameters of 2,404 patients registered between 1995 and 1999 were collected in a central database, before the patients began clozapine-treatment, weekly for the first 18 weeks, and then monthly throughout the duration of therapy. On the basis of conventional criteria, different risk levels have been identified with total leukocyte <3. 0x10(9)/L and/or an absolute neutrophil count <1.5x10(9)/L leading to immediate discontinuation of the drug.. The analysis shows that 0.9% of the patients developed neutropenia and 0.7% agranulocytosis, mainly during the first 18 weeks of clozapine treatment. Drug discontinuation led to the normalization of hematologic parameters in all cases, and the use of growth factors reduced the risk of infectious complications. Transient leukocytosis and eosinophilia were also observed but these did not have any serious clinical effects.. The ICLOS study confirms that regular hematologic monitoring is highly effective in minimizing the incidence of clozapine-associated blood dyscrasias. The lower than initially expected rates of agranulocytosis and associated deaths are encouraging in view of the benefits of this drug in treatment-resistant schizophrenia and other neurologic disorders.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Eosinophilia; Female; GABA Antagonists; Granulocyte Colony-Stimulating Factor; Humans; Incidence; Italy; Leukocytosis; Male; Middle Aged; Neutropenia; Paraproteinemias; Retrospective Studies; Risk Factors; Schizophrenia; Serotonin Antagonists; Thrombocytopenia

Topics: Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Clozapine; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Psychiatric Status Rating Scales; Schizophrenia; Treatment Outcome

Topics: Agranulocytosis; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clozapine; Dibenzothiazepines; Humans; Olanzapine; Patient Compliance; Pirenzepine; Practice Patterns, Physicians'; Quality of Life; Quetiapine Fumarate; Risperidone

Recent case studies suggest that impaired granulopoiesis, well-known to occur during clozapine treatment, may also be observed when olanzapine is administered. The underlying mechanisms are unknown, but haematopoietic cytokines such as granulocyte colony-stimulating factor (G-CSF) are likely to be involved.. We measured the plasma levels of G-CSF and of other cytokines longitudinally in a female patient who developed granulocytopenia twice, first during clozapine treatment and again when olanzapine was administered.. G-CSF levels, but not those of other cytokines, closely paralleled granulocyte counts, yielding a significant positive correlation. G-CSF was not detectable in plasma when granulocytopenia occurred. Granulocytopenia resolved spontaneously despite continuing treatment with olanzapine.. The present case suggests that clozapine and olanzapine both are able to induce transient granulocytopenia through a similar or common mechanism that does not involve a compensatory increase in G-CSF levels.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Clozapine; Cytokines; Female; Granulocyte Colony-Stimulating Factor; Granulocytes; Hospitalization; Humans; Leukocyte Count; Olanzapine; Pirenzepine; Remission, Spontaneous; Schizophrenia

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

Topics: Agranulocytosis; Anticonvulsants; Antipsychotic Agents; Carbamazepine; Clozapine; Drug Interactions; Humans; Risk

Topics: Adverse Drug Reaction Reporting Systems; Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Humans; Olanzapine; Pirenzepine; Quetiapine Fumarate

Clinical reports emphasize the therapeutic usefulness of granulocyte colony-stimulating factor (G-CSF) in clozapine-induced granulocytopenia. Only sparse information exists, however, on the natural course of endogenous G-CSF plasma levels in this condition.. We monitored G-CSF and white blood cell (WBC) counts in a 73-year-old patient who developed granulocytopenia while being treated with clozapine for schizoaffective disorder. Clozapine treatment was discontinued immediately, and G-CSF serum levels were determined repeatedly during the clinical course.. Whereas WBC counts increased again within 6 days after discontinuation of clozapine, G-CSF level decreased significantly within the same period. The rapid decrease of endogenous G-CSF levels paralleled by a normalization of neutrophil count was interpreted as the result of an intact regulatory mechanism of granulocytopoesis. Therefore G-CSF therapy was not initiated. Owing to lack of therapeutic alternatives, it was decided to reintroduce clozapine. G-CSF levels decreased further, accompanied by an increase of WBCs, indicating stable bone marrow functioning.. Based on this observation, we assume that the course of G-CSF and WBC counts indicated an abortive form of toxic bone marrow damage with subsequent recovery. We conclude that monitoring of G-CSF levels may serve as a useful tool in the follow-up of patients in whom clozapine-induced bone marrow damage is suspected.

Topics: Aged; Agranulocytosis; Antipsychotic Agents; Clozapine; Female; Granulocyte Colony-Stimulating Factor; Humans; Leukocyte Count; Neutropenia; Psychotic Disorders; Remission Induction; Time Factors; Treatment Outcome

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Clozapine; Female; Humans; Olanzapine; Pirenzepine; Schizophrenia

Topics: Agranulocytosis; Antipsychotic Agents; Blood Cell Count; Clozapine; Humans; Thrombocytosis

Topics: Agranulocytosis; Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Female; Hematopoietic Cell Growth Factors; Humans; Male

How to best treat psychotic patients who have had past clozapine-induced agranulocytosis or granulocytopenia remains a problem.. We report 3 patients with chronic schizophrenia who had previously stopped clozapine due to hematologic side effects. The patients evidenced improvement with olanzapine that equated to 16- to 31-point decreases in rating scale scores during 1-year follow-up without any hematologic abnormalities.. The results suggest that olanzapine may be useful in treating patients with clozapine-induced granulocytopenia without the risk of recurrence of hematologic side effects.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Clozapine; Follow-Up Studies; Humans; Leukocyte Count; Male; Olanzapine; Pirenzepine; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Topics: Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Clozapine; Drug Interactions; Humans; Olanzapine; Pirenzepine

Topics: Agranulocytosis; Antithyroid Agents; Clozapine; Female; Fever; Humans; Incidence; Leukocyte Count; Male

Therapy of schizophrenia with clozapine is associated with the unpredictable development of severe neutropenia and agranulocytosis in 1% to 2% of patients. The mechanism of this effect is unknown but may involve reactive products of clozapine generated by either hepatic metabolism or oxidation by the peroxidase-peroxide system of activated neutrophils.. Involvement of reactive metabolites was tested with in vitro cytotoxicity assays with use of peripheral blood mononuclear cells isolated from 3 groups of subjects: normal control subjects, patients with schizophrenia who tolerated clozapine therapy (control patients), and patients with schizophrenia in whom agranulocytosis developed while taking clozapine (patients with agranulocytosis). Cell viability was determined after incubations with clozapine and rat liver microsomes or clozapine and horseradish peroxidase-peroxide (HRP-H2O2).. In microsomal incubations, clozapine significantly increased the cell death in all groups: control subjects (8.8%+/-1.6%), control patients (7.4%+/-0.4%), and patients with agranulocytosis (9.1%+/-1.5%). However, differences between mean values were not statistically significant. In similar incubations with HRP-H2O2, clozapine significantly increased toxicity (P < .05) in cells from patients with agranulocytosis (22%+/-4.6%) compared with those from normal control subjects (7.7%+/-4.1%) or control patients (6.5%+/-4.4%).. These results suggest that both generating systems metabolized clozapine to toxic products. Some products may play a role in clozapine-induced agranulocytosis. Of diagnostic relevance is the observation the HRP-H2O2 produces significantly greater toxicity in cells from patients with agranulocytosis than in cells from control patients. Although the exact mechanism(s) of drug activation in vivo remains unclear, the bioactivation of clozapine by HRP-H2O2 may be a useful in vitro tool for predicting which patients are at risk for agranulocytosis before initiation of therapy.

Topics: Agranulocytosis; Animals; Case-Control Studies; Cell Death; Clozapine; Humans; Microsomes, Liver; Rats; ROC Curve; Schizophrenia

Suicide is one of the most serious of schizophrenic symptoms and claims the life of 9% to 13% of patients. The annual rate of suicide in schizophrenic patients is reported to be in the range of 0.4% to 0.8%, a rate that has remained constant despite the introduction of antipsychotic therapy and attendant case-management systems. The risk of suicide is not significantly different in neuroleptic-resistant or -responsive schizophrenic patients. A study of 421 schizophrenic patients reported no significant difference in the incidence of lifetime and current episodes of suicidality in treatment-resistant and -responsive patients. A number of studies with clozapine, an atypical antipsychotic, have demonstrated an 80% to 85% reduction in suicide in neuroleptic-resistant patients. This is accompanied by a decrease in depression and psychopathology and improved cognition. Clozapine's modulation of serotonergic, noradrenergic, cholinergic, and dopamine function may be the biological basis for the reduction in suicide. Weekly contact with patients, for white blood cell monitoring, has also been put forward as one explanation. To further confirm suicide risk reduction as a benefit of clozapine therapy, the International Clozaril/Leponex Suicide Prevention Trial (InterSePT) is currently being conducted. This large, prospective treatment study will compare the rate of suicide attempts and completions in schizophrenic patients at high risk of suicide randomly assigned to receive clozapine or olanzapine. The bias of weekly visits will be excluded. Results should be available in 2001.

Topics: Agranulocytosis; Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Drug Resistance; Humans; Prospective Studies; Risk Assessment; Schizophrenia; Schizophrenic Psychology; Suicide; Suicide Prevention; Treatment Outcome

Topics: Agranulocytosis; Antipsychotic Agents; Bacteremia; Clozapine; Communication Barriers; Fatal Outcome; Humans; Male; Middle Aged; Patient Care Team; Quality Assurance, Health Care; Risk Management; Schizophrenia, Paranoid

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Drug Monitoring; Genetic Predisposition to Disease; Hematopoietic Cell Growth Factors; Humans; Immunity, Innate; Leukocyte Count

The atypical antipsychotic agent clozapine is known to be effective in schizophrenic patients refractory to other medications; however, it induces agranulocytosis in approximately 1-2%. In Jews, this complication is associated with the haplotype HLA B38,DR4,DQ3. The aim of the present study was to determine which human leukocyte antigen (HLA) antigens are involved in clozapine-induced agranulocytosis. We performed HLA typing in 88 Jewish Israeli schizophrenic patients and in 127 ethnically matched healthy individuals. Thirty-eight patients responsive to standard antipsychotic medications were treated with haloperidol, and 50 refractory patients received clozapine. A trend was noted for elevated rates of HLA B38 among control individuals and clozapine-treated patients of Ashkenazi origin compared to individuals of non-Ashkenazi origin, but the findings failed to reach statistical significance. No association was found between HLA class I antigens and the response to haloperidol or clozapine. Neutropenia developed in two clozapine-treated patients and agranulocytosis in one. Two of these three patients were of Ashkenazi origin, and both demonstrated the HLA B38 phenotype. Although the findings did not reach a statistical significance because of the small number of patients, they may support an association between clozapine-induced neutropenia/agranulocytosis and Ashkenazi origin and the HLA B38 phenotype. The rate of agranulocytosis in our sample (2%) is similar to the usual cumulative risk of agranulocytosis but in contrast to its high frequency among Jewish American patients. One possible explanation for this difference is the high rate of Ashkenazi patients in the American sample and the preponderance of non-Ashkenazi patients in our population.

Topics: Adolescent; Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Female; HLA Antigens; Humans; Israel; Jews; Male; Middle Aged; Phenotype; Risk Factors; Schizophrenia

People prescribed clozapine for treatment-resistant schizophrenia have mandatory haematological monitoring through a case register for identifying reversible neutropenia.. To quantify risk factors for agranulocytosis in subjects receiving clozapine.. Data from 12,760 subjects registered to receive clozapine from January 1990 to April 1997 were analysed. Risk factors for agranulocytosis were quantified using a Cox proportional-hazards regression analysis.. The risk for agranulocytosis in Asian subjects was 2.4 times that in Caucasians (P = 0.03). There was an age-related increase in risk of 53% per decade (P = 0.0001).. The case register yielded valuable information for guiding research into the causes of the haematological reactions.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Agranulocytosis; Antipsychotic Agents; Asia; Caribbean Region; Clozapine; Drug Administration Schedule; Female; Humans; Ireland; Male; Middle Aged; Neutropenia; Patient Compliance; Product Surveillance, Postmarketing; Registries; Risk; Schizophrenia; Suicide; United Kingdom

A 46-year-old woman is described with a clozapine-induced agranulocytosis. She was treated with a broad-spectrum antibiotic and supportive care was provided with granulocyte colony-stimulating factor (G-CSF). Immune-mediated mechanisms of clozapine-induced agranulocytosis and the role of haematopoietic growth factors are discussed.

Topics: Agranulocytosis; Antipsychotic Agents; Cilastatin; Cilastatin, Imipenem Drug Combination; Clozapine; Disease-Free Survival; Drug Combinations; Drug Therapy, Combination; Female; Granulocyte Colony-Stimulating Factor; Humans; Imipenem; Leukocyte Count; Middle Aged; Netherlands; Schizophrenia

To further substantiate reports of an association between the major histocompatibility complex subtypes and clozapine-induced agranulocytosis, HLA typing was performed in 61 Jewish Israeli schizophrenic patients, in 11 of whom agranulocytosis developed following clozapine treatment and in 50 (controls) of whom it did not. Of the 11 agranulocytosis patients, seven (63%) were of Ashkenazi origin and four (37%) of Sephardi origin. There was no difference in ethnic origin between the arganulocytosis and non-agranulocytosis groups (chi 2 = 2.4, d.f. = 1, P = 0.11), although the agranulocytosis patients had a higher frequency of the HLA B38 antigen (8/11 or 72% vs. 6/50 or 12%; chi 2 = 18.7, d.f. = 1, P < 0.001). These results suggest that major histocompatibility complex gene products could be involved in clozapine-mediated haematological complications.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Female; Genes, MHC Class I; Genes, MHC Class II; Genetic Predisposition to Disease; Haplotypes; Histocompatibility Testing; HLA-B Antigens; HLA-B38 Antigen; Humans; Israel; Jews; Male; Middle Aged; Schizophrenia

Olanzapine was shown to be oxidized to a reactive intermediate by HOCl, which is the major oxidant produced by activated neutrophils. A mass spectrum obtained using a flow system in which the reactants were fed into a mixing chamber and the products flowed directly into a mass spectrometer revealed a reactive intermediate at m/z 311. This is 2 mass units less than the protonated molecular ion of parent olanzapine and suggests that the reactive intermediate is a nitrenium ion. The reactive intermediate could be trapped with glutathione or N-acetylcysteine to produce two conjugates. These data are analogous to results we reported previously with the structurally related atypical antipsychotic agent clozapine. However, the clozapine and olanzapine reactive metabolites showed differences in their ability to cause toxicity to human neutrophils. Toxicity to neutrophils was observed only at high concentrations of clozapine (>50 microM) when HOCl was used to generate reactive metabolite. In contrast, concentration-dependent toxicity (p < 0.05) was observed when neutrophils were incubated with clozapine (0-20 microM) and H2O2 to generate clozapine reactive metabolite. No toxicity was observed with clozapine alone (at concentrations of > 50 microM). Similar results were observed in monocytes and HL-60 cells. Olanzapine reactive metabolite only seemed to cause slight toxicity at the highest concentrations tested (20 microM), even when the reactive metabolite was generated using H2O2. Neutrophils from two patients with a history of clozapine-induced agranulocytosis seemed to be more sensitive to the toxic effects of the clozapine reactive metabolite; however, the numbers are too small to draw any definite conclusions.

Topics: Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Clozapine; HL-60 Cells; Humans; Hypochlorous Acid; Neutrophils; Olanzapine; Oxidation-Reduction; Pirenzepine

Clozapine is an atypical antipsychotic drug indicated for patients with schizophrenia in whom traditional antipsychotic drugs (such as haloperidol or the phenothiazines) are ineffective, or in those who experience intolerable adverse effects. Clozapine treatment may be complicated by the development of life-threatening agranulocytosis, so regular haematological monitoring is required.. To determine the incidence of clozapine-induced agranulocytosis in Australia and the importance of monitoring white blood cell counts in patients treated with clozapine.. Review of haematological monitoring for the first three years (June 1993-July 1996) of operation of the Australian Clozaril (clozapine; Novartis Australia) Patient Monitoring System (CPMS) central database.. In the 4061 patients prospectively monitored by the CPMS, the incidence of agranulocytosis, neutropenia and leukopenia combined was 2.6% (n = 104); the incidence of agranulocytosis was 0.9% (n = 37). So far there have been no deaths in Australia from the complications of clozapine-induced agranulocytosis.. The incidence of agranulocytosis and neutropenia associated with clozapine use in Australia is similar to that in the rest of the world. Monitoring the white blood cell counts of patients being treated with clozapine ensures minimal risk to patients who develop agranulocytosis.

Topics: Adult; Age Distribution; Agranulocytosis; Antipsychotic Agents; Australia; Clozapine; Female; Humans; Incidence; Leukocyte Count; Male; Neutropenia; Population Surveillance; Prospective Studies; Schizophrenia; Sex Distribution

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Clozapine; Female; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Risk Factors; Schizophrenia; Treatment Outcome

Lithium administration was used in a patient with a clozapine-induced neutropenia and in another with complete agranulocytosis to assess whether lithium could stimulate neutrophil production. In both cases, following lithium administration, the neutrophil count was increased to the normal range within 6 days. In the patient who had presented a neutropenia, clozapine treatment was then reinstated in the presence of lithium and continued without the neutrophil count dropping into the yellow-alert range thereafter.

Topics: Adult; Agranulocytosis; Antimanic Agents; Antipsychotic Agents; Clozapine; Female; Humans; Leukocyte Count; Lithium Carbonate; Middle Aged; Neurosyphilis; Neutropenia; Schizophrenia

Topics: Adult; Agranulocytosis; Antiviral Agents; Clozapine; Contraindications; Drug Synergism; Hepatitis, Chronic; Humans; Interferon-alpha; Male; Schizophrenia

Topics: Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Clozapine; Drug Administration Schedule; Humans; Olanzapine; Pirenzepine; Time Factors

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Humans; Male; Middle Aged; Schizophrenia

We investigated three patients who developed agranulocytosis and seven patients who demonstrated neutropenia during therapy with clozapine as well as five patients who were asymptomatic while on clozapine. One of the three agranulocytic patients had previously developed severe neutropenia during clozapine therapy. We examined mature neutrophils to determine if these cells demonstrated increased susceptibility to clozapine or clozapine metabolites that had been generated chemically. Increased susceptibility was found in the cells of some patients, but it was not a consistent finding. We also examined the effects of clozapine or its chemically-generated metabolites on the development of haematopoietic precursor cells derived from the peripheral blood. Clozapine metabolites, but not clozapine, directly inhibited colony formation of all lineages in a dose-dependent manner; there was no evidence of a specific sensitivity of the myeloid precursors. Acute sera from one of the three patients who developed agranulocytosis was inhibitory to the growth of all precursor cells at a concentration of 10% but none of the plasma were inhibitory. In six patients with neutropenia or agranulocytosis, attempts were made to isolate antigen-specific T cells, wherein the antigen was a hapten carrier complex of clozapine metabolites covalently bound to leukocyte macromolecules. No clozapine metabolite-specific clones to these antigens were detected.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clone Cells; Clozapine; Female; Hematopoietic Stem Cells; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Neutropenia; Neutrophils; Oxidation-Reduction; T-Lymphocytes

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Humans; Leukocyte Count; Male; Middle Aged; Psychiatric Status Rating Scales; Recurrence; Schizophrenia, Paranoid

To describe a patient with neutropenic fever complicated by hyperglycemia, lactic acidosis, and fatal myocardial failure associated with clozapine therapy.. A 37-year-old Ashkenazic Jewish man was admitted for agranulocytosis and fever, which developed after 11 weeks of clozapine monotherapy for drug-resistant schizophrenia. Complete blood counts and a routine serum chemical analysis had been normal before the treatment was initiated, and remained within normal limits during the first 10 weeks of the treatment. On the day of admission, the patient deteriorated rapidly and developed extreme hyperglycemia, severe lactic acidosis, recurrent cardiac arrest, cardiogenic shock, and coma. He died 36 hours later despite intensive treatment.. Clozapine intake reduced fatal aganulocytosis, associated with hyperglycemia, lactic acidosis, and heart failure. White blood cell count monitoring was insufficient to predict these adverse effects.. Clozapine should be avoided in high-risk patients (e.g., the elderly, women, Ashkenazic Jews).

Topics: Acidosis, Lactic; Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Fatal Outcome; Heart Arrest; Humans; Hyperglycemia; Jews; Leukocyte Count; Male; Risk Factors

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Eosinophilia; Humans; Schizophrenia

To determine the prevalence of neutropenia and agranulocytosis in patients taking clozapine since its introduction into New Zealand in April 1988.. Data was collected by Sandoz Pharma (NZ) Ltd on blood counts from all patients prescribed clozapine as part of its worldwide monitoring programme for this drug. The data was analysed by one of the authors (AEC). Case histories to illustrate the principal ways in which falls in white cells present.. A total of 693 patients have been exposed to clozapine between April 1988 and June 1995. The cumulative agranulocytosis rate for the first 7 years of use was 1.15%. There were eight cases of agranulocytosis and no deaths. An additional 14 cases neutropenia were reported (2.02%).. The agranulocytosis and neutropenia rates reported from New Zealand compare favourably with those from larger overseas studies though the exposed patient base is modest.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Agranulocytosis; Antipsychotic Agents; Clozapine; Drug Monitoring; Female; Humans; Leukocyte Count; Male; Middle Aged; Neutropenia; New Zealand; Prevalence; Schizophrenia

Topics: Agranulocytosis; Case Management; Clozapine; Female; Humans; Lithium; Male; Poisoning; Psychotropic Drugs

Genes of the major histocompatibility complex (MHC) are associated with susceptibility to different immune and nonimmune mediated diseases. We had reported that the drug adverse reaction, clozapine-induced agranulocytosis (CA), is associated with different HLA types and HSP70 variants in Ashkenazi Jewish and non-Jewish patients, suggesting that a gene within the MHC region is associated with CA. This study was designed to find common genetic markers for this disorder in both ethnic groups. The tumor necrosis factor (TNF) microsatellites d3 and b4 were found in higher frequencies in both Jewish and non-Jewish patients: 51 of 66 (77%) and 48 of 66 (57%), respectively. Comparisons of these frequencies with those of controls, 28 of 66 (42%) and 18 of 66 (27%), were statistically significant (corrected P value = .001 for the d3 allele and .0005 for the b4 allele). On the other hand, the TNF microsatellite b5 was underrepresented in the group of patients, 9 of 66 (14%), when compared with the control subjects, 43 of 66 (65%) (corrected P value = .0005), probably related to protection from CA. Our results show a strong association of some genetic variants of the TNF loci with susceptibility to CA in two different ethnic groups suggesting involvement of TNF and/or associated gene(s) products in the pathogenesis of this hematologic-drug adverse reaction.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Europe; Female; Gene Frequency; Genetic Linkage; Humans; Jews; Major Histocompatibility Complex; Male; Polymorphism, Genetic; Tumor Necrosis Factor-alpha; United States

Forty-three schizophrenic patients participating in this study were serotyped for human leukocyte antigens (HLA-A, -B, -C, -DR, -DQ antigens). Thirty-six of them were hospitalised in two state mental hospitals and 7 in our general hospital, psychiatric unit. The patients from our unit were typed for HLA before commencing clozapine treatment whereas the patients from state hospitals were typed after commencing treatment. Three out of 43 patients developed agranulocytosis. One had a combination of both 'high-risk' haplotypes (HLA-B16(38,39), DR4, DQ3 and HLA-DR2, DQ1), another had HLA-DR2, DQ1, whereas the last had a totally different haplotype. Between non-agranulocytic patients 1 was found to carry the HLA-B16(38,39), DR4, DQ3 haplotype and 14 (out of 40) had the HLA-DR2, DQ1. Taking into account other factors supposed to be involved (a noxious metabolite, and the presence of a humoral cytotoxic factor) we must admit that despite the finding of a high-risk haplotype in Jewish populations there are other aspects of this question awaiting clarification.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Female; Haplotypes; Histocompatibility Testing; HLA Antigens; Humans; Male; Middle Aged; Risk Factors; Schizophrenia

Clozapine is associated with a high incidence of agranulocytosis. We had previously found that it is oxidized by granulocytes, or simply HOCl, to a reactive metabolite that irreversibly binds to the cells, and we proposed that this reactive metabolite is responsible for clozapine-induced agranulocytosis. The reactive metabolite appeared to be a nitrenium ion formed by chlorination of the nitrogen bridge between the two aromatic rings. If this is correct, analogs that contain this structural feature should also be oxidized to a reactive intermediate while those not possessing this feature would, at least, not form the same type of reactive intermediate and, therefore, may not induce agranulocytosis. We tested the first part of this hypothesis with three clozapine analogs that do contain a nitrogen bridge and three that do not. Consistent with the hypothesis, the three analogs that do contain the nitrogen bridge formed reactive intermediates that could be trapped with glutathione when oxidized by HOCl, myeloperoxidase or activated neutrophils. In contrast, we found no evidence of a reactive intermediate on oxidation of analogs that contained an oxygen or sulfur bridge rather than a nitrogen bridge. If such reactive metabolites are responsible for drug-induced agranulocytosis, it should be possible to use such a simple screening method to test drugs at an early stage in their development for the potential to induce agranulocytosis.

Topics: Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Binding Sites; Chromatography, High Pressure Liquid; Chromatography, Liquid; Clozapine; Dibenzazepines; Glutathione; Granulocytes; Humans; Hydrogen Peroxide; Hypochlorous Acid; Lymphocyte Activation; Mass Spectrometry; Neutrophils; Nitrogen; Olanzapine; Oxidation-Reduction; Peroxidase; Pirenzepine; Structure-Activity Relationship

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Humans; Schizophrenia

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Eosinophilia; Humans; Male

Clozapine is associated with a 0.8% incidence of agranulocytosis. Bioactivation to an unstable protein-reactive metabolite, identified as a nitrenium intermediate, has been implicated in the toxicity. In this study, we investigated whether the reactive metabolite is cytotoxic toward polymorphonuclear leukocytes and mononuclear leukocytes using horseradish peroxidase and H2O2 to generate the metabolite in situ. In the absence of a full metabolizing system (i. e., lack of horseradish peroxidase and/or H2O2), clozapine (0-100 microM) and its stable metabolites were not cytotoxic. With a full metabolizing system, both clozapine (30 microM) and demethylclozapine exhibited cytotoxicity toward polymorphonuclear leukocytes (50.7 +/- 7.7% and 17.6 +/- 1.2% cell death, respectively) and mononuclear leukocytes (36.6 +/- 2.1% and 24.6 +/- 4.1%, respectively), whereas clozapine N-oxide was not cytotoxic. Exogenous glutathione (GSH), N-acetylcysteine and ascorbic acid all protected the cells. Bioactivation of clozapine and demethylclozapine, but not the N-oxide, was accompanied by depletion of intracellular GSH. [14C]Clozapine was metabolized to the previously identified C6 and C9 glutathionyl conjugates; GSH conjugates were also detected when demethylclozapine and clozapine N-oxide were bioactivated by horseradish peroxidase and H2O2. In conclusion, using a novel in vitro assay, we have shown that clozapine and its stable metabolites are not cytotoxic per se but are bioactivated to cytotoxic metabolites. The cytotoxic metabolite of clozapine is identical to the protein-reactive metabolite that has been characterized previously. These cytotoxic metabolites may play an important role in the pathogenesis of clozapine agranulocytosis; the mechanism by which this occurs is currently being investigated.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Biotransformation; Cell Survival; Clozapine; Glutathione; Horseradish Peroxidase; Humans; Male; Neutrophils; Peroxidase

Topics: Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Clozapine; Drug Interactions; Humans; Olanzapine; Pirenzepine; Schizophrenia

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Eosinophilia; Humans

In patients with Parkinson' disease and dopaminergic psychosis, clozapine treatment is recommended as the drug is free from extrapyramidal side effects and does not worsen motor symptoms of the underlying disease. The use of clozapine, however, is limited due to its hematotoxic side effects. For treatment of clozapine-induced agranulocytosis, granulocyte colony-stimulating factors (G-CSF) are recommended. We report the case of a 72-years-old male patient with clozapine-induced agranulocytosis and thrombopenia. Neutropenia was successfully treated with G-CSF, but thrombopenia persisted and resolved spontaneously after 14 days. Bone marrow toxicity of clozapine is not restricted to white cell maturation, but may also impair thrombocytopoesis.

Topics: Aged; Agranulocytosis; Antiparkinson Agents; Antipsychotic Agents; Clozapine; Dopamine Agents; Humans; Leukocyte Count; Male; Parkinson Disease; Platelet Count; Psychoses, Substance-Induced; Thrombocytopenia

Topics: Adult; Agranulocytosis; Clozapine; Drug Therapy, Combination; Female; Humans; Psychotic Disorders; Risperidone

This study evaluates clozapine and its present role in the pharmacotherapy of schizophrenia.. Clozapine's current clinical status is reviewed, as is its position with respect to other treatment options.. Clozapine represents the prototype of "atypical" neuroleptics, with evidence of clinical efficacy in both positive and negative symptoms, as well as a diminished risk of extrapyramidal side effects. It is the only neuroleptic to date that has established itself as having little, if any, risk of tardive dyskinesia. More recent research has focused on its potential for overall savings in health care costs, as well as possible benefits in the area of neuropsychological functioning.. Evidence suggesting that the course of schizophrenia can be altered by effective treatment favours a systematic approach that optimizes treatment options. While clozapine does not represent a 1st-line agent because of its risk of agranulocytosis, it has an integral role to play in treatment-resistant schizophrenia or in individuals experiencing intolerable side effects with conventional neuroleptics.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Cost-Benefit Analysis; Dyskinesia, Drug-Induced; Humans; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Chronic Disease; Clozapine; Female; Humans; Leukocyte Count; Psychiatric Status Rating Scales; Recurrence; Schizophrenia, Paranoid; Substance Withdrawal Syndrome; Suicide, Attempted

Clozapine is effective in treating patients with schizophrenia who do not respond to conventional neuroleptic drugs. The drug is unique in that it is available only with a US Food and Drug Administration-mandated system for weekly monitoring of patients' white blood cell counts. No study has been conducted to evaluate the cost-effectiveness of this mandatory monitoring system.. A benchmark case was established by utilizing cumulative incidence rates of agranulocytosis from a recent study with a large sample of clozapine-treated patients. We assumed a 20% mortality among patients with agranulocytosis, $30.61 in monitoring costs each week, and 14.4 years of remaining life expectancy after detection of agranulocytosis. Based on these bench-mark assumptions, cost-effectiveness ratios in dollars per quality-adjusted life-year were calculated for the first, second, and third 6-month periods during which a patient was receiving clozapine. Sensitivity analyses were performed with more conservative assumptions in 5 alternative scenarios.. In the benchmark case, costs per quality-adjusted life-year gained were $61,694, $925,418, and $420,644 for the first, second, and third 6-month periods of clozapine treatment, respectively. In the alternative scenarios, these costs ranged from $7923 to $46,056 for the first 6-month period and from $54,025 to $690,850 for the second and third 6-month periods.. While the costs of monitoring patients with schizophrenia in the first 6-month period of clozapine treatment seem to be justifiable, monitoring thereafter may not be cost-effective because of the very low incidence of agranulocytosis in the later periods.

Topics: Adult; Adverse Drug Reaction Reporting Systems; Age of Onset; Agranulocytosis; Clozapine; Cost-Benefit Analysis; Drug Costs; Drug Monitoring; Humans; Incidence; Leukocyte Count; Middle Aged; Quality-Adjusted Life Years; Schizophrenia

Topics: Adult; Agranulocytosis; Clozapine; Granulocyte Colony-Stimulating Factor; Humans; Leukocyte Count; Male; Neutrophils; Schizophrenia

Clozapine can cause reversible agranulocytosis and neutropenia. This study documents the occurrence of blood dyscrasias and identifies predisposing risk factors.. An analysis was made of the haematological, demographic, and dosage data from a central database on 6316 patients receiving clozapine over four and a half years in the UK and Ireland.. During the study period, 2.9% of the patients developed neutropenia and 0.8% developed agranulocytosis. The peak incidence of both disorders was in the first 6-18 weeks of treatment. Fatal agranulocytosis occurred in 0.03% of patients. After the first year of treatment, the incidence of agranulocytosis significantly decreased to the order noted with some phenothiazines.. The use of a patient monitoring service kept the haematological risks associated with using clozapine within acceptable limits, particularly in view of the benefits of this medication in treatment-resistant schizophrenia.

Topics: Adult; Adverse Drug Reaction Reporting Systems; Aged; Agranulocytosis; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Ireland; Male; Middle Aged; Neutropenia; Risk Factors; Schizophrenia; United Kingdom

Topics: Agranulocytosis; Antipsychotic Agents; Bone Marrow; Clozapine; Drug Monitoring; Female; Humans; Male; Psychotic Disorders; Risk Factors; Schizophrenia; Schizophrenic Psychology

Clozapine is the only medication distributed in the U.S. through a national patient registry system that provides the medication only if results of patients' weekly blood tests show no evidence of significant white blood cell suppression, an effect that can be fatal if it progresses to advanced agranulocytosis. This study assessed morbidity and mortality related to agranulocytosis during the first five years of the national registry system.. Data from the national registry database maintained by the U.S. manufacturer of clozapine was used to determine the level of treating systems' adherence to the mandated program of weekly white blood cell counts, number of instances in which clozapine treatment was denied because of prior determination of white blood cell suppression, and number of cases of agranulocytosis and deaths related to agranulocytosis among treated patients from February 1990, when clozapine was commercially introduced in the U.S., through December 1994. The actual numbers of cases of agranulocytosis and related deaths were compared with expected outcomes based on clinical research done before the drug became available commercially.. Approximately 97 percent of treating systems had a high overall level of adherence to the registry protocol. In 28 instances, the pretreatment authorization requirement resulted in denial of clozapine; after additional data were considered, 15 of the patients were cleared for treatment. The actual incidences of 382 cases of agranulocytosis and 12 related deaths were lower than the expected 995 cases and 149 deaths.. The clozapine national registry system fostered early detection of white blood cell suppression, prevented retreatment with clozapine of patients who had previously developed white blood cell suppression, and brought about lower than expected rates of agranulocytosis and associated deaths.

Topics: Adverse Drug Reaction Reporting Systems; Agranulocytosis; Antipsychotic Agents; Cause of Death; Clozapine; Cross-Sectional Studies; Drug Monitoring; Humans; Incidence; Leukocyte Count; Patient Compliance; Schizophrenia; Schizophrenic Psychology; United States

The Clozapine Resource Centre in British Columbia is a centralized information source for all physicians wishing to prescribe clozapine and also performs back-up hematological and compliance monitoring. Laboratories fax weekly hematology results to physicians and to the center. The center enters results in a national database and compiles twice-weekly noncompliance reports; physicians are notified of abnormal results, and caregivers of noncompliance. The centralized system obviates the practice in some jurisdictions of hiring case coordinators to oversee these procedures and may reduce physician reluctance to prescribe clozapine. It improves coordination among monitoring and treatment parties and ensures better continuity of care.

Topics: Adverse Drug Reaction Reporting Systems; Agranulocytosis; Antipsychotic Agents; British Columbia; Clozapine; Continuity of Patient Care; Database Management Systems; Drug Monitoring; Humans; Patient Care Team; Schizophrenia; Schizophrenic Psychology

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Monitoring; Humans; Liver Function Tests; Male; Psychiatric Status Rating Scales; Schizophrenia, Paranoid

During a 5-year period, 6 patients with clozapine-associated agranulocytosis who received granulocyte colony-stimulating factor (G-CSF) were compared with 5 subjects who did not receive this treatment. Seven patients were asymptomatic, and the weekly leukocyte count alone indicated agranulocytosis. The average duration of agranulocytosis was not significantly different between the treated and untreated groups (6.5 vs. 6.6 days), though the treated group had a significantly shorter average duration of hospitalization (8.2 vs. 13.5 days). G-CSF administration was well tolerated, and no adverse effects were noted. Incidentally noted was the recent addition of ranitidine (with the potential for bone marrow toxicity) to clozapine for 2 patients. Currently, weekly white cell and differential counts remain the main tools for detecting incipient or occurring agranulocytosis. Until efficacy studies prove otherwise, G-CSF administered soon after the diagnosis of clozapine-associated agranulocytosis may shorten the duration of hospitalization and thus prove cost-effective.

Topics: Adult; Aged; Agranulocytosis; Clozapine; Female; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Humans; Male; Middle Aged; Prognosis

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans

Topics: Aged; Agranulocytosis; Antipsychotic Agents; Clozapine; Delusions; Female; Humans; Schizophrenia

Before clozapine was marketed, 4 cases of agranulocytosis occurred amongst the 2,900 patients exposed to the drug in the clinical studies from 1962 to 1972. At that time, the frequency of 0.14% was considered comparable to that published with some phenothiazines. After clozapine was launched in different countries, several notifications of agranulocytosis/granulocytopenia were reported, with a high mortality ratio in some countries. This outbreak of agranulocytosis has led to the implementation of recommendations, particularly a strict worldwide hematologic surveillance with a discontinuation of clozapine when the white blood cells drop below a critical level. This article emphasizes the positive impact of these precautionary measures on the present incidence of the agranulocytosis and on the mortality ratio.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Global Health; Humans

The use of clozapine is limited by the risk of agranulocytosis. The incidence of agranulocytosis after 1 year was .80 percent in 11,555 patients registered in the Clozaril Patient Management System (CPMS) who received clozapine from February 1990 to April 1991. We noticed a tendency for white-cell counts to spike upward before agranulocytosis occurred. We analyzed the CPMS data to test whether a white-cell count spike at least 15 percent above the previous measurement predicted agranulocytosis within 75 days, with a 21-day lag to allow white-cell counts to decline to levels indicative of agranulocytosis. The occurrence of a spike, entered as a time-dependent covariate in proportional hazards regression, significantly predicted development of agranulocytosis (risk ratio, 3.02; 95% confidence interval, 1.38 to 6.57). Spikes were sensitive though nonspecific predictors, occurring frequently in patients who did not develop agranulocytosis. These results, while exploratory, indicate the potential usefulness of these spikes as guidelines to govern the use of clozapine.

Topics: Agranulocytosis; Clozapine; Follow-Up Studies; Humans; Leukocytes; Risk Factors; Treatment Outcome

Agranulocytosis is the most serious side effect of clozapine therapy, occurring in approximately 1% of all treated patients. Despite careful blood monitoring, a significant number of cases of agranulocytosis and resulting fatalities have occurred. Strategies are needed to manage clozapine-induced agranulocytosis more safely.. This report describes the management of three state hospital inpatients who developed clozapine-induced agranulocytosis. All patients were diagnosed as having chronic paranoid schizophrenia according to DSM-III-R criteria and had previously failed to respond to treatment with standard antipsychotic medications. After onset of agranulocytosis, all patients were transferred to a medical service in a university hospital and treated with recombinant granulocyte colony-stimulating factor (filgrastim).. White blood count and absolute neutrophil count returned to within normal limits in each patient after 5 to 8 days of treatment with filgrastim 300 micrograms/day subcutaneously. No side effects were observed during filgrastim treatment.. Treatment with filgrastim appears to be safe and effective in decreasing the duration of clozapine-induced agranulocytosis. While further studies are necessary to establish the safety and effectiveness of this treatment, filgrastim should presently be considered a treatment of choice for clozapine-induced agranulocytosis.

Topics: Adult; Agranulocytosis; Chronic Disease; Clozapine; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Leukocyte Count; Male; Middle Aged; Neutrophils; Recombinant Proteins; Schizophrenia, Paranoid; Treatment Outcome

Genes of the major histocompatibility complex (MHC) have been associated with susceptibility to drug-induced adverse reactions. We previously found that clozapine-induced agranulocytosis (CA) is associated with the HLA-DRB1*0402, DRB4*0101, DQB1*0302, DQA1*0301 haplotype in Ashkenazi Jewish patients and with the HLA-DRB1*1601, DRB5*02, DQB1*0502, DQA1*0102 haplotype in non-Jewish patients. In the present study, we tested the hypothesis that the variants of the heat-shock protein 70 (HSP-70) encoded by the HSP-70 loci located within the MHC region and known to be involved in apoptosis and regulation of cell proliferation could play an important role in molecular mechanisms of CA. First, we analyzed HSP70-2 polymorphism in risk-associated haplotypes from HLA homozygous cells and normal individuals and confirmed that the HSP70-2 9-kb variant was associated invariably with DR4 (HLA-DRB1*0402, DQB1*0302) and DR2 (HLA-DRB1*01601, DQB1*0502, DQA1*0102 and HLA-DRB1*1501, DQB1*0602) haplotypes, which were the haplotypes found increased in Jewish and non-Jewish patients with CA, respectively. The 9.0-kb variant was also found to be associated with HLA-B44, DRB1*0401 and HLA-B44, DRB1*07 haplotypes. Second, in patients with CA (12 Ashkenazi Jewish and 20 non-Jewish patients), HSP70-1 A and HSP70-2 9.0-kb variants were associated with the MHC haplotypes found by us to be markers of susceptibility to CA. The clozapine-treated control group had an excess number of HSP70-1 C and HSP70-2 8.5-kb variants, consistent with genetic resistance to CA associated with those variants. This finding supports our hypothesis that a dominant gene within the MHC region (marked by HSP70-1 and HSP70-2), but not necessarily HLA, is associated with CA in two different ethnic groups.

Topics: Agranulocytosis; Apoptosis; Clozapine; Disease Susceptibility; Gene Frequency; Genes, Dominant; Genetic Markers; Genetic Predisposition to Disease; Genetic Variation; Haplotypes; HLA Antigens; HSP70 Heat-Shock Proteins; Humans; Jews; Major Histocompatibility Complex; Polymorphism, Restriction Fragment Length; White People

We previously reported preliminary results of association of clozapine-induced agranulocytosis (CA) with HLA-B38, DR4, DQ3 in five Ashkenazi Jewish patients and with HLA-DR2, DQ1 in four non-Jewish patients. In the present study, 31 additional patients with CA, 10 Ashkenazi Jewish, and 21 of non-Jewish ancestry, were studied. HLA alleles and haplotypes were compared among 52 patients (33 Ashkenazi Jewish, 19 non-Jewish) matched for ethnic background and clinical status. Our results show two associations and define the HLA allele markers for the Ashkenazi Jewish and non-Jewish haplotypes associated with CA. The most important markers for susceptibility for CA in Ashkenazi Jewish patients were DRB1*0402, DQB1*0302, and DQA1*0301, and in non-Jewish patients, HLA-DR*02, DQB1*0502, and DQA1*0102. HLA-DRB1*011 and DQB1*0301 were underrepresented in Ashkenazi Jewish patients when compared with controls. We hypothesize that genes of the major histocompatability complex, other than class I and class II, are responsible for CA; among them are the variants of the heat-shock proteins 70 or the tumor necrosis factor loci.

Topics: Adult; Agranulocytosis; Alleles; Base Sequence; Clozapine; DNA Primers; Female; Gene Frequency; Genes, MHC Class I; Genes, MHC Class II; Haplotypes; HLA-B Antigens; HLA-B38 Antigen; HLA-DQ Antigens; HLA-DR2 Antigen; HLA-DR4 Antigen; Humans; Jews; Male; Molecular Sequence Data

Before clozapine was marketed, 4 cases of agranulocytosis occurred amongst the 2,900 patients exposed to the drug in the clinical studies from 1962 to 1972. At that time the frequency of 0.14% was considered comparable to that published with some phenothiazines. After clozapine was launched in different countries, several notifications of agranulocytosis/granulocytopenia were reported, with a high mortality ratio in some countries. This outbreak of agranulocytosis has led to the implementation of recommendations, particularly a strict worldwide hematologic surveillance with a discontinuation of clozapine when the white blood cells drop below a critical level. This article emphasizes the positive impact of these precautionary measures on the present incidence of the agranulocytosis and on the mortality ratio.

Topics: Agranulocytosis; Clozapine; Cross-Cultural Comparison; Drug Monitoring; Humans; Leukocyte Count; Risk Factors; Schizophrenia; Schizophrenic Psychology

Clozapine's monitoring, with a co-responsibility between psychiatrists and pharmacists, was very efficient for the prevention of neutropenia's side effects. This intensive drug safety has lowered the agranulocytosis' cases in France to a 0.5% prevalence. However the cost of clozapine led to a strict estimation for Health expenditures. Our study, trained in an university department of psychiatry in Sainte-Anne Hospital (Paris), has included 14 patients treated with clozapine during at least 12 months and has displayed a decrease of 10% in their annual global cost, comparing to the same group of patients treated by classical neuroleptics during the preceding year. This global cost includes the treatment, the blood monitoring and the cost of different hospital or community cares. Quality of life, in clozapine group, was much improved as illustrated by lowing full time hospitalization relayed earlier by community care and precocious social readaptation.

Topics: Agranulocytosis; Clozapine; Cost-Benefit Analysis; Day Care, Medical; Drug Monitoring; France; Humans; Patient Admission; Patient Care Team; Quality of Life; Schizophrenia; Schizophrenic Psychology

Topics: Agranulocytosis; Clozapine; Drug Monitoring; Humans; Leukocyte Count; Neutropenia; Physician-Patient Relations; Risk Factors; Schizophrenia; United States

Topics: Agranulocytosis; Clozapine; Dose-Response Relationship, Drug; Drug Monitoring; Europe; Genetic Markers; Humans; Jews; Leukocyte Count; United States

Agranulocytosis and hepatotoxic reactions are rare but severe side-effects of neuroleptic treatment. This article presents the case of a schizophrenic patient who concurrently developed agranulocytosis and acute hepatic drug reaction as a result of a combination of chemically different neuroleptic drugs. After restoration the patient was successfully treated with clozapine for six months without the hematologic disorders recurring.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Chemical and Drug Induced Liver Injury; Clozapine; Humans; Leukocyte Count; Male; Schizophrenia

Symptomatic antiphospholipid antibody has rarely been described in patients treated with neuroleptic drugs. We report the appearance of this antibody in association with retinal artery occlusion, in a 40-year-old man treated by neuroleptic drugs who later developed acute agranulocytosis following clozapine.

Topics: Adult; Agranulocytosis; Antibodies, Antiphospholipid; Antipsychotic Agents; Clozapine; Humans; Male; Retinal Artery Occlusion

Topics: Agranulocytosis; Clinical Trials as Topic; Clozapine; Cost-Benefit Analysis; Drug Administration Schedule; Humans; Prescription Fees; Psychiatric Status Rating Scales; Risk Factors; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Topics: Agranulocytosis; Clozapine; Ethnicity; Humans; Neutropenia; Parkinson Disease; Tremor

Clozapine, a dibenzodiazepine antipsychotic, is associated with a 0.8% incidence of agranulocytosis. This clinically restrictive toxicity has been attributed to its chemically reactive metabolites. The generation of such metabolites--assessed via covalent binding and formation of thioether adducts--was investigated using human, rat and mouse liver microsomes and human neutrophils and bone marrow cells. In every instance, one major glutathione adduct of clozapine--C-6 glutathionyl clozapine--was formed in the presence of added glutathione. Adduct formation by the neutrophils and myeloid cells was dependent on cell activation by phorbol myristate acetate. Small fractions of drug underwent covalent binding to microsomes (1-6.8%) and to protein coincubated with neutrophils (0.47%) and myeloid cells (0.21%). Clozapine did not deplete intracellular glutathione in activated neutrophils. Clozapine was also metabolized in vivo to glutathione conjugates in rats and mice, the conjugates eliminated in bile over a 3-hr period representing 38% and 33% of the dose, respectively. In addition to the principal clozapine adduct found in vitro, the C-8 glutathionyl derivative of deschloroclozapine was excreted by both species. It is concluded that clozapine undergoes bioactivation in several tissues and considerable bioactivation in vivo. The reactive metabolites generated by neutrophils and myeloid cells may play an important role in the metabolic causation of clozapine-induced agranuiocytosis.

Topics: Adult; Agranulocytosis; Animals; Antipsychotic Agents; Biotransformation; Bone Marrow; Bone Marrow Cells; Catalysis; Clozapine; Humans; Male; Mice; Microsomes, Liver; Neutrophils; Oxidation-Reduction; Peroxidase; Rats; Rats, Wistar; Reference Values

We hypothesized that patients who had experienced clozapine-induced agranulocytosis would have abnormalities in their free radical scavenging enzyme activity (FRESA) and levels of related trace metals. We therefore measured FRESA profiles and related trace metals in four groups: post-clozapine agranulocytosis (POST CLOZ AGRAN) (N = 9); clozapine no agranulocytosis (CLOZ NO AGRAN) (N = 12); West Coast controls (WC CONTROLS) (N = 14); and Long Island Jewish Medical Center controls (LIJ CONTROLS) (N = 12). Glutathione peroxidase (GSH-Px, P1) levels in plasma were slowest in the POST CLOZ AGRAN group (34.3 +/- 6.9 IU/dl [standard deviation; SD]; p < 0.002); red blood cell glutathione peroxidase (GSH-Px, RBC) was highest in the WC CONTROLS (38.7 +/- 4.7 IU/g hemoglobin [Hgb]; p < 0.008); and selenium (SE) levels in plasma were lower in both the POST CLOZ AGRAN group (111.6 +/- 14.7 ng/ml) and the CLOZ NO AGRAN group(115.0 +/- 17.8) than in the WC CONTROLS (142.5 +/- 18.3; p < 0.0006). SE was also lower in the POST CLOZ AGRAN group than in the LIJ CONTROLS (129.1 +/- 21.6; p < 0.04). The presence of at least one of the following: (1) GSH-Px, P1 < 37.6 IU/dl; (2) GSH-Px, RBC < 31.0 IU/g Hgb; or (3) SE < 112.4 ng/ml, distinguished POST CLOZ AGRAN subjects from the WC CONTROLS, but not from the LIJ CONTROLS. Data from this cross-sectional pilot study suggest that abnormalities in the body's antioxidant defense system may be involved in the pathogenesis of clozapine-associated agranulocytosis. If confirmed in large-scale, prospective studies, these preliminary findings have potential clinical application in the screening and prophylaxis of clozapine agranulocytosis.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Catalase; Clozapine; Cross-Sectional Studies; Female; Free Radicals; Glutathione Peroxidase; Hemoglobinometry; Humans; Male; Middle Aged; Pilot Projects; Reference Values; Risk Factors; Selenium; Superoxide Dismutase; Trace Elements

Topics: Agranulocytosis; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Granulocyte Colony-Stimulating Factor; Humans; Leukocyte Count; Male; Middle Aged; Schizophrenia; Schizophrenic Psychology

Is clozapine-induced agranulocytosis amenable to treatment with recombinant granulocyte colony-stimulating factor (rG-CSF)? Will this treatment provide benefits in terms of morbidity, mortality, and costs compared with current treatment?. Five patients with clozapine-induced agranulocytosis (granulocytes < 500/cu mm) were treated with the rG-CSF filgrastim, in addition to standard agranulocytosis therapy protocol.. Time from onset until resolution of agranulocytosis was 8.2 +/- 2.1 days compared with a historical study of seven cases where filgrastim was not used and 15.7 +/- 3.7 days were required for resolution.. rG-CSF (filgrastim) may be an effective and cost-reducing way to provide improved treatment for clozapine-induced agranulocytosis. More research is required.

Topics: Adult; Aged; Agranulocytosis; Clozapine; Drug Administration Schedule; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Male; Middle Aged; Recombinant Proteins; Schizophrenia; Treatment Outcome

A 20-year-old woman had for the preceding 11 weeks been receiving clozapine (225 mg/d) for an endogenous psychosis when she developed a urinary tract infection with fever. The blood count showed 2100 white cells/microliter without any neutrophils, the count having been normal 5 days previously. Physical examination was normal except for a fever of 39 degrees C and parodontitis. The red cell count was 3.9 mill/microliters, platelet count 443,000/microliters. Bone marrow biopsy revealed almost complete stop of proliferation and maturation in granulocytopoiesis so that granulocyte colony-stimulating factor (300 micrograms daily subcutaneously) had to be administered in addition to supportive measures. The granulocyte count at first fell to 1400 cells/microliter, but nine days after starting the drug myeloblasts, promyelocytes and myelocytes reappeared in peripheral blood for the first time. On the tenth day, administration of the growth factor was discontinued. An overshoot granulocytopoiesis occurred in bone marrow on the 13th day; on the 22nd day after treatment had been started the patient had a normal blood picture and was discharged.

Topics: Adult; Agranulocytosis; Blood Cell Count; Bone Marrow; Clozapine; Female; Granulocyte Colony-Stimulating Factor; Humans; Psychotic Disorders; Urinary Tract Infections

Topics: Adult; Agranulocytosis; Clozapine; Dose-Response Relationship, Drug; Female; Granulocyte Colony-Stimulating Factor; Humans; Leukocyte Count; Neutropenia; Schizophrenia; Schizophrenic Psychology

Clozapine is an atypical antipsychotic drug with a very low incidence of extrapyramidal effects, used in the treatment of schizophrenic patients refractory or intolerant to classical neuroleptics. Its use is limited due to the potential risk of producing agranulocytosis in 1 to 2% of patients. Despite the severity of this complication, the Federal Drug Administration allowed its use as long as its prescription is associated to a drug surveillance program that controls regularly the white cell count of patients using the drug. Three hundred three patients (210 male) have been admitted to a clozapine drug surveillance program. Two patients had a transitory leukopenia with less than 2000 leukocytes/ml and less than 1000 neutrophyls/ml, that reverted after discontinuing the drug. One patient, whose case is described, had a severe agranulocytosis with less than 500 neutrophyls/ml that required hospital admission.

Topics: Adult; Adverse Drug Reaction Reporting Systems; Agranulocytosis; Clozapine; Humans; Male; Neutropenia; Schizophrenia

Topics: Agranulocytosis; Clozapine; Drug Monitoring; Humans; Psychotic Disorders; Risk Factors; Schizophrenia; United States

Clozapine's use has been restricted to the treatment of schizophrenic patients unresponsive to conventional antipsychotics, secondary to its propensity to cause agranulocytosis. Because of this restriction, side effects associated with clozapine's use have probably not been fully elucidated. The authors describe a case of a male schizophrenic who developed clozapine-induced agranulocytosis and subsequently a neutropenic enterocolitis. Neutropenic enterocolitis related to clozapine-induced neutropenia or agranulocytosis has not previously been reported in the literature. The history of clozapine, its side effects, and the phenomenon of neutropenic enterocolitis are briefly reviewed.

Topics: Agranulocytosis; Clozapine; Enterocolitis; Humans; Male; Middle Aged; Neutropenia; Schizophrenia; Treatment Outcome

Topics: Agranulocytosis; Clozapine; Drug Administration Schedule; Humans; Leukocyte Count; Male; Middle Aged; Recurrence; Schizophrenia; Schizophrenic Psychology

Despite its potentially fatal side effect--agranulocytosis--clozapine has become an important drug in antipsychotic treatment. With this in mind, this report presents the case of a 23-year-old schizophrenic who had suffered from agranulocytosis after simultaneous short-term treatment with butyrophenone and phenothiazine neuroleptics 3 years ago. After nonresponse to two other classic neuroleptics, the administration of high-dose clozapine led to a full recovery without the recurrence of hematologic disorders during 24 months of follow-up examinations. Although patients with a known history of agranulocytosis are usually excluded from treatment with clozapine, we propose that, in very severe or otherwise therapy-resistant cases, clozapine be administered and then white blood cell counts monitored very stringently. Although a single case can prove little, our case provides further evidence for the presumption that noncross-reactivity exists between clozapine and other neuroleptic drugs in the induction of agranulocytosis.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Leukocyte Count; Schizophrenia; Schizophrenic Psychology

Clozapine may produce agranulocytosis in 1-2% of patients treated with it for 4 weeks or longer. Three mechanisms have been suggested: a direct toxic effect of metabolite of clozapine, an immunologic mechanism or a combination of both. N-desmethylclozapine, the major metabolite of clozapine, has been reported to be more toxic than clozapine itself (Gerson et al., 1994). In this study, plasma levels of clozapine and desmethylclozapine were measured in five patients who developed agranulocytosis. The levels of both parent compound and metabolite were within the range found in other patients and below the toxic range. If a toxic mechanism is involved in clozapine-induced agranulocytosis, an additional vulnerability factor must be important.

Topics: Adult; Agranulocytosis; Clozapine; Female; Humans; Male; Schizophrenia

The aim of the study was to shed more light on the incidence and course of clozapine-induced transient white blood count (WBC) disorders.. In an analysis of our clozapine drug monitoring program, we evaluated the data of 68 patients receiving clozapine for the first time. Incidence rates were calculated by actuarial life table analysis. The potential influence of sex, age, dose, and plasma level was evaluated using discriminant analysis.. Two patients developed progressive neutropenia, leading to agranulocytosis in one case. We also found the following transient hematologic dysfunctions: neutropenia (22.0%), eosinophilia (61.7%), and leukocytosis (40.9%). One patient showed chronic leukocytosis. Additionally, minor changes in the number of lymphocytes, monocytes, and basophilic granulocytes were detected in the study population.. Hematologic side effects are frequently induced by the atypical antipsychotic clozapine. Next to agranulocytosis, a progressive and potentially lethal hematologic adverse effect, most of the WBC disorders are transient and appear to be harmless.

Topics: Actuarial Analysis; Adult; Agranulocytosis; Austria; Clozapine; Drug Monitoring; Eosinophilia; Female; Humans; Incidence; Leukocytosis; Male; Neutropenia; Prevalence; Prospective Studies; Schizophrenia

Topics: Agranulocytosis; Clozapine; Cost-Benefit Analysis; Costs and Cost Analysis; Drug Monitoring; Histocompatibility Testing; Humans; Leukocyte Count

The use of clozapine has been limited by the risk of agranulocytosis. The cumulative incidence of agranulocytosis is 0.80% after 1 year and 0.91% after 1 1/2 years. Risk is greatest during the first 3 months of treatment and greater among women and the elderly. White-cell counts tend to spike upward before the occurrence of agranulocytosis. The occurrence of a white-cell count spike of > or = 15% above the previous count predicts development of agranulocytosis within 75 days (risk ratio = 3.02; 95% confidence interval, 1.38-6.57). Our results indicate that hematologic monitoring is necessary and effective. They also suggest that the frequency of monitoring could be reduced after the initial period of maximal risk.

Topics: Adult; Age Factors; Agranulocytosis; Clozapine; Cohort Studies; Confidence Intervals; Drug Monitoring; Female; Humans; Incidence; Leukocyte Count; Male; Neutrophils; Product Surveillance, Postmarketing; Risk Factors; Schizophrenia; Sex Factors; United States

Serum drawn from patients during clozapine-induced agranulocytosis was toxic to human polymorphonuclear leukocytes (PMNs). Toxicity was produced by an immunoglobulin fraction, predominantly of the IgM class. The offending drug was not necessary at this stage to produce cytotoxicity. These effects were observed by inhibiting post-phagocytosis glycolysis, by ejection of trypan blue, or by enhanced release of 51Cr from lysed-labeled PMNs. Direct chemical toxicity, produced by clozapine or its metabolites, was tested by similar procedures. At a concentration of 10(-5) M in a colloidal milieu produced by dilution with AB serum, no cytotoxicity was observed; however, in aqueous medium. N-desmethylclozapine was toxic to PMNs and proliferating lymphocytes. Post-recovery serum appeared to be inert, but cytotoxicity was restored by adding clozapine or N-desmethylclozapine to the sensitive patient's serum. At this stage, cytotoxicity as measured by 51Cr release was abrogated by anti-IgG or anti-IgM. These relationships favor an immunologic mechanism that damages peripheral PMNs. Development of colony-forming units-granulocyte (CFU-G) was similarly inhibited in normal marrow cultures by cytotoxic serum alone, whereas no metabolite had such an effect at the same concentration (10(-5) M).

Topics: Agranulocytosis; Bone Marrow; Carbon Dioxide; Carbon Radioisotopes; Chromium Radioisotopes; Clozapine; Cytotoxicity, Immunologic; Cytotoxins; Dose-Response Relationship, Immunologic; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunoglobulin G; Immunoglobulin M; Neutrophils; Trypan Blue

Topics: Agranulocytosis; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Clozapine; Drug Therapy, Combination; Homicide; Humans; Informed Consent; Lung Neoplasms; Male; Middle Aged; Neutropenia; Schizophrenia; Schizophrenic Psychology; Treatment Refusal

Topics: Agranulocytosis; Cause of Death; Chronic Disease; Clozapine; Drug Monitoring; Humans; Risk Factors; Schizophrenia; Schizophrenic Psychology; Suicide; Suicide Prevention; Survival Analysis

Topics: Agranulocytosis; Clozapine; Drug Monitoring; Humans; Neutropenia; Psychotic Disorders; Risk Factors; Survival Analysis; United Kingdom

Topics: Agranulocytosis; Clozapine; Female; Humans

Clozapine, a novel antipsychotic drug that is particularly effective in treatment-resistant schizophrenia, causes severe agranulocytosis of unknown aetiology in approximately 0.8% of U.S. patients. We evaluated potential toxic mechanisms of drug-induced agranulocytosis. Clozapine, the two major metabolites N-desmethylclozapine and N-oxide clozapine, and five other clozapine derivatives were screened for toxicity to normal haemopoietic precursors. For all compounds except N-des-methylclozapine, toxicity to CFU-GM, BFU-E and CFU-GEMM occurred at concentrations at least 10 times the normal serum levels reported in unaffected patients. In contrast, the LD50 for N-desmethylclozapine was 2.5 micrograms/ml for CFU-GM, 3.2 micrograms/ml for BFU-E, and 2.4 micrograms/ml for CFU-GEMM, only 3-6 times the normal serum concentration. Bone marrow from patients with acute clozapine-induced agranulocytosis was not more sensitive to clozapine or N-desmethylclozapine than bone marrow from normal donors. These studies suggest that N-desmethylclozapine, the major metabolite of clozapine, is itself toxic or is further metabolized to an unstable compound which is toxic to haemopoietic precursors of both myeloid and erythroid lineages.

Topics: Agranulocytosis; Cell Survival; Cells, Cultured; Clozapine; Colony-Forming Units Assay; Dose-Response Relationship, Drug; Hematopoiesis; Hematopoietic Stem Cells; Humans

Topics: Agranulocytosis; Clozapine; Humans

Clozapine has been utilized in Denmark since the early 1970s. This study examines doses, concomitant psychotropics, and leukocyte counts.. All psychiatric hospitals in Denmark were asked for copies of all their clozapine monitoring forms, which were then personally reviewed by the authors.. Forms from 656 patients were collected from 32 hospitals. The male/female ratio was 2/1; the median age, 38 years (range, 18-80). Thirty-five percent received concomitant antipsychotics, 28% benzodiazepines, 19% anticholinergics, 11% antidepressants, 8% antiepileptics, (carbamazepine, valproate, and phenobarbital), and 2% lithium. While there were no gender differences with respect to concurrent psychotropics, women received lower doses of clozapine than men (median dose, women 300 mg/day and men 400 mg/day, p < .02). Ten percent had had a neutrophil count < 2000/microL (3.2% < 1500/microL). Five percent had repeated neutrophil counts < 2000/microL (1.5% < 1500/microL). There were two cases of agranulocytosis; both patients fully recovered upon withdrawal of clozapine. Clozapine was discontinued because of hematologic abnormalities in only five other cases (0.8%).. While use of concomitant psychotropics during clozapine treatment should be limited because of an increased risk of complications, a totally restrictive policy might deprive certain patients of the benefits of clozapine treatment. There appears to be a benign form of granulocytopenia that does not always necessitate discontinuation, provided there is close follow-up.

Topics: Adolescent; Adult; Aged; Agranulocytosis; Antidepressive Agents; Clozapine; Denmark; Drug Monitoring; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Leukocyte Count; Male; Middle Aged; Neutrophils; Parasympatholytics; Patient Compliance; Patient Dropouts; Psychotropic Drugs; Schizophrenia; Treatment Outcome

Topics: Agranulocytosis; Clozapine; Drug Therapy, Combination; Female; Humans; Methimazole; Middle Aged; Thyrotoxicosis

Topics: Agranulocytosis; Clozapine; Humans; Incidence; Leukocyte Count; Risk Factors; United States

Topics: Adverse Drug Reaction Reporting Systems; Agranulocytosis; Clozapine; Humans; Schizophrenia; Schizophrenic Psychology

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

To report a case of clozapine- and molindone-induced agranulocytosis and to discuss treatment using filgrastim, a granulocyte colony-stimulating factor.. A 64-year-old woman who had been on long-term clozapine therapy for schizophrenia was hospitalized with presumed drug-induced agranulocytosis. She had also been on short-term molindone therapy. A bone marrow biopsy and the initial white blood cell (WBC) count were consistent with drug-induced agranulocytosis. Following seven days of treatment with subcutaneous filgrastim 300 micrograms/d, her absolute neutrophil count was above 500 x 10(6)/L.. Reports in the literature discussing antipsychotic drug-induced agranulocytosis are reviewed. A relationship between treatment with filgrastim and WBC response is postulated.. Filgrastim may be useful in ameliorating the effects of clozapine- and molindone-induced agranulocytosis.

Topics: Agranulocytosis; Clozapine; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Injections, Subcutaneous; Middle Aged; Molindone; Recombinant Proteins

A case of clozapine-induced agranulocytosis that was treated with a granulocyte colony-stimulating cytokine is presented. The hematological status normalized. Two colony-stimulating factors are marketed for activating bone marrow function. Their utility in clozapine a granulocytoses is not clear, but they offer a potential new therapeutic option.

Topics: Agranulocytosis; Clozapine; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leukocyte Count; Recombinant Proteins; Schizophrenia

After 10 weeks of treatment with clozapine, severe agranulocytosis was diagnosed in a 33-year-old female. The patient was treated with filgrastim (granulocyte colony-stimulating factor [G-CSF]) 5 micrograms kg-1 day-1. The neutrophil count was 0.234 x 10(9) l-1 on admission, with a further decrease the next day to < 0.050 x 10(9) l-1, and this complete agranulocytosis continued for 10 days. As no response was obtained after 1 week the dosage of filgrastim was increased to 10 micrograms kg-1 day-1 with immediate improvement. A rapid and pronounced leucocytosis developed with maximal value of neutrophil granulocytes (including immature forms) of 33.108 x 10(9) l-1 on day 12 after admission. The patient only had minor infectious complications during the neutropenic period. In conclusion, early treatment with filgrastim seems warranted in severe cases of clozapine-induced agranulocytosis. A dosage of 10 micrograms kg-1 day-1 can be recommended.

Topics: Adult; Agranulocytosis; Clozapine; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Recombinant Proteins

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Drug Interactions; Drug Monitoring; Drug Resistance; Humans; Leukocyte Count; Schizophrenia

Topics: Adolescent; Adult; Agranulocytosis; Clozapine; Female; Humans; Male; Middle Aged; Schizophrenia

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

Topics: Agranulocytosis; Clozapine; Humans; Male; Middle Aged

Clozapine-induced agranulocytosis is usually reversible after discontinuation of the drug. A patient who developed agranulocytosis after termination of clozapine therapy responded to treatment with granulocyte macrophage colony stimulating factor.

Topics: Agranulocytosis; Clozapine; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leukocyte Count; Middle Aged; Schizophrenia

Topics: Adolescent; Agranulocytosis; Clozapine; Humans; Leukocyte Count; Male; Schizophrenia; Schizophrenic Psychology

Topics: Agranulocytosis; Clozapine; Cost-Benefit Analysis; Costs and Cost Analysis; Histocompatibility Testing; HLA Antigens; Humans; Leukocyte Count

Topics: Adult; Agranulocytosis; Clozapine; Colony-Stimulating Factors; Humans; Male

Topics: Adult; Agranulocytosis; Clozapine; Diagnosis, Differential; Female; Humans; Recurrence

Topics: Agranulocytosis; Bipolar Disorder; Clozapine; Diagnosis, Differential; Female; Humans; Middle Aged; Recurrence

The effects of clozapine on positive and negative symptoms were studied in 103 patients with treatment-refractory schizophrenia. The evaluation of symptom profile was made before and after clozapine treatment. Overt psychopathology did not vary significantly before clozapine treatment. Significant decreases in positive and negative symptoms were noted by the third month on clozapine. No further significant progress could be observed after 6 months of treatment. No fatal cases were observed, although two patients developed agranulocytosis during clozapine treatment.

Topics: Adult; Agranulocytosis; Clozapine; Dose-Response Relationship, Drug; Female; Humans; Leukopenia; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Topics: Adult; Agranulocytosis; Clozapine; Humans; Male; Neutropenia; Psychiatric Status Rating Scales; Psychoses, Substance-Induced; Schizophrenia; Schizophrenic Psychology; Substance Withdrawal Syndrome

A case report of clozapine-induced agranulocytosis in a patient treated concomitantly with lithium is reported. The possible role of lithium in the mechanism of clozapine myelosuppression is discussed.

Topics: Agranulocytosis; Clozapine; Drug Therapy, Combination; Female; Granulocytes; Humans; Leukocyte Count; Lithium; Middle Aged; Psychotic Disorders; Time Factors

Topics: Agranulocytosis; Clozapine; Emergencies; Humans; Status Epilepticus; Tachycardia; Unconsciousness

Clozapine is an atypical antipsychotic agent that is more effective than standard neuroleptic drugs in the treatment of patients with refractory schizophrenia. Unlike classic neuroleptic agents, clozapine is not associated with the development of acute extrapyramidal symptoms or tardive dyskinesia. The main factor limiting its use is the risk of potentially fatal agranulocytosis, estimated to occur in 1 to 2 percent of treated patients. After clozapine was approved by the Food and Drug Administration, it became available for marketing in the United States in February 1990 only as part of a special surveillance system (the Clozaril Patient Management System, or CPMS), in which a weekly white-cell count was required for the patient to receive a supply of the drug.. We evaluated the CPMS data for February 1990 through April 1991 by survival analysis to determine the incidence of agranulocytosis and the effects of potential risk factors such as age and sex. Data were available for 11,555 patients who received clozapine during the period after marketing began.. Agranulocytosis developed in 73 patients, resulting in death from infectious complications in 2 patients. Episodes of agranulocytosis occurred in 61 patients within three months after they began treatment. The cumulative incidence of this side effect was 0.80 percent (95 percent confidence interval, 0.61 to 0.99) at 1 year and 0.91 percent (95 percent confidence interval, 0.62 to 1.20) at 1 1/2 years. The risk of agranulocytosis increased with age and was higher among women.. The occurrence of agranulocytosis is a substantial hazard of the administration of clozapine, but this hazard can be reduced by monitoring the white-cell count. The increasing risk of agranulocytosis with age and the reduced incidence after the first six months of treatment provide additional guidelines for the prescription and monitoring of clozapine treatment in the future.

Topics: Adult; Agranulocytosis; Clozapine; Drug Monitoring; Female; Follow-Up Studies; Humans; Incidence; Leukocyte Count; Male; Middle Aged; Proportional Hazards Models; Risk Factors; United States

Topics: Agranulocytosis; Clozapine; Humans; Neutropenia; Risk Factors

The decision whether or not to stop clozapine therapy in schizophrenic patients depends on a lot of factors involving the benefit/risk ratio. Thus, authors successively analyse various data: the clinical status of the patient is the first one. The evaluation has to take into account short and long-term efficacies; the problem of the minimal duration of clozapine therapy required before concluding to ineffectiveness is still open: from 4 to 12 months; the question of efficacy of the drug according to the type of symptoms is also quite difficult. Efficacy on positive symptoms among schizophrenic patients seems most prominent; negative symptoms also improve but the reasons why are quite difficult to evaluate. It is sometimes difficult to indicate if the improvement in negative symptoms is independent of the improvement in positive symptoms; the patient's request and his feeling (including tolerability) are another decisional factor; because of the lack of dystonia and other extrapyramidal side effects, some patients are more compliant under clozapine therapy; the side effect (hematologic, cardiovascular, hepatic and central nervous systems) lead to discontinuation of clozapine treatment when severe. The most frequent ones are: sedation, EEG alteration, seizures, increase of liver enzymes, hypotension/collapse, hypersalivation, fever (> 38), ECG alteration, tachycardia, gastro-intestinal adverse effects, weight gain, and leucopenia. In the event of a white blood cell count (WBC) below 3,500/mm3, the patient should be evaluated immediately with respect to the WBC and the differential count (DC). Should the results confirm a WBC below 3,500/mm3 and/or reveal an absolute neutrophil granulocyte count of 2,000 to 1,500/mm3, the leucocytes and the granulocytes must be checked at least twice a week.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Agranulocytosis; Clozapine; Humans; Schizophrenia

Clozapine is an atypical antipsychotic drug which must only be prescribed for the treatment resistant schizophrenic patients. Contra-indications and precautionary measures (F.e no use of a drug that can enhance the potential for a granulocytoxic reaction) have to be well known and respected. There is an increased risk of granulocytopenia, and 1 or 2% of granulocytopenia may induce an agranulocytosis. This risk is compared with what is observed with other psychotropic drugs, phenothiazines particularly. Beyond clozapine adverse effects, three cases of severe cardio-vascular and respiratory dysregulation, one case of sudden death, and one case of induced coma are presented in detail from the literature: possible interactions between clozapine and adjunctive medications are discussed. Appropriate patients should be proposed a treatment by clozapine, in principle without association to any other psychotropic drug and in all the necessary precautions.

Topics: Agranulocytosis; Clozapine; Drug Synergism; Hematologic Diseases; Humans; Neuroleptic Malignant Syndrome; Schizophrenia

Topics: Adult; Agranulocytosis; Clozapine; Female; Humans; Leukopenia; Male; Middle Aged; Psychotic Disorders; Recurrence

Topics: Agranulocytosis; Antibodies; Clozapine; Female; Humans; Middle Aged; Peroxidase

Clozapine, an atypical neuroleptic, is an effective medication in a subgroup of schizophrenic patients who have either failed to respond to the typical neuroleptics or experienced intolerable side effects such as neuroleptic malignant syndrome and disabling tardive dyskinesia. Its efficacy for persistent and disabling akathisia is less clear. Akathisia, especially the chronic and disabling form, can be a treatment dilemma for the clinician and the patient.. We describe three representative case illustrations of schizophrenic patients who had severe, persistent treatment-resistant akathisia. Two of them had refractory psychoses and the third had multiple disabling side effects during treatment with typical neuroleptics. Two had tardive dyskinesia. These patients were treated with clozapine while other neuroleptics were discontinued.. During a 2-year follow-up, these patients made impressive social and vocational strides coinciding with a fairly rapid remission of akathisia (under 3 months) and a lesser though notable improvement in the psychoses. Tardive dyskinesia also remitted, though over a period of 6 to 12 months.. Our experience leads us to suggest a trial of clozapine in a subgroup of schizophrenic patients, who in addition to refractory psychoses have persistent disabling akathisia. However, given the risk of agranulocytosis with clozapine, we suggest that the usual treatment strategies for akathisia be tried before clozapine is initiated in the approved manner. Future controlled trials of clozapine that specifically investigate persistent akathisia may answer this question more conclusively.

Topics: Adult; Agranulocytosis; Akathisia, Drug-Induced; Antipsychotic Agents; Chronic Disease; Clozapine; Dyskinesia, Drug-Induced; Female; Follow-Up Studies; Humans; Male; Middle Aged; Psychomotor Agitation; Schizophrenia; Schizophrenic Psychology; Social Adjustment

Topics: Agranulocytosis; Bone Marrow; Clozapine; Female; Granulocyte Colony-Stimulating Factor; Humans; Middle Aged; Recombinant Proteins

Topics: Adult; Agranulocytosis; Clozapine; Female; Granulocyte Colony-Stimulating Factor; Humans; Leukocyte Count; Male; Neutropenia; Neutrophils

We describe a protocol for the use of an unregistered antipsychotic medicine, clozapine, in a mental health service. Traditionally, prescribing of unregistered medicines has been a matter between prescriber and patient alone. However, clozapine carries a high risk of agranulocytosis and its use requires strict adherence to monitoring procedures. Persons most likely to benefit from it include many who, because of their psychosis, may be unable to give truly informed consent or to react appropriately to adverse reactions. We have designed a protocol which seeks to ensure that this medicine is given only to those whose severity of illness and lack of response to all other reasonable treatment outweighs the risk of agranulocytosis, that it is used with maximum safety and that only persons who have been shown to benefit from the medicine continue to receive it after an initial trial. Although this protocol has been accepted by the medical staff, questions of clinical autonomy and liability in the event of medical misadventure remain.

Topics: Adult; Agranulocytosis; Clinical Protocols; Clozapine; Drug and Narcotic Control; Humans; Middle Aged; New Zealand; Schizophrenia

Topics: Agranulocytosis; Clozapine; Humans

Topics: Agranulocytosis; Clozapine; Female; Humans; Incidence; Male; Risk Factors; United States

This paper describes a statistical analysis of the simultaneous occurrence of 48 human leucocyte antigens (HLAs) in an attempt to predict whether a patient treated with clozapine will develop granulocytopenia or agranulocytosis. Whereas the numerical results show that use of HLAs does not appear to satisfy the intended purpose, emphasis is placed on the statistical methodology recommended for a problem of this type. Other work in this area is critically discussed.

Topics: Agranulocytosis; Clozapine; Discriminant Analysis; HLA Antigens; Humans

The clinical use of clozapine in psychiatry is restricted by the associated risk of agranulocytosis. This risk is significantly higher than that associated with conventional antipsychotic medications. In order to identify a possible parameter to detect susceptible individuals before treatment, 103 patients with a history of clozapine-induced granulocytopenia or agranulocytosis and 95 matched control patients were typed for human leucocyte antigen (HLA)-A, -B, -C, -DR, -DQ and for a number of neutrophil-specific alloantigens. No significant association between certain HLA alleles or neutrophil antigens and susceptibility to clozapine-induced granulocytopenia or agranulocytosis was observed.

Topics: Agranulocytosis; Clozapine; Haplotypes; HLA Antigens; Humans; Retrospective Studies

In order to determine associations between the major histocompatibility complex (MHC) and the development of clozapine-induced agranulocytosis, HLA typing was performed in a group of 42 clozapine-treated patients, of whom 11 had developed this adverse reaction. Among the patients with agranulocytosis, 7 (63%) were of Ashkenazi Jewish background and 4 (37%) were non-Jewish. An association between the HLA-B38, -DR4, -DQw3 haplotype and clozapine-induced agranulocytosis was found in all Jewish cases (7/7; 100%); in contrast only 4 of 21 (19%) Jewish control (nonagranulocytic) patients carried this haplotype. Among non-Jewish patients the HLA-DR2, -DQw1 haplotype was present in 4 of 4 (100%) patients with clozapine-induced agranulocytosis and in only 3 of 10 (30%) ethnically matched control patients. Our results indicate that gene products within the MHC could be involved in clozapine-mediated haematological toxicity.

Topics: Agranulocytosis; Clozapine; Haplotypes; Humans; Jews; Major Histocompatibility Complex; United States

Studies were conducted on serum samples collected from 15 patients during the course of clozapine-induced agranulocytosis. During acute phases of agranulocytosis, serum was cytotoxic to peripheral polymorphonuclear neutrophils (PMNs), as indicated by complement-dependent suppression of postphagocytosis respiratory burst and by increased retention of trypan blue dye by test PMNs. Cytotoxicity was removed by adsorption with allogeneic PMNs, was attenuated by antibody to immunoglobulin M but not by antibody to immunoglobulin G antigen-binding fragment, was not dialyzable, and was partially removed by 2-mercaptoethanol and dialysis. Three patients in a longitudinal study all had perturbed postphagocytosis respiratory burst 20 days before agranulocytosis developed. In all patients cytotoxicity disappeared less than 40 days after treatment when the offending drug was discontinued. Trypan blue dye reactivity was similar when tested. At 20% of culture medium, all serum samples partially suppressed development of colony-forming units of granulocytes and macrophages (CFU-GM) in marrow cultures. At 40% of culture medium, agranulocytosis serum suppressed CFU-GM completely but did not inhibit development of colony-forming units of erythroblasts (CFU-E) or burst-forming units of erythroblasts (BFU-E). Addition of clozapine alone or to agranulocytosis serum neither enhanced nor suppressed toxicity to peripheral PMNs. Neither clozapine nor its toxic metabolic end-products directly produced equivalent cytotoxicity to cellular function or proliferation at 10(-5)mol/L. Serum from patients given clozapine who did not have agranulocytosis and samples from allogeneic normal subjects were not cytotoxic to test PMNs. Cytotoxicity was specific to granulocyte cell lines because development of CFU-GM was inhibited by agranulocytosis serum, whereas CFU-E and BFU-E were not similarly affected. Further studies are in progress to distinguish between immunogenic and non-immunogenic mechanisms.

Topics: Adult; Agranulocytosis; Blood Proteins; Bone Marrow; Bone Marrow Cells; Cell Survival; Cells, Cultured; Clozapine; Cytotoxins; Female; Granulocytes; Hematopoietic Stem Cells; Humans; Male; Middle Aged; Neutrophils; Trypan Blue

Topics: Adult; Agranulocytosis; Clozapine; HLA-B Antigens; HLA-B38 Antigen; Humans; Male

This article describes clozapine-induced agranulocytosis in a psychotic patient. The importance of instructions to medical personnel is stressed especially if the patient is unable to mention symptoms. Leucocyte counts should be performed every week during the first 18 weeks of treatment, thereafter every month. In case of suspicion of infection immediate leukocyte count and differential are necessary.

Topics: Adult; Agranulocytosis; Candidiasis; Clozapine; Female; Humans; Leukocyte Count; Male

Approximately 30% of schizophrenic patients defined as treatment refractory significantly improve with clozapine. However, clozapine produces agranulocytosis in approximately 1% to 2% of patients in the United States. The mechanism of clozapine-induced agranulocytosis has not been established, but evidence suggests an immune-mediated mechanism.. Human leukocyte antigen (HLA) typing was performed in a native American with clozapine-induced agranulocytosis.. Our findings support previous observations of a role of the HLA-B16, DR4, DQw3 haplotype in predicting susceptibility to agranulocytosis in clozapine-treated patients.. We suggest that HLA typing of clozapine candidates may be useful for predicting the risk for clozapine-induced agranulocytosis.

Topics: Adult; Agranulocytosis; Clozapine; Haplotypes; Histocompatibility Testing; HLA Antigens; HLA-B Antigens; HLA-DQ Antigens; HLA-DR4 Antigen; Humans; Indians, North American; Male; Risk Factors

Granulocytopenia and agranulocytosis are severe side effects of clozapine therapy. Even if these side effects are detected early and if clozapine is discontinued, patients suffering from agranulocytosis are extremely endangered by infectious diseases for up to 3 to 4 weeks until hematologic recovery. Therefore, any treatment that reduces this critical time span would decrease the risks of clozapine treatment.. The case of a patient in whom severe agranulocytosis developed after 7 weeks of clozapine treatment is presented.. After clozapine discontinuation, treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF), a glycoprotein that has been shown to stimulate the proliferation of precursor cells in the bone marrow and their differentiation into granulocytes and macrophages, was initiated. Under GM-CSF treatment, total granulocyte count rose from 63/cu mm to a value greater than 1500/cu mm within 5 days without complications or major side effects.. This case report suggests that treatment with GM-CSF may lower the risks associated with clozapine-induced agranulocytosis and therefore may indirectly improve the safety of clozapine therapy.

Topics: Adult; Agranulocytosis; Clozapine; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leukocyte Count; Male; Psychotic Disorders; Time Factors

The use of clozapine, a unique antipsychotic drug, has been restricted due to a 1-2% incidence of drug-induced agranulocytosis. Metabolic activation of clozapine in neutrophils or stem cells could be the molecular mechanism underlying this side effect. Clozapine oxidation by human myeloperoxidase and horseradish peroxidase was evident from the disappearance of the UV absorbance at 290 nm. High performance liquid chromatography analysis revealed the formation of at least four radioactive peaks as a result of clozapine metabolism, including radioactivity coeluting with the protein. The tight association of radioactivity with the enzymatic protein was metabolism-dependent. This protein binding, which correlates with the total metabolism of clozapine, was reduced in the presence of glutathione and was absent in the presence of ascorbate. Similarly, in the presence of both reducing agents, the metabolite peaks in the high performance liquid chromatography radiogram, which are not associated with protein, disappeared. In contrast, in the presence of glutathione, two additional metabolites were found that could be isolated and identified by NMR and mass spectroscopy as clozapine glutathionyl adducts. Evidence for one-electron transfer reactions or the intermediate formation of a clozapine radical during the peroxidase-mediated metabolism of clozapine stems from the observation of thiyl and ascorbyl radicals in the presence of glutathione and ascorbate, respectively. The ascorbyl radical was detected by direct ESR spectroscopy in a peroxidase system. Its steady state concentration was significantly increased in the presence of clozapine. Glutathionyl radical formation was demonstrated by radical trapping with 5,5-dimethyl-1-pyrroline N-oxide in a peroxidase system. Again, the radical adduct concentration was significantly increased in the presence of clozapine. Similarly, when oxygen consumption was measured in peroxidase systems in the presence of glutathione or NADPH, the rate of oxygen uptake was markedly enhanced upon addition of clozapine. Thus, the data support the possibility of clozapine activation to free radical metabolites, which may cause oxidative stress or lead to adduct formation. Further, it can be concluded from these data that radical scavengers such as ascorbic acid, when coadministered with clozapine to patients, may reduce oxidative stress and protein adduct formation.

Topics: Agranulocytosis; Ascorbic Acid; Clozapine; Free Radicals; Glutathione; Horseradish Peroxidase; Humans; Peroxidase

Topics: Agranulocytosis; Carbamazepine; Clozapine; Humans; Male; Middle Aged; Monitoring, Physiologic; Schizophrenia

Topics: Agranulocytosis; Clozapine; Finland; Humans; Jews; United States

Topics: Agranulocytosis; Clozapine; Humans; Schizophrenia; Time Factors

Topics: Agranulocytosis; Autoimmune Diseases; Clozapine; Hematologic Diseases; Hematopoiesis; Humans; Risk Factors; Time Factors

Topics: Adult; Agranulocytosis; Clozapine; Female; Humans; Leukocyte Count; Male; Middle Aged; Risk Factors; Schizophrenia

Topics: Agranulocytosis; Antitrust Laws; Clozapine; Costs and Cost Analysis; Humans; Monitoring, Physiologic; Schizophrenia

Topics: Agranulocytosis; Clozapine; Drug Industry; Monitoring, Physiologic; Schizophrenia

Topics: Agranulocytosis; Clozapine; Costs and Cost Analysis; Humans; Schizophrenia

Topics: Agranulocytosis; Clozapine; Drug and Narcotic Control; Humans; Schizophrenia; United States; United States Food and Drug Administration

Topics: Adult; Agranulocytosis; Clozapine; Female; Humans; Neutrophils; Trifluoperazine

Topics: Agranulocytosis; Chronic Disease; Clozapine; Community Mental Health Services; Cost Control; Cost-Benefit Analysis; Dibenzazepines; Humans; Leukocyte Count; Schizophrenia; Schizophrenic Psychology

Topics: Agranulocytosis; Clozapine; Cost-Benefit Analysis; Humans; Monitoring, Physiologic; Schizophrenia; Schizophrenic Psychology

Clozapine, an effective but expensive drug treatment for patients with severe, chronic schizophrenia who are unresponsive to conventional antipsychotics, is associated with a high risk of agranulocytosis, which is sometimes fatal. Weekly blood tests to detect evidence of this side effect are required. To estimate the number of potential candidates for this treatment and the national cost of administering the drug to this population, the authors used data from three recent patient surveys conducted in New York State. Depending on the criteria used to exclude unsuitable candidates, between 133,000 and 189,000 individuals will be eligible for treatment with clozapine nationally at a cost of $1.2 to $1.7 billion annually.

Topics: Adult; Affective Disorders, Psychotic; Aftercare; Agranulocytosis; Chronic Disease; Clozapine; Community Mental Health Services; Cost Control; Cost-Benefit Analysis; Dibenzazepines; Female; Humans; Length of Stay; Male; Middle Aged; New York; Psychiatric Status Rating Scales; Risk Factors; Schizophrenia; Schizophrenic Psychology

Agranulocytosis develops in approximately 1% of patients with chronic schizophrenia treated with the atypical neuroleptic drug clozapine. Previous studies have not identified the mechanism or risk factors for this adverse reaction. Because of an observed association between Jewish ethnic background and the development of agranulocytosis in our patient sample treated with clozapine for refractory symptoms, HLA typing was performed in 31 patients (19.4% of whom had developed agranulocytosis). The HLA-B38 phenotype was found in 83% of patients who developed agranulocytosis and in 20% of clozapine-treated patients who did not develop agranulocytosis. Because B38 is part of a haplotype known to occur frequently in the Ashkenazi Jewish population, the frequencies of the combined alleles HLA-B38, DR4, and DQw3 were examined. The incidence of HLA-B38, DR4, DQw3 was significantly increased in patients with agranulocytosis (five of five patients) compared with control patients of Ashkenazi Jewish ancestry (two of 17 patients). These findings indicate that genetic factors marked by major histocompatibility complex haplotypes may be associated with the susceptibility of Jewish schizophrenic patients treated with clozapine to develop agranulocytosis. We postulate that gene products contained in the haplotype may be involved in mediating drug toxicity.

Topics: Agranulocytosis; Clozapine; Haplotypes; HLA Antigens; HLA-B Antigens; HLA-DQ Antigens; HLA-DR4 Antigen; Humans; Jews; Schizophrenia

Topics: Agranulocytosis; Clozapine; Dyskinesia, Drug-Induced; Humans; Leukocyte Count; Mental Health Services; Schizophrenia; United States

Topics: Agranulocytosis; Clozapine; Ethics, Medical; Humans; Monitoring, Physiologic; Risk Factors; Schizophrenia; Schizophrenic Psychology

Topics: Agranulocytosis; Clozapine; Dibenzazepines; Humans; Societies, Pharmaceutical; United States

These discussions are selected from the weekly staff conferences in the Department of Medicine, University of California, San Francisco. Taken from a transcription, it has been edited by Homer A. Boushey, MD, Professor of Medicine, and Nathan M. Bass, MD, PhD, Associate Professor of Medicine, under the direction of Lloyd H. Smith, Jr, MD, Professor of Medicine and Associate Dean in the School of Medicine.

Topics: Adult; Agranulocytosis; Clozapine; Dibenzazepines; Female; Humans; Male; Schizophrenia; Seizures

Topics: Agranulocytosis; Clozapine; Costs and Cost Analysis; Dibenzazepines; Humans; Malpractice; Product Surveillance, Postmarketing; Schizophrenia; United States

Topics: Agranulocytosis; Chronic Disease; Clozapine; Community Mental Health Services; Cost Control; Dibenzazepines; Hospitals, Psychiatric; Hospitals, State; Humans; Leukocyte Count; Schizophrenia; Schizophrenic Psychology; United States

Topics: Agranulocytosis; Clozapine; Dibenzazepines; Drug Labeling; Humans; Leukocyte Count; Risk Factors; Schizophrenia; Schizophrenic Psychology; United States; United States Food and Drug Administration

In a large state hospital population, more treatment-resistant schizophrenic patients may be clinically eligible to receive clozapine than the hospital can afford to pay for, given the costs of the medication and its mandatory monitoring system. The authors review clinical criteria for selecting patients and discuss two ethical principles that might be useful: select patients on the principle of providing the greatest good for the greatest number of patients (based on expected outcomes such as likelihood of discharge and benefit to the milieu) and give priority to patients for whom the fewest treatment alternatives are available. Issues such as family pressures for administration of clozapine to a relative must also be dealt with.

Topics: Adult; Agranulocytosis; Clozapine; Cost Control; Dibenzazepines; Ethical Theory; Ethics, Medical; Humans; Informed Consent; Mandatory Programs; Mentally Ill Persons; Patient Selection; Resource Allocation; Risk Assessment; Risk Factors; Schizophrenia; Schizophrenic Psychology; Social Control, Formal; United States

The long-term efficacy of clozapine therapy and its effect on health care costs were examined over a two-year period. Patients on clozapine showed marked clinical improvement as measured by the Brief Psychiatric Rating Scale. They also had significantly lower rates of rehospitalization and hospitalization costs than a comparison group of schizophrenic patients who received standard neuroleptic treatment and who were considerably less psychotic at hospital admission. By the second year of the study, savings on mental health care costs averaged $20,000 for each patient on clozapine therapy. The savings were due largely to the patients' change in residence from costly inpatient facilities to less expensive settings in the community.

Topics: Agranulocytosis; Chronic Disease; Clozapine; Cohort Studies; Cost Control; Dibenzazepines; Dose-Response Relationship, Drug; Follow-Up Studies; Humans; Patient Readmission; Schizophrenia; Schizophrenic Psychology; Seizures

In the Federal Republic of Germany adverse drug reactions (ADR) have been continuously assessed at the departments of Psychiatry of Berlin and Munich since May 1979. About 13,000 neuroleptic-treated inpatients were monitored until August 1988. Approximately 1100 patients were exposed to clozapine, 6800 to haloperidol and 6000 to perazine, the two most frequently used neuroleptic drugs. In this 9-year period seven cases of agranulocytosis were observed, all in women. One case occurred with clozapine in monotherapy, the other six with perazine, three times in monotherapy, once in combination with trimethoprim/sulfamethoxazole and in one case each in combination with tricyclic antidepressants. Significant leucopenia (less than or equal to 3000/mm3) was observed in an additional eight cases. On four occasions each butyrophenones (twice in combination with TCA) and tricyclic neuroleptics (once in combination with TMS) were involved. The number of exposed patients per drug is too small for calculation of statistically valid incidence rates, especially in view of the frequent polypharmacy. The course of agranulocytosis was benign in all seven cases and required no other treatment than drug withdrawal in three cases. The early detection by regular WBCs is supposed to be mainly responsible for this and is therefore recommended at weekly intervals. This measure of safety appears most important for all medium potency tricyclic neuroleptics. As to treatment of agranulocytosis, additional measures (antibiotics, intensive medical care) depend upon the severity of the clinical picture.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Female; Germany, West; Humans; Leukocyte Count; Leukopenia; Male; Middle Aged; Neutropenia; Perazine

Topics: Agranulocytosis; Clozapine; Dibenzazepines; Humans; Risk Factors; Schizophrenia; United States; United States Food and Drug Administration

The Clozaril Patient Management System (CPMS) has been developed to provide a 100% fail-safe system for monitoring white blood cell counts (WBCs) in patients being treated with clozapine (Clozaril/Leponex) in the United States and to provide comprehensive data collection on the incidence and development of agranulocytosis. CPMS provides a case administrator and a registered pharmacist. Their role is to support the physician by facilitating the determination of WBC's at a national laboratory and by distributing clozapine to the patient. Specific tasks of the case administrator include: keeping track of outpatient phlebotomy appointments, following up missed appointments, ensuring that WBCs are obtained and analyzed weekly by the national laboratory, following up the results of these tests, providing liason with the pharmacy, maintaining a data base for all patients receiving clozapine and conveying these data to the physician. Initial experience with this program in Cleveland is described in this paper. The characteristics of patients enrolled in CPMS, satisfaction with the program and its success in meeting predetermined objectives are described. Experience with 31 patients in this outpatient setting suggests that CPMS can be an effective, reliable system for assisting in blood monitoring of patients being treated with clozapine.

Topics: Adult; Agranulocytosis; Bloodletting; Clozapine; Dibenzazepines; Female; Humans; Leukocyte Count; Male; Middle Aged; Monitoring, Physiologic; Patient Compliance

Clozapine, an atypical neuroleptic with unique clinical and preclinical properties, represents a potentially valuable addition to the psychopharmacopeia. Its development and use have been limited by its higher frequency, compared with other pharmacologic treatments, of the potentially fatal side effect of agranulocytosis. This article describes the natural history of five cases of agranulocytosis that occurred in the course of clozapine treatment. The cases were generally uniform as to onset, recovery, and hematologic features. No patient had hematologic reactions to treatment with psychotropic agents before or after clozapine treatment. These findings, along with other work in progress, suggest that clozapine's granulocytoxic effects are produced by a highly specific immune-mediated mechanism.

Topics: Adult; Agranulocytosis; Antibody Formation; Bone Marrow Cells; Clozapine; Dibenzazepines; Drug Hypersensitivity; Female; Humans; Leukocyte Count; Psychotic Disorders; Psychotropic Drugs

Topics: Agranulocytosis; Clozapine; Dibenzazepines; Female; Humans; Middle Aged; Schizophrenia

Topics: Acute Disease; Adult; Agranulocytosis; Bone Marrow; Chemical and Drug Induced Liver Injury; Clozapine; Dibenzazepines; Humans; Male; Schizophrenia

Topics: Agranulocytosis; Clozapine; Dibenzazepines; Humans; Psychotic Disorders

Topics: Adolescent; Adult; Agranulocytosis; Clozapine; Dibenzazepines; Female; Humans; Male; Middle Aged

Topics: Agranulocytosis; Clozapine; Dibenzazepines; Humans

Topics: Agranulocytosis; Clozapine; Dibenzazepines; Dyskinesia, Drug-Induced; Humans; Leukemia

Topics: Agranulocytosis; Clozapine; Dibenzazepines; Drug Administration Schedule; Female; Humans; Psychotic Disorders

Topics: Acute Disease; Agranulocytosis; Clozapine; Female; Humans; Middle Aged

Topics: Adult; Agranulocytosis; Clozapine; Dibenzazepines; Female; Humans; Middle Aged; Schizophrenia

The frequency of agranulocytosis in association with clozapine therapy has been estimated and compared with data reported for phenothiazine-induced agranulocytosis. Apart from the "epidemic" in Finland, where the frequency was 21 times that in other countries, there is no evidence that clozapine-related agranulocytosis is more common than the phenothiazine-related disorder. Furthermore, results are given to show that strict adherence to precautionary measure (e.g. weekly blood counts) reduces the mortality-rate of this condition.

Topics: Agranulocytosis; Clozapine; Dibenzazepines; Europe; Finland; Humans

Within six months of the introduction of the new antipsychotic drug clozapine in Finalnd, 17 cases of neutropenia or agranulocytosis were recorded amongst about 3000 patients treated. Agranulocytosis was fatal in eight patients, and in addition, two patients developed thrombocytopenia, and one patient leukaemia. As additional cases might well have been overlooked as banal infections, the risk of developing agranulocytosis during clozapine treatment was at least 0.5%. Impaired elimination of the drug or increased susceptibility of granulocyte precursors to clozapine, possibly due to some inherited characteristic, might explain the high incidence of complications.

Topics: Adolescent; Adult; Aged; Agranulocytosis; Clozapine; Dibenzazepines; Drug Contamination; Drug Therapy, Combination; Female; Finland; Hematologic Diseases; Humans; Male; Middle Aged

An epidemic of agranulocytosis and granulocytopenia occurred in 1975 in conjunction with clozapine treatment of mental patients in Finland. An attempt was made to assess the epidemiologic and genetic factors contributing to the adverse drug effect. The estimated incidence rate in Finland was 2.1/1000 patient-months. This figure could not be compared with rates from other countries because of the inexact nature of the figures reported so far. All 16 cases occurred in seven hospitals in southwestern Finland, whereas the overall hospital net use of the drug was geographically evenly distributed. The difference between the observed and the proportionally expected incidence of cases amongst the hospitals where clozapine was used was statistically significant. The average consumption of the drug did not differ between the hospitals where cases occurred and those where no definite cases could be diagnosed. Six-generation pedigree analyses failed to reveal significant parental consanguinity or genetic kinship between probands. Neither did the birth places of the ancestors of the probands disclose a typical isolate pattern. In conclusion, the cases appeared to be confined to a few hospitals in southwestern Finland. Although a genetic factor is not excluded, we found no evidence in support of a genetic mechanism.

Topics: Agranulocytosis; Clozapine; Dibenzazepines; Finland; Humans; Pedigree

The occurrence of a sudden outbreak of agranulocytosis in Finland among patients being treated with clozapine led to intensive investigations in an attempt to find a local precipitating factor. Granulocytopenia after clozapine was found to have the same characteristics as that reported after phenothiazines. No local factor, either genetic or environmental, was found which could have been responsible for the increased frequency of occurrence in Finland. The need to be aware of the risk and to take appropriate precautionary measures (e.g. weekly leucocyte counts in the first months) is emphasized.

Topics: Adolescent; Adult; Aged; Agranulocytosis; Clozapine; Dibenzazepines; Female; Finland; Humans; Male; Middle Aged; Phenothiazines; Time Factors

Two personally observed cases of severe agranulocytosis within 3 months, one of them fatal, could be attributed to the new dibenzodiazepine derivative Clozapine (Leponex). Clozapine, a very effective neuroleptic for the treatment of acute and chronic schizophrenia, has been found before to induce agranulocytosis of the metabolic type, as phenothiazines are known to do. An inquiry in al Swiss medical departments and mental hospitals revealed a total of 20 cases of Clozapine induced agranulocytosis in some 50% of institutions responding. 9 of these were observed in Eastern Switzerland. This time-space clustering recalls the "finnish epidemic" of 1975 in Southern Finland. Possible explanations for this phenomenon are discussed. Calculations of the incidence suggest a higher rate of agranulocytosis induced by Clozapine than has been assumed for the phenothiazines. Clozapine should therefore be restricted to schizophrenic patients and initially (6 weeks) be given only on a stationary basis under regular blood controls.

Topics: Adult; Agranulocytosis; Clozapine; Dibenzazepines; Female; Humans; Middle Aged; Schizophrenia; Switzerland

Topics: Agranulocytosis; Clozapine; Dibenzazepines; Humans; Tranquilizing Agents

Topics: Adult; Agranulocytosis; Clozapine; Dibenzazepines; Female; Humans; Male; Middle Aged

Topics: Agranulocytosis; Clozapine; Dibenzazepines; Europe; Finland; Humans