clozapine and Neutropenia

Rechallenge/continuation of clozapine in association with colony-stimulating factors (CSFs) following neutropenia/agranulocytosis has been reported, but many questions remain unanswered about efficacy and safety. This systematic review aims to assess the efficacy and safety of rechallenging/continuing clozapine in patients following neutropenia/agranulocytosis using CSFs.. MEDLINE, Embase, PsycInfo, and Web of Science databases were searched from inception date to July 31, 2022. Articles screening and data extraction were realized independently by two reviewers, according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 systematic review guidance. Included articles had to report on at least one case where clozapine was rechallenged/continued using CSFs despite previous neutropenia/agranulocytosis.. Eight hundred forty articles were retrieved; 34 articles met the inclusion criteria, totaling 59 individual cases. Clozapine was successfully rechallenged/continued in 76% of patients for an average follow-up period of 1.9 years. There was a trend toward better efficacy reported in case reports/series, compared with consecutive case series (overall success rates of 84% and 60%, respectively,. Although limited by the relatively small number of published cases, factors such as time of onset to first neutropenia and severity of the episode did not seem to impact the outcome of a subsequent clozapine rechallenge using CSFs. While the efficacy of this strategy remains to be further adequately evaluated in more rigorous study designs, its long-term innocuity warrants considering its use more proactively in the management of clozapine hematological adverse events as to maintain this treatment for as many individuals as possible.

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

Clozapine is the most effective treatment for people with treatment-resistant schizophrenia. However, it is prescribed less often than guidelines indicate.. To personalize clozapine treatment, we investigated the efficacy of clozapine as first- or second-line treatment and investigated whether there are factors that were associated with efficacy and side effects.. We collected a unique cohort of over 800 clozapine users diagnosed with a schizophrenia spectrum disorder. We meta-analyzed factors that were associated with response during clozapine treatment. Additionally, we conducted genetic association analyses to investigate the relations between side effects and symptom severity during clozapinetreatment.. From our meta-analyses, we found that clozapine was more effective when used as a first- or second-line treatment. Furthermore, we found that younger age, less negative symptoms and the paranoid subtype of schizophreniawere associated with a better clozapine response. Several specific locations on genes (loci) were associated with clozapine-induced agranulocytosis and neutropenia, while polygenic risk scores were associated with symptom severity.. We found that clozapine could be effective earlier in treatment and identified factors that could aid the prediction of< response to clozapine treatment in the future. These finding could contribute to the start of a personalized clozapine treatment.

Topics: Antipsychotic Agents; Clozapine; Humans; Neutropenia; Precision Medicine; Schizophrenia

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

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

Clozapine is licensed for treatment-resistant psychosis and remains underutilised. This may berelated to the stringent haematological monitoring requirements that are mandatory in most countries. We aimed to compare guidelines internationally and develop a novel Stringency Index. We hypothesised that the most stringent countries would have increased healthcare costs and reduced prescription rates.. We conducted a literature review and survey of guidelines internationally. Guideline identification involved a literature review and consultation with clinical academics. We focused on the haematological monitoring parameters, frequency and thresholds for discontinuation and rechallenge after suspected clozapine-induced neutropenia. In addition, indicators reflecting monitoring guideline stringency were scored and visualised using a choropleth map. We developed a Stringency Index with an international panel of clozapine experts, through a modified-Delphi-survey. The Stringency Index was compared to health expenditure per-capita and clozapine prescription per 100 000 persons.. One hundred twocountries were included, from Europe (. Recommendations on how haematological function should be monitored in patients treated with clozapine vary considerably between countries. It would be useful to standardise guidelines on haematological monitoring worldwide.

Topics: Antipsychotic Agents; Australia; Clozapine; Humans; Neutropenia; Psychotic Disorders

Clozapine is considered to be the most effective antipsychotic medication for schizophrenia. However, it is associated with several adverse effects such as leukopenia, and the underlying mechanism has not yet been fully elucidated. The authors performed a genome-wide association study (GWAS) in a Chinese population to identify genetic markers for clozapine-induced leukopenia (CIL) and clozapine-induced neutropenia (CIN).. A total of 1879 patients (225 CIL cases, including 43 CIN cases, and 1,654 controls) of Chinese descent were included. Data from common and rare single nucleotide polymorphisms (SNPs) were tested for association. The authors also performed a trans-ancestry meta-analysis with GWAS results of European individuals from the Clozapine-Induced Agranulocytosis Consortium (CIAC).. The authors identified several novel loci reaching the threshold of genome-wide significance level (P < 5 × 10. The associations provide novel and valuable understanding of the genetic and immune causes of CIL and CIN, which is useful for improving clinical management of clozapine related treatment for schizophrenia. Causal variants and related underlying molecular mechanisms need to be understood in future developments.

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

Clozapine remains the only drug treatment likely to benefit patients with treatment resistant schizophrenia. Its use is complicated by an increased risk of neutropenia and so there are stringent monitoring requirements and restrictions in those with previous neutropenia from any cause or from clozapine in particular. Despite these difficulties clozapine may yet be used following neutropenia, albeit with caution. Having had involvement with 14 cases of clozapine use in these circumstances we set out our approach to the assessment of risks and benefits, risk mitigation and monitoring with a practical guide.

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

Wider use of clozapine, one of the most effective antipshychotic drugs, is precluded by its propensity to cause agranulocytosis. Currently, clozapine is used for treatment-resistant schizophrenia, with mandatory blood count monitoring for the duration of treatment. Agranulocytosis occurs in up to 0.8% of patients and presents a significant medical challenge, despite decreasing mortality rates. In this paper, we review the epidemiology of clozapine-induced agranulocytosis (CLIA), advances in identifying genetic risk factors, and the preventive measures to reduce the risk of CLIA. We discuss the pathogenesis of CLIA, which, despite receiving considerable scientific attention, has not been fully elucidated. Finally, we address the clinical management and suggest the approach to clozapine re-challenge in patients with a previous episode of neutropenia. With a significant proportion of clozapine recipients in Western hemisphere being Black, we comment on the importance of recognizing benign ethnic neutropenia as a potential impediment to clozapine administration. This review aims to aid haematologists and psychiatrists to jointly manage neutropenia and agranulocytosis caused by clozapine.

Topics: Black People; Clozapine; Humans; Neutropenia; Risk Factors

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

In most countries, clozapine can only be prescribed with regular monitoring of white blood cell counts because of concerns that clozapine has a stronger association with neutropenia than other antipsychotics. However, this has not been previously demonstrated conclusively with meta-analysis of controlled studies.. The aim of this study was to assess the strength of the association between clozapine and neutropenia when compared to other antipsychotic medications by a meta-analysis of controlled studies. An electronic search of Medline (1948-2018), PsycINFO (1967-2018) and Embase (1947-2018) using search terms (clozapine OR clopine OR clozaril OR zaponex) AND (neutropenia OR agranulocytosis) was undertaken. Random-effects meta-analysis using Mantel-Haenszel risk ratio was used to assess the strength of the effect size.. We located 20 studies that reported rates of neutropenia associated with clozapine and other antipsychotic medications. The risk ratio was not significantly increased in clozapine-exposed groups compared to exposure to other antipsychotic medications (Mantel-Haenszel risk ratio = 1.45, 95% confidence interval = [0.87, 2.42]). This also applied to severe neutropenia (absolute neutrophil count < 500 per µL) when compared to other antipsychotics (Mantel-Haenszel risk ratio = 1.65, 95% confidence interval = [0.58, 4.71]). The relative risk of neutropenia associated with clozapine exposure was not significantly associated with any individual antipsychotic medication.. Data from controlled trials do not support the belief that clozapine has a stronger association with neutropenia than other antipsychotic medications. This implies that either all antipsychotic drugs should be subjected to haematological monitoring or monitoring isolated to clozapine is not justified.

Topics: Antipsychotic Agents; Clozapine; Controlled Clinical Trials as Topic; Humans; Neutropenia

Clozapine is associated with life-threatening neutropenia. There are no previous meta-analyses of the epidemiology of clozapine-associated neutropenia.. To determine the cumulative incidence of mild, moderate and severe neutropenia, incidence of death related to severe neutropenia, case fatality rate of neutropenia and the longitudinal incidence of neutropenia following exposure to clozapine.. A systematic search of Medline, EMBASE and PsycINFO using search terms [clozapine OR clopine OR zaponex OR clozaril] AND [neutropenia OR agranulocytosis].. Random effects meta-analysis to determine event rates and longitudinal incidence of events per 100 person-years of exposure.. A total of 108 studies were included. The incidence of clozapine-associated neutropenia was 3.8% (95% CI: 2.7-5.2%) and severe neutropenia 0.9% (95% CI: 0.7-1.1%). The incidence of death related to neutropenia following prescription of clozapine was 0.013% (95% CI: 0.01-0.017%). The case fatality rate of severe neutropenia was 2.1% (95% CI: 1.6-2.8%). The peak incidence of severe neutropenia occurred at one month of exposure and declined to negligible levels after one year of treatment.. Severe neutropenia associated with clozapine is a rare event and occurs early with a substantial decline in risk after one year of exposure. Death from clozapine-associated neutropenia is extremely rare. Implications for haematological monitoring are discussed.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Clozapine; Female; Humans; Incidence; Male; Middle Aged; Neutropenia; Risk Factors; Young Adult

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

Clozapine is the most effective medication for treatment-refractory schizophrenia; however, its use is contraindicated in people who have had previous clozapine-induced neutropenia. Co-prescription of granulocyte-colony stimulating factor may prevent recurrent neutropenia and allow continuation or rechallenge of clozapine.. Systematic review of literature reporting the use of granulocyte-colony stimulating factor to allow rechallenge or continuation of clozapine in people with previous episodes of clozapine-induced neutropenia. The efficacy of granulocyte-colony stimulating factor and predictors of successful rechallenge will be determined to elucidate whether evidence-based recommendations can be made regarding the use of granulocyte-colony stimulating factor in this context.. A total of 17 articles were identified that reported on clozapine rechallenge with granulocyte-colony stimulating factor support. In all, 76% of cases were able to continue clozapine at median follow-up of 12 months. There were no clear clinical or laboratory predictors of successful rechallenge; however, initial neutropenia was more severe in successful cases compared to unsuccessful cases. Cases co-prescribed lithium had lower success rates of rechallenge (60%) compared to those who were not prescribed lithium (81%). The most commonly reported rechallenge strategy was use of filgrastim 150-480 µg between daily to three times a week. There were no medication-specific side effects of granulocyte-colony stimulating factor reported apart from euphoria in one case. Three cases who failed granulocyte-colony stimulating factor had bacterial infection at time of recurrent neutropenia. No deaths were reported.. Preliminary data suggest granulocyte-colony stimulating factor is safe and effective in facilitating rechallenge with clozapine. Clinical recommendations for use are discussed.

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

Clozapine is associated with hematological abnormalities, with neutropenia and agranulocytosis of most concern. Granulocyte colony-stimulating factor (G-CSF) has been used to support clozapine rechallenge after neutropenia with the aim of maintaining the neutrophil count. This study aims to explore the practice, use, safety, and efficacy of G-CSF in this context.. We conducted a systematic review to identify all studies investigating or describing G-CSF as a prophylaxis to enable continued clozapine treatment during a rechallenge.. We identified 32 reports of patients who received G-CSF either regularly (n = 23) or as required (n = 9) to support clozapine rechallenge after an episode of neutropenia necessitating discontinuation of clozapine. Seventy-five percent (n = 24) of published cases remained on clozapine with the use of continual prophylactic G-CSF or after single G-CSF administrations (n = 8). Seventy percent (n = 16) of patients in receipt of continual prophylactic G-CSF were successfully maintained on clozapine. However, 1 of the 3 episodes of rechallenge in those with a history of severe agranulocytosis (absolute neutrophil count <0.1 × 10/L) had a recurrence of agranulocytosis at week 9.. Our findings suggest that G-CSF can sometimes be safely used to support the maintenance of normal neutrophil counts and clozapine use after neutropenia. Publication bias is an important limitation, however. Also, few reports clearly documented the presence or absence of an independent nonclozapine cause of the index neutropenia, which may have increased success rates. Furthermore, adverse events were not systematically recorded. Prospective studies are needed to determine safety because if agranulocytosis occurs on clozapine while supported by G-CSF, there is no obvious alternate rescue therapy to promote granulopoiesis. From the available data, it is not possible to recommend this course of action for someone with a true clozapine agranulocytosis.

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

The antipsychotic clozapine is uniquely effective in the management of schizophrenia; however, its use is limited by its potential to induce agranulocytosis. The causes of this, and of its precursor neutropenia, are largely unknown, although genetic factors have an important role. We sought risk alleles for clozapine-associated neutropenia in a sample of 66 cases and 5583 clozapine-treated controls, through a genome-wide association study (GWAS), imputed human leukocyte antigen (HLA) alleles, exome array and copy-number variation (CNV) analyses. We then combined associated variants in a meta-analysis with data from the Clozapine-Induced Agranulocytosis Consortium (up to 163 cases and 7970 controls). In the largest combined sample to date, we identified a novel association with rs149104283 (odds ratio (OR)=4.32, P=1.79 × 10

Topics: Carrier Proteins; Case-Control Studies; Clozapine; Exome; Female; Genome-Wide Association Study; HLA-DQ beta-Chains; Humans; Male; Neutropenia; Odds Ratio; Schizophrenia; Solute Carrier Organic Anion Transporter Family Member 1B3

Clozapine is an atypical antipsychotic known for its efficacy in refractory schizophrenia. One of the adverse effects is neutropenia. This dysplasia is a rare but major side effect which leads to a discontinuation and constitutes further contraindication. Thereafter, therapeutic options decrease dramatically. Mechanisms involved are not well known at this time and can be combined. A toxic hypothesis may be more likely than an immune-allergic one.. We have reviewed publications on Medline describing procedures that allowed clozapine rechallenge after blood dyscrasia in refractory schizophrenia. Three different procedures were found: simple rechallenge, rechallenge with lithium and rechallenge with Granulocyte - colony stimulating factor (G-CSF). Rechallenge could be simple or multiple.. These past years, clozapine have been rechallenged successfully after neutropenia thanks to different procedures, the different options being simple rechallenge, rechallenge with lithium and/or rechallenge with G-CSF. Lithium as G-CSF are used to increase neutrophil blood rate and prevent neutropenia recurrence after clozapine rechallenge. G-CSF was first used within the context of chemotherapy and extends now to clozapine-induced neutropenia. Both for lithium and G-CSF, numerous procedures are reviewed and cannot be compared.. Publications are limited but increasing, and they point out that a careful rechallenge can be successful. However, interesting data can be extracted. First, clozapine is more likely to be incriminated in neutropenia when patients receive many drugs, but a careful study could prevent some discontinuation. Indeed, other drugs or a hematologic disease could be involved. Moreover, several contributing factors have been found such as HLA group and drug interaction. Ethnic origin also affects neutrophil rate. That is why, in Great Britain, a subgroup of patients "benign ethnic neutropenia" has been introduced to enlarge threshold and allow these patients to access clozapine despite lower blood counts. Then, rechallenge choice has to be done on a case-by-case basis and only after considering the benefits and risks of such a treatment. Most of the time, clinical advice of rechallenge arises from the inefficiency of other antipsychotics and even sismotherapy failure. Patients and sometimes families have to be informed and give their consent. Preventive measures have been found such as taking a hematologic recommendation and doing twice-a-week blood sample monitoring. With regards lithium and G-CSF, some efficient doses are assumed (lithium: 0,4-1,1 mEq/L and G-CSF>0,3 mg/week). Lithium as G-CSF may have other adverse effects which need to be considered. There is no successful rechallenge reported after agranulocytosis. Some publications highlight that if neutropenia occurs on rechallenge, it will do so more quickly and more severe than at the time of initial trial of clozapine.. There is emerging evidence of successful clozapine rechallenging. However, further investigations are required as randomized controlled trials to reassess guidelines and establish the safety and effectiveness of the different procedures. Because of the practical and ethical difficulties of designing such studies, referral hospitals could be elected, and common background writing proposed in order to ease data comparison.

Topics: Antipsychotic Agents; Clozapine; Drug Resistance; Humans; Neutropenia; Psychotic Disorders; Schizophrenia

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 widely prescribed for treatment refractory patients with schizophrenia, but its use is limited by potentially life threatening adverse effects. Rechallenge after these complications has been occasionally attempted in patients with severe psychotic symptoms.. To review the outcome of clozapine rechallenge after potentially life threatening adverse effects.. Electronic, all-language, literature search (1972-2011) followed by demographic and clinical data extraction. The outcome of rechallenge was considered favorable when the lower bound of the 95% confidence interval (CI) of the proportion of patients who could continue clozapine was >50%.. Altogether, 138 patients (mean age: 36.3years, 65.7% male, 57.6% Caucasian, virtually all with schizophrenia spectrum diagnosis) underwent clozapine rechallenge after developing neutropenia (n=112), agranulocytosis (n=15), neuroleptic malignant syndrome (NMS) (n=5), myocarditis (n=4), pericarditis (n=1) and lupus erythematosus (n=1). Rechallenge strategies were heterogeneous and not systematically evaluated. Clozapine rechallenge was successful in 78/112 patients (69.6%, CI: 60.6-77.4) after neutropenia, 3/15 (20%, CI: 7.1-45.2) after agranulocytosis, 5/5 (100%, CI: 56-100) after NMS, 3/4 (75%, CI: 30-95) after myocarditis, 1/1 after pericarditis, and 0/1 after clozapine-induced lupus. Successfully rechallenged patients were followed for 16-96weeks. None of the rechallenged patients died.. Although controlled studies are clearly needed, using a priori, confidence interval-based criteria, case reports/series suggest that in refractory patients who benefited from clozapine, careful rechallenge can be considered after neutropenia and NMS, but not after agranulocytosis and myocarditis.

Topics: Adult; Antipsychotic Agents; Clozapine; Databases, Bibliographic; Female; Humans; Lupus Erythematosus, Systemic; Male; Middle Aged; Myocarditis; Neuroleptic Malignant Syndrome; Neutropenia; Young Adult

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

Although the role of clozapine is well established for treatment-resistant schizophrenia, it is rarely used in pediatric populations, mainly due to its potentially serious adverse effects.. To summarize practical aspects of use of clozapine in treating children with schizophrenia and management of associated adverse effects.. Available studies in the literature using clozapine in the pediatric population are summarized and the NIMH experience in treating refractory childhood-onset schizophrenia cases with clozapine is discussed.. Despite a higher incidence of adverse effects in children, clozapine appears to be a uniquely beneficial second-line agent for treating children with refractory schizophrenia.

Topics: Adolescent; Age of Onset; Akathisia, Drug-Induced; Antipsychotic Agents; Child; Child, Preschool; Clozapine; Drug Resistance; Humans; Neutropenia; Schizophrenia; Seizures; Weight Gain

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

Approximately 1-2% of patients treated with the atypical antipsychotic clozapine develop severe neutropenia and agranulocytosis. The usual recommendation is to discontinue treatment with the drug when the peripheral neutrophil count drops below 1,500/mm3.. We have reviewed several reports describing procedures that allowed the patients to continue clozapine treatment despite the occurrence of these haematological side effects.. The therapeutic procedures described (symptomatic treatment of neutropenia by co-administration of lithium or granulopoiesis-stimulating factors, management of the adjunctive medication) seem to be efficient strategies that allow continuation of clozapine treatment despite the occurrence of neutropenia. However, these types of therapy have only been used in a limited number of cases, and the evidence supporting their use remains anecdotal.. Although the procedures adopted in the cases described in this review are uncommon, they potentially provide an alternative to the discontinuation of clozapine treatment in patients with complex symptomatologies for whom treatment with other antipsychotic medication is insufficient.

Topics: Antipsychotic Agents; Clozapine; Colony-Stimulating Factors; Hematopoiesis; Humans; MEDLINE; Neutropenia; Recombinant Proteins

Clozapine is a distinctive antipsychotic agent, having a unique clinical profile and an idiosyncratic safety profile. More so than with other agents, the weighting of its adverse event profile is critical, in order to counterbalance its clear clinical advantages. The safety issues with clozapine are in a number of areas, some of which are considered medical emergencies and potentially life-threatening. These include haematological (neutropenia and agranulocytosis), CNS (seizures), cardiovascular (myocarditis and cardiomyopathy), metabolic (diabetes), gastrointestinal and neuromuscular. Understanding the safety profile of clozapine allows an informed use of the agent that can maximise its clear clinical benefit and minimise the known risks.

Topics: Antipsychotic Agents; Cardiomyopathies; Clozapine; Diabetes Mellitus; Humans; Muscle, Skeletal; Myocarditis; Neutropenia; Psychotic Disorders; Risk Factors; Seizures; 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

Clozapine, a dibenzodiazepine antipsychotic, is the most effective medication for treatment-resistant schizophrenia. However, its use has been limited by the high risk of neutropenia. In children, the rate of neutropenia is higher when compared to adults. We decided to explore the use of lithium to manage neutropenia in childhood-onset schizophrenia (COS) through a systematic audit of COS cases.. Medical records were reviewed for patients with COS who had been treated with the combination of clozapine and lithium carbonate.. Seven patients were found to have been treated with both clozapine and lithium. After initiation of lithium, ANC increased significantly in six out of seven subjects by 29 to 106% with a mean of 66%. In addition, six out of seven subjects continued using both clozapine and lithium for over 2 years (range: 2.0-7.2 years) and do not have immediate plans for discontinuation of either medications.. Our study bolsters support for the use of lithium in the management of neutropenia in children treated with clozapine. Although the coadministration of lithium and clozapine appears effective in the management of neutropenia, it is not without its risks and clinicians must be diligent in their joint use of these medications.

Topics: Adolescent; Antidepressive Agents; Antipsychotic Agents; Child; Clozapine; Cohort Studies; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Lithium Carbonate; Male; Neutropenia; Severity of Illness Index; Time Factors; Treatment Outcome

The atypical antipsychotic clozapine carries a high risk of inducing agranulocytosis. We attempted to investigate whether eosinophilia during clozapine treatment has predictive value for subsequent neutropenia/agranulocytosis. One hundred and seventy-seven patients were studied in a prospective naturalistic design using haloperidol as the reference compound. Clozapine was found to differ from haloperidol in respect to their influence on neutrophil granulocytes. In the clozapine group patients with eosinophilia showed a decrease in neutrophil count (less than 2000/mm3 neutrophil granulocytes) significantly more often than patients without eosinophilia.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Biomarkers; Clozapine; Eosinophilia; Female; Haloperidol; Humans; Male; Middle Aged; Neutropenia; Prospective Studies; Schizophrenia

Childhood-onset schizophrenia is a rare but severe form of the disorder that is often treatment-refractory. In this study, the efficacy and adverse effects of clozapine and haloperidol were compared for children and adolescents with early-onset schizophrenia.. Twenty-one patients (mean [+/-SD] age, 14.0 +/- 2.3 years) with onset of Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition-defined schizophrenia that began by age 12 years and who had been nonresponsive to typical neuroleptics participated in the study. Patients were randomized to a 6-week double-blind parallel comparison of clozapine (mean [+/-SD] final dose, 176 +/- 149 mg/d), or haloperidol, (16 +/- 8 mg/d).. Clozapine was superior to haloperidol on all measures of psychosis (P = .04-.002). Positive and negative symptoms of schizophrenia improved. However, neutropenia and seizures were major concerns. To date, one third of the group has discontinued using clozapine.. Clozapine has striking superiority for positive and negative symptoms in treatment-refractory childhood-onset schizophrenia. However, due to possibly increased toxic effects in this pediatric population, close monitoring for adverse events is essential.

Topics: Adolescent; Age Factors; Age of Onset; Child; Child, Preschool; Clozapine; Double-Blind Method; Drug Administration Schedule; Haloperidol; Humans; Neutropenia; Psychiatric Status Rating Scales; Schizophrenia, Childhood; Seizures; Severity of Illness Index; Treatment Outcome

Myelotoxicity continues to hinder the widespread use of clozapine in the United States. It has been theorized that eosinophilia predicts later agranulocytosis and that agranulocytosis occurs due to an immunologic mechanism. Our study compares the rates of these dyscrasias in clozapine-treated patients and a control group.. Forty-one patients taking clozapine and 29 patients taking haloperidol were monitored for a period of 6 months. Rates of eosinophilia and neutropenia were compared between the two treatment groups.. Treatment-emergent eosinophilia occurred frequently in both haloperidol- and clozapine-treated patients. No significant difference was seen between groups in the incidence of eosinophilia and neutropenia.. We find no statistical difference between the rates of eosinophilia or neutropenia in haloperidol- and clozapine-treated patients. This study does not support the use of eosinophilia as a reliable predictor of neutropenia.

Topics: Adult; Clozapine; Double-Blind Method; Eosinophilia; Female; Haloperidol; Humans; Incidence; Male; Neutropenia; Probability; Retrospective Studies; Schizophrenia

In order to assess the safety and some efficacy aspects of clozapine under UK conditions, 54 in-patients with severe treatment-resistant schizophrenic disorders were evaluated using several scales before and during treatment. Of the 54 evaluated, 26 completed the 26-week study. Of these patients, 20 showed improvement in psychopathology, often to a marked degree, involving both positive and negative symptoms. Some oral-facial extrapyramidal side-effects decreased as well. Two patients developed neutropenia, but recovered on discontinuation of clozapine. The most frequent adverse event was hypersalivation, and five patients suffered from seizures. It is concluded that clozapine is worth considering for the treatment of severe treatment-resistant patients in the UK.

Topics: Adult; Chronic Disease; Clozapine; Drug Resistance; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Neutropenia; Schizophrenia; Schizophrenic Psychology; Sialorrhea; Treatment Outcome; United Kingdom

Neutropenia and agranulocytosis (N&A) are relatively rare, but potentially fatal adverse drug reactions (ADR). This study presents cases of N&A related to one or more antipsychotic drugs (APDs) in psychiatric inpatients. Data on APD utilization and reports of N&A caused by APDs were analyzed by using data from an observational pharmacovigilance program in German-speaking countries-Arzneimittelsicherheit in der Psychiatrie (AMSP)-from 1993 to 2016. 333,175 psychiatric inpatients were treated with APDs for schizophrenia and other indications during the observation period. A total of 124 cases of APD-induced N&A were documented, 48 of which fulfilled the criteria for agranulocytosis, corresponding to a rate of 0.37, respectively, 0.14 in 1000 inpatients treated with APDs. Neutropenia was more often detected in women, whereas there was no difference regarding sex in cases of agranulocytosis. Clozapine had the highest relative risk for inducing N&A and was imputed alone as a probable cause of N&A in 60 cases (1.57‰ of all patients exposed). Perazine showed the second highest relative risk with 8 cases and an incidence 0.52‰, followed by quetiapine (15 cases resp. 0.23‰ of all patients exposed) and olanzapine (7 cases; 0.13‰ of all patients exposed). N&A most often occurred during the first 3 months of treatment. Overall N&A are severe and potentially fatal complications that can occur during treatment with APDs. The results from this study largely agree with the currently available literature, highlighting the positive effects of alertness and established appropriate monitoring.

Topics: Antipsychotic Agents; Clozapine; Female; Humans; Neutropenia; Pharmacovigilance; Schizophrenia

The risk of idiosyncratic drug-induced agranulocytosis (IDIAG) markedly constrains the use of clozapine, a neuroleptic with unparalleled efficacy. Most clozapine patients experience an early inflammatory response, likely a necessary step in IDIAG onset. However, most patients do not progress to IDIAG, presumably because of the requirement of specific human leukocyte antigen (HLA) haplotypes, T cell receptors, and other unknown factors. We established that clozapine activates inflammasomes and that myeloperoxidase bioactivation of clozapine generates neoantigens, but the connection between these early mechanistic events remained unknown and, thus, was the aim of this work. We found that the myeloperoxidase inhibitor PF-1355 attenuated myeloperoxidase activity in phorbol myristate acetate (PMA)-differentiated THP-1 macrophages, and it also attenuated clozapine-induced release of inflammatory mediators (e.g., IL-1β, CXCL1, and C-reactive protein). In vivo, pretreatment of Sprague Dawley rats with PF-1355 significantly attenuated clozapine-induced increases in neutrophil mobilization from the bone marrow to the blood and spleen, as determined using differential blood counts and flow cytometry. Moreover, the clozapine-triggered release of inflammatory mediators (e.g., IL-1β, calprotectin, CXCL1, and α-1-acid glycoprotein) from the liver, spleen, and bone marrow was dampened by myeloperoxidase inhibition. These data support the working hypothesis that oxidation of clozapine to a reactive metabolite by myeloperoxidase is critical for induction of the inflammatory response to clozapine. Ultimately, a better mechanistic understanding of the early events involved in the immune response to clozapine may elucidate ways to prevent IDIAG, enabling safer, more frequent therapeutic use of this and potentially other highly efficacious drugs.

Topics: Animals; Antipsychotic Agents; Clozapine; Coloring Agents; Humans; Inflammation; Inflammation Mediators; Neutropenia; Peroxidase; Rats; Rats, Sprague-Dawley

Neutropenia is a noteworthy side effect of clozapine, which might warrant this drugs' discontinuance for safety. Studies have revealed that the risk of neutropenia increases with concurrent administration of valproate, but the evidence was limited. Conversely, lithium may have an ameliorating effect on clozapine-induced neutropenia. This study explored the effects of valproate and lithium on white blood cell counts in patients treated with clozapine.. We retrospectively investigated the electronic medical records from one tertiary psychiatric hospital in Taiwan and enrolled patients discharged between January 1, 2006, and December 31, 2017, with clozapine prescriptions. We scrutinized their demographic data, medications, and hematological results at discharge and during follow-up outpatient clinic visits over the subsequent 3 years. Patients were classified into four groups: clozapine only (CLO), clozapine and valproate (CLO + VAL), clozapine and lithium (CLO + Li), and clozapine, valproate, and lithium (CLO + VAL + Li). We also identified hematological events (neutropenia or leukocytosis) of these patients during outpatient follow-ups.. Of the included 1084 patients, 55(5.1%) developed neutropenia. Concurrent valproate use (odds ratio [OR] = 3.49) and older age (p = .007) were identified as risk factors. Moreover, 453 (41.79%) patients developed leukocytosis. Younger age; male sex; and concurrent use of lithium (OR = 3.39, p < .001), clozapine daily dosage, and benzodiazepines were the risk factors for leukocytosis.. Concurrent valproate use and older age are associated with the development of neutropenia in patients treated with clozapine. Concurrent lithium usage, younger age, male sex, and concurrent benzodiazepine use might be related to leukocytosis.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Humans; Leukocytosis; Lithium; Male; Neutropenia; Retrospective Studies; Valproic Acid

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

To minimise infection during COVID-19, the clozapine haematological monitoring interval was extended from 4-weekly to 12-weekly intervals in South London and Maudsley NHS Foundation Trust.. To investigate the impact of this temporary policy change on clinical and safety outcomes.. All patients who received clozapine treatment with extended (12-weekly) monitoring in a large London National Health Service trust were included in a 1-year mirror-image study. A comparison group was selected with standard monitoring. The proportion of participants with mild to severe neutropenia and the proportion of participants attending the emergency department for clozapine-induced severe neutropenia treatment during the follow-up period were compared. Psychiatric hospital admission rates, clozapine dose and concomitant psychotropic medication in the 1 year before and the 1 year after extended monitoring were compared. All-cause clozapine discontinuation at 1-year follow-up was examined.. Of 569 participants, 459 received clozapine with extended monitoring and 110 controls continued as normal. The total person-years were 458 in the intervention group and 109 in the control group, with a median follow-up time of 1 year in both groups. During follow-up, two participants (0.4%) recorded mild to moderate neutropenia in the intervention group and one (0.9%) in the control group. There was no difference in the incidence of haematological events between the two groups (IRR = 0.48, 95% CI 0.02-28.15,. There was no evidence that the incidence of severe neutropenia was increased in those receiving extended monitoring.

Topics: Antipsychotic Agents; Clozapine; Cohort Studies; COVID-19; Humans; Neutropenia; State Medicine

Clozapine is the treatment of choice in refractory psychosis. In most countries, clozapine must be stopped indefinitely if white blood cells fall below a defined threshold during routine monitoring. Despite evidence of severe adverse consequences of clozapine discontinuation, published accounts on the lived experiences and perspectives of patients and carers are scarce.. We completed semi-structured interviews with patients (n = 4) and family carers (n = 4) on experiences of clozapine cessation following suspected drug-induced neutropenia. Interviews were audio-recorded, transcribed and analysed thematically.. The two overarching themes comprised:(i) stress of clozapine below threshold neutrophil results and (ii) patient and carer priorities.. There is a suggested need for evidence-based pharmacological and psychological approaches to support patients and carers after clozapine cessation. Such approaches will minimise the potentially negative physical and emotional sequela in the aftermath of a below threshold neutrophil result and reduce the likelihood of experiencing additional health and social inequalities after clozapine discontinuation.

Topics: Antipsychotic Agents; Caregivers; Clozapine; Humans; Neutropenia; Psychotic Disorders; Records

Clozapine is a first-line therapy and the only FDA-approved drug for patients with treatment-resistant schizophrenia (TRS). However, frequent measurement of absolute neutrophil count (ANC) is required to monitor for potential adverse severe neutropenia from clozapine therapy. We evaluated 3 point-of-care (POC) instruments that perform the complete blood count (CBC) with differential to assess their analytical performance and potential to meet the clinical need for clozapine therapy management.. A CBC with differential was performed on 104 residual whole blood specimens using 3 CBC analyzers (Sight OLO, PixCell HemoScreen, and Sysmex pocH-100i) to assess analytical precision, linearity, and accuracy vs the ADVIA 2120i and manual differential reference methods. Clinical concordance of ANC between POC devices and manual differential at medical decision points for mild, moderate, or severe neutropenia, and the threshold for clozapine therapy discontinuation (1.0 × 109/L) were determined.. For CBC parameters, a CV ≤ 6.4% was observed on the OLO, CV ≤ 6.2% for the HemoScreen, and CV ≤ 5.1% with the pocH-100i. Each device accurately identified ANC with the greatest mean bias ±0.42 × 109/L using the pocH-100i vs manual differential. For results near the medical decision points (ANC <1.5 × 109/L), clinical concordance of ANC results was 55.6% for the OLO, 89.5% for the HemoScreen, and 82.4% for the pocH-100i.. The HemoScreen device demonstrated the best clinical concordance in ANC values at medical decision thresholds for clozapine therapy management.

Topics: Blood Cell Count; Clozapine; Humans; Neutropenia; Point-of-Care Systems; Psychiatry

Topics: Clozapine; Drug Development; Genome-Wide Association Study; Humans; Neutropenia; Quantitative Trait Loci

Clozapine is an atypical antipsychotic used for treatment-resistant schizophrenia and is known to cause serious side effects, such as leukopenia and neutropenia. We encountered the case of a 44-year-old female patient with a good response to clozapine, who experienced inflammatory reaction and cytopenia after coronavirus disease 2019 (COVID-19) vaccination. Soon after clozapine discontinuation, the inflammatory reaction resolved, and cell counts recovered. There are only a few reports on the interaction between clozapine and COVID-19 vaccine. Our findings suggest that caution is required when a patient who is receiving clozapine scheduled for COVID-19 vaccination, owing to the possibility of cytopenia. Moreover, blood tests and the measurement of clozapine concentration should be performed before and after the inoculation to ensure patient safety.

Topics: Adult; Clozapine; COVID-19; COVID-19 Drug Treatment; COVID-19 Vaccines; Female; Humans; Neutropenia; RNA, Messenger; Schizophrenia; Vaccination

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

Little is known about the genetic basis of clozapine-related neutropaenia. This study aims to explore candidate genes and pathways involved in clozapine-related neutropaenia.. This study conducted a two-stage integrative analysis of the summary statistics from the genome-wide association study (GWAS, n = 552) of the lowest absolute neutrophil count (ANC) during clozapine treatment and the summary data of the expressed quantitative trait locus (eQTL). First, we use the probabilistic Mendelian randomization (PMR-Egger) to identify genes whose expression is causally related to ANC, and then use Bayesian co-localization analysis to investigate whether there are shared causal variants between them [posterior probability for hypotheses 4 (PP.H4) > 0.80]. Finally, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were conducted to explore the pathways that may be associated with ANC during clozapine treatment.. PMR-Egger analysis identified 146 genes that may be causally associated with ANC after Bonferroni correction (P-value < 3.25e-6). Bayesian co-localization analysis identified six further genes whose gene expression shared common variants with ANC, including NT5E (PP.H4 = 0.96), GLDC (PP.H4 = 0.82), NUDT17 (PP.H4 = 0.88), MSH4 (PP.H4 = 0.88), PTER (PP.H4 = 0.89) and SERPINB6 (PP.H4 = 0.83). Enrichment analysis identified 52 GO terms and seven pathways associated with ANC, such as NAD metabolic process, drug catabolic process and glyoxylate and dicarboxylate metabolism.. This study identified multiple candidate genes and pathways that may be involved in clozapine-related neutropaenia, providing novel clues for the mechanism of clozapine-related neutropaenia.

Topics: Bayes Theorem; Clozapine; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Neutropenia; Polymorphism, Single Nucleotide; Quantitative Trait Loci

This was an observational, retrospective analysis of patients registered with clozapine haematological monitoring systems in two large mental health trusts, chosen because they serve an ethnically diverse population. The first objective was to establish certified BEN prevalence in current users of clozapine. The second objective was to explore the stage of treatment at which BEN was identified. The third objective was to evaluate the extent of unrecognised BEN in patients registered on the Central Non-Rechallenge Database (CNRD), a database for patients whose haematological parameters fall below set thresholds when receiving clozapine treatment, meaning they cannot ordinarily be prescribed clozapine again.. The study population comprised of 2020 patients on the clozapine register. 111 patients were monitored under BEN criteria. BEN was mostly identified after a below threshold haematological result or clozapine rechallenge (68%) compared to at clozapine initiation (32%). Eight of the 18 (42%) black patients registered on the CNRD were classified as BEN after assessment by a haematologist. Of these 8 patients, none would have met CNRD criteria again if monitored with BEN criteria at clozapine initiation.. Current evidence suggests that BEN remains an uncommonly recognised haematological phenotype. Improved timely identification of BEN will reduce unnecessary interruption or discontinuation of clozapine treatment. Our results suggest consideration should also be given to determining BEN status prior to initiating clozapine. Moreover, adoption of current FDA BEN monitoring criteria in the UK may further reduce clozapine discontinuation due to perceived neutropenia as drug toxicity, particularly in treatment-refractory schizophrenia patients.

Topics: Antipsychotic Agents; Clozapine; Hospitals; Humans; Neutropenia; Prevalence; Retrospective Studies; State Medicine

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Clozapine; Hematopoietic Stem Cell Transplantation; Humans; Immunotherapy, Adoptive; Lymphoma, Large B-Cell, Diffuse; Male; Neutropenia; Receptors, Chimeric Antigen; Schizophrenia; Treatment Outcome

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

Monitoring of white cell counts during clozapine treatment leads to cessation of therapy if levels fall below predetermined values. Reductions in white cell counts, driven by lower levels of lymphocytes, have been observed with coronavirus disease 2019 (COVID-19). Neutropenia during COVID-19 has not been reported. We present data for 56 patients who were taking clozapine and had COVID-19.. We included patients who were taking clozapine at the time they tested positive for COVID-19. We compared absolute neutrophil counts, lymphocyte counts and white cell counts between baseline and the first week of infection, and baseline and the second week of infection.. We observed reductions in absolute neutrophil counts (p = 0.005), lymphocyte counts (p = 0.003) and white cell counts (p < 0.001) between baseline and the first 7 days of COVID-19. All cell counts had returned to baseline levels by days 8 to 14. Six patients experienced neutropenia (absolute neutrophil counts < 2.0 × 109/L) and of those, 4 underwent mandatory cessation of clozapine. For 3 patients, clozapine treatment had been established for more than 6 months with no previous neutropenia, neutrophil levels returned to baseline within 2 weeks and no further neutropenia was observed on restarting treatment.. This was a retrospective chart review; larger cohorts are required. Clozapine plasma levels were largely not measured by clinicians.. These data strongly suggest that mild neutropenia in the acute phase of COVID-19 in patients who are well established on clozapine is more likely to be a consequence of the virus than of clozapine treatment.

Topics: Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Clozapine; COVID-19; Female; Humans; Leukocyte Count; Leukopenia; Lymphocyte Count; Lymphopenia; Male; Middle Aged; Neutropenia; Neutrophils; Psychotic Disorders; Retrospective Studies; SARS-CoV-2; Schizophrenia; Young Adult

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

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Japan; Neutropenia; Registries

Clozapine has a unique efficacy profile among individuals suffering from treatment-resistant schizophrenia, but is associated with hematological side effects. The use of granulocyte colony-stimulating factors (G-CSF) to allow clozapine continuation or rechallenge has emerged as a promising option, but evidence is still scarce.. To describe the largest case series so far published regarding this practice.. Using G-CSF, three out of eight patients could maintain clozapine despite neutropenia episodes that otherwise would have required treatment discontinuation. The only side effect reported was mild short-lived back pain, over a mean 3-year follow-up period. In all but one case, filgrastim was used on an "as-needed" basis at doses of 300 mcg administered subcutaneously.. These results suggest that the "as-needed" use of G-CSF is well-tolerated and may allow clozapine rechallenge in some well-selected patients, adding to the paucity of data regarding long-term safety and efficacy of this strategy. More research may help to better define potential candidates and optimal regimen of such practice.

Topics: Adult; Aged; Antipsychotic Agents; Clozapine; Databases, Factual; Female; Filgrastim; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Humans; Male; Middle Aged; Neutropenia; Quebec; Retrospective Studies; Schizophrenia, Treatment-Resistant; Young Adult

Topics: Antipsychotic Agents; Australia; Black People; Clinical Protocols; Clozapine; Ethnicity; Humans; Middle East; Neutropenia

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Male; Neutropenia; Time Factors

Topics: Adolescent; Antipsychotic Agents; Clozapine; Female; Humans; Neutropenia; Quinolones; Schizophrenia; Serotonin Agents; Thiophenes

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

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

Clozapine is known as one of the atypical antipsychotics which is placed in the second line of medical treatment for schizophrenia due to its hematologic complications. It is used in cases of resistance to treatment. Some side effects of clozapine include leukopenia, granulocytopenia, fever, hepatotoxicity, sedation, dizziness, hypotension, weight gain, constipation, and seizure. Neutropenia and hepatotoxicity have been separately reported after taking atypical antipsychotics, including clozapine. However, simultaneous occurrence of these two complications is rare and has not been reported with clozapine use. This study reports a case of concurrent hepatotoxicity and neutropenia induced by clozapine. The patient was a 58-year-old man who started taking clozapine for the first time in March 2017, about seven weeks before his recent admission, because of a history of treatment-resistant schizophrenia. He had been referred to the emergency department of a general hospital with symptoms of weakness, lethargy, fever, and chills. The laboratory results showed neutropenia with a frequency of 352 × 103 (17.5%) and hepatotoxicity with alanine transferase (ALT) = 139 u/L, aspartate transferase (AST) = 214 u/L, total bilirubin = 11.5 mg/dL, and direct bilirubin = 9.3 mg/Dl, caused by taking clozapine. The symptoms were attenuated within eight days after discontinuation of clozapine. Moreover, the patient's para-clinical complications including neutropenia, and raised transaminases and bilirubin returned to normal. It was concluded that clozapine can simultaneously cause neutropenia and hepatotoxicity; physicians are recommended to be aware of this issue to prevent mortality through appropriate and timely diagnosis.

Topics: Antipsychotic Agents; Chemical and Drug Induced Liver Injury; Clozapine; Humans; Lithium Carbonate; Male; Middle Aged; Neutropenia; Schizophrenia

Topics: Antipsychotic Agents; Betacoronavirus; Clinical Laboratory Techniques; Clozapine; Consensus; Coronavirus Infections; COVID-19; COVID-19 Testing; Humans; Neutropenia; Pandemics; Pneumonia, Viral; SARS-CoV-2; Schizophrenia

A 48-year-old man with a history of schizophrenia was diagnosed with B-cell lymphoma of the small bowel. Neutropaenia occurred secondary to chemotherapy, which led to clozapine being discontinued, which resulted in the deterioration of his mental state, in turn, affecting the treatment of lymphoma. Clozapine was later reintroduced alongside granulocyte colony-stimulating factor, leading to improved mental state without any further incidences of neutropaenia.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antipsychotic Agents; Clozapine; Drug Administration Schedule; Drug Therapy, Combination; Granulocyte Colony-Stimulating Factor; Humans; Lymphoma, B-Cell; Male; Middle Aged; Neutropenia; Schizophrenia; Treatment Outcome

Topics: Adult; Antipsychotic Agents; Clozapine; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Humans; Male; Neutropenia; Recurrence; Schizophrenia; Young Adult

Topics: Antipsychotic Agents; Clozapine; Humans; Neutropenia

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

Individuals of African ancestry in the United States and Europe are at increased risk of developing schizophrenia and have poorer clinical outcomes. The antipsychotic clozapine, the only licensed medication for treatment-resistant schizophrenia, is under-prescribed and has high rates of discontinuation in individuals of African ancestry, due in part to increased rates of neutropenia. The genetic basis of lower neutrophil levels in those of African ancestry has not previously been investigated in the context of clozapine treatment. We sought to identify risk alleles in the first genome-wide association study of neutrophil levels during clozapine treatment, in 552 individuals with treatment-resistant schizophrenia and robustly inferred African genetic ancestry. Two genome-wide significant loci were associated with low neutrophil counts during clozapine treatment. The most significantly associated locus was driven by rs2814778 (β = -0.9, P = 4.21 × 10

Topics: Alleles; Antipsychotic Agents; Black People; Clozapine; Duffy Blood-Group System; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Male; Neutropenia; Neutrophils; Polymorphism, Single Nucleotide; Receptors, Cell Surface; Risk Factors; 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

Regular haematological monitoring during clozapine treatment reduces the risk of complications and death from clozapine-related blood dyscrasias. However, many patients in the course of clozapine treatment develop neutropenia unrelated to drug treatment which leads to treatment discontinuation. The minimum haematological threshold allowed for the continuation of clozapine treatment was recently lowered in the US, but not in the UK. In this case series, we present four cases where lowering the haematological cut-off to that used in the US, allowed treatment continuation. Lowering the current UK threshold for clozapine cessation could avoid unnecessary interruptions in treatment with minimal impact on safety.

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

To provide additional data concerning the safety, effectiveness and local prescribing trends of clozapine in elderly patients.. Retrospective observational case-series analysis.. Data were collected from the medical files of 167 patients prescribed clozapine.. All patients prescribed clozapine in the last 15 years by the psychogeriatric service in Christchurch, New Zealand. The subjects were mostly aged over 65; however, patients under 65 are also accepted into the service on a case by case basis if they have an age-related health condition.. Twenty-five (15.0%) patients had their clozapine stopped due to a significant adverse reaction, including eleven who developed significant neutropenia. Seventy-four (44.3%) of the patients had no recorded side effects at all. Sixty-five (38.9%) of our elderly patients died while taking clozapine, though none of these deaths was felt to be related to clozapine use. Several patients safely initiated clozapine in either their own home or a nursing home without requiring hospital admission. Only two patients ceased clozapine due to ineffectiveness, and one hundred, forty-two (86.1%) of the patients had positive comments in their medical record regarding the benefits of clozapine for their particular case.. We found clozapine could be used safely and effectively in our patient group, for a wider range of indications and at lower doses than younger patients. Data collection regarding cause of death in elderly patients who were ever prescribed clozapine was problematic, and more research into this area is required.

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Clozapine; Drug Prescriptions; Drug Resistance; Female; Humans; Male; Middle Aged; Neutropenia; New Zealand; Practice Guidelines as Topic; Practice Patterns, Physicians'; Psychotic Disorders; Retrospective Studies

Systematic information about Latino clozapine users is still scarce. Our aim was to evaluate the risk of clozapine-associated neutropenia in a Chilean cohort using the last Food and Drug Administration's recommendations for clozapine monitoring. Findings should improve clinical practice and promote changes in clozapine guidelines in Latin America. We conducted a retrospective observational study of 5380 Chilean clozapine users that started clozapine treatment between 2003 and 2015. The absolute risk of severe neutropenia was 0.61% (33/5380) with an incidence of 0.086 cases per 100 person-years of follow-up. 87.9% of cases with severe neutropenia appeared during first 18 weeks. Cases of mild neutropenia were 3.9% of total sample and occurred almost constantly without a specific risk time. 77.5% of cases of moderate or severe neutropenia didn't present an event of mild neutropenia before. 22.8% of clozapine users (1227/5380) discontinued treatment for any cause and 4.2% (225/5380) due to neutropenia in any severity level. Clozapine-associated neutropenia risk in Latino users is similar than in the rest of the world. The evidence of a very low risk for severe neutropenia and the behaviour of mild neutropenia cases confirm the feasibility of changes in Latin American clozapine guidelines using current Food and Drug Administration's recommendations as a model.

Topics: Adult; Chile; Clozapine; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neutropenia

The use of clozapine is limited due to the occurrence of neutropenia, and the rare but life threatening adverse event of agranulocytosis. There is little epidemiological research into clinical factors that may impact on this risk. We conducted a case control study examining the clinical risk factors for neutropenia patients treated with clozapine.. A case-control study was conducted within a database of anonymised electronic clinical records. All patients who discontinued clozapine due to a neutropenic event were included as cases. Matched controls were selected from patients with a documented clozapine exposure at the time of the clozapine neutropenic event of the case patient, matched by duration of clozapine treatment.. 136 cases and 136 controls were included. In multivariable analysis, the concurrent use of sodium valproate was associated with neutropenia (Odds Raito (OR) 2.28, 95%CI: 1.27-4.11, p=0.006). There was a dose-response effect, with greater associations for higher doses. Patients who discontinued clozapine due to neutropenia were more likely to be of black ethnicity (OR 2.99, p<0.001), were younger (t=5.86, df=267, p<0.001), and received lower doses of clozapine (t=-2.587, p=0.01) than those who did not develop neutropenia.. We identified an association between the concurrent use of sodium valproate and an increased risk of clozapine associated neutropenia. These results, taken in combination with the results from previous case series, suggest that the risk of clozapine associated neutropenia could be reduced by avoiding concurrent valproate treatment.

Topics: Adolescent; Adult; Aged; Antimanic Agents; Antipsychotic Agents; Case-Control Studies; Clozapine; Female; Humans; Male; Middle Aged; Neutropenia; Registries; Valproic Acid; Young Adult

Clozapine is the gold-standard medicine for treating refractory schizophrenia but there are some notable serious adverse events (AE). We aimed to analyse reported rates of clozapine cardiac and haematological AEs in Australia.. Using data from the Therapeutic Goods Administration, we examined all reported clozapine AEs (1993-2014) with a specific focus on neutropenia, myocarditis and cardiomyopathy. We related AEs to clozapine-dispensing data in Queensland, scaled up to Australia.. There were 8561 AEs reported: neutropenia (13.7%), myocarditis (9.3%) and cardiomyopathy (3.8%). Reported rates of myocarditis and cardiomyopathy increased after 1999 following a myocarditis case series from Sydney. Cardiomyopathy AE rates have remained stable since then but myocarditis AEs have increased steadily. Neutropenia was more common in women, while cardiomyopathy and myocarditis were more common in men. There were five, 13, and two reported deaths from neutropenia, myocarditis, and cardiomyopathy, respectively.. The rates of serious AEs (including deaths) are low and likely an underestimate of true rates and need to be considered by clinicians in balancing the risks and benefits. Continued education on the monitoring and treatment of these AEs for consumers, carers and health professionals is essential and reporting these to the relevant national reporting agency is crucial.

Topics: Adult; Antipsychotic Agents; Australia; Cardiomyopathies; Clozapine; Female; Humans; Male; Myocarditis; Neutropenia; Schizophrenia; Young Adult

The aim of this study was to investigate clozapine use and its associated adverse effects in patients in Japan.. We analyzed data recorded from July 2009 to January 2016 (N = 3780 patients) in the Clozaril Patient Monitoring Service, which was established in Japan in 2009 and includes all Japanese patients who have been prescribed clozapine.. The treatment discontinuation rate was 23.9% (869/3780 cases). The average ± SD treatment duration was 234.9 ± 306.9 days (median, 115 days), and the average ± SD dosage was 186.41 ± 151.6 mg/d. The estimated treatment continuation rates resulting from all-cause discontinuation were 78.2 after 1 year and 72.9% after 2 years of treatment. The incidence of neutropenia/leucopenia was 5.4% (206/3780 cases). The average ± SD dose before discontinuation was 233.36 ± 168.15 mg (median, 200 mg; range, 4-600 mg). The incidence of glucose intolerance was 15.4% (583/3780 cases). Of 3780 patients, 98 (2.67%) developed glucose intolerance before and after taking clozapine administration, whereas 485 patients (12.8%) developed glucose intolerance after taking clozapine. The average ± SD time from treatment initiation to new onset of glucose intolerance was 382.2 ± 420.2 days (median, 216 days; range, 4-2053 days).. The data obtained in this study, particularly regarding the incidence of clozapine-induced adverse events, will enable the optimal and safe use of clozapine in Japanese patients with treatment-resistant schizophrenia.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Child; Clozapine; Female; Glucose Intolerance; Humans; Japan; Leukopenia; Male; Middle Aged; Neutropenia; Young Adult

Clozapine is the drug of choice for treatment-resistant schizophrenia. While pediatric clozapine use is not contraindicated, the literature describing its clinical application is limited. The primary objective of this study was to assess the use of clozapine in a child and adolescent population by characterizing the documented safety and clinical benefits of the medication.. A multicenter retrospective study at sites in the United States and Australia included children and adolescents admitted to a psychiatric unit who were administered at least one dose of clozapine. Information related to demographics, patient history, past treatments, clozapine, and adverse events was collected.. Eighty-two patients from eight sites were included in this study. Patients were predominantly clozapine naive (76.8%), and most had a discharge diagnosis of a primary psychotic disorder (61%) or bipolar disorder (25.6%). Four clozapine discontinuations occurred during hospitalization due to severe neutropenia, ileus, need for diagnostic clarification, and significant psychomotor retardation. The remainder (n = 78) were discharged on a mean clozapine dose of 218.1 ± 142.2 mg. Sedation (26.8%) and sialorrhea (17.1%) were the most common documented adverse events. The mean number of previously trialed antipsychotics before clozapine was 3.5 ± 1.4 (range 1-10). Improvement with clozapine was documented as significant (31.7%), moderate (32.9%), minimal (12.2%), no improvement (2.4%), and not described (20.7%).. In this cohort, 95% of pediatric patients admitted with or started on clozapine during an acute psychiatric hospitalization were discharged on the medication. The high incidence of adverse events should reinforce to clinicians the need for vigilant monitoring. Pediatric guidelines recommend clozapine for refractory schizophrenia but stress the critical need to ensure an accurate diagnosis. Limited data exist for the use of clozapine in pediatric patients with other diagnoses.

Topics: Adolescent; Antipsychotic Agents; Australia; Bipolar Disorder; Child; Clozapine; Female; Humans; Male; Neutropenia; Psychiatric Department, Hospital; Psychotic Disorders; Retrospective Studies; Sialorrhea

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

This case report describes a case of a woman with treatment-resistant schizophrenia, who experienced neutropenia induced by olanzapine and clozapine, and reached symptomatic stabilization with a combination of two depot antipsychotics. This report presents a brief review about the incidence of haematologic events by antipsychotics and the evidence of antipsychotic combination in the treatment.

Topics: Adult; Antipsychotic Agents; Clozapine; Delayed-Action Preparations; Drug Resistance; Drug Therapy, Combination; Female; Humans; Neutropenia; Olanzapine; Schizophrenia

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

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Histocompatibility Testing; HLA Antigens; Humans; Neutropenia; Schizophrenia, Paranoid

The aim of this study was to determine whether patient characteristics such as age, sex, race/ethnicity, and frequency of monitoring play a role in clozapine-related blood dyscrasias. This study examined all neutropenic events to identify any potential demographic qualities that may pose increased risk to individuals receiving clozapine treatment in accordance with the FDA guidelines released in 2005. These guidelines required the addition of absolute neutrophil count (ANC) tests in addition to white blood cell (WBC) counts to regular monitoring and a reduction in the frequency of testing to once monthly after 1 year of satisfactory WBC counts and ANCs. The previous schedule neither included ANC testing nor allowed for further reductions in the frequency of testing after 1 year, with patients continuing to be tested every 2 weeks indefinitely. This is a retrospective, closed chart review of all patients who received clozapine at the State Psychiatric Center and experienced a leukopenic/neutropenic event and/or who had a substantial drop in WBC/ANC from January 2009 to December 2011. A subset of patients who were identified as achieving 'non-rechallengeable' status with either an ANC and/or WBC threshold value from 2001 to 2014 were also examined. This protocol was approved by the New York State Psychiatric Institute Institutional Review Board. A total of 193 patients were included in the study. Males experienced more total events at 6.4 events per person compared with 5.2 events per woman. White patients had 6.5 total events per person compared with 4.2 total events per Black patient; however, Black patients experienced more moderate leukopenia/granulocytopenia events compared with Whites. Regardless of race or ethnicity, patients in the 40-49-year age range had the most events at 8.1 events per person and also presented with the highest number of moderate leukopenia/granulocytopenia events as did those scheduled for weekly monitoring. Conversely, the majority of patients with no recorded events were female and either 20-29 or 60-69 years of age. In total, 16 patients were exclusively designated as non-rechallengeable from 2001 to 2014 and only had one single blood event prompting this clozapine monitoring status. Of these 16 patient events, seven were White males, eight were White females, and one was a Black female with roughly 40% of those patients in the 50-59-year age group. Currently published predictions on possible demographic risk groups may not

Topics: Adult; Age Factors; Aged; Antipsychotic Agents; Clozapine; Drug Monitoring; Female; Humans; Leukocyte Count; Leukopenia; Male; Middle Aged; Neutropenia; Predictive Value of Tests; Racial Groups; Retrospective Studies; Risk Factors; Sex Factors; Time Factors; Treatment Outcome; Young Adult

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Clozapine; Female; Humans; Male; Neutropenia; Parkinson Disease; Psychotic Disorders

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

To rechallenge with clozapine for a patient who previously has experienced neutropenia or leucopenia or during clozapine treatment is a difficult clinical decision. Herein, we analyzed the results of such a rechallenge in 19 patients. We analyzed all the reports, from the database of the pharmacovigilance department of the Argentine National Administration of Drugs, Foods, and Medical Devices, of patients who were rechallenged with clozapine after a leucopenia or a neutropenia. Nineteen cases of rechallenge after leucopenia or neutropenia were reported between 1996 and 2014. One third of the patients re-exposed to clozapine developed a new hematologic adverse reaction. The second blood dyscrasia was less severe in 83% of the cases and had a shorter median latency as compared with the first (8 weeks vs 182 weeks, P = 0.0045). There were no significant differences for demographic and clinical characteristics of patients who developed a second dyscrasia as compared with those who did not. The present study shows that almost 70% of the patients rechallenged with clozapine after a leucopenia or a neutropenia did not develop a new hematological adverse effect, whereas the remaining 30% had a faster but less serious neutropenia.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Humans; Leukopenia; Male; Middle Aged; Neutropenia; Paraproteinemias; Pharmacovigilance; Young Adult

Topics: Anti-Bacterial Agents; Clozapine; Humans; Leukocyte Count; Male; Middle Aged; Neutropenia; Schizophrenia

To determine if clozapine can be safely utilized in psychiatric patients with benign neutropenia.. A single-center, retrospective chart review study of records from 2001 to 2014 was conducted in an inpatient psychiatric hospital. Patients included had benign neutropenia prior to receiving clozapine and received clozapine using modified monitoring guidelines. All available laboratory values for absolute neutrophil count (ANC) before initiation and during treatment were evaluated. The primary endpoint was difference in ANC after initiation of clozapine from before clozapine.. A total of 26 patients were reviewed. The mean age at clozapine initiation was 34 years. The majority were African-American (73% [n = 19]), with more men than women (73% [n = 19] vs 27% [n = 7]). The mean lowest ANC value was not significantly different after clozapine initiation compared to before (1.5× 10³ cells/mm³ and 1.4 × 10³ cells/mm³, respectively; P = .22). The overall mean ANC was significantly higher after initiation than before (2.63 × 10³ cells/mm³ and 2.13 × 10³ cells/mm³, respectively; P < .001). There were no cases of severe neutropenia (ANC < 0.5 × 10³ cells/mm³), and no patient was discontinued for falling below modified guideline limits. There were fewer occurrences of mild neutropenia (ANC < 2.0 × 10³ cells/mm³) after clozapine initiation than before (16.0% and 31.4%, respectively; P < .001). There were also fewer occurrences of moderate neutropenia (ANC < 1.5 × 10³ cells/mm³), with 2.1% after clozapine and 13.3% before (P < .001).. Twenty-six patients with benign neutropenia were safely treated with clozapine. Pre-clozapine neutropenia did not predict increased risk for severe neutropenia with clozapine. Patients had significantly fewer episodes of mild and moderate neutropenia after receiving clozapine compared to before.

Topics: Adult; Child; Clozapine; Female; Guideline Adherence; Hospitals, Psychiatric; Humans; Infant; Leukocyte Count; Male; Middle Aged; Neutropenia; Psychotic Disorders; Retrospective Studies; Risk; Young Adult

Our case report addresses the use of clozapine in patients who have a history of quetiapine XR-induced neutropenia. There are no current guidelines for this situation.. We present the case of a young woman treated with clozapine at a first-episode psychosis clinic after a moderate quetiapine XR-induced neutropenia (0,5-1,0 × 10(9)  L(-1) ).. The patient was successfully treated with clozapine and lithium, with less psychotic symptoms and a better level of functioning. The neutrophil count remained normal during the treatment period, which has been longer than a year.. The outcome of this case supports the notion that clinicians could consider introducing clozapine in treatment-refractory patients who have a history of quetiapine XR-induced neutropenia, with close blood monitoring. Lithium co-administration may play a role in maintaining a normal neutrophil count.

Topics: Antipsychotic Agents; Clozapine; Delayed-Action Preparations; Drug Resistance; Female; Humans; Leukocyte Count; Neutropenia; Neutrophils; Quetiapine Fumarate; Schizophrenia; 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

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Antipsychotic Agents; Carboplatin; Carcinoma, Squamous Cell; Clozapine; Esophageal Neoplasms; Humans; Male; Neutropenia; Paclitaxel; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Female; Humans; Neutropenia; Schizophrenia, Paranoid; Young Adult

Genetic testing in psychiatry promises to improve patient care through advances in personalised medicine. However, there are few clinically relevant examples.. To determine whether patients with a well-established genetic subtype of schizophrenia show a different response profile to the antipsychotic clozapine than those with idiopathic schizophrenia.. We retrospectively studied the long-term safety and efficacy of clozapine in 40 adults with schizophrenia, half with a 22q11.2 deletion (22q11.2DS group) and half matched for age and clinical severity but molecularly confirmed to have no pathogenic copy number variant (idiopathic group).. Both groups showed similar clinical improvement and significant reductions in hospitalisations, achieved at a lower median dose for those in the 22q11.2DS group. Most common side-effects were similarly prevalent between the two groups, however, half of the 22q11.2DS group experienced at least one rare serious adverse event compared with none of the idiopathic group. Many were successfully retried on clozapine.. Individuals with 22q11.2DS-schizophrenia respond as well to clozapine treatment as those with other forms of schizophrenia, but may represent a disproportionate number of those with serious adverse events, primarily seizures. Lower doses and prophylactic (for example anticonvulsant) management strategies can help ameliorate side-effect risks. This first systematic evaluation of antipsychotic response in a genetic subtype of schizophrenia provides a proof-of-principle for personalised medicine and supports the utility of clinical genetic testing in schizophrenia.

Topics: Adult; Antipsychotic Agents; Clozapine; DiGeorge Syndrome; Dose-Response Relationship, Drug; Drug Substitution; Female; Hospitalization; Humans; Male; Middle Aged; Myocarditis; Neutropenia; Schizophrenia; Seizures; Treatment Outcome; Young Adult

Certain patients with treatment-refractory schizophrenia may be rechallenged with clozapine following previous neutropenia. Evidence guiding patient selection and the effectiveness of lithium and granulocyte-colony stimulating factor (G-CSF) in rechallenge is limited, and factors associated with successful outcomes are unclear.. Outcomes were studied in patients rechallenged with clozapine at a tertiary referral center between January 2007 and December 2013, following 1 or more previous trials terminated due to neutropenia, defined as an absolute neutrophil count (ANC) < 1.5 × 10(9)/L. Demographic characteristics, details of each clozapine trial including ANC, and coprescribed medication were extracted, and factors associated with rechallenge outcomes were examined.. Nineteen patients underwent clozapine rechallenge following previous neutropenia; 4 (21%) experienced further neutropenia, 2 of which developed agranulocytosis. Compared to successfully rechallenged patients, unsuccessfully rechallenged patients were significantly older (t = 2.10, P = .05), experienced onset of neutropenia sooner (W = 10.0, P = .03), and were more commonly coprescribed valproate. In addition to 5 patients with benign ethnic neutropenia (BEN), 8 patients not of an ethnicity associated with BEN also had idiopathic low neutrophil counts at baseline; lithium and G-CSF coprescription facilitated successful rechallenge in these patients.. In this selected population, the initial neutropenia was unlikely to be related to clozapine in a substantial proportion of cases. This group was successfully rechallenged following careful consideration of the risks and benefits, and lithium and G-CSF contributed to allowing continued clozapine therapy. In addition to black patients, other ethnic groups can have persistently low ANC unrelated to clozapine.

Topics: Adult; Antimanic Agents; Antipsychotic Agents; Clozapine; Cohort Studies; Drug Therapy, Combination; Female; Granulocyte Colony-Stimulating Factor; Humans; Leukocyte Count; Lithium Compounds; Male; Middle Aged; Neutropenia; Neutrophils; Outcome Assessment, Health Care; Schizophrenia; Valproic Acid; Young Adult

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

The literature describing the long-term use of lithium carbonate to reinstate reduced levels of white blood cell counts in patients treated with clozapine is scarce. We describe a case of successful recommencement of clozapine on a patient who developed risk level of neutropenia which was corrected by lithium carbonate. He was followed up for a period of one year.. We report a 40-year-old Sri Lankan male who developed neutropenia and low white blood cell counts following commencement of clozapine. We were successful in restarting clozapine after the addition of lithium carbonate to increase the cell counts. Clozapine was increased to 700 mg a day with 500 mg of lithium carbonate. The patient remains stable after one year with no further episodes of neutropenia.. Lithium carbonate can successfully be used to treat clozapine-induced neutropenia.

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Lithium Compounds; Male; Neutropenia; Schizophrenia

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

Topics: Antipsychotic Agents; Child; Clozapine; Female; Humans; Leukopenia; Neutropenia; Schizophrenia, Paranoid; Time Factors

The purpose of this study was to retrospectively analyze rates of neutropenia and risk factors for neutropenia in hospitalized children and adolescents treated with clozapine.. A retrospective chart review was conducted for all patients who received clozapine at any time during a hospitalization at the National Institute of Mental Health (NIMH) between 1990 and 2011. All patients satisfied screening criteria for the NIMH childhood-onset schizophrenia study, including onset of psychosis before the age of 13 years. Absolute neutrophil count (ANC) values recorded during inpatient hospitalization were extracted for 87 eligible patients with a mean age of 13.35±2.46 years at hospitalization and a mean length of stay of 117±43 days.. Mild neutropenia only (lowest ANC<2000/mm3 but>1500/mm3) was observed in 27 (31%) patients and moderate neutropenia (any ANC<1500/mm3) was observed in 17 (20%) patients. There were no cases of agranulocytosis or severe infection. Significant risk factors for mild neutropenia compared with no hematologic adverse effects (HAEs) were male gender (p=0.012) and younger age (p<0.001). Male gender was also a significant risk factor for moderate neutropenia compared with no HAEs (p=0.003). If a child of African American ethnicity developed neutropenia during hospitalization at all that child was significantly more likely to develop moderate neutropenia than mild neutropenia only (p=0.017). African American boys had the highest rate of moderate neutropenia at 47%. Sixteen of the 17 patients exhibiting moderate neutropenia were successfully treated with clozapine by the time of discharge; 8 of these 16 required adjunctive lithium carbonate administration to maintain ANC>2000/mm3.. Our study shows that the rates of neutropenia in clozapine-treated children and adolescents are considerably higher than in the adult population. Younger age, African American ethnicity, and male gender were significant risk factors. These are also risk factors for benign neutropenia in healthy children and adolescents. Despite these high rates of neutropenia, all but one of the patients with neutropenia during hospitalization were successfully discharged on clozapine.

Topics: Adolescent; Age Factors; Age of Onset; Antipsychotic Agents; Black or African American; Child; Clozapine; Female; Hospitalization; Humans; Length of Stay; Leukocyte Count; Male; National Institute of Mental Health (U.S.); Neutropenia; Retrospective Studies; Risk Factors; Schizophrenia; Severity of Illness Index; Sex Factors; United States

The frequency of agranulocytosis induced by psychoactive drugs is estimated the first year of around 0.8% under clozapine, against 0.13% under chlorpromazine (King and Wager, 1998 [3]). It is associated with a mortality rate of 5 to 10%, and requires heavy treatment, usually in an intensive care unit. The objective of this paper is to present a practical therapeutic answer (clozapine rechallenge with filgrastim) through a case report following a neutropenia episode preventing clozapine use.. B.N. aged 35, native of Martinique, shows a resistant schizophrenia disorder "ultra sensitive" to clozapine. Without any treatment, after 4 years in stable clinical state under clozapine, B.N. suffered three neutropenia episodes when absorbing clozapine (2008, 2010 and 2011). First, a literature survey was conducted along with a consultation of the head of pharmacovigilance regional center and the hematology referee. Then, a 4th clozapine treatment was decided under cover of filgrastim (G-CSF), the role of which is to limit the risk of a new neutropenia. After stopping all psychoactive drugs, except morphine, the subject benefited from a first 0.3mg filgrastim injection, the day before re-introducing 25mg clozapine. Before treatment: Leucocytes=4.8 G/L while absolute neutrophils count=2.4 G/L. Filgrastim injections were carried out at a rate of two 0.3mg injections per week. Clozapine was increased to reach 25mg every 3 days and electroconvulsivotherapy continued fortnightly while supervision was double: on the first hand, daily and clinical search for an increase in body temperature and signs of treatment intolerance, and on the other hand biological surveillance with NFS three times a week besides weekly clozapinemia. The well-informed consent of the patient was obtained.. Signs of improvement were noticed as early as the 8th day and after 8 weeks of treatment and 31 sessions of ECT, the patient was stabilized under clozapine at 300 mg per day. The evolution is clearly favorable, as PANNS evolved from 158 to 90. Neutropenia episodes were not observed with a lowest measured rate of 1.9 G/L neutrophils. The filgrastim dosage was then reduced to 0.3mg per week from the 7th week onwards, along with the pursuit of a weekly NFS supervision throughout the treatment. Tolerance is satisfying, with an improvement in lipid check, glycaemia, blood pressure and QT intervals during ECG.. The B.N. case isn't an isolated one as several articles refer to filgrastim use, combined with clozapine. This confirms the role of hematopoietic cytokines (mainly G-CSF) in neutropenia episodes induced by clozapine. Filgrastim dosage appears to be an important point with regards to the risk of a new neutropenia episode. Let's mention also that it is not a harmless treatment, it could hide the occurrence of neutropenia, besides it's expensive and invasive. Clinical and biological supervision is essential as the probability of an enhanced malignant hemopathy is low but nonetheless present. We also noticed a "biased notoriety of the clozapine", with the association with other hematotoxic molecules, the existence of a circadian rhythm of neutrophils or G-CSF, along with transitional or ethnical neutropenia. These points should be discussed thoroughly before exclusively accusing clozapine; this in turn would have consequences regarding the possibility of treatment resumption. Finally, association with lithium is also an option; several cases have already been reported.

Topics: Adult; Clozapine; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance; Drug Substitution; Drug Therapy, Combination; Electroconvulsive Therapy; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Injections; Leukocyte Count; Male; Martinique; Neutropenia; Neutrophils; Psychiatric Status Rating Scales; Recombinant Proteins; Retreatment; Schizophrenia

Topics: Aged; Antipsychotic Agents; Clozapine; Female; Humans; Male; Middle Aged; Neutropenia; Retrospective Studies; Schizophrenia

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

Topics: Adult; Antineoplastic Agents; Antipsychotic Agents; Bleomycin; Breast Neoplasms; Carcinoma; Cisplatin; Clozapine; Etoposide; Female; Humans; Intestinal Neoplasms; Male; Middle Aged; Neoplasms; Neutropenia; Schizophrenia; Seminoma; Testicular Neoplasms

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

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

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

Clozapine is the treatment of choice for treatment-resistant schizophrenia, but it is associated with a risk of neutropaenia and agranulocytosis. Clozapine use is regulated by mandatory blood monitoring in the UK, requiring cessation of treatment should the absolute neutrophil count (ANC) drop below specified values. Benign reductions in the ANC in non-white populations are common, and this can preclude a patient from receiving treatment with clozapine. A diagnosis of benign ethnic neutropaenia can reduce these treatment restrictions (UK specific), but the degree of neutropaenia can be significant enough to still prevent treatment. In this report, we show that response to granulocyte colony stimulating factor (G-CSF) may be quite variable and difficult to predict, but with careful monitoring it can be used to increase the ANC count and allow continued treatment with clozapine.

Topics: Adult; Antipsychotic Agents; Black People; Clozapine; Drug Interactions; Drug Monitoring; Drug Resistance; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Immunologic Factors; Leukocyte Count; Male; Neutropenia; Neutrophils; Polyethylene Glycols; Recombinant Proteins; Schizophrenia; Severity of Illness Index; Treatment Outcome; United Kingdom; Young Adult

The atypical antipsychotic clozapine is very effective for treatment of schizophrenia, but it causes agranulocytosis requiring drug cessation in up to 2% of cases. There has been some success rechallenging with clozapine at a later date or giving granulocyte colony stimulating factor or lithium while continuing clozapine. However, there are still some patients for whom these strategies do not work yet who cannot be controlled on other medications. This paper proposes that for such individuals, cerebroventricular administration of clozapine via Ommaya catheters could allow continued use of clozapine therapy. Direct infusion into cerebrospinal fluid means far smaller amounts of drug would be needed for efficacy, and clozapine concentrates in the central nervous system where it would not be exposed to bone marrow stem cells to cause agranulocytosis. This treatment paradigm would also provide a means for court-ordered clozapine therapy and a possible delivery system for future therapeutics based on trophic factors such as brain-derived neurotrophic factor.

Topics: Animals; Antipsychotic Agents; Clozapine; Humans; Infusions, Intraventricular; Models, Biological; Neutropenia; Schizophrenia

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 the treatment of choice in refractory schizophrenia. Its more extensive use is limited by adverse effects and the need for regular blood monitoring. However, black patients are disadvantaged with respect to clozapine usage. Lower baseline Absolute Neutrophil Count compared with Whites leads to a greater frequency of blood testing, treatment interruptions and discontinuation. This may in part be explained by Benign Ethnic Neutropenia, but too few black patients are thus registered. The four cases described in this report underline some of the difficulties if this problem is under-recognized. Moreover, in our sample of 191 clozapine recipients in an inner London hospital, black patients account for approximately half, but only a small proportion, 8/95 (8.4%) are registered as having Benign Ethnic Neutropenia. None of the Benign Ethnic Neutropenia-registered patients discontinued treatment for haematological reasons. To optimize clozapine treatment and improve long-term outcomes, a significantly greater proportion of Black patients should be registered as having Benign Ethnic Neutropenia.

Topics: Adult; Black People; Clozapine; Female; Humans; London; Male; Middle Aged; Neutropenia; Registries

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

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

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

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Male; Neutropenia; Psychotic Disorders

Topics: Antipsychotic Agents; Clozapine; Humans; Male; Middle Aged; Neutropenia; Psychotic Disorders; Time Factors

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

Clozapine is known to induce neutropenia as well as agranulocytosis. Some cases of olanzapine- and risperidone-induced neutropenia and agranulocytosis have also been reported. We prospectively investigated schizophrenia patients treated with second generation antipsychotics with respect to alterations of white blood cell counts.. In an analysis of our drug monitoring program, we studied white blood cell counts in 104 patients receiving different second generation antipsychotics other than clozapine for at least six months and compared them with those of 28 patients receiving clozapine.. We found neutropenia (neutrophils <2 000/microL) in the mixed group in 17.6% and in 11.8% of patients treated with clozapine during the first 6 months. There was no statistically significant difference between those groups with respect to the risk to develop neutropenia during the investigation period. There was no case of agranulocytosis. Neutropenia was transient in all patients. Eosinophilia occurred in some patients that developed neutropenia later on but had no significant predictive value.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Monitoring; Eosinophilia; Female; Humans; Incidence; Leukocyte Count; Male; Neutropenia; Prospective Studies; Time Factors

Topics: Antipsychotic Agents; Clozapine; Humans; Male; Middle Aged; Neutropenia; Retreatment; Schizophrenia; Treatment Outcome

Topics: Adolescent; Clozapine; Humans; Male; Neutropenia; Psychotic Disorders

Topics: Black or African American; Clozapine; Humans; Lithium; Male; Neutropenia; Time Factors; Treatment Outcome

Topics: Adult; Africa, Western; Antipsychotic Agents; Black or African American; Clozapine; Dose-Response Relationship, Drug; Emigrants and Immigrants; Granulocytes; Humans; Leukocyte Count; Lithium Carbonate; Male; Neutropenia; Neutrophils; Schizophrenia, Paranoid; United States

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Synergism; Humans; Lithium Carbonate; Male; Neutropenia; Schizophrenia; Treatment Outcome

Topics: Antimanic Agents; Antipsychotic Agents; Aripiprazole; Child; Clozapine; Female; Humans; Lithium Carbonate; Neutropenia; Piperazines; Quinolones; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Drug Resistance; Drug Therapy, Combination; Humans; Male; Middle Aged; Neutropenia; Recurrence; Risperidone; Schizophrenia, Paranoid; Severity of Illness Index

Topics: Adolescent; Antipsychotic Agents; Clozapine; Ethnicity; Humans; Neutropenia; Schizophrenia, Paranoid

Treatment resistance in early onset schizophrenia (EOS) is one of the most challenging problems in child and adolescent psychiatry. We retrospectively examined the therapeutic dosage, clinical response, and side effect profiles of long-term clozapine treatment in Korean children and adolescents with refractory EOS or very early onset schizophrenia (VEOS).. 26 refractory patients treated with clozapine for more than 1 year were analyzed. Efficacy was determined by comparing hospitalization rate and duration, before and after clozapine treatment. Tolerability was assessed through review of documented adverse events.. A significant reduction in hospital days per year was observed in 25 (96.2%) patients after clozapine treatment compared to before clozapine. Long-term benefit of the treatment was supported by a further reduction of the hospitalization rate in 14 patients treated with clozapine for more than 3 years. Neutropenia developed in 26.9% patients at 1 year and there was no agranulocytosis. Overall, eight male patients (8/12, 66.7%) and one female patient (1/14, 7%) developed neutropenia and out of the nine patients, seven patients were maintained and two patients were successfully rechallenged on clozapine.. These findings suggest that long-term clozapine treatment may effectively reduce the amount of time Asian patients with refractory EOS or VEOS spend in the hospital. However careful monitoring of adverse events is required.

Topics: Adolescent; Age of Onset; Antipsychotic Agents; Asian People; Clozapine; Dose-Response Relationship, Drug; Drug Resistance; Female; Hospitalization; Humans; Korea; Length of Stay; Male; Neutropenia; Psychiatric Status Rating Scales; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Time Factors; Treatment Outcome

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

Topics: Antipsychotic Agents; Clozapine; Diphenhydramine; Humans; Hypnotics and Sedatives; Leukopenia; Male; Middle Aged; Neutropenia; Schizophrenia, Paranoid

Topics: Antipsychotic Agents; Chemotherapy, Adjuvant; Clozapine; Drug Administration Schedule; Humans; Neutropenia; Psychotic Disorders; Risk Factors; Valproic Acid

To document and measure various parameters and outcomes in patients prescribed clozapine in a forensic psychiatric setting.. A retrospective file review was conducted on patients prescribed clozapine. Parameters and outcomes were recorded and compared against a group prescribed other antipsychotics, matched for sex and diagnosis.. Patients prescribed clozapine had higher rates of substance misuse syndromes and comorbidity when compared to patients prescribed other antipsychotics. Clozapine was found to be effective in treatment of psychosis. High rates of adverse effects were noted. Discontinuation of clozapine for a variety of reasons was common.. Patients identified as treatment resistant who are prescribed clozapine are often more complex in the pattern of illness and subsequent needs. Clozapine is effective in the treatment of psychosis in this forensic service. Its benefits need to be balanced against the potential for adverse effects and problems ensuring adherence. Regular, objective monitoring of clinical and adverse effects would aid patient safety, clinical decision-making and future research.

Topics: Adult; Antipsychotic Agents; Clozapine; Crime; Diagnosis, Dual (Psychiatry); Drug Monitoring; Drug Resistance; Forensic Psychiatry; Health Status; Hospitals; Humans; Incidence; Male; Middle Aged; Neutropenia; New South Wales; Patient Dropouts; Prisoners; Psychotic Disorders; Retrospective Studies; Risk Factors; Schizophrenia; Schizophrenic Psychology; Seizures; Substance-Related Disorders

The aim of the present paper was to examine the concept of benign ethnic neutropenia and to consider the implications of ethnicity in the current clozapine regulatory system.. The case of a young Palestinian man who lost access to clozapine due to a fall in his neutrophil count, is presented herein, and a brief review of ethnic variations in neutrophil levels is given.. This patient's clozapine was ceased, with unfortunate consequences, despite his having normal immune function.. By using normative haematological data established in white populations, the Australian clozapine regulatory system places some non-white patients at a considerable disadvantage.

Topics: Adult; Antimanic Agents; Antipsychotic Agents; Arabs; Australia; Clozapine; Genetic Predisposition to Disease; Humans; Leukocyte Count; Lithium Compounds; Male; Neutropenia; Neutrophils; Psychotic Disorders; Withholding Treatment

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Cell Count; Clozapine; Electroconvulsive Therapy; Female; Humans; Leukocyte Count; Neutropenia; Olanzapine; Patient Compliance; Recurrence; Schizophrenia, Paranoid

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Humans; Male; Neutropenia; Olanzapine; Schizophrenia

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Drug Therapy, Combination; Female; Humans; Neutropenia; Olanzapine; Schizophrenia

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

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Delayed-Action Preparations; Female; Humans; Leukopenia; Middle Aged; Neutropenia; Olanzapine; Schizophrenia

Topics: Age Factors; Antipsychotic Agents; Child; Clozapine; Haloperidol; Humans; Neutropenia; Randomized Controlled Trials as Topic; Schizophrenia; Sleep Stages; Treatment Outcome

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

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Granulocyte Colony-Stimulating Factor; Humans; Injections, Intramuscular; Male; Neutropenia; Schizophrenia, Paranoid; Time Factors

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: Adult; Chronotherapy; Clozapine; Humans; Male; Neutropenia; Schizophrenia, Paranoid

Topics: Adult; Circadian Rhythm; Clozapine; Female; Humans; Neutropenia

Further treatment with clozapine is contraindicated in any patient who has previously experienced leucopenia or neutropenia during clozapine therapy.. To investigate the results of such a rechallenge in 53 patients.. An analysis was made of the demographic, haematological and outcome data of patients in the UK and Ireland who were rechallenged with clozapine following leucopenia or neutropenia during previous clozapine therapy.. Of 53 patients who were rechallenged, 20 (38%) experienced a further blood dyscrasia. In 17 of these 20 patients (85%) the second blood dyscrasia was more severe (P<0.001), in 12 (60%) it lasted longer (P=0.0368) and in 17 (85%) it occurred more quickly on rechallenge (P<0.001). Of the original 53 patients, 55% (29 patients) are still receiving clozapine.. No clear risk factor for repeat blood dyscrasias was identified. Despite this, after risks and benefits have been considered, rechallenge may well be justified in some patients.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Administration Schedule; Female; Humans; Leukopenia; Male; Middle Aged; Neutropenia; Recurrence; Risk Assessment; Schizophrenia; Time Factors

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

Topics: Antipsychotic Agents; Clozapine; Humans; Neutropenia; Schizophrenia; Withholding Treatment

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: Antipsychotic Agents; Clozapine; Humans; Leukopenia; Neutropenia; Schizophrenia

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

Topics: Clozapine; Female; Humans; Middle Aged; Neutropenia; Time Factors

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

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

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

According to the recommended guidelines by Novartis, neutropenia in the range of a white blood cell count less than 3000 per mm, or an absolute neutrophil count (ANC) less than 1500 per mm, is classified as being in the 'red-alert zone' during clozapine treatment. If a patient's blood test result falls into this zone, immediate discontinuation of clozapine is recommended, and reinstitution is prohibited. However, in some patients, it is not entirely feasible to implement this standard guideline because of the lack of effective alternatives to clozapine treatment. Through retrospective chart reviews, five patients who had been maintained on clozapine treatment despite red-alert zone neutropenia were selected. The haematological and clinical courses of these patients were followed for more than 600 days and were compared with those of two control patients who discontinued clozapine due to neutropenia. In all five patients, no additional episodes of neutropenia occurred during the observation period despite continued clozapine treatment. However, three of them maintained a lower neutrophil count for the remaining observation period. Four patients responded favourably to clozapine treatment as judged by Clinical Global Impression score. Given the limitations of a retrospective chart review and the small number of patients, we cannot draw any definite conclusions. However, while the guidelines for the prevention of agranulocytosis should be generally followed, it may be that judicious continuation of clozapine treatment is less risk-prone than previously considered in selected cases where only a few feasible alternatives to clozapine are available. Moreover, there is an apparent necessity to develop new measures or methods that can differentiate between benign neutropenia and that leading to fatal agranulocytosis.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Neutropenia; Retrospective Studies; Schizophrenia

Topics: Adult; Antipsychotic Agents; Circadian Rhythm; Clozapine; Drug Administration Schedule; Drug Monitoring; Follow-Up Studies; Humans; Leukocyte Count; Male; Neutropenia; Schizophrenia, Paranoid; Treatment Outcome

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Male; Neutropenia; Schizophrenia, Paranoid

Olanzapine is an atypical antipsychotic with a low incidence of extrapyramidal-motoric side effects. Its chemical structure is related to clozapine, which is known to induce neutropenia in up to 3% and agranulocytosis in approximately 1% of patients. It has been discussed controversially whether olanzapine also has a potential to induce neutropenia and agranulocytosis. Up to now, seven case reports of haematopoetic disturbances during olanzapine treatment have been published, including one case of olanzapine-induced agranulocytosis (Naumann et al. 1999), two cases of neutropenia (Steinwachs et al. 1999) and one leucopenia (Meissner et al. 1999). We report three subjects with reversible neutropenia under olanzapine, with rapid normalisation of neutrophil cell counts after discontinuation of olanzapine. In one case neutropenia occurred after administration of a single dose of olanzapine, in another case after 6 weeks of treatment. In both cases, patients had no clinical complications. In the third case, neutropenia appeared after 1.5 years of treatment followed by development of pneumonia. Two cases were recorded within the German drug surveillance project (AMSP); the third case was observed in a randomised, double-blind, multicentre study comparing olanzapine with clozapine.

Topics: Adult; Aged; Antipsychotic Agents; Atrophy; Benzodiazepines; Clozapine; Female; Frontal Lobe; Humans; Neutropenia; Olanzapine; Parietal Lobe; Schizophrenia

Clozapine, an atypical antipsychotic drug, is associated with a high risk of neutropenia and agranulocytosis, necessitating the immediate discontinuation of the drug. We report the case of a patient who developed clozapine-induced neutropenia. Assessments revealed a pronounced diurnal variation in the number of circulating neutrophils (1200-1900/mm(3) in the morning and 2200-2700/mm(3) in the afternoon). Due to these circadian changes, we decided to continue clozapine treatment.

Topics: Adult; Antipsychotic Agents; Circadian Rhythm; Clozapine; Humans; Male; Neutropenia; Schizophrenia, Paranoid

Clozapine, an atypical antipsychotic, is the most effective medication for treatment-resistant schizophrenia, but its use is limited by the high risk of neutropenia and agranulocytosis. In children, the rate of clozapine-induced neutropenia is even higher than in adults. We report two cases of children 7- and 12-years old diagnosed with very early onset schizophrenia, who developed neutropenia when treated with clozapine. In both cases addition of lithium carbonate elevated the white blood count (WBC) allowing clozapine rechallenge. WBC and total neutrophil count remained stable long-term with coadministration of clozapine (400-425 mg per day) and lithium with the blood level of 0.8-1.1 microg/mL. This report supports the use of adjunct lithium for clozapine-induced neutropenia as a safe and successful strategy in children.

Topics: Antipsychotic Agents; Child; Clozapine; Drug Therapy, Combination; Humans; Leukocyte Count; Lithium Carbonate; Male; Neutropenia; Schizophrenia, Childhood

Topics: Anti-Infective Agents; Bipolar Disorder; Chronic Disease; Clozapine; Drug Synergism; Female; Humans; Middle Aged; Neutropenia; Panic Disorder; Selective Serotonin Reuptake Inhibitors; Thrombocytopenia; Trimethoprim, Sulfamethoxazole Drug Combination

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

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

Topics: Adult; Clozapine; Humans; Leukocyte Count; Male; Neutropenia; Neutrophils; Schizophrenia, Paranoid

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

Topics: Adolescent; Aged; Anti-Inflammatory Agents; Antipsychotic Agents; Clozapine; Diagnosis, Differential; Female; Humans; Hydrocortisone; Injections, Intravenous; Leukocyte Count; Leukocytes; Male; Middle Aged; Neutropenia; Neutrophils

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: Adolescent; Antipsychotic Agents; Clozapine; Drug Interactions; Erythromycin; Fever; Humans; Male; Neutropenia; Pharyngitis; Schizophrenia

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

We report a 2-year experience with olanzapine treatment (20 mg daily) in a 65-year-old male patient with treatment-resistant paranoid schizophrenia, who had previously developed leucopenia and neutropenia first on clozapine and, subsequently, also on risperidone. Olanzapine seems to be safe in this patient, since no major decreases of haematological parameters were observed. The only exception was a brief decrease of leucocyte and neutrophil (but not erythrocyte or platelet) counts during influenza-like viral infection. However, the control of psychotic symptoms on olanzapine is not as good as on clozapine.

Topics: Aged; Antipsychotic Agents; Benzodiazepines; Clozapine; Drug Monitoring; Humans; Leukopenia; Male; Neutropenia; Olanzapine; Pirenzepine; Risk Factors; Risperidone; Schizophrenia, Paranoid

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: Antipsychotic Agents; Benzodiazepines; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Leukocyte Count; Male; Middle Aged; Neutropenia; Olanzapine; Pirenzepine; Psychotic Disorders; Schizophrenia; Time Factors

The atypical antipsychotic clozapine is effective in the treatment of patients with refractory schizophrenia. It carries a well-known risk of neutropenia and agranulocytosis, which necessitates the immediate discontinuation of clozapine.. We report a patient who developed neutropenia on clozapine, but behind the cell count decrease showed to be a diurnal variation of the white blood cells (WBC).. Due to the lack of efficacy of subsequent treatment of conventional and other atypical neuroleptics, treatment with clozapine was restarted after discontinuation. When the morning count of WBC began to fall, WBC count was repeated in the afternoons.. Careful blood cell monitoring showed a pronounced diurnal variation of WBC (2.9-4.2x10(9)/l in the morning and 3.6-7.1x10(9)/l in the afternoon) and granulocytes (0.8-1.4x10(9)/l and 2.9-5.5x10(9)/l, respectively).. Some patients may thus have a spuriously low cell count and may be unnecessarily denied effective treatment.

Topics: Adult; Antipsychotic Agents; Cell Count; Circadian Rhythm; Clozapine; Humans; Leukocytes; Male; Neutropenia; Schizophrenia

Olanzapine is a new antipsychotic drug, pharmacodynamically similar to clozapine, but putatively devoid of haematological iatrogenicity. We report a case of relapse of previously clozapine-induced neutropenia after olanzapine treatment.

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

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

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Humans; Lithium Carbonate; Male; Neutropenia; Schizophrenia

A 17-year-old boy suffering from a severe schizophrenic disorder of the paranoid type and mental retardation did not respond to treatment with typical antipsychotics, whereas under clozapine treatment he showed a favourable response. Discontinuation of clozapine led to an acute psychotic relapse. During clozapine treatment the patient developed severe neutropenia.. Due to the history of unsatisfactory response to traditional antipsychotics, clozapine treatment was continued despite white blood cell (WBC) decline. Concomitant treatment with G-CSF was followed by a rapid normalisation of WBC.. This case report is not intended to challenge the clinical practice of discontinuing clozapine upon the development of neutropenia/agranulocytosis, but rather to stimulate further research in the pathophysiology and clinical consequences of a clozapine rechallenge after a WBC decline, especially in patients with a rather complex symptomatology where no sufficient therapeutic results can be achieved with any other pharmacological intervention than clozapine.

Topics: Adolescent; Antipsychotic Agents; Clozapine; Granulocyte Colony-Stimulating Factor; Humans; Intellectual Disability; Male; Neutropenia; Schizophrenia, Paranoid

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Administration Schedule; Drug Hypersensitivity; Eosinophilia; Female; Humans; Neutropenia; Schizophrenia, Paranoid

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

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; Anti-HIV Agents; Antipsychotic Agents; Clozapine; Drug Interactions; Drug Therapy, Combination; HIV Infections; Humans; Lamivudine; Male; Neutropenia; Psychotic Disorders; Zidovudine

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

Both diarrhea and colitis associated with clozapine have been reported. We present a case of clozapine-associated neutropenia complicated by cytomegalovirus colitis. The definitive diagnosis was suggested on biopsy which showed eosinophilic intranuclear inclusions suggestive of cytomegalovirus infection, and confirmed on immunohistochemistry. Neutropenia or agranulocytosis in association with clozapine treatment may be complicated by colitis. In such cases, investigations for cytomegalovirus may be indicated.

Topics: Adult; Antipsychotic Agents; Clozapine; Colitis; Cytomegalovirus Infections; Female; Humans; Neutropenia

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: Adult; Chronic Disease; Clozapine; Eosinophilia; Eosinophils; Humans; Leukocyte Count; Male; Neutropenia; Schizophrenia

A 40-year-old chronic schizophrenic patient whose psychosis and associated violent behaviour resolved on clozapine, required chemotherapy for a testicular teratoma with pulmonary metastases. His treatment was initially delayed due to refusal to consent.. The patient finally agreed to orchidectomy and cytotoxic therapy, and following agreement by the CPMS, clozapine continued to be dispensed despite neutropenia and 'red alert' status on full blood count.. This is the only patient to continue clozapine despite 'red alert' status, and as such is an exceptional case, but may open the way for such patients in the future.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Antipsychotic Agents; Chemotherapy, Adjuvant; Clozapine; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Male; Neutropenia; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Teratoma; Testicular Neoplasms; Treatment Refusal; Violence

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

Topics: Adult; Clozapine; Drug Therapy, Combination; Humans; Leukopenia; Lithium Carbonate; Male; Neutropenia; Schizophrenia

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

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: Aged; Aged, 80 and over; Clozapine; Dementia; Drug Synergism; Drug Therapy, Combination; Female; Glaucoma; Humans; Leukocyte Count; Methazolamide; Neutropenia; Parkinson Disease

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: Clozapine; Humans; Neutropenia; Predictive Value of Tests; Quality of Life; Risk Factors; Schizophrenia; Schizophrenic Psychology

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

Topics: Adult; Clozapine; Humans; Leukocyte Count; Male; Neutropenia; Schizophrenia, Paranoid

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

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

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

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

Blood dyscrasias are frequently reported to be induced by the atypical antipsychotic clozapine. Next to agranulocytosis, a potentially lethal form of these side effects, hematologic disturbances include leucocytosis, eosinophilia, and neutropenia. Neutropenia is of considerable clinical relevance because it can be a sign of incipient agranulocytosis. In an analysis of our clozapine drug monitoring program, we have analyzed the data from 68 patients receiving clozapine for the first time. Neutrophil granulocytes dropped to 290 and 660/mm3 in 2 patients, both recovered after the discontinuation of clozapine. Another patient with a granulocyte count of 1800/mm3 was stopped because regular white blood cell monitoring was not possible. Eight additional patients demonstrated a transient decrease of granulocytes during ongoing clozapine administration. This amounts to a cumulative incidence of transient neutropenia of 22 percent (95% confidence interval 7.5%-36.5%).

Topics: Adult; Clozapine; Female; Humans; Male; Neutropenia

An incidence of drug-induced neutropenia of 2.5% has been found in the first 1000 patients to be treated with clozapine in the UK. The majority of affected patients experienced mild neutropenia (n = 22) with only 3 patients developing agranulocytosis. Data collected from these 25 patients suggest that the mechanism of neutropenia may be multifactorial. Laboratory investigation using liquid culture systems and immunofluorocytometry has identified clozapine and its major metabolite N-desmethyl clozapine as exhibiting toxic effects against myeloid maturation and myeloid mitotic compartments, respectively. Increased susceptibility to the toxic effects of clozapine was shown in 1 patient who had previously developed clozapine-associated neutropenia. No clinical or laboratory evidence of drug-induced antineutrophil or antimyeloid precursor antibodies was found.

Topics: Bone Marrow; Bone Marrow Cells; Cells, Cultured; Cellular Senescence; Clozapine; Fluorescent Antibody Technique; Humans; Immunoglobulin A; Immunoglobulin M; Incidence; Mitosis; Neutropenia; Neutrophils; Retrospective Studies; United Kingdom

Topics: Adult; Clozapine; Female; Humans; Neutropenia

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