clozapine and Leukopenia

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

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

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

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

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

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

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

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

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

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

Topics: Anemia; Antipsychotic Agents; Clozapine; Humans; Leukopenia

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

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

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

Clozapine is an antipsychotic with clozapine-induced agranulocytosis (CIA) as a rare, but potentially life-threatening side-effect, for which the white blood cell count and absolute neutrophil count are routinely monitored. Observed leukopenia may lead to more frequent monitoring, or even acute discontinuation of clozapine treatment. COVID-19 may cause deviating blood parameters such as leukopenia, and more exceptionally even granulocytopenia, just as clozapine does. In case of a SARS-CoV-2 infection and leukopenia, it is important to differentiate whether the reduced white blood cell count is caused by clozapine - in which case it needs to be stopped immediately - or as a consequence of infection with the coronavirus. In case of a mild leukopenia, based on a lymphopenia, clozapine can be safely continued with more frequent blood monitoring. Additionally, the dosage of clozapine should be reduced by half, due to the risk of a sudden increase of clozapine serum levels.

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

The clozapine-derivative quetiapine has been shown in some cases to cause leukopenia and neutropenia.. We reported on a case of a young female diagnosed with treatment-resistant schizophrenia. After failed trials of three antipsychotic medications and despite a history of quetiapineinduced leukopenia, clozapine treatment was introduced due to the severity of the patient's symptoms, the limited effective treatment options, and a lack of guidelines on this issue.. Over a ten-week period of clozapine treatment at 700 mg per day, the patient developed agranulocytosis. Her white blood cell count sharply dropped to 1.6 × 10. The safety of clozapine in a patient who has previously experienced leukopenia and neutropenia with quetiapine requires further investigation. Increased attention should be paid to such cases. Careful monitoring and slow titration are advisable.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Humans; Leukopenia; Quetiapine Fumarate; Schizophrenia; Treatment Outcome

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

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

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

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

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

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

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

Clozapine has shown superior efficacy over other antipsychotics. However, its use is complicated by the development of life-threatening hematologic adverse effects.. This paper reports the incidence of clozapine-induced hematologic toxicity in Saudi Arab patients.. King Khalid University Hospital, Riyadh, Saudi Arabia.. Medical data of Saudi Arab hospitalized patients receiving clozapine was retrospectively reviewed during the period between August 2009 and August 2012. White blood cell (WBC) counts and differentials were recorded in a specific form to watch for any hematologic toxicity. The hematologic toxicities included in this report are: eosinophilia, thrombocytopenia, lymphocytopenia, and agranulocytosis/neutropenia/leukopenia combined.. Complete WBC count.. During the study period 147 charts were reviewed. The mean age of patients was 38 ± 11.42 years and 52 % were males. During the study period 61 patients (42 %) developed 82 blood dyscrasias. Sixteen patients (10.9 %) developed agranulocytosis, neutropenia and leukopenia combined, while nineteen patients (12.9 %) developed lymphocytopenia, and seven patients (4.8 %) developed thrombocytopenia. Eosinophilia developed in 40 patients (27.2 %). During the first 18 weeks of therapy with clozapine, 21 (26 %) hematologic side effects were developed.. The data collected in this study does appear to indicate there may be an increased incidence of blood dyscrasias in Saudi Arabs which warrants further, more detailed, study. It would be of concern to psychiatric clinicians if the case of a genetic predisposition to clozapine-induced blood dyscrasias were proven in the future.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Monitoring; Drug Therapy, Combination; Eosinophilia; Female; Hospitals, University; Humans; Incidence; Leukocyte Count; Leukopenia; Male; Medical Records; Middle Aged; Platelet Count; Retrospective Studies; Saudi Arabia; Severity of Illness Index; Thrombocytopenia

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

Clozapine has been reported to cause agranulocytosis, neutropenia, and leucopenia that usually occur within 18 weeks of initiation of treatment. We report a case of delayed onset leucopenia after 11 years of treatment with clozapine, which reversed within a few days after discontinuation of medication.

Topics: Antipsychotic Agents; Clozapine; Humans; Leukopenia; Male; Middle Aged; Schizophrenia; Time Factors

A patient with a 28-year history of schizophrenia was treated with a wide range of antipsychotic medications since diagnosis. She had experienced no clinically significant symptomatic relief until she commenced treatment on clozapine. Her psychotic symptoms, self care, and general sense of well-being improved significantly. After 6 years of successful treatment, she developed leukopenia and clozapine was discontinued. The following issues will be discussed in the article: rechallenge with clozapine following leukopenia during previous therapy and the choice of and haematological monitoring needs with other antipsychotic medications after clozapine-induced blood dyscrasia.

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

Topics: Antipsychotic Agents; Clozapine; Female; Humans; Leukopenia

A clinical file review was conducted of clozapine use in three aged psychiatry services in Melbourne, Australia, to compare its safety and tolerability with findings reported in the literature.. The review period spanned the intervals from 2008 to the services' origins between 11 and 15 years earlier. The files of all patients treated with clozapine during this period were checked with respect to adverse effects and the reasons for ceasing treatment.. Clozapine was prescribed to 75 patients (mean age 74.2 years, range 65-89) with doses ranging from 25-800 mg daily (mean 296 mg). Treatment was stopped within the review period in 37 (49%) cases. Reasons for discontinuation included death (n=14), non-fatal adverse events (n=12), patient choice (n=8) and other factors (n=3). While none of the 14 deaths could be linked directly to treatment, orthostatic hypotension might have contributed to a single fatal cerebrovascular accident. There were three cases of "red alert" leukopenia, none of which progressed to agranulocytosis. In general, side effects were more frequent than in a previous report concerning aged patients, most probably because clozapine doses were higher. CONCLUSIONS; Most of the adverse events leading to treatment cessation occurred within the first month, emphasising the need for slow titration. Strict monitoring procedures ensured that there were no fatal haematological adverse events.

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Australia; Clozapine; Female; Geriatric Assessment; Humans; Leukopenia; Male; Patient Satisfaction; Retrospective Studies; Survival Analysis

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

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

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

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

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

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

A case of clozapine-induced leukopenia successfully treated with lithium is reported.. A 55-year-old man with paranoid schizophrenia who had been stable on clozapine for more than 10 years was admitted to an inpatient behavioral health unit with leukopenia associated with clozapine use. This patient's history was significant for four previous hospitalizations for psychiatric issues, none of which occurred while he was using clozapine. On admission, the patient's clozapine was discontinued and he was started on olanzapine. On hospital day 4, his white blood cell (WBC) count had risen to 3400/mm(3) and clozapine was resumed due to increasing auditory hallucinations and suicidal ideation. On hospital day 5, his WBC count decreased to 2900/mm(3) and clozapine was again stopped. The patient was given lithium carbonate 300 mg at bedtime, and olanzapine was discontinued. The next day, clozapine was restarted at 12.5 mg daily at bedtime. On hospital day 11, his WBC count had risen to 5400/mm(3). The patient was discharged on clozapine 25 mg at bedtime, with a WBC count of 3400/mm(3). The patient has not been rehospitalized and has not had significant changes in his WBC count or absolute neutrophil count (ANC) for more than 14 months.. A 55-year-old man with schizophrenia developed clozapine- induced leukopenia after more than 10 years of treatment. Lithium was used to stimulate leukocyte production, and clozapine was restarted successfully. The patient was maintained on clozapine and lithium without significant changes in his WBC count or ANC.

Topics: Antimanic Agents; Antipsychotic Agents; Clozapine; Humans; Leukopenia; Lithium Carbonate; Male; Middle Aged; Schizophrenia

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

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

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

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

Clozapine is a well-known antipsychotic to cause fatal agranulocytosis but there are only a few case reports about the risk of leukopenia and agranulocytosis associated with other atypical antipsychotics. Olanzapine has structural pharmacological similarities to those of clozapine and reports about haematological adverse effects of olanzapine include three groups: the first group includes cases of olanzapine-induced neutropenia, the second informing that olanzapine is safe after clozapine induced agranulocytosis and the third group forms prolongation of clozapine-induced leukopenia with olanzapine use. The aim of this paper is to report a case of prolongation of clozapine-induced leukopenia despite olanzapine treatment and discuss leukopenia caused by atypical antipsychotic use in the light of recent and limited literature.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Chronic Disease; Clozapine; Humans; Leukopenia; Male; Olanzapine; Schizophrenia

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

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

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

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

Topics: Adult; Anti-Obesity Agents; Antipsychotic Agents; Bipolar Disorder; Clozapine; Drug Interactions; Drug Therapy, Combination; Fructose; Humans; Leukopenia; Male; Topiramate; United Kingdom; Weight Gain

The combination of clozapine and other potentially leukopenic drugs may pose a greater risk for neutropenia. However, neutropenia may not always be due to clozapine. When adding potentially leukopenic drugs, clinicians should look for possible alternatives especially as clozapine is often a drug used as the last resort in treatment refractory schizophrenia.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Clozapine; Drug Resistance; Female; Humans; Leukocyte Count; Leukopenia; Lithium Carbonate; Male; Middle Aged; Valproic Acid

Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Clozapine; Drug Therapy, Combination; Female; Hodgkin Disease; Humans; Leukopenia; Remission Induction; Risperidone; Treatment Outcome; Valproic Acid

Olanzapine is an atypical antipsychotic medication frequently used in the management of psychotic states. While it has proved to be safe compared to clozapine with regard to haematotoxicity, because it has only been available for a few years, full documentation of its haematological side-effects remains incomplete. We report a case of olanzapine-induced leukopenia with associated neutropenia. Since clozapine-induced haematotoxicity has been associated with characteristic human leukocyte antigen (HLA) groups, HLA typing was determined in this patient. Following failure with typical antipsychotic medication, the patient received 10 mg/day of olanzapine. Three weeks later, he developed fever and a significant decrease in leukocyte count. Olanzapine was immediately discontinued. HLA typing was determined. The white cell count returned to normal and the fever, most probably secondary to the low white cell count, subsided with antibiotic treatment. HLA typing results were: A1 24, B7, B35, DRB1*15, DRB1*11, DRB3*01-03, DRB5*01-02. Olanzapine may induce serious leukopenia and neutropenia. HLA typing in this single patient demonstrated a distinct haplotype compared to that previously observed in clozapine-induced haematoxicity.

Topics: Clozapine; Haplotypes; Histocompatibility Testing; Humans; Leukocyte Count; Leukopenia; Male; Middle Aged; Risk Factors; Schizophrenia

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

Four patients affected by severe Parkinson's disease developed leucopenia (900-1200 WBC) during treatment of psychosis (3) or untreatable insomnia (1) with clozapine (37.5-75 mg/day). Clozapine withdrawal was followed by recovery of leucopenia (4000-6000 WBC) in two weeks with no need for the administration of leucokines. After 1-6 months olanzapine was administered (increasing the dose from 2.5 to 10 mg/day) to treat persisting disturbances, but the drug induced severe worsening of parkinsonism and also this drug had to be withdrawn.

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Benzodiazepines; Clozapine; Dose-Response Relationship, Drug; Female; Hallucinations; Humans; Leukopenia; Male; Olanzapine; Parkinson Disease; Pirenzepine; Psychotic Disorders; Sexual Dysfunctions, Psychological; Sleep Initiation and Maintenance Disorders

Topics: Adult; Clozapine; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Leukopenia; Middle Aged; Paroxetine; Psychotic Disorders

Topics: Africa; Antipsychotic Agents; Black People; Clozapine; Contraindications; Humans; Leukopenia; Schizophrenia; West Indies

This study was done to test the hypothesis that serum concentration of norclozapine is a risk factor for leukopenia during treatment with clozapine.. Maximum decreases in leukocyte counts in 44 unselected patients treated with clozapine were determined and then correlated with drug doses and serum concentrations of clozapine, norclozapine, and clozapine-N-oxide.. White cell and granulocyte counts decreased by up to 60%-73%, but there were no positive correlations between these decrements and drug dose, drug level, ratio of drug level to drug dose, or ratio of norclozapine level to clozapine level, nor were the decreases related to age or gender.. While these results do not suggest in vivo hemotoxicity of norclozapine, further study of patients with clinically significant leukopenia is required.

Topics: Clozapine; Female; Follow-Up Studies; Humans; Leukocyte Count; Leukopenia; Male; Middle Aged; Psychotic Disorders; Risk Factors

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

This pharmaco-epidemiologic study was undertaken to determine if the combination of clozapine and valproate poses an increased risk of blood dyscrasias, liver function abnormalities, or other side effects and to develop dosing guidelines when the combination is utilized.. The charts of 55 patients receiving clozapine and valproate concurrently between May 8, 1989, and May 8, 1992, were reviewed to determine the indication for and length of time on each medication, abnormalities in liver function test results, blood cell dyscrasias, seizures, nausea, vomiting, sedation, sialorrhea, and enuresis. In addition, the efficacy of the combination was measured.. The combination of clozapine and valproate was efficacious and well tolerated in the majority of patients. Major adverse effects such as blood dyscrasias or seizures were not experienced by the study population. The side effect that led to discontinuation of the combination most frequently was sedation.. The combination of clozapine and valproate is safe and efficacious.

Topics: Adult; Clozapine; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Incidence; Leukopenia; Liver; Liver Function Tests; Male; Middle Aged; Psychotic Disorders; Seizures; Sleep; Treatment Outcome; Valproic Acid

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

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

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

The main side effects of 7921 hospitalized patients taken clozapine from July in 1980 to October in 1988 were investigated. In these cases, there were 600 patients with the main side effects caused by clozapine. They included 312 patients with leukocytosis (52.0%), 114 patients with leukopenia (19.0%), (included 16 patients with agranulocytosis), 53 patients with EEG abnormal (8.9%), 35 patients with fever (5.9%), 32 patients with EKG abnormal (5.3%), 14 patients with rash (2.3%), 12 patients with epileptic seizure (2.0%), 11 patients with posture hypotension (1.8%), 8 patients with paralytic intestinal obstruction (1.3%), 6 patients with SGPT raised (1.0%) and 3 patients with conscious disturbances (0.5%). The causes and treatments of the main side effects mentioned above were discussed.

Topics: Adolescent; Adult; Aged; Child; Clozapine; Electroencephalography; Epilepsy; Female; Humans; Intestinal Pseudo-Obstruction; Leukocytosis; Leukopenia; Male; Middle Aged

Topics: Clozapine; Humans; Leukopenia; Schizophrenia

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

A retrospective study was performed to evaluate the effect of long-term treatment with clozapine in 96 schizophrenic or schizoaffective patients hospitalized at the Psychiatric Research Center in Uppsala during the period 1974-1986. All patients had previously been treated with different neuroleptics but with inadequate response or distressing side effects. The mean duration of the disorder at the start of clozapine treatment was 8 years and 9 months and the mean duration of the treatment 3 years and 11 months. Clozapine treatment was discontinued in 36% of the patients, mainly due to lack of efficacy, poor compliance or temporary withdrawal of the drug from the market in 1975. In two patients the reason was leukopenia or agranulocytosis. In another 10 patients a transient decrement of WBC was seen, which was normalized during ongoing treatment. Four patients died when on clozapine during the follow-up period, but no causal relationship to the treatment could be established. Eighty-five per cent of the patients could be discharged from the hospital. Of the 62 patients who were still on clozapine after 2 years, 18% had full time and 21% half-time employment. A global evaluation of the clinical efficacy revealed a significant improvement in 43% and a moderate improvement in 38% of the patients compared to previous neuroleptic treatments. Common but usually mild side effects were sedation, hypersalivation, weight gain, and obstipation. Four patients had grand mal seizures. No extrapyramidal side effects were observed during clozapine treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Clozapine; Dibenzazepines; Employment; Female; Humans; Leukopenia; Male; Psychotic Disorders; Retrospective Studies; Schizophrenia; Sweden