clozapine and Hematologic-Diseases

Clozapine, an atypical antipsychotic with documented efficacy in the management of treatment-resistant schizophrenia, is associated with the risk of adverse hematological outcomes. Of particular concern are reductions in white blood cells (WBC) and absolute neutrophil counts (ANC). Individuals who display moderate leukopenia (3000/mm(3) > WBC ≥ 2000/mm) upon initiation of clozapine therapy are at increased risk of developing agranulocytosis, defined as an ANC less than 500/mm. Complications of agranulocytosis can be severe and include increased risk of infection and mortality.. The primary objective of this study was to examine data on clozapine recipients who experienced adverse drug reactions (ADRs) related to decreases in WBC or ANC and ascertain whether other drugs and/or drug interactions had played a role. The analysis included multiple classes of medications.. A retrospective chart review was performed of open and closed medical records of all inpatient recipients of clozapine at a state psychiatric center between January 1, 2004 and June 30, 2011. Laboratory records of patients prescribed clozapine were examined for abnormal WBC counts or ANC. A hematological ADR was considered to have occurred if there was a substantial drop in either WBC or ANC or mild or moderate leukopenia or granulocytopenia. Each episode was analyzed for medications that might have contributed to the ADR. Data were collected for all scheduled and STAT medications started at any point during the clozapine patient's hospitalization. The following seven medication groups, based on the Therapeutic Classification System of the American Hospital Formulary System (AHFS), were chosen for analysis because they were consistently used in the majority of the patient population: antihistamines, anti-infectives, autonomic agents, cardiovascular agents, antipsychotics, vitamins, and gastrointestinal agents. Pearson correlation coefficients were calculated to identify associations between the presence of hematological ADRs and medications administered concomitantly with clozapine.. The following significant correlation coefficients were found between the use of a class of medications and the occurrence of a hematological ADR: antiinfective agents 0.409 (p < 0.01), gastrointestinal agents 0.329 (p < 0.01), and autonomic agents 0.309 (p < 0.01). In the subset of patients who were prescribed a proton-pump inhibitor or ranitidine concomitantly with clozapine, 24/26 (96%) experienced a hematological ADR.. Autonomic agents, anti-infective agents, and proton pump inhibitors and other gastrointestinal agents were all associated with hematological ADRs when co-prescribed with clozapine. Medications from these classes should be initiated cautiously in patients being treated with clozapine to avoid precipitous drops in ANC or WBC that may increase the risk of agranulocytosis.

Topics: Antipsychotic Agents; Clozapine; Female; Hematologic Diseases; Humans; Male; Middle Aged; Polypharmacy; Schizophrenia

Clozapine is the most effective antipsychotic medication for treatment-refractory schizophrenia and is also approved for suicidality in schizophrenia patients. However, it can cause significant medical morbidity and requires intensive medical monitoring once prescribed. Perhaps due to lack of familiarity with its use, it is underused in clinical practice and its initiation often delayed. This article reviews the literature on clozapine in order to measure its potential effectiveness against its adverse effects and ultimately aims to serve as a useful summary for clinicians in their everyday prescribing.

Topics: Antipsychotic Agents; Clozapine; Drug Monitoring; Heart Diseases; Hematologic Diseases; Humans; Metabolic Diseases; Practice Guidelines as Topic; Practice Patterns, Physicians'; Quality of Life; Schizophrenia; Suicide Prevention; Venous Thromboembolism; Weight Gain

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

The extensive pharmacological evaluation of JL 13 as an atypical antipsychotic drug has revealed a close similarity to clozapine, however with some major advantages. JL 13 was characterized as a weak D(2) antagonist, both in vitro and in vivo, with a strong affinity for the D(4) and the 5-HT(2A) receptors. It has no affinity for the 5-HT(2C) receptor. In vivo microdialysis experiments in rat showed that JL 13, like clozapine, preferentially increased extracellular dopamine concentrations in the prefrontal cortex compared to nucleus accumbens or striatum. Behavioral studies showed that JL 13, like clozapine, has the profile of an atypical antipsychotic. Thus, JL 13 did not antagonize apomorphine-induced stereotypy nor did it produce catalepsy, but it antagonized apomorphine-induced climbing in rodents. It was inactive against d-amphetamine-induced stereotypy but antagonized d-amphetamine-induced hyperactivity in the mouse. Likewise, in the paw test, it was more effective in prolonging hindlimb retraction time than prolonging forelimb retraction time. Like other antipsychotic drugs, JL 13 reversed the apomorphine- and amphetamine-induced disruption of prepulse inhibition. In a complex temporal regulation schedule in the dog, JL 13 showed a high resemblance with clozapine without inducing sialorrhea, palpebral ptosis or any significant motor side effects. In rats and squirrel monkeys JL 13 induced a high degree of generalization (70%) to clozapine. Regarding behavioral toxicology, JL 13 did not produce dystonia or Parkinsonian symptoms in haloperidol-sensitized monkeys. After acute administration, again like clozapine, JL 13 induced only a transient increase in circulating prolactin. Last but not the least, regarding a possible hematological toxicity, unlike clozapine, JL 13 did not present sensitivity to peroxidase-induced oxidation. Moreover, its electrooxidation potential was close to that of loxapine and far from that of clozapine. Taking all these preclinical data into account, it appears that JL 13 is a promising atypical antipsychotic drug.

Topics: Animals; Antipsychotic Agents; Brain; Cebidae; Clozapine; Discrimination Learning; Discrimination, Psychological; Dopamine Antagonists; Drug Evaluation, Preclinical; Hematologic Diseases; Hyperprolactinemia; Mice; Oxazepines; Piperazines; Psychotropic Drugs; Pyridines; Rats; Saimiri; Tissue Distribution

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

Topics: Antipsychotic Agents; Clozapine; Hematologic Diseases; Humans; Leukocyte Disorders

Leponex (clozapine) is an atypical neuroleptic indicated in severe schizophrenia, launched in France in December 1991. The safety and efficacy data pertaining to 1,062 patients treated on a compassionate needs basis between May 1989 and December 1991 constitute the first French experience on the drug. The results of an interim analysis pertaining to 602 patients, i.e. available data on 03-15-1992, generally collected on a retrospective basis, by means of a specific questionnaire are reviewed. The population included patients with severe and long-standing schizophrenia i.e. 15.71 +/- 9.3 years, resistant to usual neuroleptic therapy (90.86% of cases), and rarely with a history of intolerance to this class (2.49%). The indication was in the majority of the cases a paranoid schizophrenia (67.2%). The mean maintenance daily dose was 419 mg/d (+/- 152). Overall, with respect to associated drugs, neuroleptics were recorded in 16.4%, another psychotropic drug in 44.7% and symptomatic treatments for extrapyramidal disorders in 21.3% of patients. Of interest is the fact that, for those patients started on Leponex more recently, the drug is more often prescribed on a single basis. Leponex was stopped in 24.3% for the following reasons: adverse events 10.6%, lack of efficacy 6%, non compliance 3.8%, other reasons 3.8%. The adverse event profile is consistent with the literature data, taking into account the fact that certain adverse events were more commonly described: fatigue of lower limbs 11.8%, leucocytosis 19.8% and eosinophilia 4.3%.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Clozapine; Female; Follow-Up Studies; France; Hematologic Diseases; Humans; Male; Middle Aged; Retrospective Studies; Schizophrenia; Schizotypal Personality Disorder; Treatment Outcome

In the United Kingdom, patients on clozapine whose hematological parameters fall below certain thresholds are placed on the Central Non-Rechallenge Database (CNRD), meaning that they cannot be prescribed clozapine again except under exceptional circumstances. This practice was discontinued in the United States in 2015 by expanding the hematological monitoring guidelines, allowing more patients to receive clozapine. Our objective was to investigate the implications this policy change would have on clozapine utilization in the United Kingdom.. This was an observational, retrospective analysis of patients registered on the CNRD in a large mental health trust. The first objective was to compare the number of patients placed on the CNRD under the United Kingdom and the US Food and Drug Administration (FDA) criteria. The second objective was to explore the hematological and clinical outcomes of CNRD patients. The third objective was to investigate the hematological outcomes of patients rechallenged on clozapine after nonrechallengeable status.. One hundred and fifteen patients were placed on CNRD from 2002 to 2019, of whom 7 (6%) met the equivalent criteria for clozapine discontinuation under the FDA guidelines. Clinical outcomes, as measured by the Clinical Global Impression-Severity scale, were worse 3 months after clozapine cessation than on clozapine (t = -7.4862; P < .001). Sixty-two (54%) patients placed on CNRD were rechallenged. Fifty-nine of those (95%) were successfully rechallenged; 3 patients were placed back on CNRD, only one of which would have had to stop clozapine again under FDA criteria.. Implementation of the updated FDA's monitoring criteria in the United Kingdom would significantly reduce clozapine discontinuation due to hematological reasons. The evidence suggests an urgent need for revising the UK clozapine monitoring guidelines to improve outcomes in treatment-resistant schizophrenia.

Topics: Adult; Antipsychotic Agents; Clozapine; Databases, Factual; Female; Hematologic Diseases; Humans; Male; Middle Aged; Practice Guidelines as Topic; Retrospective Studies; Schizophrenia, Treatment-Resistant; United Kingdom; Withholding Treatment

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 the antipsychotic of choice for treatment-resistant schizophrenia and is linked to a need for mandatory hematological monitoring. Besides agranulocytosis, other hematological aberrations have resulted in premature termination in some cases. Considering clozapine's role in immunomodulation, we proceeded to investigate the impact of clozapine on the following 3 main hematological cell lines: red blood cells, platelets, white blood cells (WBCs), and its differential counts. Data were extracted from patients initiated on clozapine between January 2009 and December 2010 at a single hospital. Patients with a preclozapine complete blood count, who were receiving clozapine during the 1-year follow-up period, were included in the present investigation. Counts of red blood cells, platelets, WBC, and its differential including neutrophils, lymphocytes, monocytes, eosinophils, and basophils were extracted and trajectories plotted. One hundred one patients were included in this study and 66 remained on clozapine at the end of 1 year. There was a synchronized but transient increase in WBC, neutrophils, monocytes, eosinophils, basophils, and platelets beginning as early as the first week of clozapine treatment. There were no cases of agranulocytosis reported in this sample, and five developed neutropenia. A spike in neutrophils immediately preceded the onset of neutropenia in three of the five. The cumulative incidence rates were 48.9% for neutrophilia, 5.9% for eosinophilia, and 3% each for thrombocytosis and thrombocytopenia. Early hematological aberrations are visible across a range of cell lines, primarily of the myeloid lineage. These disturbances are transient and are probably related to clozapine's immunomodulatory properties. We do not suggest discontinuing clozapine as a consequence of the observed aberrations.

Topics: Adult; Antipsychotic Agents; Blood Cell Count; Clozapine; Drug Monitoring; Female; Follow-Up Studies; Hematologic Diseases; Humans; Incidence; Male; Middle Aged; Retrospective Studies; Schizophrenia; Young Adult

There are very few studies in the literature regarding clozapine use in children <13 years of age. In this retrospective chart review, we compared the safety of clozapine--as determined by hematological and cardiometabolic changes - to that of non-clozapine antipsychotics used in the treatment of childhood-onset schizophrenia (COS).. The clozapine treatment group (CTG) consisted of 17 COS patients (mean age 10.4 ± 2 years) who were hospitalized in a psychiatric ward between the years 2005 and 2012. The control group consisted of 19 COS patients (mean age 10.1 ± 1.4 years) who were hospitalized in the same ward during the same time period, and were treated with non-clozapine antipsychotics. A retrospective chart review was conducted. Hematological (white blood cells, absolute neutrophil count [ANC], red blood cells, platelets), metabolic (aspartate transaminase, alanine transaminase, triglycerides, total cholesterol, bilirubin) and cardiac (heart rate) values were extracted from the medical charts.. The average follow-up periods for the CTG and the control group were 332.9 ± 200.5 days and 291.7 ± 157 days, respectively. In the CTG, moderate neutropenia (ANC<1500/mm(3)) and mild neutropenia (1500/mm(3)100 beats per minute) at release from the hospital, compared with only one child (5%) in the control group (p=0.006).. It appears that clozapine use in very early onset schizophrenia is safe. Although hematological adverse effects did occur in our study, the rates were not much higher than those seen in the control group. We found that the hematological abnormalities in the CTG were mostly transient, and that treatment with clozapine can be safely continued or renewed.

Topics: Antipsychotic Agents; Case-Control Studies; Child; Clozapine; Hematologic Diseases; Humans; Medical Records; Retrospective Studies; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Drug Monitoring; Hematologic Diseases; Humans; India; Time Factors

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

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

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

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

Topics: Clozapine; Hematologic Diseases; Humans; Monitoring, Physiologic; Schizophrenia

Topics: Adult; Alanine Transaminase; Alkaline Phosphatase; alpha-Amylases; Aspartate Aminotransferases; Bilirubin; Blood Sedimentation; Chemical and Drug Induced Liver Injury; Clozapine; Creatinine; Dibenzazepines; Female; gamma-Glutamyltransferase; Hematologic Diseases; Hemoglobins; Humans; L-Lactate Dehydrogenase; Leukocytes; Male; Middle Aged; Psychotic Disorders

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

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