clozapine and Drug-Hypersensitivity

A 57-year-old female patient with a diagnosis of schizo-affective disorder since 1986 was commenced on clozapine due to persistent positive and negative psychotic symptoms in September 2014. After commencement of clozapine she was delusion free and demonstrated an improvement in negative symptoms. Three months after commencement of clozapine she developed a hypersensitivity reaction. Her symptoms continued to deteriorate despite being prescribed an anti-histamine. Clozapine was discontinued 6 days after the appearance of a generalised pruritic rash, as it was believed to be the probable cause. There was complete resolution of symptoms 1 week after discontinuation of clozapine. Clozapine was replaced with olanzapine and amisulpride. There has been no similar cutaneous or allergic reactions for the past 30 months.

Topics: Antipsychotic Agents; Clozapine; Drug Hypersensitivity; Female; Humans; Middle Aged; Psychotic Disorders

Hypersensitivity drug reactions (HDRs) are common among drugs, despite this, there are no validated in vitro or in vivo methods for screening the sensitizing potential of drugs in the preclinical phase. We previously developed the THP-1 activation assay, based on CD86 upregulation and IL-8 production, for the in vitro identification of drugs able to induce selective dendritic cell activation. In this paper, we investigated the predictive capacity of the method toward drugs associated with HDRs for which a correlation with specific human leukocyte antigens (HLA) have been demonstrated. For that purpose, abacavir, carbamazepine and clozapine were used. Metformin was used as negative control. Dose- and time-course experiments were conducted. The surface markers CD86, CD54 and HLA-DR were evaluated by flow cytometry analysis, whereas IL-8 release by ELISA. Abacavir, carbamazepine and clozapine gave positive results with CD86 upregulation and/or IL-8 release, with abacavir also inducing HLA-DR. The test reveals the ability of drugs to induce dendritic cell activation (signals 1/2), that preceded the adaptive immune response, which will be manifested only in a minority of patients carrying the specific HLA genotypes. The idea is to integrate this simple method during drug development to identify the potential of drugs to induce hypersensitivity reactions in the pre-clinical phase.

Topics: B7-2 Antigen; Carbamazepine; Cell Survival; Clozapine; Dideoxynucleosides; Drug Hypersensitivity; Genotype; HLA Antigens; Humans; Intercellular Adhesion Molecule-1; Interleukin-8; Metformin; THP-1 Cells

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

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

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Diagnosis, Differential; Dose-Response Relationship, Drug; Drug Hypersensitivity; Humans; Male; Myocarditis; Olanzapine; Psychotic Disorders; Retreatment

Clozapine has proven effective in reducing morbidity and suicidality in chronic non-remitting patients with schizophrenia. Occasionally, despite good therapeutic response, clozapine must be stopped due to dangerous side effects such as agranulocytosis. Drug-induced eosinophilia is a non-dose-dependent side effect of clozapine. In cases of mild increments of eosinophils and if the patient is asymptomatic, there is no need to make an immediate decision. However, if the increment is severe and producing symptoms, withdrawing the probable causative drug is warranted. There is a possible association between eosinophilia and myocarditis, a life-threatening condition. The efficacy of corticosteroid therapy in the treatment of eosinophilia has not been clearly established. We present a case report where switching from clozapine to quetiapine maintained the improvement in clinical status, after remittance of eosinophilia.

Topics: Adult; Antipsychotic Agents; Clozapine; Dibenzothiazepines; Drug Hypersensitivity; Eosinophilia; Eosinophils; Humans; Leukocyte Count; Male; Patient Readmission; Quetiapine Fumarate; Schizophrenia; Schizophrenic Psychology

A rare, but frequently fatal, side effect of the antipsychotic drug clozapine is myocarditis. We report a case of hypersensitivity myocarditis secondary to clozapine administration that was diagnosed in vivo for the first time through endomyocardial biopsy and was successfully treated with corticosteroids. Histologic diagnosis was based on the evidence of eosinophilic infiltration of the endomyocardium and eosinophil degranulation. Endomyocardial biopsy was performed in order to establish or exclude a clear-cut relationship between cardiac dysfunction and clozapine, and was crucial to establish a correct diagnosis and appropriate treatment. Clozapine withdrawal and targeted 8-day, low-dose corticosteroid therapy resolved the symptoms and restored cardiac function.

Topics: Clozapine; Drug Hypersensitivity; Female; Humans; Male; Myocarditis

Topics: Adult; Aged; Antipsychotic Agents; Cardiomyopathies; Clozapine; Death, Sudden, Cardiac; Drug Hypersensitivity; Female; Humans; Male; Myocarditis; Parkinson Disease; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Drug Hypersensitivity; Exanthema; Fever; Humans; Pleural Effusion

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

Topics: Adult; Clozapine; Drug Hypersensitivity; Female; Humans; Lymphocyte Activation; Parotitis; Schizophrenia, Paranoid

Topics: Acids; Adult; Antipsychotic Agents; Chlorpromazine; Clozapine; Cross Reactions; Drug Hypersensitivity; Humans; Male; Psychotic Disorders

Topics: Adult; Clozapine; Diagnosis, Differential; Dose-Response Relationship, Drug; Drug Hypersensitivity; Eosinophilia; Fever of Unknown Origin; Humans; Male; Schizophrenia; Schizophrenic Psychology

Clozapine, an 'atypical' antipsychotic drug, rarely induces allergic complications, which usually present as cutaneous reactions. We report the case of a 69-year-old woman, suffering from chronic schizophrenia, who developed an allergic asthmatic reaction following clozapine therapy. Intensive-care treatment was necessary. The reaction could be repeated by further exposure to the drug. Skin tests for hypersensitivity were negative.

Topics: Aged; Asthma; Clozapine; Dose-Response Relationship, Drug; Drug Hypersensitivity; Female; Humans; Schizophrenia, Paranoid

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

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