Prevalence and nature of side effects during clozapine maintenance treatment and the relationship with clozapine dose and plasma concentration

Clozapine is associated with non-neurological side effects that can be subjectively unpleasant and/or clinically serious. We sought to: (i) assess the nature and prevalence of side effects experienced by patients receiving maintenance treatment with clozapine and (ii) explore the relationship between clozapine plasma concentration and side effect burden. Patients were receiving clozapine maintenance treatment. Open questioning followed by systematic enquiry using the Antipsychotic Non-neurological Side Effects Rating Scale were used to assess side effects. Trough plasma clozapine and norclozapine concentrations were measured. One hundred and three patients participated. On open questioning, 61 patients reported a total of 117 side effects, whereas systematic enquiry identified an additional 649 side effects, with each patient reporting at least one. Clozapine plasma concentrations were significantly but weakly correlated with total Antipsychotic Non-neurological Side Effects Rating Scale score (Pearson correlation=0.29, P<0.004). Patients with a plasma clozapine concentration >0.25 mg/l were significantly more likely to have moderate/severe side effects than patients with lower plasma concentrations (63/76 vs. 12/23, χ2=9.07, d.f.=1, P<0.01). The side-effect burden associated with maintenance clozapine treatment is high and the true extent can only be ascertained by systematic inquiry. The use of target plasma concentrations below those used for acute treatment should be explored as a strategy for minimizing side effects.

[1]  H. Refsum,et al.  The effect of variable cigarette consumption on the interaction with clozapine and olanzapine , 2006, European Journal of Clinical Pharmacology.

[2]  Peter B. Jones,et al.  Randomized controlled trial of the effect on Quality of Life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). , 2006, Archives of general psychiatry.

[3]  Chuangyue Wang,et al.  Serum concentrations of clozapine and norclozapine in the prediction of relapse of patients with schizophrenia , 2006, Schizophrenia Research.

[4]  J. Lieberman,et al.  Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. , 2006, The American journal of psychiatry.

[5]  Peter B. Jones,et al.  Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. , 2005, Schizophrenia bulletin.

[6]  S. Preskorn,et al.  Examining Concentration-Dependent Toxicity of Clozapine: Role of Therapeutic Drug Monitoring , 2005, Journal of psychiatric practice.

[7]  R. Baldessarini,et al.  Clozapine toxicity associated with smoking cessation: case report. , 2005, American journal of therapeutics.

[8]  C. Eap,et al.  Increased Clozapine Plasma Concentrations and Side Effects Induced by Smoking Cessation in 2 CYP1A2 Genotyped Patients , 2005, Therapeutic drug monitoring.

[9]  W. Fleischhacker,et al.  Extrapyramidal side effects of clozapine and haloperidol , 1995, Psychopharmacology.

[10]  G. Dunn,et al.  Reliability of the antipsychotic non-neurological side effects rating scale (ANNSERS) , 2005 .

[11]  U. Fuhr,et al.  Time response of cytochrome P450 1A2 activity on cessation of heavy smoking , 2004, Clinical pharmacology and therapeutics.

[12]  Arif Khan,et al.  Dosing strategies for antidepressant clinical trials: a commentary. , 2004, Journal of clinical psychopharmacology.

[13]  Amin Rostami-Hodjegan,et al.  Influence of Dose, Cigarette Smoking, Age, Sex, and Metabolic Activity on Plasma Clozapine Concentrations: A Predictive Model and Nomograms to Aid Clozapine Dose Adjustment and to Assess Compliance in Individual Patients , 2004, Journal of clinical psychopharmacology.

[14]  H. Gaertner,et al.  Side effects of clozapine , 2004, Psychopharmacology.

[15]  Z. Husain,et al.  Clozapine: A Clinical Review of Adverse Effects and Management , 2003, Annals of clinical psychiatry : official journal of the American Academy of Clinical Psychiatrists.

[16]  S. Gilbody,et al.  Newer atypical antipsychotic medication in comparison to clozapine: a systematic review of randomized trials , 2002, Schizophrenia Research.

[17]  P. Perry.  Therapeutic drug monitoring of antipsychotics. , 2001, Psychopharmacology bulletin.

[18]  T. Erni,et al.  Prevalence of extrapyramidal syndromes in psychiatric inpatients and the relationship of clozapine treatment to tardive dyskinesia , 2000, Schizophrenia Research.

[19]  E. Perucca,et al.  Relationship between plasma concentrations of clozapine and norclozapine and therapeutic response in patients with schizophrenia resistant to conventional neuroleptics , 2000, Psychopharmacology.

[20]  D. Celermajer,et al.  Myocarditis and cardiomyopathy associated with clozapine , 1999, The Lancet.

[21]  R. Bentall,et al.  A comparison of patients' and prescribers' beliefs about neuroleptic side‐effects: prevalence, distress and causation , 1998, Acta psychiatrica Scandinavica.

[22]  R. Conley,et al.  Evaluation of treatment-resistant schizophrenia. , 1997, Schizophrenia bulletin.

[23]  H. Freeman,et al.  Neutropenia and Agranulocytosis in Patients Receiving Clozapine in the UK and Ireland , 1996, British Journal of Psychiatry.

[24]  J. McEvoy,et al.  Response of patients with treatment-refractory schizophrenia to clozapine within three serum level ranges. , 1996, The American journal of psychiatry.

[25]  C. Paton,et al.  Measurement of clozapine and norclozapine in plasma/serum by high performance liquid chromatography with ultraviolet detection. , 1995, Biomedical chromatography : BMC.

[26]  S Pollack,et al.  Clinical effects of clozapine in chronic schizophrenia: response to treatment and predictors of outcome. , 1994, The American journal of psychiatry.

[27]  S. Potkin,et al.  Plasma clozapine concentrations predict clinical response in treatment-resistant schizophrenia. , 1994, The Journal of clinical psychiatry.

[28]  D. Marinkovic,et al.  The side-effects of clozapine: A four year follow-up study , 1994, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[29]  R. Baldessarini,et al.  Clozapine and metabolites: concentrations in serum and clinical findings during treatment of chronically psychotic patients. , 1994, Journal of clinical psychopharmacology.

[30]  R. Baker,et al.  The prevalence of akathisia in patients receiving stable doses of clozapine. , 1994, The Journal of clinical psychiatry.

[31]  P. McKenna,et al.  The Safety and Efficacy of Clozapine in Severe Treatment-Resistant Schizophrenic Patients in the UK , 1993, British Journal of Psychiatry.

[32]  R. Cadoret,et al.  Dr. Perry and Associates Reply , 1991 .

[33]  R. Cadoret,et al.  Clozapine and norclozapine plasma concentrations and clinical response of treatment-refractory schizophrenic patients. , 1991, The American journal of psychiatry.

[34]  G. Honigfeld,et al.  A two-year clinical and economic follow-up of patients on clozapine. , 1990, Hospital & community psychiatry.

[35]  D. Naber,et al.  The European experience with use of clozapine. , 1990, Hospital & community psychiatry.

[36]  T. Barnes.  A Rating Scale for Drug-Induced Akathisia , 1989, British Journal of Psychiatry.

[37]  G Honigfeld,et al.  Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. , 1988, Archives of general psychiatry.

[38]  J. Kane,et al.  Research diagnoses for tardive dyskinesia. , 1982, Archives of general psychiatry.

[39]  G. Simpson,et al.  A RATING SCALE FOR EXTRAPYRAMIDAL SIDE EFFECTS , 1970, Acta psychiatrica Scandinavica. Supplementum.