Clozapine Plasma Level Monitoring for Prediction of Rehospitalization Schizophrenic Outpatients

Abstract

Introduction: The aim of this naturalistic exploratory study was to examine whether blood antipsychotic drug concentrations can predict rehospitalizations in chronically medicated patients.

Methods: The study included schizophrenic outpatients under clozapine (CLZ) maintenance treatment, supervised by therapeutic drug monitoring (TDM). Patients were observed for a period of 21 months. Their on average monthly measured plasma levels and the date of rehospitalizations were recorded. The variability of the first 3 CLZ plasma levels, measured in 3.6 months, was compared between patients with and without rehospitalization.

Results: 23 patients participated of which 6 patients were rehospitalized. Mean plasma concentrations of CLZ were similar in patients without (471±180 ng/mL) and with rehospitalization (446±266 ng/mL). However; coefficients of variation (CV) of plasma concentrations in the first 3 blood samples differed significantly between the rehospitalized and non-rehospitalized groups (37.1% vs. 13.0%, respectively, p=0.012). A CV ≥19.8% was predictive for later rehospitalization with 100% sensitivity and 70.6% specificity.

Discussion: Variability in CLZ plasma concentrations may be useful in identifying patients at risk of relapsing under maintenance therapy. Because of the small number of patients the findings need to be confirmed in a larger study.

References

• 1 American Psychiatric Association . Practice guidelines for the treatment of patients with schizophrenia.  Am J Psychiatry. 1997;  154 (suppl 4) 1-63
• 2 Baumann P, Hiemke C, Ulrich S. et al . Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie. The AGNP-TDM expert group consensus guidelines: therapeutic drug monitoring in psychiatry.  Pharmacopsychiatry. 2004;  37 243-265
• 3 Beasley Jr CM, Stauffer VL, Liu-Seifert H. et al . All-cause treatment discontinuation in schizophrenia during treatment with olanzapine relative to other antipsychotics: an integrated analysis.  J Clin Psychopharmacol. 2007;  27 252-258
• 4 Davis JM. Overview: maintenance therapy in psychiatry, I: schizophrenia.  Am J Psychiatry. 1975;  132 1237-1245
• 5 Diaz FJ, de Leon J, Josiassen RC. et al . Plasma clozapine concentration coefficients of variation in a long-term study.  Schizophr Res. 2005;  72 131-135
• 6 Dossenbach M, Arango-Davila C, Ibarra HS. et al . Response and relapse in patients with schizophrenia treated with olanzapine, risperidone, quetiapine, or haloperidol: 12-month follow-up of the Intercontinental Schizophrenia Outpatient Health Outcomes (IC-SOHO) Study.  J Clin Psychiatry. 2005;  66 1021-1030
• 7 Freeman DJ, Oyewumi LK. Will routine therapeutic drug monitoring have a place in clozapine therapy?.  Clin Pharmacokinet. 1997;  32 93-100
• 8 Gaertner I, Gaertner HG, Vonthein R. et al . Therapeutic drug monitoring of clozapine in relapse prevention: a five-year prospective study.  J Clin Psychopharmacol. 2001;  21 305-310
• 9 Gilbert PL, Harris MJ, McAdams LA. et al . Neuroleptic withdrawal in schizophrenic patients: a review of the literature.  Arch Gen Psychiatry. 1995;  52 173-188
• 10 Hiemke CH, Dragicevic A, Gründer G. et al . Therapeutic monitoring of new antipsychotic drugs.  Ther Drug Monit. 2004;  26 156-160
• 11 Hogarty GE, Schooler NR, Ulrich R. et al . Fluphenazine and social therapy in the aftercare of schizophrenic patients: relapse analyses of a two-year controlled study of fluphenazine decanoate and fluphenazine hydrochloride.  Arch Gen Psychiatry. 1979;  36 1283-1294
• 12 Hogarty GE, Ulrich RF. The limitations of antipsychotic medication on schizophrenia relapse and adjustment and the contributions of psychosocial treatment.  J Psychiatr Res. 1998;  32 243-250
• 13 Kurz M, Hummer M, Kemmler G. et al . Long-term pharmacokinetics of clozapine.  Br J Psychiatry. 1998;  173 341-344
• 14 Liebermann JA, Stroup TS, MacEvoy JP. et al . Effectiveness of antipsychotic drugs in patients with chronic schizophrenia.  N Engl J Med. 2005;  353 1209-1223
• 15 Liu HC, Chang WH, Wei FC. et al . Monitoring of plasma clozapine levels and its metabolites in refractory schizophrenic patients.  Ther Drug Monit. 1996;  18 200-207
• 16 Ng W, Uchida H, Ismail Z. et al . Clozapine exposure and the impact of smoking and gender: a population pharmacokinetic study.  Ther Drug Monit. 2009;  31 360-366
• 17 Palego L, Biondi L, Giannaccini G. et al . Clozapine, norclozapine plasma levels, their sum and ratio in 50 psychotic patients: influence of patient-related variables.  Prog Neuropsychopharmacol Biol Psychiatry. 2002;  26 473-480
• 18 Rostami-Hodjegan A, Amin AM, Spencer EP. 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.  J Clin Psychopharmacol. 2004;  24 70-78
• 19 Sachse J, Köller J, Härtter S. et al . Automated analysis of quetiapine and other antipsychotic drugs in human blood by high performance-liquid chromatography with column-switching and spectrophotometric detection.  J Chromatogr B Analyt Technol Biomed Life Sci. 2006;  830 342-348
• 20 Stroup TS, McEvoy JP, Swartz MS. et al . The National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project: schizophrenia trial design and protocol development.  Schizophr Bull. 2003;  29 15-31
• 21 Ulrich S, Baumann B, Wolf R. et al . Therapeutic drug monitoring of clozapine and relapse – a retrospective study of routine clinical data.  Int J Clin Pharmacol Ther. 2003;  41 3-13
• 22 Xiang YQ, Zhang ZY, Weng JZ. et al . Serum concentrations of clozapine and norclozapine in the prediction of relapse of patients with schizophrenia.  Schizophr Res. 2006;  83 201-210

Correspondence