Pharmacopsychiatry 2003; 36(4): 156-160
DOI: 10.1055/s-2003-41201
Original Paper
© Georg Thieme Verlag Stuttgart · New York

Delirium During Clozapine Treatment: Incidence and Associated Risk Factors

F. Centorrino1 , M. J. Albert1 , G. Drago-Ferrante1 , A. E. Koukopoulos1 , J. M. Berry1 , R. J. Baldessarini1
  • 1Department of Psychiatry & Neuroscience Program, Harvard Medical School, Boston, MA, USA; Bipolar & Psychotic Disorders Program, McLean Division of Massachusetts General Hospital; and the International Consortium for Bipolar Disorder Research; Belmont, MA, USA
Supported, in part by NIH grant MH-47 370, an award from the Bruce J. Anderson Foundation, and by the McLean Private Donors Neuropsychopharmacology Research Fund (to RJB).
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Publikationsverlauf

Received: 31.5.2002 Revised: 26.7.2002

Accepted: 26.9.2002

Publikationsdatum:
07. August 2003 (online)

Background: Incidence and risk factors for delirium during clozapine treatment require further clarification. Methods: We used computerized pharmacy records to identify all adult psychiatric inpatients treated with clozapine (1995-96), reviewed their medical records to score incidence and severity of delirium, and tested associations with potential risk factors. Results: Subjects (n = 139) were 72 women and 67 men, aged 40.8 ± 12.1 years, hospitalized for 24.9 ± 23.3 days, and given clozapine, gradually increased to an average daily dose of 282 ± 203 mg (3.45 ± 2.45 mg/kg) for 18.9 ± 16.4 days. Delirium was diagnosed in 14 (10.1 % incidence, or 1.48 cases/person-years of exposure); 71.4 % of cases were moderate or severe. Associated factors were co-treatment with other centrally antimuscarinic agents, poor clinical outcome, older age, and longer hospitalization (by 17.5 days, increasing cost); sex, diagnosis or medical co-morbidity, and daily clozapine dose, which fell with age, were unrelated. Conclusions: Delirium was found in 10 % of clozapine-treated inpatients, particularly in older patients exposed to other central anticholinergics. Delirium was inconsistently recognized clinically in milder cases and was associated with increased length-of-stay and higher costs, and inferior clinical outcome.

References

  • 1 American Psychiatric Association: Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC; American Psychiatric Association 1994
  • 2 Baldessarini R J. Drugs and the treatment of psychiatric disorders: Antipsychotic and antianxiety agents. Chapt 18 in Goodman and Gilman’s The Pharmacological Basis of Therapeutics, ninth edition. Edited by Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman AG New York; McGraw-Hill 1996: pp 399-430
  • 3 Baldessarini R J, Frankenburg F R. Clozapine. A novel antipsychotic agent.  N Engl J Med. 1991;  324 746-754
  • 4 Baldessarini R J, Tarazi F I. Drugs and the treatment of psychiatric disorders: Antipsychotic and antimanic agents. Chapt 20 in Goodman and Gilman’s The Pharmacologic Basis of Therapeutics. Edited by Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman AG New York, NY; McGraw-Hill 2001: pp 485-520
  • 5 Berggren D, Gustafson Y, Eriksson B, Bucht G, Hansson L I, Reiz S, Winblad B. Postoperative confusion after anesthesia in elderly patients with femoral neck fractures.  Anesthesia Analgesia. 1987;  66 497-504
  • 6 Breitbart W, Marotta R, Platt M M, Weisman H, Derevenco M, Grau C, Corbera K, Raymond S, Lund S, Jacobson P. A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients.  Am J Psychiatry. 1996;  153 231-237
  • 7 Byerly M J, Weber M T, Brooks D L, Snow L R, Worley M A, Lescouflair E. Antipsychotic medications and the elderly: effects on cognition and implications for use.  Drugs Aging. 2001;  18(1) 45-61
  • 8 Caine E D, Lyness J M. Delirium, Dementia and other amnestic and cognitive disorders. Chapt 10 in Kaplan & Sadock’s Comprehensive Textbook of Psychiatry, seventh edition, vol 1. Edited by Sadock BJ, Sadock VA Baltimore; Lippincott Williams & Wilkins 1999: pp 854-923
  • 9 Carter J, Thrasher S, Thornicroft G. Cognitive impairment and clozapine.  Br J Psychiatry. 1994;  164 132-133
  • 10 Centorrino F, Eakin M, Bahk W -M, Kelleher J P, Goren J L, Salvatore P, Egli S, Baldessarini R J. Inpatient antipsychotic drug use in 1998: Comparisons to 1993 and 1989. Am J Psychiatry Nov 2002; in press
  • 11 Centorrino F, Price B H, Tuttle M, Bahk W -M, Hennen J, Albert M, Baldessarini R J. EEG abnormalities during treatment with typical and atypical antipsychotics.  Am J Psychiatry. 2002;  159 109-115
  • 12 Chong S A, Remington G. Clozapine augmentation: safety and efficacy.  Schizophrenia Bull. 2000;  26 421-440
  • 13 Cobb C D, Anderson C B, Seidel D R. Possible interaction between clozapine and lorazepam.  Am J Psychiatry. 1991;  148 1606-1607
  • 14 Fann J R. The epidemiology of delirium: a review of studies and methodological issues.  Semin Clin Neuropsychiatry. 2000;  5(2) 64-74
  • 15 Folstein M F, Bassett S S, Romanoski A J, Nestadt G. The epidemiology of delirium in the community: the Eastern Baltimore Mental Health Survey.  Int Psychogeriatrics. 1991;  3 169-176
  • 16 Francis J. Drug-induced delirium.  CNS Drugs. 1996;  5 103-114
  • 17 Gaertner H J, Fischer E, Hoss J. Side effects of clozapine.  Psychopharmacology. 1989;  99 (Suppl) S97-100
  • 18 Gardner D M, Baldessarini R J, Benzo J, Zarate CA J r, Tohen M. Switching between clozapine and risperidone treatment.  Can J Psychiatry. 1997;  42 430-431
  • 19 Granacher R P, Baldessarini R J. Physostigmine. Its use in acute anticholinergic syndrome with antidepressant and antiparkinson drugs.  Arch Gen Psychiatry. 1975;  32 375-380
  • 20 Grohmann R, Ruther E, Sassim N, Schmidt L G. Adverse effects of clozapine.  Psychopharmacology. 1989;  99 (Suppl) S101-104
  • 21 Itil T, Fink M. Anticholinergic drug-induced delirium: experimental modification, quantitative EEG and behavioral correlations.  J Nerv Ment Dis. 1966;  143 492-507
  • 22 Jackson C W, Markowitz J S, Brewerton T D. Delirium associated with clozapine and benzodiazepine combinations.  Ann Clin Psychiatry. 1995;  7 139-141
  • 23 Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine.  Arch Gen Psychiatry. 1988;  45 789-796
  • 24 Lipowski Z J. Update on delirium.  Psychiatr Clin No Am. 1992;  15 335-346
  • 25 Lu M L, Lane H Y, Chen K P, Jann M W, Su M H, Chang W H. Fluvoxamine reduces the clozapine dosage needed in refractory schizophrenic patients.  J Clin Psychiatry. 2000;  61 594-599
  • 26 Naber D, Holzbach R, Perro C, Hippius H. Clinical management of clozapine patients in relation to efficacy and side-effects.  Br J Psychiatry. 1992;  160 (Suppl 17) 54-59
  • 27 Olesen O V, Linnet K. Fluvoxamine-clozapine drug interaction: Inhibition in vitro of five cytochrome P450 isoforms involved in clozapine metabolism.  J Clin Psychopharmacol. 2000;  20 35-42
  • 28 Procyshyn R M, Thompson D, Tse G. Pharmacoeconomics of clozapine, risperidone and olanzapine: A review of the literature.  CNS Drugs. 2000;  13 47-76
  • 29 Schmidt L G, Grohmann R, Strauss A, Spiess-Kiefer C, Lindmeier D, Müller-Oerlinghausen B. Epidemiology of toxic delirium due to psychotropic drugs in psychiatric hospitals.  Compr Psychiatry. 1987;  28 242-249
  • 30 Schuster P, Gabriel E, Kufferle B, Strobl G, Karobath M. Reversal by physostigmine of clozapine-induced delirium.  Clin Toxicol. 1977;  10 437-441
  • 31 Smith L W, Dimsdale J E. Postcardiotomy delirium: Conclusions after 25 years.  Am J Psychiatry. 1989;  146 452-458
  • 32 Stahl S M. Antipsychotic polypharmacy: Therapeutic option or dirty little secret?.  J Clin Psychiatry. 1999;  60 425-426
  • 33 Szymanski S, Jody D, Leipzig R, Masiar S, Lieberman J. Anticholinergic delirium caused by retreatment with clozapine.  Am J Psychiatry. 1991;  148 1752-1753
  • 34 Taylor D, Lewis S. Delirium.  J Neurol Neurosurg Psychiatry. 1993;  56 742-751
  • 35 Trzepacz P T, Brown T M, Stoudemire A. Treatments of psychiatric disorders: Substance-induced delirium. In Treatments of Psychiatric Disorders, vol 1. Edited by Gabbard GO Washington, DC; American Psychiatric Press 1995: pp 445-478
  • 36 Viner M W, Escobar J I. An apparent neurotoxicity associated with clozapine.  J Clin Psychiatry. 1994;  55 38-39
  • 37 Wahlbeck K, Cheine M, Essali A, Adams C. Evidence of clozapine’s effectiveness in schizophrenia: A systematic review and meta-analysis of randomized trials.  Am J Psychiatry. 1999;  156 990-999
  • 38 Wilkins-Ho M, Hollander Y. Toxic delirium with low-dose clozapine.  Can J Psychiatry. 1997;  42 429-430
  • 39 Young C R, Bowers MB J r, Mazure C M. Management of the adverse effects of clozapine.  Schizophrenia Bull. 1998;  24 381-390
  • 40 Zarate C A Jr., Tohen M, Baldessarini R J. Clozapine in severe mood disorders.  J Clin Psychiatry. 1995;  56 411-417

Dr. Franca Centorrino

Chief, Bipolar & Psychotic Disorders Clinic

McLean Hospital

115 Mill Street

Belmont, MA 02478

USA

Telefon: 1 (617) 855 21 36

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