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.
Key words
Anticholinergic - Clozapine - Delirium
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
Phone: 1 (617) 855 21 36
Fax: +1 (617) 855 20 00
Email: centorf@mcleanpo.mclean.org