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Commentary on Letter: Atypical Antipsychotics and Coma
LETTERS Commentary on Letter: Drs. Sadek and Atypical Antipsychotics Rockwood Reply and Coma SIR: Dr. Sadek and Dr. Rockwood (AJGP 11:112–113) reported a patient with dementia with Lewy bodies (DLB) who became comatose after mistakenly receiving a dose of 175 mg. of clozapine. This error led the authors to conclude that “extreme caution” should be used when prescribing atypical antipsychotics to patients with DLB. They specifically cited a need for “careful monitoring,” perhaps by hospitalizing such patients when treating them with these drugs. The patient’s toxic response to such a very large dose of clozapine is not consistent with “neuroleptic sensitivity,” but is rather a more predictable and expected consequence that might just as easily happen in patients with any type of dementia, not to mention many other geriatric patients. This case should be seen in the context of the valuable and widespread practice of safely using low- dose atypicals in DLB. The impracticality and inappropriateness of hospitalizing all such patients to treat them with safe regimens is clear. Errors can occur with any class of medication, but such errors usually do not lead to generalizations about the danger of the type of drug involved. Michael Serby, M.D. Department of Psychiatry Beth Israel Medical Center, New York, NY, e-mail: [email protected] Steven C. Samuels, M.D. Department of Psychiatry, Mount Sinai/Bronx VAMC
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SIR: We are glad for the opportunity to respond to Drs. Serby and Samuels’ comments regarding clozapine sensitivity in patients who have with dementia with Lewy bodies (DLB). Neuroleptic sensitivity to clozapine is known, but often unpredictable. Burke et al. described two patients with DLB who developed neuroleptic sensitivity to clozapine, showing not extrapyramidal side effects, but an increase in confusion and behavioral symptoms.1 Monitoring DLB patients when starting antipsychotics is necessary because of their sometimes exquisite sensitivity to neuroleptic drugs.2 McKeith and O’Brien3 have argued that clinicians should be aware of the typical triad of clinical features that characterize the disorder and either avoid antipsychotics or prescribe them with extreme caution in such patients. They recommend that if it is felt necessary to prescribe neuroleptics to patients with DLB, close monitoring in a hospital setting would be advisable, particularly during the first week of prescription. There is no conclusive evidence to point to the specific dosage of clozapine from which a toxic reaction of 12 days of coma might be expected. Indeed, we can find no large, randomized, controlled studies to support clozapine use in patients with DLB. Available reports have claimed a dose range of 6.25 mg to 200 mg to be safe and well tolerated in elderly dementia patients. For example, Barak et al.4 conducted a computerized literature search (MEDLINE, 1966 to 1997) for clozapine use in 133 elderly patients and concluded that “clozapine at a relatively low mean dose (134 mg
daily) seems to be safe, tolerated, and effective in elderly psychiatric patients.” Another group conducted a 12-week, double-blind comparison study to assess the efficacy and tolerability of clozapine and chlorpromazine in a group of elderly inpatients. Medications were titrated on the basis of clinical response and side effects, to a maximum dose of 300 mg/ day of clozapine or 600 mg/day of chlorpromazine. The study concluded that, with careful monitoring and titration of dosage, both clozapine and chlorpromazine were fairly well tolerated in this population.5 In a randomized, double-blind study in patients 72 years or older, clozapine, at daily doses of 50 mg, was found to safely and significantly improve druginduced psychosis without worsening parkinsonism.6 Jeste et al. reported a dose of 50 mg–100 mg of clozapine to be safe and well tolerated in the elderly dementia population.7 Still, these studies did not specifically address DLB, and a report of three dementia patients treated with clozapine revealed that one patient had delirium with a first dose of 37.5 mg.8 Another report mentioned that cholinergic-agonist effects of clozapine may, however, mitigate potential adverse cognitive effects associated with the cholinergic-blocking actions of some antipsychotic agents, but concluded that large, rigorous trials comparing the cognitive effects of antipsychotics with diverse pharmacodynamic actions are lacking in elderly subjects and are needed.9 From these reviews, there is no evidence that coma for 12 days is a predictable reaction to 175 mg of clozapine. In consequence, given that we have seen it occur, we are persuaded of the need to be extremely cautious when using clozapine in patients who have dementia with Lewy bodies.
Am J Geriatr Psychiatry 11:3, May-June 2003
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SIR: We are glad for the opportunity to respond to Drs. Serby and Samuels’ comments regarding clozapine sensitivity in patients who have with dementia with Lewy bodies (DLB). Neuroleptic sensitivity to clozapine is known, but often unpredictable. Burke et al. described two patients with DLB who developed neuroleptic sensitivity to clozapine, showing not extrapyramidal side effects, but an increase in confusion and behavioral symptoms.1 Monitoring DLB patients when starting antipsychotics is necessary because of their sometimes exquisite sensitivity to neuroleptic drugs.2 McKeith and O’Brien3 have argued that clinicians should be aware of the typical triad of clinical features that characterize the disorder and either avoid antipsychotics or prescribe them with extreme caution in such patients. They recommend that if it is felt necessary to prescribe neuroleptics to patients with DLB, close monitoring in a hospital setting would be advisable, particularly during the first week of prescription. There is no conclusive evidence to point to the specific dosage of clozapine from which a toxic reaction of 12 days of coma might be expected. Indeed, we can find no large, randomized, controlled studies to support clozapine use in patients with DLB. Available reports have claimed a dose range of 6.25 mg to 200 mg to be safe and well tolerated in elderly dementia patients. For example, Barak et al.4 conducted a computerized literature search (MEDLINE, 1966 to 1997) for clozapine use in 133 elderly patients and concluded that “clozapine at a relatively low mean dose (134 mg
daily) seems to be safe, tolerated, and effective in elderly psychiatric patients.” Another group conducted a 12-week, double-blind comparison study to assess the efficacy and tolerability of clozapine and chlorpromazine in a group of elderly inpatients. Medications were titrated on the basis of clinical response and side effects, to a maximum dose of 300 mg/ day of clozapine or 600 mg/day of chlorpromazine. The study concluded that, with careful monitoring and titration of dosage, both clozapine and chlorpromazine were fairly well tolerated in this population.5 In a randomized, double-blind study in patients 72 years or older, clozapine, at daily doses of 50 mg, was found to safely and significantly improve druginduced psychosis without worsening parkinsonism.6 Jeste et al. reported a dose of 50 mg–100 mg of clozapine to be safe and well tolerated in the elderly dementia population.7 Still, these studies did not specifically address DLB, and a report of three dementia patients treated with clozapine revealed that one patient had delirium with a first dose of 37.5 mg.8 Another report mentioned that cholinergic-agonist effects of clozapine may, however, mitigate potential adverse cognitive effects associated with the cholinergic-blocking actions of some antipsychotic agents, but concluded that large, rigorous trials comparing the cognitive effects of antipsychotics with diverse pharmacodynamic actions are lacking in elderly subjects and are needed.9 From these reviews, there is no evidence that coma for 12 days is a predictable reaction to 175 mg of clozapine. In consequence, given that we have seen it occur, we are persuaded of the need to be extremely cautious when using clozapine in patients who have dementia with Lewy bodies.
Am J Geriatr Psychiatry 11:3, May-June 2003