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Letter to the Editor   |    
Biperiden for Excessive Sweating From Clozapine
CHARLES RICHARDSON, M.D.; DEANNA L. KELLY, PHARM.D., B.C.P.P.; ROBERT R. CONLEY, M.D.
Am J Psychiatry 2001;158:1329-a-1330. doi:10.1176/appi.ajp.158.8.1329-a

To the Editor: Although clozapine remains the gold standard for use with treatment-resistant psychosis, its use is complicated by numerous side effects that limit its acceptability. We report a case of excessive sweating caused by clozapine use that was reversed by biperiden therapy.

Mr. A was a 31-year-old white man with a 13-year history of schizophrenia. His distressing delusions and hallucinations were resistant to treatment with adequate trials of typical antipsychotics, risperidone, and olanzapine. Clozapine treatment produced a robust response but was accompanied by continuous generalized sweating. During sequential trials of chlorpromazine, clozapine, and olanzapine, the sweating occurred only during clozapine treatment.

The inconvenience of changing saturated clothes and linens nightly led Mr. A to request clozapine discontinuation, despite his acknowledgment of frequent suicide attempts during treatment with all other antipsychotics. Dose reductions led to a worsening of his symptoms but did not diminish the sweating. Trials of propranolol, up to 240 mg/day, followed by clonidine, 1.2 mg/day, resulted in no significant reduction in the sweating. Biperiden, titrated to 6 mg/day, resulted in the prompt cessation of generalized sweating without exacerbation of other anticholinergic side effects. Sialorrhea was also eliminated with biperiden therapy.

Excessive sweating occurred in 6% of 842 patients receiving clozapine in clinical trials (PDR), but its cause is puzzling given clozapine’s reported antagonism of α1 and muscarinic receptors. We initially hypothesized that excessive sweating was due to clozapine’s effect on circulating norepinephrine (1), but neither propranolol nor clonidine reversed the condition.

Studies have provided evidence that clozapine is a partial agonist at the M1, M2, and M3 subtypes of the muscarinic receptor (2) and a full agonist at the M4 receptor (3). Muscarinic receptor subtypes are heterogeneously expressed in the autonomic nervous system. Exocrine glands express M1 and M3 receptors (4). Talsaclidine, an M1 agonist, consistently produced hypersalivation in human volunteers and led to generalized muscarinic symptoms, including sweating, at higher doses (5). Sweating and sialorrhea caused by clozapine treatment were eliminated by treatment with biperiden, which possesses relative selectivity for the M1 receptor (6). This case supports the view that some of clozapine’s side effects are due to its partial agonist effects at subtypes of the muscarinic receptor.

Pickar D, Owen RR, Litman RE, Konicki PE, Gutierrez R, Rapaport MH: Clinical and biologic response to clozapine in patients with schizophrenia: crossover comparison with fluphenazine. Arch Gen Psychiatry  1992; 49:345-353
[PubMed]
 
Olianas MC, Maullu C, Onali P: Mixed agonist-antagonist properties of clozapine at different human cloned muscarinic receptor subtypes expressed in Chinese hamster ovary cells. Neuropsychopharmacology  1999; 20:263-270
[PubMed]
[CrossRef]
 
Zorn SH, Jones SB, Ward KM, Liston DR: Clozapine is a potent and selective muscarinic M4 receptor agonist. Eur J Pharmacol 1994; 269:R1-R2
 
Caulfield MP: Muscarinic receptors: characterization, coupling and function. Pharmacol Ther  1993; 58:319-379
[PubMed]
[CrossRef]
 
Adamus WS, Leonard JP, Troger W: Phase I clinical trials with WAL 2014, a new muscarinic agonist for the treatment of Alzheimer’s disease. Life Sci  1995; 56:883-890
[PubMed]
[CrossRef]
 
Bolden C, Cusack B, Richelson E: Antagonism by antimuscarinic and neuroleptic compounds at the five cloned human muscarinic cholinergic receptors expressed in Chinese hamster ovary cells. J Pharmacol Exp Ther  1992; 260:576-580
[PubMed]
 
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References

Pickar D, Owen RR, Litman RE, Konicki PE, Gutierrez R, Rapaport MH: Clinical and biologic response to clozapine in patients with schizophrenia: crossover comparison with fluphenazine. Arch Gen Psychiatry  1992; 49:345-353
[PubMed]
 
Olianas MC, Maullu C, Onali P: Mixed agonist-antagonist properties of clozapine at different human cloned muscarinic receptor subtypes expressed in Chinese hamster ovary cells. Neuropsychopharmacology  1999; 20:263-270
[PubMed]
[CrossRef]
 
Zorn SH, Jones SB, Ward KM, Liston DR: Clozapine is a potent and selective muscarinic M4 receptor agonist. Eur J Pharmacol 1994; 269:R1-R2
 
Caulfield MP: Muscarinic receptors: characterization, coupling and function. Pharmacol Ther  1993; 58:319-379
[PubMed]
[CrossRef]
 
Adamus WS, Leonard JP, Troger W: Phase I clinical trials with WAL 2014, a new muscarinic agonist for the treatment of Alzheimer’s disease. Life Sci  1995; 56:883-890
[PubMed]
[CrossRef]
 
Bolden C, Cusack B, Richelson E: Antagonism by antimuscarinic and neuroleptic compounds at the five cloned human muscarinic cholinergic receptors expressed in Chinese hamster ovary cells. J Pharmacol Exp Ther  1992; 260:576-580
[PubMed]
 
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