Benztropine Equivalents for Antimuscarinic Medication

To the Editor: Michael J. Minzenberg, M.D., et al. (1) are to be congratulated for developing a benztropine equivalent table, as we previously did (2), by reviewing in vitro studies and asking experienced clinicians. However, measuring serum antimuscarinic activity may provide better knowledge (3).

The in vitro literature (1, 2) suggests that haloperidol has negligible antimuscarinic binding activity (10 g of haloperidol equals 1 mg of benztropine) (2). Although our senior pharmacologist also concluded that the clinical antimuscarinic binding activity of haloperidol was negligible (2), the psychiatrists working with Dr. Minzenberg et al. proposed that 13 mg of haloperidol equals 1 mg of benztropine (1). Our recent study (3) also suggested that haloperidol probably has negligible antimuscarinic clinical activity. The mean serum antimuscarinic activity in pmol/ml in 16 patients taking haloperidol was 0.40 (95% confidence interval [CI]=0.30–0.51). This low serum antimuscarinic activity appeared to represent nonspecific antimuscarinic binding (the “noise” of the measuring system) since haloperidol levels (or doses) were not correlated with serum antimuscarinic activity.

Clozapine differs in that its in vitro tables suggest that 1 mg of benztropine equals 15 mg (2) or 8 mg (1) of clozapine; the clinical tables suggest that 1 mg of benztropine equals 375 mg (2) or 85 mg (1) of clozapine. Our recent study agreed that clozapine probably has important antimuscarinic activity (3). The mean serum antimuscarinic activity in 20 patients taking antiparkinsonian medications with mean doses of two benztropine equivalents was approximately 1 pmol/ml (1.05, 95% CI=0.66–1.44) (3). The antimuscarinic activity of 100 mg/day of clozapine in 17 patients was approximately 1 pmol/ml (1.38, 95% CI=0.83–1.93). The mean antimuscarinic activity of 300 mg/day of clozapine in 25 patients was approximately 2 pmol/ml (1.91, 95% CI=1.42–2.40). The mean antimuscarinic activity of 600 mg/day of clozapine in 27 patients was approximately 3 pmol/ml (2.81, 95% CI=2.16–3.46).

To estimate clozapine equivalence, one can approximate that 1 benztropine equivalent equals 0.5 pmol/ml of serum antimuscarinic activity. Using the serum muscarinic activity data of the three clozapine doses, one can estimate that 1 mg of benztropine equals 50 mg of clozapine (obtained from the 100-mg data) to 75 mg of clozapine (obtained from the 300-mg data) to 100 mg of clozapine (obtained from the 600-mg data). Thus, the clozapine equivalent of 1 mg/day of benztropine ranges from 50 to 100 mg/day of clozapine. The misleading fact that clozapine is an agonist for some muscarinic receptors, the M₄, and may cause hypersalivation instead of dry mouth may confound clinicians.