Low-Dose Mirtazapine: A New Option in the Treatment of Antipsychotic-Induced Akathisia. A Randomized, Double-Blind, Placebo- and Propranolol-Controlled Trial

Preliminary evidence indicates a beneficial effect of serotonin 2A (5-HT 2A) receptor antagonists in antipsychotic-induced akathisia (AIA). We investigated the antiakathisia effect, safety, and tolerability of low-dose mirtazapine, an agent with marked 5-HT 2A antagonism. In a 7-day double-blind trial, 90 antipsychotic-treated patients meeting DSM-IV criteria for AIA were randomly assigned to mirtazapine ( n = 30; 15 mg), propranolol ( n = 30; 80 mg), or placebo ( n = 30). Primary outcome measures were between-group differences in Barnes Akathisia Scale (BAS) global scores and in the proportion of responders (reduction of ≥ 2 points on BAS). Analysis was by intention to treat. Twenty-four patients (26.6%) who were assigned treatment did not complete the study (7 mirtazapine, 8 propranolol, 9 placebo), due to lack of response ( n = 19) and adverse events ( n = 5). Both mirtazapine and propranolol significantly reduced AIA severity (BAS: −34% mirtazapine and −29% propranolol vs. placebo −11%; p = .012 and p = .023, respectively). Thirteen (43.3%) mirtazapine and 9 (30.0%) propranolol-treated patients versus 2 (6.7%) placebo-treated patients responded (the corresponding odds ratios 10.7 [95% confidence interval (CI), 2.1–53.3] and 6.0 [95% CI, 1.1–30.7]). Five (16.7%) of 30 propranolol-treated patients and none in the mirtazapine and placebo groups ( p = .0195 for both) prematurely discontinued the study due to clinically significant hypotension or bradycardia. The comparable efficacy and better tolerability of low-dose mirtazapine versus propranolol, the current first-line treatment for AIA, position mirtazapine as a favorable candidate for the treatment of acute AIA and may improve current therapeutic practices.