Two randomized placebo-controlled trials to evaluate the efficacy and tolerability of mirtazapine for the treatment of obstructive sleep apnea

Abstract

Objective: Mirtazapine is an a2A antagonist and mixed 5-HT2/5-HT3 antagonist that has been proposed as a potential treatment for obstructive sleep apnea (OSA). A small, randomized, controlled trial has previously found an approximate halving in the severity of OSA with daily doses of 4.5 and 15 mg. We aimed to confirm and extend these findings in 2 randomized placebo-controlled, proof-of-concept trials.

Methods: Two randomized, double-blind, placebo-controlled trials of mirtazapine for OSA (apnea-hypopnea index 10-40/h). Study 1: 3-way crossover, dose-finding study testing the self-administration of mirtazapine (7.5, 15, 30, and/or 45 mg) or placebo 30 minutes prior to bedtime for 2 weeks at each dose. Twenty patients were randomly assigned to 1 of 6 different dose-sequence groups, with each patient exposed to a maximum of 3 doses. Study 2: 3-arm, randomized, parallel-group trial of mirtazapine at 15 mg or mirtazapine 15 mg + Compound CD0012 or placebo for 4 weeks in 65 patients with OSA.

Results: Two patients withdrew from Study 1 after complaints of unacceptable lethargy. Fifteen patients were withdrawn from study 2, 7 after complaints of unacceptable lethargy or other side-effects. No measurement of sleep apnea improved due to mirtazapine in either study. Weight gain was significantly greater on mirtazapine than on placebo in both trials.

Conclusions: Mirtazapine did not improve sleep apnea in either trial. Mirtazapine caused weight gain, which may further worsen OSA. Therefore, mirtazapine is not recommended for the treatment of OSA.

Figure 1

Effects of the various doses of mirtazapine on the apnea hypopnea index (AHI), compared with placebo. Estimates of the end of treatment AHI are derived from mixed-model estimates. Squares indicate the mean (bars = 95% confidence intervals) effects for each dose. Stars indicate significant worsening of the AHI, compared with placebo, adjusted for each patient's baseline value (P < 0.05) with doses of 15 mg and 30 mg. The point estimate of the AHI from the diagnostic sleep studies is included for comparison to show that placebo was not associated with a worsening of sleep apnea.

Figure 2

Two-week weight gain associated with each dose of mirtazapine compared with placebo. Squares indicate the mean (bars = 95% confidence intervals) effects for each dose. Stars indicate significantly greater weight gain compared with placebo (P < 0.05) was observed with all doses.