Two randomized placebo-controlled trials to evaluate the efficacy and tolerability of mirtazapine for the treatment of obstructive sleep apnea.
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 Fifteen patients were withdrawn from study 2, 7 after complaints of unacceptable lethargy or other side-effects.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.
NHMRC Centre for Sleep Medicine, Woolcock Institute of Medical Research, University of Sydney, NSW Australia.
Nathaniel S
NS
Marshall
Brendon J
BJ
Yee
Anup V
AV
Desai
Peter R
PR
Buchanan
Keith K H
KK
Wong
Renee
R
Crompton
Kerri L
KL
Melehan
Nadene
N
Zack
Srinivas G
SG
Rao
R Michael
RM
Gendreau
Jay
J
Kranzler
Ronald R
RR
Grunstein
D000328:Adult; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004361:Drug Tolerance; D005260:Female; D006634:Histamine H1 Antagonists / Q000627:therapeutic use*; D006801:Humans; D006993:Hypnotics and Sedatives / Q000627:therapeutic use; D008297:Male; D008803:Mianserin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000078785:Mirtazapine; D017286:Polysomnography; D020181:Sleep Apnea, Obstructive / Q000175:diagnosis / Q000188:drug therapy*; D012895:Sleep, REM / Q000502:physiology; D016896:Treatment Outcome
D006634:Histamine H1 Antagonists; D006993:Hypnotics and Sedatives; D008803:Mianserin; D000078785:Mirtazapine