Efficacy and safety of esmirtazapine in adult outpatients with chronic primary insomnia: a randomized, double-blind placebo-controlled study and open-label extension

Abstract

Study Objectives: Esmirtazapine (1.5-4.5 mg) has demonstrated short-term sleep-promoting effects in nonelderly outpatients with chronic insomnia. This phase 3, randomized, double-blind study (NCT00631657) and its open-label extension (NCT00750919) investigated efficacy and safety of long-term esmirtazapine treatment in adult outpatients with chronic insomnia. Methods: Participants were randomized to receive esmirtazapine 4.5 mg or placebo for 6 months; those receiving esmirtazapine were then rerandomized to esmirtazapine or placebo for an additional 7 days. Participants could enter the 6-month open-label extension with esmirtazapine 4.5 mg. The primary objective of the double-blind study was to assess long-term efficacy of esmirtazapine vs placebo on self-reported total sleep time. Assessing long-term safety and tolerability were secondary and primary objectives of the double-blind and extension studies, respectively. Results: Overall, 457 participants received treatment in the double-blind study (esmirtazapine, n = 342; placebo, n = 115) and 184 participants (prior esmirtazapine, n = 136; prior placebo, n = 48) received esmirtazapine in the extension. In the double-blind study, a 48.7-minute increase in average nightly total sleep time was observed for esmirtazapine vs placebo (95% confidence interval, 35.0-62.5; P <.0001) at months 4-6. There was no evidence of residual effects on nextday alertness or daytime functioning and no evidence of rebound insomnia or withdrawal symptoms upon treatment discontinuation. Esmirtazapine was generally well tolerated; somnolence and weight gain were the most common adverse events. Conclusions: Esmirtazapine improved sleep duration vs placebo over at least 6 months. There was no evidence of next-day residual effects or of withdrawal symptoms or rebound insomnia following abrupt treatment discontinuation.

Alliance for Sleep Clinical Practice Guideline on Switching or Deprescribing Hypnotic Medications for Insomnia

“…Another randomized placebo-controlled trial comprised of 457 adults with chronic insomnia studied the effects of esmirtazapine 4.5 mg or placebo for 6 months followed by a 7-day discontinuation period [ 94 ]. Following the treatment period, the esmirtazapine group was double-blind re-randomized 1:2 to continue esmirtazapine ( n = 65) or abruptly switch to placebo ( n = 137).…”

Insomnia medications: History, characteristics, and guidelines for optimal use in clinical practice

“…A series of double‐blind, placebo‐controlled studies has been carried out with the S‐isomer of mirtazapine, esmirtazapine, dosed from 1.5 to 4.5 mg, demonstrating robust efficacy for both sleep onset and maintenance difficulties as well as a relatively favourable safety profile in the treatment of patients with insomnia (Ivgy‐May, Roth et al, 2015; Ivgy‐May, Ruwe et al, 2015; Ivgy‐May et al, 2020). However, these studies are of uncertain relevance to the use of racemic mirtazapine because when dosing the racemate, the blood levels of the R‐isomer are higher than the S‐isomer and the R‐isomer has a longer elimination half‐life.…”

Efficacy and safety of esmirtazapine in adult insomnia: unsupported statements about residual daytime effects

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Confirmation that 5-hydroxytryptamine receptor 2A/2C antagonists such as esmirtazapine work for insomnia, based on 2009-2010 trials, is welcome news. 1 Research has shown that 5-hydroxytryptamine receptor 2A/2C antagonists such as mirtazapine and trazodone have a long history of use for insomnia, 2-4 but large double-blind insomnia studies have been lacking. Ivgy-May et al 1 do make some assertions that require caveats.The authors state without supporting data or references that esmirtazapine has a shorter half-life than the racemic mixture.

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