(217) Effectiveness of low-dose amitriptyline and mirtazapine in insomnia disorder: a randomised, double-blind, placebo-controlled trial in general practice (the DREAMING study)

Background: The antidepressants amitriptyline and mirtazapine are widely prescribed in low doses for several months to patients with insomnia disorder, although they are not licensed for this indication. Placebo-controlled studies on the short and long-term effectiveness of these drugs in patients with insomnia disorder are lacking.

Objectives: To assess the effectiveness of low-dose mirtazapine and amitriptyline in patients with insomnia disorder in general practice.

Methods:

Design: Pragmatic, double-blind, individually randomised, placebo-controlled trial
Setting: 64 general practices
Participants: 80 patients (18-85 years) with insomnia disorder experiencing difficulty maintaining sleep or early-morning awakening problems for whom non-pharmacological treatment was insufficient.
Interventions: 16-week treatment with either mirtazapine (7.5-15 mg/day) or amitriptyline (10-20 mg/day) or placebo: single dose at start and in the final two weeks with optional double dose regime following a GP consultation in week 3.
Main outcome measures: insomnia severity at week 6 measured with the Insomnia Severity Index (ISI, range 0-28) measured at baseline, 6, 12, 20 and 52 weeks; total score, clinically relevant ‘improvement’ (more than 7 points lower than baseline) and ‘recovery’ (total score 10 or lower) Secondary outcomes included self-reported sleep; daytime functioning; tolerability and adherence.
Analysis: Descriptive statistics and linear mixed model, logistic generalized estimating equations and Poisson mixed model regression analyses.

Results: In the intention-to-treat analyses ISI scores in the mirtazapine and amitriptyline group were statistically significantly lower compared to the placebo group at week 6 (mean difference −6.0 points, 95% confidence interval −9.0 to −3.1; and −3.4 points, −6.3 to −0.4, respectively).
At 6 weeks, mirtazapine, and not amitriptyline, resulted in statistically significantly higher improvement and recovery rates compared to placebo (52 and 40 compared to 14% and 56 and 36 compared to 14% respectively). At 12 weeks nearly half of the participants in each treatment group reported improvement or recovery and from that point in time onwards no statistically significant differences in ISI were observed.

Conclusions: Low-dose mirtazapine resulted in a statistically significant and clinically relevant reduction of insomnia severity compared to placebo at 6 weeks, but provided at later time points no benefit over placebo anymore. The statistically significant reduction found with low-dose amitriptyline only at week 6 was not clinically relevant.