Effectiveness of low-dose amitriptyline and mirtazapine in patients with insomnia disorder with sleep maintenance problems: a randomised, double-blind, placebo-controlled trial in general practice (DREAMING).

Background: Low-dose amitriptyline and mirtazapine are widely prescribed off-label for insomnia disorder. However, evidence from placebo-controlled studies is lacking.

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

Design And Setting: Pragmatic, double-blind, randomised, placebo-controlled trial in general practice.

Methods: Patients (18-85 years) with insomnia disorder with sleep maintenance problems for whom non-pharmacological treatment was insufficient were randomised to either mirtazapine (7.5-15 mg/day) or amitriptyline (10-20 mg/day) or placebo for 16 weeks (optional double dose regime in week 3-14).

Primary Outcome: Insomnia Severity Index (ISI) total score at week 6 (range 0-28, assessed at baseline, 6, 12, 20 and 52 weeks), clinically relevant 'improvement' (>7 points lower than baseline) and 'recovery' (total score ≤10).

Results: 80 participants were included. At 6 weeks, in the intention-to-treat analyses, mirtazapine and amitriptyline led to statistically significantly lower ISI scores compared to placebo (mean difference -6.0 points, 95% confidence interval -9.0 to -3.1; and -3.4 points, -6.3 to -0.4, respectively). From 12 weeks onwards no statistically significant differences in ISI scores were observed. Mirtazapine, but not amitriptyline, resulted in statistically significantly higher improvement and recovery rates compared to placebo at week 6 (52 and 40 compared to 14%, 56 and 36 compared to 14% respectively).

Conclusion: Compared to placebo low-dose mirtazapine provided a statistically significant and clinically relevant reduction of insomnia severity at 6 weeks, but not at later time points. Low-dose amitriptyline resulted in a statistically significant reduction at 6 weeks only which was not clinically relevant.