Abstract Introduction Mirtazapine has complex pharmacologic properties, with lower doses exerting sedative effects through antihistaminergic activity and higher doses showing activating, noradrenergic effects. Low-dose mirtazapine (7.5–15 mg) is often prescribed off-label for insomnia, though it frequently causes troublesome daytime drowsiness. We speculated that an ultra-low dose (3.75 mg) might improve insomnia while minimizing next-day sedation. We present two cases demonstrating that even ultra-low doses can lead to significant residual sedation, suggesting that this adverse effect may not be dose-dependent. Report of case(s) A 60-year-old veteran with obstructive sleep apnea on AutoCPAP, periodic limb movement disorder (PLMD), and insomnia secondary to PLMD had an Insomnia Severity Index (ISI) of 20 and Epworth Sleepiness Scale (ESS) of 11. PLMD was partially stabilized on gabapentin. Trazodone 50 mg nightly reduced PLMD frequency but failed to improve insomnia. Trazodone was replaced with mirtazapine 3.75 mg nightly. After one month, ISI improved to 7, but ESS increased to 24, consistent with significant next-day sleepiness. Upon discontinuation of ultra-low dose mirtazapine, ESS returned to baseline. A consult for CBT-I was placed. An 81-year-old veteran with depression, insomnia, and chronic pain, controlled on duloxetine 60 mg, had an initial ISI of 24 and ESS of 7. Mirtazapine 3.75 mg nightly was started for nocturnal sleep fragmentation. After two months, ISI improved to 12, but ESS rose to 21, again indicating prominent residual sedation. Mirtazapine 3.75 mg nightly was substituted with Doxepin 10 mg nightly, which provided similar efficacy with tolerability. Conclusion Ultra-low dose mirtazapine (3.75 mg) may improve insomnia symptoms and ISI scores, but next-day residual sedation remains a clinically significant concern. Prior studies have shown daytime drowsiness in up to 54% of patients taking 7.5–15 mg, often described as a “hungover” feeling. These cases demonstrate that sedation can occur even at ultra-low doses, potentially limiting its clinical utility for insomnia management. Clinicians should routinely screen for next-day sedation in patients prescribed low-dose mirtazapine for sleep, and future randomized controlled trials are needed to evaluate the efficacy and tolerability of ultra-low dosing. Support (if any)
Das et al. (Fri,) studied this question.