Mirtazapine for Insomnia: Dosing and Safety Considerations
Start mirtazapine 7.5 mg at bedtime for insomnia in adults, including elderly patients, and titrate to 15 mg after 1–2 weeks if needed; mirtazapine is a third-line option after benzodiazepine receptor agonists and ramelteon have failed, and is particularly appropriate when comorbid depression or anxiety is present. 1
Position in Treatment Algorithm
Mirtazapine is positioned as a third-line pharmacologic option after short-intermediate acting benzodiazepine receptor agonists (zolpidem, eszopiclone, zaleplon, temazepam) and ramelteon have been considered and found insufficient. 1
The American Academy of Sleep Medicine states that sedating antidepressants including mirtazapine should be considered when first-line benzodiazepine receptor agonists or ramelteon have failed, or when comorbid depression/anxiety is present. 2, 1
All patients must receive Cognitive Behavioral Therapy for Insomnia (CBT-I) as initial treatment before or alongside any pharmacotherapy, as it demonstrates superior long-term efficacy with sustained benefits after medication discontinuation. 2
Starting Dose and Titration Schedule
Adults (Including Elderly):
Start with 7.5 mg at bedtime as the recommended initial dose for insomnia treatment. 1, 3, 4
If insufficient response after 1–2 weeks, increase to 15 mg at bedtime; this is the FDA-approved starting dose for depression but represents a titration step for insomnia. 5, 4
Maximum dose for insomnia is typically 15–30 mg at bedtime, though doses up to 45 mg may be used when treating comorbid depression. 6, 1, 5
Dose changes should not be made in intervals of less than 1–2 weeks to allow sufficient time for evaluation of response to a given dose. 5
Key Dosing Principle:
- Mirtazapine must be taken nightly on a scheduled basis, not PRN (as needed), because it has a half-life of 20–40 hours and requires several days to reach steady-state blood levels; it cannot provide immediate "on-demand" sedation like short-acting hypnotics. 2, 7
Evidence for Efficacy in Older Adults
The 2025 MIRAGE trial (the highest-quality and most recent evidence) demonstrated that mirtazapine 7.5 mg significantly reduced insomnia severity in adults aged 65 and older with chronic insomnia. 3
After 28 days, the mean change in Insomnia Severity Index (ISI) score was significantly greater in the mirtazapine group (−6.5 points) compared to placebo (−2.9 points), with a p-value of 0.003. 3
Mirtazapine was superior to placebo on subjective wake after sleep onset, total sleep time, and sleep efficiency. 3
A 2025 trial in general practice showed that low-dose mirtazapine (7.5–15 mg) led to a statistically significant and clinically relevant reduction of insomnia severity at 6 weeks (mean difference −6.0 points on ISI compared to placebo), though this effect was not sustained at later time points. 4
Safety Considerations and Adverse Effects
Common Adverse Effects:
Sedation, increased appetite, and weight gain are more common with mirtazapine than with placebo. 7
In the MIRAGE trial, 6 participants in the mirtazapine group (versus 1 in placebo) discontinued treatment due to adverse events, though no severe adverse events occurred. 3
Weight gain is a clinically relevant concern: in one case series, 7 of 11 perimenopausal women demonstrated weight gain following mirtazapine intake. 8
Advantages Over Other Antidepressants:
Mirtazapine has minimal cardiovascular and anticholinergic effects, and essentially lacks serotonergic effects such as gastrointestinal symptoms, insomnia, and sexual dysfunction that are common with SSRIs. 7
Sleep disturbances and anxiety symptoms may improve in the first week of treatment, though full antidepressant effect takes 2–4 weeks. 7
Drug Interactions Requiring Dose Adjustment:
Decrease mirtazapine dose with concomitant use of strong CYP3A4 inhibitors (ketoconazole, clarithromycin) or cimetidine; conversely, increase dose if these inhibitors are discontinued. 5
Increase mirtazapine dose with concomitant use of strong CYP3A inducers (carbamazepine, phenytoin, rifampin); conversely, decrease dose if the inducer is discontinued. 5
Critical Safety Warnings:
Screen patients for personal or family history of bipolar disorder, mania, or hypomania prior to initiating mirtazapine, as antidepressants can precipitate manic episodes. 5
At least 14 days must elapse between discontinuation of an MAOI antidepressant and initiation of mirtazapine, and vice versa. 5
Gradually reduce the dosage of mirtazapine rather than stopping abruptly whenever possible, as adverse reactions may occur upon discontinuation or dose reduction. 5
Clinical Contexts Where Mirtazapine Is Particularly Appropriate
Patients with comorbid depression and insomnia, where mirtazapine may address multiple symptoms simultaneously. 1
Patients with comorbid anxiety and insomnia, as mirtazapine is recommended when comorbid depression/anxiety is present. 2, 1
Palliative care patients with refractory insomnia, where mirtazapine 7.5–30 mg at bedtime is listed as an acceptable pharmacologic option, especially when depression and anorexia are also present. 6, 1
Patients who have failed or cannot tolerate first-line agents (benzodiazepine receptor agonists, ramelteon). 1
Common Pitfalls to Avoid
Do not use mirtazapine as first-line therapy for primary insomnia; FDA-approved hypnotics (zolpidem, eszopiclone, zaleplon, temazepam) or ramelteon should be tried first. 2, 1
Do not prescribe mirtazapine PRN for occasional insomnia; it requires nightly scheduled dosing to maintain therapeutic blood levels. 2
Do not prescribe mirtazapine without attempting CBT-I first or alongside medication, as behavioral interventions provide more sustained effects than medication alone. 2, 1
Do not fail to counsel patients about expected weight gain and increased appetite, as this is a common reason for discontinuation. 3, 7, 8
Do not combine mirtazapine with other sedating medications without careful consideration of additive CNS depression, particularly in elderly patients at risk for falls. 6
Monitoring and Follow-Up
Reassess patients after 1–2 weeks to evaluate efficacy on sleep latency, sleep maintenance, and daytime functioning, and monitor for adverse effects including morning sedation, increased appetite, and weight gain. 5, 4
Regular follow-up is essential to assess medication effectiveness, side effects, and the ongoing need for pharmacotherapy. 1
Employ the lowest effective maintenance dosage, and taper medication when conditions allow, using CBT-I to facilitate successful discontinuation. 2, 1