Mirtazapine for Sleep: Off-Label Use, Dosing, and Precautions
Direct Recommendation
Mirtazapine can be used off-label for insomnia, but only as a third-line option after FDA-approved hypnotics have failed, and it must be combined with Cognitive Behavioral Therapy for Insomnia (CBT-I). The starting dose is 7.5 mg at bedtime, titratable to 15–30 mg, with particular caution required in patients over 65 due to increased fall risk and adverse effects. 1, 2
Evidence Quality and Guideline Position
The American Academy of Sleep Medicine positions mirtazapine as a third-line pharmacologic option after short/intermediate-acting benzodiazepine receptor agonists (BzRAs) and ramelteon have been considered, emphasizing that its efficacy for chronic primary insomnia is not well established. 1, 2
The evidence supporting mirtazapine for insomnia is limited in quality and generalizability, consisting primarily of off-label use reports rather than robust placebo-controlled trials in primary insomnia populations. 2
However, a 2025 randomized controlled trial (the MIRAGE study) demonstrated that mirtazapine 7.5 mg significantly reduced Insomnia Severity Index scores by -6.5 points versus -2.9 for placebo (p=0.003) in adults ≥65 years with chronic insomnia, providing the first high-quality evidence in older adults. 3
A separate 2025 trial (DREAMING study) showed that low-dose mirtazapine (7.5–15 mg) produced clinically relevant improvement at 6 weeks (52% improvement rate vs 14% placebo), but this effect was not sustained at 12 weeks or beyond. 4
Dosing Algorithm
Starting Dose
- Begin with 7.5 mg at bedtime for all patients, including those over 65, as this dose provides strong sedation through histamine H₁-receptor antagonism while minimizing noradrenergic activation. 1, 2, 3
Dose Titration
If sleep improvement is insufficient after 1–2 weeks, increase to 15 mg at bedtime; paradoxically, lower doses are more sedating than higher ones due to differential receptor occupancy. 1, 2
If 15 mg remains inadequate after another 1–2 weeks, titrate to 30 mg at bedtime, which is the upper limit for insomnia treatment unless comorbid depression requires higher doses (up to 45 mg). 1, 2
Duration and Monitoring
Reassess efficacy and adverse effects after 2–4 weeks, evaluating sleep-onset latency, total sleep time, nocturnal awakenings, and daytime functioning. 1
Mirtazapine requires consistent nightly dosing—not PRN use—because it has a 20–40 hour half-life and takes several days to reach steady-state therapeutic levels. 1, 5
Special Precautions in Patients Over 65
Increased Adverse Event Risk
In the MIRAGE trial, 6 of 30 participants (20%) in the mirtazapine group discontinued treatment due to adverse events (vs 1 of 30 in placebo), primarily sedation, dizziness, and increased appetite. 3
Older adults are at heightened risk for falls, cognitive impairment, and morning sedation when using any sedating medication, including mirtazapine. 1
Dose Adjustment
- Start at 7.5 mg in patients ≥65 years and titrate cautiously; the MIRAGE and DREAMING trials both used 7.5–15 mg as the therapeutic range in older adults, demonstrating efficacy without requiring higher doses. 3, 4
Monitoring Requirements
Screen for orthostatic hypotension, falls, and cognitive changes at each follow-up visit (weeks 2,4,6, and 12), as older adults are more vulnerable to these effects. 1, 3
Avoid combining mirtazapine with other sedating agents (e.g., benzodiazepines, Z-drugs, antihistamines) because additive CNS depression markedly increases fall risk, respiratory depression, and cognitive impairment. 1, 2
Clinical Contexts Where Mirtazapine Is Appropriate
Comorbid Depression or Anxiety
- Mirtazapine is particularly suitable when the patient has comorbid depression or anxiety, as it simultaneously addresses mood symptoms and insomnia through its noradrenergic and specific serotonergic effects. 1, 2, 5
Palliative Care Settings
- In palliative care patients with refractory insomnia, the National Comprehensive Cancer Network lists mirtazapine 7.5–30 mg at bedtime as an acceptable option, especially when the patient also has depression and loss of appetite. 1, 2
After First-Line Agents Have Failed
- Consider mirtazapine only after FDA-approved hypnotics (eszopiclone, zolpidem, zaleplon, ramelteon, low-dose doxepin, suvorexant) have been tried and failed or are contraindicated. 1, 2
Mandatory Concurrent Behavioral Therapy
The American Academy of Sleep Medicine and the American College of Physicians issue a strong recommendation that all adults with chronic insomnia receive CBT-I as first-line treatment before or alongside any pharmacotherapy, including mirtazapine. 1
CBT-I provides superior long-term efficacy compared with medication alone, with sustained benefits after treatment discontinuation, whereas mirtazapine's effects cease when stopped. 1, 4
Core CBT-I components—stimulus control, sleep restriction, relaxation techniques, and cognitive restructuring—should be implemented concurrently with mirtazapine to maximize sleep improvement and facilitate eventual medication tapering. 1
Common Adverse Effects
Sedation, increased appetite, and weight gain are more common with mirtazapine than placebo, occurring in a dose-dependent manner. 5, 4
Mirtazapine has minimal cardiovascular and anticholinergic effects and essentially lacks serotonergic side effects such as gastrointestinal symptoms, insomnia, and sexual dysfunction. 5
The elimination half-life of 20–40 hours enables once-daily bedtime dosing but also means that morning sedation can persist, particularly in older adults. 5
Common Pitfalls to Avoid
Do not prescribe mirtazapine as a first-line agent for primary insomnia; guideline societies explicitly position it as third-line after FDA-approved hypnotics. 1, 2
Do not use mirtazapine PRN (as needed); it requires consistent nightly dosing to maintain therapeutic blood levels and sedating effects. 1
Do not initiate mirtazapine without concurrent CBT-I, as behavioral therapy is mandated as first-line treatment and provides more durable benefits than medication alone. 1
Do not combine mirtazapine with other sedating medications (benzodiazepines, Z-drugs, antihistamines) without careful assessment, as additive CNS depression significantly increases fall risk, especially in older adults. 1, 2
Do not assume mirtazapine is safer than FDA-approved hypnotics; the evidence does not support a superior safety profile, and discontinuation rates due to adverse events can be substantial (20% in the MIRAGE trial). 3