Can long-term mirtazapine be used for insomnia?

Long-Term Mirtazapine for Insomnia

Mirtazapine 7.5–15 mg nightly can be used long-term for chronic insomnia, particularly when first-line agents have failed or when comorbid depression/anxiety is present, though it should always be combined with Cognitive Behavioral Therapy for Insomnia (CBT-I) and periodically reassessed for continued necessity.

Position in Treatment Algorithm

• The American Academy of Sleep Medicine positions mirtazapine as a third-line option for insomnia, after benzodiazepine receptor agonists (BzRAs) or ramelteon have failed 1, 2
• First-line pharmacotherapy includes short/intermediate-acting BzRAs (eszopiclone, zolpidem, zaleplon) or ramelteon 2
• Second-line options include low-dose doxepin 3–6 mg for sleep maintenance or suvorexant for sleep maintenance 2
• Mirtazapine becomes particularly appropriate when comorbid depression or anxiety is present, as it simultaneously addresses both mood and sleep disturbances 1, 2

Evidence for Long-Term Efficacy

• A 2025 randomized, double-blind, placebo-controlled trial (MIRAGE study) in older adults demonstrated that mirtazapine 7.5 mg significantly reduced Insomnia Severity Index scores by -6.5 points compared to -2.9 points with placebo after 28 days 3
• The 2025 DREAMING trial showed that mirtazapine 7.5–15 mg produced a clinically relevant reduction in insomnia severity at 6 weeks (mean difference -6.0 points on ISI compared to placebo), with 52% achieving improvement and 56% achieving recovery 4
• A 2015 retrospective study found that mirtazapine remained efficacious for at least 3 months in 86.95% of patients with chronic insomnia, with the lowest dose (7.5 mg) corresponding to the highest response rate (52.5%) 5
• Importantly, the DREAMING trial showed that statistical significance was lost at 12 weeks and beyond, though this may reflect the pragmatic trial design and high placebo response rates in general practice settings 4

Dosing Strategy

• Start at 7.5 mg at bedtime, which provides maximal histamine H₁ receptor blockade for sedation with minimal antidepressant effects 1, 6
• If inadequate response after 1–2 weeks, increase to 15 mg at bedtime 1, 6
• The maximum dose for insomnia is typically 30 mg, though higher doses paradoxically may be less sedating due to increased noradrenergic activity 1, 6
• Evidence suggests that lower doses (7.5–15 mg) produce higher response rates than higher doses (15–30 mg), with 100% responders at lower doses versus 53.84% at higher doses 5

Mechanism and Pharmacokinetics

• Mirtazapine promotes sleep primarily through potent histamine H₁ receptor antagonism, with additional effects on serotonin 5-HT₂ and 5-HT₃ receptors 3, 7
• The drug has a half-life of 20–40 hours, requiring consistent nightly dosing rather than PRN use to maintain therapeutic blood levels 1
• At low doses, the sedating antihistaminergic effects predominate, while higher doses engage more noradrenergic activity that can reduce sedation 7

Safety Profile and Adverse Events

• The MIRAGE study found that 6 participants (20%) in the mirtazapine group discontinued due to adverse events compared to 1 (3.3%) in the placebo group, though no severe adverse events occurred 3
• Common adverse effects include daytime sedation, increased appetite, weight gain, and dizziness 1, 3
• Mirtazapine has minimal anticholinergic effects compared to other sedating antidepressants like amitriptyline, making it safer in elderly patients 6, 7
• The drug carries no abuse potential and is not a controlled substance, unlike BzRAs 7

Duration of Treatment and Reassessment

• The American Academy of Sleep Medicine recommends attempting to taper and discontinue mirtazapine after 3–6 months of stable sleep to determine if continued medication is necessary 1
• Periodic reassessment every 4–6 weeks is essential to evaluate ongoing efficacy, adverse effects, and the possibility of tapering 2
• Unlike short-term hypnotics (which FDA labeling limits to <4 weeks), mirtazapine's antidepressant properties may justify longer-term use when comorbid mood disorders are present 2, 6

Mandatory Integration with CBT-I

• All pharmacotherapy for insomnia must be supplemented with CBT-I, which provides superior long-term outcomes and sustained benefits after medication discontinuation 1, 2
• CBT-I includes stimulus control, sleep restriction, relaxation techniques, and cognitive restructuring, and can be delivered via individual therapy, group sessions, telephone, web-based modules, or self-help books 2
• Combining mirtazapine with CBT-I facilitates eventual medication tapering and prevents relapse 1, 2

Comparison with Other Sedating Antidepressants

• Trazodone is explicitly NOT recommended by the American Academy of Sleep Medicine, producing only ~10 minutes reduction in sleep latency with no improvement in subjective sleep quality and harms outweighing benefits 2
• Low-dose amitriptyline (10–20 mg) showed only a statistically significant but not clinically relevant reduction in insomnia severity at 6 weeks in the DREAMING trial, with no difference from placebo at later time points 4
• Low-dose doxepin 3–6 mg remains the preferred sedating antidepressant for sleep maintenance insomnia due to moderate-quality evidence, minimal anticholinergic effects, and no abuse potential 2, 7

Special Populations

Elderly Patients

• The MIRAGE study specifically demonstrated efficacy and acceptable tolerability in adults ≥65 years 3
• Start at 7.5 mg in elderly patients due to increased sensitivity and fall risk 6
• Monitor closely for morning sedation, cognitive impairment, and orthostatic hypotension 1, 3

Patients with Comorbid Depression or Anxiety

• Mirtazapine is particularly appropriate when insomnia coexists with depression or anxiety, as therapeutic antidepressant doses (15–45 mg) simultaneously treat both conditions 1, 6
• The American Academy of Sleep Medicine recommends sedating antidepressants as preferred initial choices for patients with comorbid mood disorders 2

Patients with Substance Use History

• Mirtazapine is a safe alternative to BzRAs in patients with a history of substance abuse, as it has no abuse potential or DEA scheduling 7

Critical Contraindications and Warnings

• Avoid in patients taking MAO inhibitors due to risk of serotonin syndrome 6
• Monitor for serotonin syndrome when combining with other serotonergic agents (SSRIs, SNRIs), though the risk is lower than with other antidepressants 1
• Counsel patients about next-day drowsiness, especially during the first week, and advise avoiding driving or operating machinery until response is known 1
• Avoid alcohol while taking mirtazapine due to additive CNS depression 1

Common Pitfalls to Avoid

• Using mirtazapine PRN (as needed) rather than nightly scheduled dosing—the drug requires consistent administration to maintain therapeutic levels 1
• Failing to initiate CBT-I before or alongside mirtazapine, which reduces long-term success rates 1, 2
• Increasing the dose too quickly or too high—evidence shows lower doses (7.5–15 mg) are more effective for insomnia than higher doses 5
• Continuing indefinitely without reassessment—attempt tapering after 3–6 months of stable sleep to determine ongoing necessity 1
• Using mirtazapine as first-line therapy before trying FDA-approved hypnotics or low-dose doxepin, unless comorbid depression/anxiety is present 1, 2