Can mirtazapine be used to treat insomnia?

Mirtazapine for Insomnia

Mirtazapine is an effective treatment for insomnia and should be considered as a second or third-line option when first-line treatments (CBT-I and benzodiazepine receptor agonists) fail or when comorbid depression/anxiety exists. 1, 2

Treatment Hierarchy for Insomnia

First-Line Treatment

• Cognitive Behavioral Therapy for Insomnia (CBT-I) is the standard of care before any pharmacotherapy, demonstrating superior long-term outcomes with sustained benefits after discontinuation. 1

First-Line Pharmacotherapy

• When CBT-I fails or is unavailable, benzodiazepine receptor agonists (zolpidem, eszopiclone, zaleplon) or ramelteon are recommended as first-line pharmacological agents. 1
• Low-dose doxepin (3-6 mg) is particularly effective for sleep maintenance insomnia with minimal side effects. 1

Second/Third-Line: Sedating Antidepressants (Including Mirtazapine)

• Sedating antidepressants including mirtazapine, trazodone, doxepin, and amitriptyline are recommended as third-line treatment for primary insomnia, or earlier when comorbid depression/anxiety exists. 1, 3
• The American Academy of Family Physicians specifically notes that mirtazapine is potent, well-tolerated, and promotes sleep, appetite, and weight gain. 2

Mirtazapine-Specific Dosing and Efficacy

Recommended Dosing

• Start at 7.5 mg at bedtime, with a maximum of 30 mg at bedtime. 2
• Lower doses (7.5 mg) may be more sedating due to greater antihistaminic (H1) activity, while somnolence appears less frequent at higher dosages. 4

Evidence of Efficacy

• The most recent and highest quality evidence comes from the 2025 MIRAGE study, which demonstrated that mirtazapine 7.5 mg significantly reduced insomnia severity in older adults (≥65 years) compared to placebo. 5
• After 28 days, the mean change in Insomnia Severity Index (ISI) score was -6.5 in the mirtazapine group versus -2.9 in placebo (p=0.003). 5
• Mirtazapine improved subjective wake after sleep onset, total sleep time, and sleep efficiency. 5
• Earlier studies with esmirtazapine (the S-enantiomer) showed improved polysomnography-determined total sleep time by at least 25 minutes with doses of 1.5-4.5 mg. 6

Critical Safety Considerations and Adverse Effects

Common Side Effects That Limit Use

• Somnolence is the most common side effect, reported in 54% of patients (versus 18% placebo), leading to discontinuation in 10.4% of cases. 7
• Appetite increase occurs in 17% of patients (versus 2% placebo), with weight gain ≥7% of body weight in 7.5% of patients (versus 0% placebo). 7
• In the MIRAGE study, 6 participants in the mirtazapine group discontinued due to adverse events versus 1 in placebo, though no severe adverse events occurred. 5

Serious but Rare Risks

• Agranulocytosis is rare (approximately 1 in 1,000) but usually reversible when medication is stopped. 8
• QTc prolongation and Torsades de Pointes have been reported postmarketing, primarily with overdose or in patients with other risk factors. 7
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported and can be fatal; discontinue immediately if suspected. 7
• Hyponatremia may occur, with cases of serum sodium <110 mmol/L reported. 7

Metabolic Effects

• Nonfasting cholesterol increases ≥20% above normal occurred in 15% of patients (versus 7% placebo). 7
• Nonfasting triglyceride increases to ≥500 mg/dL occurred in 6% of patients (versus 3% placebo). 7

Clinical Approach and Monitoring

When to Use Mirtazapine

• Use mirtazapine when first-line treatments (BzRAs, ramelteon) have failed or are contraindicated. 1
• Prioritize mirtazapine when comorbid depression or anxiety exists, as it addresses both conditions simultaneously. 2, 3
• Consider mirtazapine in patients who experience sexual side effects from SSRIs or other antidepressants. 8
• Mirtazapine is particularly useful in patients with significant anxiety or agitation accompanying insomnia. 4, 8

Monitoring Requirements

• Use the lowest effective dose for the shortest duration possible. 1
• Regular follow-up to assess efficacy, side effects (especially weight gain and somnolence), and continued need for medication. 1, 3
• Monitor for metabolic effects including weight, cholesterol, and triglycerides. 7
• Screen for activation of mania/hypomania in patients with any personal or family history of bipolar disorder. 7

Important Caveats

• Caution patients about engaging in activities requiring alertness (driving, operating machinery) until they know how mirtazapine affects them, given the 54% incidence of somnolence. 7
• Avoid concomitant use with benzodiazepines and alcohol. 7
• Exercise caution in patients with cardiovascular disease, family history of QT prolongation, or concomitant use of QTc-prolonging medications. 7
• In pediatric patients, 49% experienced weight gain ≥7% (versus 5.7% placebo), though mirtazapine is not established as safe/effective in this population. 7

Combination and Transition Strategies

• Combine with CBT-I whenever possible for optimal outcomes. 2, 3
• If weight gain becomes problematic, consider transitioning to prolonged-release melatonin as add-on therapy to facilitate mirtazapine withdrawal while maintaining sleep improvement. 9
• When discontinuing, taper over 10-14 days to limit withdrawal symptoms. 2