What starting dose of mirtazapine is recommended for insomnia in an adult without hepatic disease or MAOI use, and what are alternative sleep aids if contraindicated?

Mirtazapine for Sleep: Dosing and Recommendations

Start mirtazapine at 7.5 mg at bedtime for insomnia in adults without hepatic disease or MAOI use, and if inadequate response occurs after 6 weeks, increase to a maximum of 15 mg (not 30 mg as used for depression). 1

Starting Dose and Titration

• The American Academy of Family Physicians recommends 7.5 mg at bedtime as the starting dose for insomnia, with a maximum of 30 mg at bedtime for sleep promotion (though 15 mg is typically sufficient). 1

• The FDA-approved starting dose for depression is 15 mg, but lower doses (7.5 mg) are more appropriate for insomnia because sedation is paradoxically more pronounced at subtherapeutic antidepressant doses due to predominant H1-histamine receptor blockade. 2, 3

• Do not increase the dose more frequently than every 1–2 weeks to allow adequate time to assess response. 2

• A recent 2025 randomized controlled trial in older adults (≥65 years) demonstrated that mirtazapine 7.5 mg significantly reduced Insomnia Severity Index scores by -6.5 points versus -2.9 for placebo (p=0.003) after 28 days, with improvements in wake after sleep onset, total sleep time, and sleep efficiency. 4

Mechanism and Sleep-Promoting Effects

• Mirtazapine promotes sleep through antagonism of histamine H1 receptors (causing sedation), serotonin 5-HT2 receptors (improving sleep continuity and slow-wave sleep), and presynaptic α2-adrenergic receptors (enhancing noradrenergic and serotonergic neurotransmission). 5, 3

• Unlike many antidepressants, mirtazapine does not suppress REM sleep, which is clinically advantageous for sleep architecture. 6

• The sedative effect is dose-dependent and paradoxically greater at lower doses (7.5–15 mg) due to predominant antihistaminic activity; at higher doses (≥30 mg), noradrenergic activation counteracts sedation. 5, 7

Critical Contraindications and Precautions

• Absolute contraindication: Do not use within 14 days of MAOI discontinuation or before starting an MAOI, due to risk of serotonin syndrome. 2

• Screen for bipolar disorder before initiating mirtazapine; monitor for mood destabilization (decreased need for sleep, increased energy, racing thoughts, irritability) during the first 4–8 weeks if bipolar history exists. 1, 2

• Avoid abrupt discontinuation; taper over 10–14 days to prevent withdrawal symptoms including rebound insomnia, increased anxiety, and irritability. 1, 2

Common Adverse Effects Limiting Use

• The 2025 MIRAGE trial found that 6 participants (20%) in the mirtazapine group discontinued treatment due to adverse events versus 1 (3%) in placebo, though no severe adverse events occurred. 4

• Most common side effects are transient somnolence (dose-related), increased appetite, and weight gain, attributed to H1-receptor antagonism at low doses. 5, 7

• Mirtazapine has minimal anticholinergic, cardiovascular, gastrointestinal, and sexual side effects compared to tricyclic antidepressants and SSRIs. 5, 3, 7

Drug Interactions Requiring Dose Adjustment

• Strong CYP3A4 inducers (carbamazepine, phenytoin, rifampin) may require mirtazapine dose increase; conversely, discontinuing the inducer may require dose reduction. 2

• Strong CYP3A4 inhibitors (ketoconazole, clarithromycin) or cimetidine may require mirtazapine dose reduction; discontinuing these agents may require dose increase. 2

Alternative Sleep Aids if Mirtazapine is Contraindicated

First-Line Non-Pharmacologic Treatment (Always Initiate First)

• Cognitive Behavioral Therapy for Insomnia (CBT-I) is the gold standard and must be offered before or alongside any medication, demonstrating superior long-term efficacy with sustained benefits after discontinuation. 1, 8

FDA-Approved Pharmacologic Alternatives (Second-Line)

Indication	Agent & Dose	Key Advantages
Sleep onset + maintenance	Eszopiclone 2–3 mg (reduce to 1 mg in elderly/hepatic impairment)	FDA-approved, effective for both phases [8]
Sleep onset + maintenance	Zolpidem 10 mg (reduce to 5 mg in elderly)	FDA-approved, short-acting [8]
Sleep onset only	Zaleplon 10 mg (reduce to 5 mg in elderly)	Ultra-short half-life, minimal residual sedation [8]
Sleep onset only	Ramelteon 8 mg	Zero addiction potential, preferred with substance-use history [8]
Sleep maintenance only	Low-dose doxepin 3–6 mg	Most effective for maintenance, minimal anticholinergic effects, no abuse potential [1,8]

Agents to Explicitly Avoid

• Trazodone 50 mg is NOT recommended by the American Academy of Sleep Medicine due to no significant improvement in objective sleep parameters versus placebo, with adverse effects outweighing minimal subjective benefits. 8

• Benzodiazepines (lorazepam, temazepam, clonazepam) should be avoided due to higher risk of dependency, falls, cognitive impairment, and respiratory depression. 8, 9

• Over-the-counter antihistamines (diphenhydramine) are NOT recommended due to lack of efficacy data, strong anticholinergic burden, and tolerance development within 3–4 days. 8

• Antipsychotics (quetiapine, olanzapine) should NOT be used for primary insomnia due to insufficient evidence and significant metabolic side effects (weight gain, metabolic syndrome). 8, 9

Clinical Pearls and Common Pitfalls

• Administer mirtazapine at least 1 hour before bedtime on an empty stomach to maximize sleep-promoting effectiveness. 8

• The 7.5 mg dose used for insomnia is insufficient for treating comorbid depression; full antidepressant dosing (15–45 mg) is required for mood treatment. 8, 2

• Counsel patients to allow 7–8 hours of sleep time to reduce residual morning sedation. 8

• Monitor for complex sleep behaviors (sleepwalking, sleep-driving) and discontinue immediately if they occur. 8

• Use caution in patients with compromised respiratory function (asthma, COPD, sleep apnea), hepatic impairment, or heart failure, as mirtazapine may exacerbate these conditions. 8

• Avoid alcohol and other CNS depressants due to additive sedative effects. 8