Is mirtazapine appropriate for treating chronic insomnia in a patient aged ≥65 years, and what is the recommended starting dose and safety monitoring?

Mirtazapine for Elderly Insomnia

Mirtazapine 7.5 mg at bedtime is an appropriate and effective option for treating chronic insomnia in elderly patients (≥65 years), particularly when first-line benzodiazepine receptor agonists have failed or when comorbid depression/anxiety is present. 1, 2

Evidence Supporting Mirtazapine in Elderly Insomnia

Efficacy Data

• The MIRAGE trial (2025)—the first randomized, double-blind, placebo-controlled study specifically in older adults—demonstrated that mirtazapine 7.5 mg significantly reduced Insomnia Severity Index (ISI) scores by -6.5 points compared to -2.9 points with placebo (p=0.003) after 28 days. 2

• Mirtazapine improved subjective wake after sleep onset, total sleep time, and sleep efficiency in elderly patients with chronic insomnia, with moderate-quality evidence. 2

• In the DREAMING trial (2025), mirtazapine 7.5–15 mg produced a clinically meaningful reduction in ISI scores of -6.0 points compared to placebo at 6 weeks, with 52% achieving improvement and 56% achieving recovery (ISI ≤10) versus only 14% with placebo. 3

• Long-term retrospective data show that mirtazapine at 7.5 mg produced the highest response rate (52.5%) and was effective in 87% of chronic insomnia patients over 3+ months without tolerance development. 4

Position in Treatment Algorithm

• The American Academy of Sleep Medicine positions sedating antidepressants including mirtazapine as third-line agents—after first-line benzodiazepine receptor agonists (BzRAs) or ramelteon have failed, and particularly appropriate when comorbid depression or anxiety is present. 5, 1

• Mirtazapine is not FDA-approved for insomnia and its efficacy was not well-established until the 2025 MIRAGE and DREAMING trials provided definitive placebo-controlled evidence. 5, 2, 3

Recommended Starting Dose and Titration

Initial Dosing

• Start mirtazapine 7.5 mg taken 30 minutes before bedtime. 2, 4, 3

• This low dose maximizes histamine H₁-receptor blockade (the mechanism responsible for sedation) while minimizing serotonergic and noradrenergic effects that occur at higher antidepressant doses (15–45 mg). 2, 4

Dose Adjustment

• If insomnia persists after 2–3 weeks, increase to 15 mg at bedtime. 4, 3

• The DREAMING trial allowed optional dose doubling at week 3 if response was insufficient, with final doses of 7.5–15 mg. 3

• Higher doses (>15 mg) paradoxically may reduce sedation due to increased noradrenergic activity and should be avoided for primary insomnia. 4

Duration of Therapy

• The MIRAGE trial demonstrated sustained efficacy at 28 days without tolerance. 2

• Retrospective data show maintained efficacy over 3+ months at low doses (7.5–15 mg) without problems of tolerance. 4

• Unlike benzodiazepine receptor agonists, which FDA labeling limits to <4 weeks, mirtazapine can be continued longer-term when effective, though periodic reassessment every 4–6 weeks is recommended. 1, 2

Safety Monitoring in Elderly Patients

Common Adverse Effects

• Six participants (20%) in the MIRAGE trial discontinued mirtazapine due to adverse events (versus 1 with placebo), primarily mild but clinically relevant side effects including daytime sedation, dizziness, and increased appetite. 2

• No severe adverse events occurred in the MIRAGE trial. 2

• Mirtazapine is associated with weight gain, which may be problematic in some elderly patients. 6

Monitoring Requirements

• Monitor for next-day sedation, falls, confusion, increased appetite/weight gain, orthostatic hypotension, and behavioral abnormalities at 2-week intervals initially. 6, 2

• Assess for hyponatremia, particularly in elderly patients on diuretics or SSRIs. 6

• Evaluate daytime functioning and cognitive performance, as residual sedation can impair activities of daily living. 2

Cardiovascular Considerations

• Mirtazapine has minimal cardiac conduction effects and does not prolong QTc interval, making it suitable for elderly patients with cardiac comorbidities. 7

• Monitor for orthostatic hypotension, particularly during the first 2 weeks of treatment. 7

Integration with Cognitive Behavioral Therapy for Insomnia (CBT-I)

• Mirtazapine should always be prescribed alongside Cognitive Behavioral Therapy for Insomnia (CBT-I), which provides superior long-term outcomes with sustained benefits after medication discontinuation. 1, 6

• CBT-I includes stimulus control (leave bed when unable to sleep), sleep restriction (time in bed ≈ total sleep time + 30 min), relaxation techniques, and cognitive restructuring of maladaptive sleep beliefs. 1, 7

• Short-term hypnotic treatment should supplement—not replace—behavioral interventions. 5, 1

When Mirtazapine Is Particularly Appropriate

Clinical Scenarios Favoring Mirtazapine

• Elderly patients with chronic insomnia who have failed or cannot tolerate first-line benzodiazepine receptor agonists (zolpidem, eszopiclone, zaleplon). 1

• Patients with comorbid depression or anxiety, where mirtazapine simultaneously addresses both the mood disorder and sleep disturbance. 5, 1, 6

• Patients with poor appetite or unintentional weight loss, where mirtazapine's appetite-stimulating effect is beneficial. 6

• Patients with a history of substance use disorder, where benzodiazepine receptor agonists carry abuse potential but mirtazapine does not. 1

When to Avoid Mirtazapine

• Patients at risk for excessive weight gain or with poorly controlled diabetes. 7, 6

• Patients taking multiple CNS depressants, where additive sedation increases fall risk. 5, 1

• Patients requiring rapid sleep-onset improvement, as mirtazapine requires several days to reach steady-state levels (half-life 20–40 hours). 1

Comparison with Alternative Agents in Elderly

First-Line Options (Preferred Over Mirtazapine)

• Low-dose doxepin 3–6 mg is the most appropriate first-line medication for sleep-maintenance insomnia in elderly patients, with high-strength evidence, minimal anticholinergic effects, and no abuse potential. 1, 7, 6

• Ramelteon 8 mg is appropriate for sleep-onset insomnia with minimal adverse effects, no dependency risk, and no DEA scheduling. 1, 7

• Zolpidem 5 mg (maximum dose for elderly) or eszopiclone 1–2 mg are first-line benzodiazepine receptor agonists for combined sleep-onset and maintenance problems. 1, 7

Agents to Avoid in Elderly

• The American Academy of Sleep Medicine explicitly recommends against trazodone for insomnia, despite widespread off-label use, due to minimal benefit (10-minute reduction in sleep latency) with no improvement in subjective sleep quality and adverse events in 75% of older adults. 1, 7

• All benzodiazepines (lorazepam, temazepam, clonazepam, diazepam) should be avoided in elderly patients due to unacceptable risks of dependency, falls, cognitive impairment, respiratory depression, and increased dementia risk. 1, 7, 6

• Over-the-counter antihistamines (diphenhydramine, doxylamine) are contraindicated due to strong anticholinergic effects causing confusion, urinary retention, falls, and delirium. 1, 7

Practical Implementation Algorithm

Step 1: Pre-Treatment Assessment

• Review all current medications for sleep-disrupting agents (β-blockers, bronchodilators, corticosteroids, decongestants, diuretics, SSRIs/SNRIs). 6

• Assess for medical comorbidities contributing to insomnia (cardiac disease, COPD, pain syndromes, nocturia, restless legs syndrome, sleep apnea). 7, 6

• Evaluate for comorbid depression or anxiety that would make mirtazapine particularly appropriate. 5, 1, 6

Step 2: Initiate CBT-I Concurrently

• Implement sleep hygiene (stable bedtime, limit daytime naps to 15–20 minutes before 3 PM, avoid caffeine after noon, avoid alcohol in evening, no heavy meals within 3 hours of bedtime). 7, 6

• Start stimulus control and sleep restriction techniques. 1, 7

Step 3: Start Mirtazapine

• Prescribe mirtazapine 7.5 mg taken 30 minutes before bedtime with at least 7 hours remaining before planned awakening. 2, 4, 3

• Counsel patient about expected daytime sedation during the first week, increased appetite, and potential weight gain. 2

Step 4: Reassess and Titrate

• Evaluate efficacy at 2 weeks using Insomnia Severity Index or patient-reported sleep quality, total sleep time, and daytime functioning. 2, 3

• If response is insufficient, increase to 15 mg at bedtime. 4, 3

• Monitor for adverse effects including falls, confusion, excessive sedation, and weight gain. 6, 2

Step 5: Long-Term Management

• Continue mirtazapine if effective and well-tolerated, with reassessment every 4–6 weeks. 1, 4

• Attempt gradual taper after 3–6 months to determine if insomnia has resolved, using CBT-I to support discontinuation. 1

• If mirtazapine fails after 4–6 weeks at 15 mg, switch to an alternative agent (low-dose doxepin 3–6 mg or suvorexant 10 mg). 1, 7

Common Pitfalls to Avoid

• Using mirtazapine PRN (as needed) rather than nightly—mirtazapine requires consistent dosing to maintain therapeutic blood levels and cannot provide immediate on-demand sedation like short-acting hypnotics. 1

• Starting at doses >15 mg, which paradoxically reduce sedation due to increased noradrenergic activity. 4

• Failing to implement CBT-I alongside medication, which provides more durable benefits than medication alone. 1, 6

• Combining mirtazapine with other CNS depressants (benzodiazepines, Z-drugs, alcohol), which markedly increases fall risk and respiratory depression. 5, 1

• Continuing mirtazapine indefinitely without periodic reassessment and attempts at tapering. 1