What can be added to a selective serotonin reuptake inhibitor (SSRI) to help a patient with depression and sleep disturbances?

Adding Medication to SSRI for Depression-Related Insomnia

For patients with depression on SSRIs experiencing sleep disturbances, add low-dose trazodone (25-100 mg at bedtime) as first-line adjunctive therapy, based on established guideline recommendations and proven efficacy in this specific population. 1

Primary Recommendation: Trazodone

Trazodone is the preferred agent for SSRI-associated insomnia based on multiple converging lines of evidence:

• Guideline support: The American Academy of Sleep Medicine specifically recommends sedating low-dose antidepressants like trazodone when treating insomnia comorbid with depression, particularly when used in conjunction with another full-dose antidepressant 1

• Proven efficacy in this exact population: A randomized controlled trial demonstrated that trazodone 100 mg significantly improved total sleep time, sleep efficiency, deep sleep (stages 3+4), and reduced awakenings in depressed patients on SSRIs, with benefits maintained after 7 days of treatment 2

• Dosing: Start with 25-50 mg at bedtime and titrate up to 100 mg as needed 1

• Mechanism: Trazodone has minimal anticholinergic activity compared to other sedating antidepressants, making it better tolerated 1

Alternative Options (In Order of Preference)

Second-Line: Mirtazapine

• Dose: 7.5-30 mg at bedtime 1
• Advantages: Particularly effective when depression is accompanied by anorexia or weight loss, as it promotes appetite and weight gain 1
• Evidence: Guideline-recommended as a sedating antidepressant option for insomnia with comorbid depression 1

Third-Line: Short-Acting Benzodiazepine Receptor Agonists

If sedating antidepressants fail or are contraindicated:

• Zolpidem 5-10 mg at bedtime: A controlled trial showed zolpidem effectively improved sleep duration, quality, and reduced awakenings when co-administered with SSRIs in depressed patients with persistent insomnia 3
• Eszopiclone 2-3 mg at bedtime: Approved for sleep-onset and maintenance insomnia with no short-term usage restriction 1
• Important caveat: FDA requires lower doses of zolpidem (5 mg for immediate-release) due to next-morning impairment risk 1

Fourth-Line: Low-Dose Atypical Antipsychotics

Consider only when other options have failed:

• Olanzapine 2.5-5 mg at bedtime: Research demonstrates it increases slow-wave sleep and sleep continuity in SSRI-resistant depressed patients 4
• Quetiapine 25-50 mg at bedtime 1
• Caution: Reserve for treatment-refractory cases due to metabolic side effects 1

Critical Safety Considerations

Trazodone-Specific Warnings

• Priapism risk: Men should discontinue immediately if erection lasts >4 hours and seek emergency care 5
• Orthostatic hypotension: May require dose reduction of concomitant antihypertensives 5
• Cardiac arrhythmias: Avoid in patients with cardiac disease history, QT prolongation, or during acute MI recovery phase 5
• Serotonin syndrome: Monitor when combining with SSRIs, though risk is lower than with other serotonergic combinations 5

General Precautions for All Agents

• Avoid antihistamines and melatonin: Over-the-counter sleep aids are not recommended for chronic insomnia due to lack of efficacy and safety data 1
• Benzodiazepine caution: Avoid in elderly patients and those with cognitive impairment due to decreased cognitive performance 1
• Combine with behavioral therapy: Pharmacotherapy should be supplemented with cognitive-behavioral therapy for insomnia (CBT-I) when possible 1

Treatment Algorithm

1. First attempt: Add trazodone 25-50 mg at bedtime, titrate to 100 mg if needed 1, 2

2. If trazodone fails or is not tolerated: Switch to mirtazapine 7.5-15 mg at bedtime 1

3. If sedating antidepressants ineffective: Add short-acting BzRA (zolpidem 5-10 mg or eszopiclone 2-3 mg) 1, 3

4. For refractory cases: Consider low-dose atypical antipsychotic (olanzapine 2.5-5 mg or quetiapine 25-50 mg) 1, 4

5. Concurrent non-pharmacologic interventions: Implement sleep hygiene education, stimulus control, and consider CBT-I referral 1

Monitoring and Follow-Up

• Assess effectiveness within 1-2 weeks of initiating treatment 1
• Monitor for adverse effects: Particularly morning sedation, dizziness, and medication-specific risks 5
• Attempt dose reduction after 9 months to reassess need for continued medication 1
• Long-term use: If chronic treatment needed, ensure patient receives adequate trial of CBT-I during pharmacotherapy 1