What are the best treatment options for insomnia in an adult patient with a history of depression, currently taking 60mg of Monoamine Oxidase Inhibitor (MAOI) daily and 50mg of trazodone, who experiences middle-of-the-night awakenings despite adequate initial sleep onset?

Treatment of MAOI-Associated Middle-of-the-Night Awakenings

Increase your trazodone to 100-150mg at bedtime, as your current 50mg dose is insufficient for treating sleep maintenance insomnia in the context of MAOI therapy. 1, 2

Why Higher-Dose Trazodone is the Optimal Solution

Your situation represents a classic case of MAOI-induced sleep maintenance insomnia that requires adequate trazodone dosing:

• Trazodone 50mg is a subtherapeutic dose for sleep maintenance insomnia. Studies demonstrate that 100mg is the minimum effective dose for treating antidepressant-associated insomnia, with optimal dosing ranging from 100-150mg taken predominantly at bedtime. 3, 2

• Trazodone has proven efficacy specifically for SSRI/antidepressant-induced insomnia, with polysomnographic studies showing it significantly increases total sleep time, improves sleep efficiency, reduces nighttime awakenings, and enhances deep sleep (stages 3+4) when dosed at 100mg or higher. 2

• The 3-9 hour half-life of trazodone supports single nighttime dosing, and studies comparing multiple daily doses to single bedtime administration show equal antidepressant efficacy with superior sleep promotion and less daytime drowsiness when given as a single bedtime dose. 3

Dosing Strategy

Start with trazodone 100mg at bedtime and titrate to 150mg if needed within 3-7 days:

• Take the entire dose 30-60 minutes before your desired bedtime (not after meals, which delays absorption). 3

• The sedative effects occur within 1-2 hours and persist through the night at these doses. 2

• If 100mg provides partial improvement but you still wake at 4-5am, increase to 150mg. 3

• Maximum effective dose for sleep is typically 150-200mg, though full antidepressant doses reach 300mg. 3

Why This Approach is Superior to Alternatives

The American Academy of Sleep Medicine explicitly recommends AGAINST trazodone for primary insomnia, but your situation is fundamentally different—you have secondary insomnia caused by MAOI therapy, which is a specific indication where trazodone has demonstrated efficacy. 4

• Your insomnia is MAOI-induced, not primary insomnia. The guideline recommendations against trazodone apply to primary insomnia, not antidepressant-associated sleep disturbance. 4, 1

• Systematic reviews support trazodone's efficacy for secondary insomnia related to antidepressant therapy, with adequate safety data at doses of 100mg and above. 1, 2

• One case report specifically documented successful treatment of phenelzine (MAOI)-associated insomnia with adjunctive medication, demonstrating that MAOI-induced sleep disturbance requires targeted treatment. 5

Alternative Options if Trazodone Fails at 150mg

If you optimize trazodone to 150mg and still experience middle-of-the-night awakenings after 2 weeks, consider these evidence-based alternatives:

First-Line Pharmacotherapy Options:

• Low-dose doxepin 3-6mg is specifically recommended for sleep maintenance insomnia, reducing wake after sleep onset by 22-23 minutes with minimal anticholinergic effects at hypnotic doses. 4

• Eszopiclone 2-3mg addresses both sleep onset and maintenance, with moderate-quality evidence showing 28-57 minute increase in total sleep time. 4

• Suvorexant 10mg (orexin receptor antagonist) reduces wake after sleep onset by 16-28 minutes and works through a completely different mechanism than other sleep medications. 4

Critical Drug Interaction Considerations:

• Avoid combining multiple sedating agents with your MAOI, as this creates additive CNS depression, respiratory depression risk, and increased fall risk. 4

• Benzodiazepines should be avoided due to higher dependency risk, cognitive impairment, and respiratory depression compared to non-benzodiazepine options. 4

• Do NOT use quetiapine or other antipsychotics despite one case report showing efficacy with phenelzine, as the American Academy of Sleep Medicine explicitly warns against antipsychotics for insomnia due to metabolic side effects and insufficient evidence. 4, 5

Behavioral Interventions to Implement Immediately

Cognitive Behavioral Therapy for Insomnia (CBT-I) should be started alongside medication optimization, as it provides superior long-term outcomes and addresses the underlying mechanisms maintaining your insomnia:

• Stimulus control: Only use your bed for sleep and sex. If you wake and cannot return to sleep within 20 minutes, get out of bed and do a quiet, non-stimulating activity until sleepy. 4

• Sleep restriction: Calculate your average total sleep time from the past week and restrict your time in bed to match this (minimum 5.5 hours). This consolidates sleep and reduces middle-of-the-night awakenings. 4

• Consistent wake time: Wake at the same time every morning regardless of how much you slept, even on weekends. This stabilizes your circadian rhythm. 4

• Avoid compensatory behaviors: Do not nap during the day or go to bed earlier to "make up" for lost sleep, as this perpetuates the pattern of early morning awakenings. 4

Common Pitfalls to Avoid

• Do not continue subtherapeutic trazodone dosing. Your provider increased you to 50mg, but this is insufficient for sleep maintenance. The evidence clearly supports 100-150mg for antidepressant-associated insomnia. 3, 1, 2

• Do not add multiple sedating medications simultaneously. Optimize trazodone first before considering alternatives. 4

• Do not use over-the-counter antihistamines (diphenhydramine, doxylamine), as they lack efficacy data, cause anticholinergic side effects, and tolerance develops within 3-4 days. 4

• Do not take trazodone earlier in the evening thinking it will help you sleep longer. The timing should remain at bedtime to maximize overnight coverage. 3

Monitoring and Follow-Up

• Reassess after 1 week at 100mg to evaluate improvement in wake after sleep onset and total sleep time. 4

• Monitor for morning sedation, though this is less common with single bedtime dosing compared to divided doses. 3

• Screen for priapism (rare but serious side effect of trazodone in men) and orthostatic hypotension, especially given your concurrent MAOI therapy. 1

• Keep a sleep diary documenting bedtime, wake time, number of awakenings, and total sleep time to objectively track improvement. 4