Can Melatonin Be Combined with Remeron (Mirtazapine) and Trazodone?
Yes, melatonin can be safely combined with both mirtazapine (Remeron) and trazodone, though this represents a multi-drug sedating regimen that requires careful monitoring for additive sedative effects and should ideally be used as a transitional strategy rather than long-term maintenance therapy.
Safety Profile of the Combination
The combination of these three agents is supported by clinical evidence:
Melatonin added to mirtazapine has been specifically studied in perimenopausal women with insomnia, where prolonged-release melatonin was successfully added to mirtazapine 15 mg, ultimately facilitating mirtazapine withdrawal while maintaining improved sleep quality 1
Triple antidepressant combinations including trazodone have been reported in treatment-resistant depression, with one case demonstrating successful addition of trazodone to paroxetine and mirtazapine without significant adverse events 2
No direct pharmacokinetic interactions are documented between these three agents, as they work through different mechanisms (melatonin via MT1/MT2 receptors, mirtazapine via histamine H1 and alpha-2 antagonism, trazodone via serotonin antagonism and reuptake inhibition) 3, 1
Critical Monitoring Considerations
The primary concern is additive sedation, which requires specific precautions:
Concurrent use of multiple sedating medications should be done with caution due to additive effects, particularly regarding daytime drowsiness, dizziness, and psychomotor impairment 4, 5
Elderly patients face increased risk of falls, confusion, and adverse effects with this combination and require dose adjustments to lower values 5
Monitor specifically for: morning grogginess (15% with trazodone alone), orthostatic hypotension (10% with trazodone), daytime sleepiness, and difficulty awakening 6
Clinical Context and Appropriateness
This combination should be evaluated against treatment guidelines:
Cognitive behavioral therapy for insomnia (CBT-I) should be first-line treatment before any pharmacotherapy 4, 5
Both trazodone and mirtazapine are considered third-line agents for insomnia by the American Academy of Sleep Medicine, after benzodiazepine receptor agonists and ramelteon 5
The American Academy of Sleep Medicine recommends against trazodone for primary insomnia based on trials showing modest improvements that don't outweigh potential harms 4
Melatonin is not recommended by VA/DOD guidelines for chronic insomnia due to lack of efficacy and safety data 4
When This Combination Makes Clinical Sense
The combination is most appropriate in specific scenarios:
Comorbid depression with insomnia, where mirtazapine and/or trazodone serve dual purposes as antidepressants and sleep aids 4, 5
Transitional therapy, such as using melatonin to facilitate withdrawal from mirtazapine while maintaining sleep quality and avoiding weight gain 1
Treatment-resistant cases where standard monotherapy has failed and the patient has insomnia as a prominent symptom 2
Dosing Considerations for Safety
When combining these agents, use conservative dosing:
Mirtazapine: Start at 7.5 mg at bedtime, maximum 30 mg for sleep (lower than antidepressant doses) 3
Trazodone: Use 25-50 mg at bedtime for insomnia, which is below the therapeutic antidepressant range 4
Melatonin: 2 mg prolonged-release formulation has been studied in combination with mirtazapine 1
Important Caveats
Regular reassessment is essential to evaluate effectiveness, side effects, and ongoing need for all three medications 4, 5
Employ the lowest effective doses and attempt to taper medications when conditions allow 4
Patient counseling is mandatory regarding potential side effects, allowing appropriate sleep time (7-8 hours), and avoiding activities requiring alertness if morning sedation occurs 4
Avoid benzodiazepines in addition to this regimen, as the sedative burden would be excessive 2