Can mirtazapine and melatonin be taken together?

Mirtazapine and Melatonin Combination Therapy

Recommendation

Yes, mirtazapine and melatonin can be safely taken together, but this combination is generally not recommended as a first-line approach for insomnia due to limited evidence supporting its efficacy and potential for additive sedative effects. 1

Rationale for Combination

• Mirtazapine is a sedating antidepressant that works through noradrenergic and specific serotonergic mechanisms, with significant histaminergic effects at lower doses (7.5-15mg) that contribute to its sedative properties 2, 3
• Melatonin binds to M1 and M2 receptors, suppressing REM sleep motor tone and normalizing circadian features of sleep 1
• Both medications have different mechanisms of action for promoting sleep, which theoretically could provide complementary effects 1, 4

Clinical Evidence and Guidelines

• According to American Academy of Sleep Medicine guidelines, sedating antidepressants like mirtazapine are considered a third-line option for insomnia treatment after short-intermediate acting benzodiazepine receptor agonists and ramelteon 1
• Melatonin is not recommended as a first-line treatment for chronic insomnia due to relative lack of efficacy and safety data 1
• One small case series demonstrated that adding prolonged-release melatonin to mirtazapine in perimenopausal women with insomnia allowed for tapering of mirtazapine while maintaining improved sleep quality 5

Dosing Considerations

• For sedative effects, mirtazapine is typically prescribed at lower doses (7.5-15mg) at bedtime, as higher doses may paradoxically be less sedating 2, 6
• Immediate-release melatonin is typically started at 3mg at bedtime for sleep disorders 1
• When combining these medications, consider starting with lower doses of each to minimize the risk of excessive sedation 6

Potential Concerns

• Additive sedative effects may occur, potentially causing:
  • Excessive daytime sleepiness 3, 7
  • Impaired cognitive and motor performance 8
  • Increased risk of falls, particularly in elderly patients 6
• Weight gain is a common side effect of mirtazapine that should be monitored 3, 5

Special Populations

• In elderly patients:
  • Lower doses of mirtazapine (7.5mg) are recommended to minimize sedation 6
  • Mirtazapine is listed on the American Geriatrics Society Beers Criteria as a potentially inappropriate medication in older adults 1
• In cancer patients with sleep disturbances, mirtazapine at 15mg has shown benefit 2, 6

Alternative Approaches

• First-line treatment for insomnia should be cognitive behavioral therapy for insomnia (CBT-I) before considering pharmacological options 1
• For pharmacological management of insomnia, the recommended sequence is:
  1. Short-intermediate acting benzodiazepine receptor agonists (e.g., zolpidem, eszopiclone) or ramelteon 1
  2. Alternate agents from the first category if initial treatment is unsuccessful 1
  3. Sedating antidepressants (including mirtazapine) 1

Monitoring Recommendations

• If using this combination, monitor for:
  • Excessive sedation and daytime drowsiness 3, 7
  • Weight gain, particularly with mirtazapine 3, 5
  • Cognitive and motor impairment 8
  • Effectiveness in improving sleep quality 5

While mirtazapine and melatonin can be used together, patients should be informed about the limited evidence supporting this combination specifically for insomnia treatment and the potential for additive sedative effects.