Is there evidence that melatonin (melatonin) causes depression?

Melatonin and Depression Risk

Based on the available evidence, melatonin does not cause depression in most individuals, and in fact, the American Academy of Sleep Medicine explicitly recommends melatonin treatment for adults with delayed sleep-wake phase disorder both with and without comorbid depression. 1

Key Evidence from Clinical Guidelines

The most relevant guideline evidence comes from the American Academy of Sleep Medicine's 2015 clinical practice guideline, which analyzed melatonin use in depressed versus non-depressed patients:

• In patients with existing depression (n=28), melatonin 5 mg improved sleep parameters significantly, with total sleep time increasing by 41.44 minutes and sleep latency decreasing by 43.52 minutes. 1

• The guideline explicitly recommends treating adults with delayed sleep-wake phase disorder "with and without depression" using strategically timed melatonin, indicating no contraindication or concern about worsening depression. 1

• The benefits/harms ratio was deemed acceptable enough to support treatment, even though the overall quality of evidence was rated as LOW. 1

Important Safety Caveats

While melatonin does not typically cause depression, there are specific warnings to consider:

• The American Psychiatric Association advises avoiding melatonin use in patients with personal or family history of psychiatric disorders, as it has been associated with increased depressive symptoms in some individuals. 2, 3

• In older adults with dementia, melatonin should be avoided entirely due to detrimental effects on mood and daytime functioning observed in this population. 4, 3

• Melatonin has been associated with impaired glucose tolerance, which could indirectly affect mood through metabolic pathways. 2, 3

Research Evidence Context

The research literature provides additional nuance:

• A 2017 systematic review of 8 clinical trials found no significant evidence that melatonin improves mood symptoms (SMD = 0.37; 95% CI [-0.05,0.37]; P = 0.09), but importantly, it also found no evidence that melatonin worsens depression. 5

• The acceptability and tolerability of melatonin in mood disorder studies was good, with no signals of depression induction. 5

• Animal models suggest melatonin may actually alleviate depressive behaviors by regulating circadian rhythms and glymphatic function, though this has not been definitively proven in humans. 6

Clinical Algorithm for Safe Use

When considering melatonin in patients with depression concerns:

1. Screen for absolute contraindications: dementia, active psychiatric instability, or strong family history of psychiatric disorders. 4, 2, 3

2. Start with 3 mg immediate-release melatonin administered 1.5-2 hours before desired bedtime. 4, 3

3. Monitor mood symptoms closely for the first 1-2 weeks, particularly in patients with pre-existing mood disorders. 3

4. If no benefit after 1-2 weeks and no adverse effects, increase by 3 mg increments up to maximum 15 mg. 4, 3

5. Choose United States Pharmacopeial Convention Verified formulations to ensure reliable dosing, as melatonin quality varies significantly. 4, 2, 3

6. Limit duration to 3-4 months for insomnia, though longer use may be appropriate for circadian rhythm disorders. 3

Common Pitfalls to Avoid

• Do not assume melatonin is contraindicated in depression – the guideline evidence explicitly supports its use in depressed patients with sleep disorders. 1

• Do not use higher doses assuming better efficacy – doses above 10 mg cause receptor desensitization and increase adverse effects without improving outcomes. 4, 3

• Do not ignore the timing of administration – melatonin taken at the wrong time can worsen circadian misalignment. 3

• Do not overlook medication interactions – use caution with warfarin, and avoid in patients with epilepsy. 4, 2, 3