Depression and depressive symptoms are common in the elderly population and contribute to a lower quality of life. One change that is common in depression is the disruption of circadian cycles, which are regulated by melatonin and other neurotransmitters. Oral melatonin and melatonin agonists are well tolerated, being the main clinical indication of insomnia. A melatonin agonist is approved as an antidepressant. Thus, the objective of the systematic review will be to provide an up-to-date synthesis of the findings of randomised controlled trials that used melatonin or melatonin agonists as a therapeutic intervention in elderly people with depression.

This systematic review protocol was registered with PROSPERO under the number CRD42023391092. We will conduct a systematic review and possible meta-analysis of the efficacy of melatonin and melatonin agonists in the treatment of depression. Comparators will include placebo and active treatments (eg, antidepressants). We will search international electronic databases, including the Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials), EMBASE, PUBMED/MEDLINE and SciELO for published randomised control trial studies, and ongoing work and trials in progress by searching key internet-based relevant databases from inception to April 2025. There will be no restrictions on the language or geography of publication. The Cochrane’s risk of bias tool for randomised trials (RoB2) will be used to appraise the risk of bias, and GRADE tools will be used to evaluate the overall quality of the included studies. A descriptive summary with data tables will be constructed, and if adequate, we will perform a meta-analysis. A random-effects model will be used when substantial heterogeneity is present, otherwise, a fixed-effects model will be considered (I²). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist will be followed for reporting.

Since this systematic review will be based only on published and retrievable literature, no ethics approval will be required. A multidisciplinary team has been assembled for this systematic review and will participate in relevant dissemination activities, namely reports, publications and presentations.

CRD42023391092.