Melatonin use during pregnancy and lactation: A scoping review of human studies

Objective: The prevalence of sleep disorders during the perinatal period is high and large health administrative database surveys have shown that the use of exogenous melatonin in pregnant populations is quite common, about 4%. Much of the concern about using melatonin during pregnancy and breastfeeding stems from animal research. Thus, the objective of this article is to provide a critical review of human studies related to exogenous melatonin use during pregnancy and breastfeeding. Methods: The electronic databases Ovid, MEDLINE, Embase, and the Cochrane Library were searched using terms and keywords related to melatonin, pregnancy, and breastfeeding. Results: Fifteen studies were included in this review. Eight focused on melatonin use during pregnancy and seven focused on melatonin use during breastfeeding. There was a variety of study designs, including case reports, cohort studies, and clinical trials. There is a lack of randomized, controlled trials examining the efficacy and safety of melatonin as a treatment for sleep disorders during pregnancy or breastfeeding and, notably, insomnia was not the primary outcome measure in any of the studies included in this review. Clinical trials that used exogenous melatonin during pregnancy and breastfeeding for other clinical conditions have not suggested major safety concerns or adverse events. Conclusion: Contrary to what animal studies have suggested, evidence from clinical studies to date suggests that melatonin use during pregnancy and breastfeeding is probably safe in humans. This review further emphasizes the need for clinical studies on sleep disorders, including exogenous melatonin, during pregnancy and lactation.

Melatonin use during pregnancy and lactation: A scoping review of human studies.

OBJECTIVE: The prevalence of sleep disorders during the perinatal period is high and large health administrative database surveys have shown that the use of exogenous melatonin in pregnant populations is quite common, about 4%. Much of the concern about using melatonin during pregnancy and breastfeeding stems from animal research. Thus, the objective of this article is to provide a critical review of human studies related to exogenous melatonin use during pregnancy and breastfeeding. METHODS: The electronic databases Ovid, MEDLINE, Embase, and the Cochrane Library were searched using terms and keywords related to melatonin, pregnancy, and breastfeeding. RESULTS: Fifteen studies were included in this review. Eight focused on melatonin use during pregnancy and seven focused on melatonin use during breastfeeding. There was a variety of study designs, including case reports, cohort studies, and clinical trials. There is a lack of randomized, controlled trials examining the efficacy and safety of melatonin as a treatment for sleep disorders during pregnancy or breastfeeding and, notably, insomnia was not the primary outcome measure in any of the studies included in this review. Clinical trials that used exogenous melatonin during pregnancy and breastfeeding for other clinical conditions have not suggested major safety concerns or adverse events. CONCLUSION: Contrary to what animal studies have suggested, evidence from clinical studies to date suggests that melatonin use during pregnancy and breastfeeding is probably safe in humans. This review further emphasizes the need for clinical studies on sleep disorders, including exogenous melatonin, during pregnancy and lactation.

Magnitude of the Placebo Response Across Treatment Modalities Used for Treatment-Resistant Depression in Adults: A Systematic Review and Meta-analysis.

Importance: The placebo effect in depression clinical trials is a substantial factor associated with failure to establish efficacy of novel and repurposed treatments. However, the magnitude of the placebo effect and whether it differs across treatment modalities in treatment-resistant depression (TRD) is unclear. Objective: To examine the magnitude of the placebo effect in patients with TRD across different treatment modalities and its possible moderators. Data Sources: Searches were conducted on MEDLINE, Web of Science, and PsychInfo from inception to June 21, 2021. Study Selection: Randomized clinical trials (RCTs) were included if they recruited patients with TRD and randomized them to a placebo or sham arm and a pharmacotherapy, brain stimulation, or psychotherapy arm. Data Extraction and Synthesis: Independent reviewers used standard forms for data extraction and quality assessment. Random-effects analyses and standard pairwise meta-analyses were performed. Main Outcomes and Measures: The primary outcome was the Hedges g value for the reported depression scales. Secondary outcomes included moderators assessed via meta-regression and response and remission rates. Heterogeneity was assessed with the I2 test, and publication bias was evaluated using the Egger test and a funnel plot. Cochrane Risk of Bias Tool was used to estimate risks. Results: Fifty RCTs were included involving various types of placebo or sham interventions with a total of 3228 participants (mean [SD] age, 45.8 [6.0] years; 1769 [54.8%] female). The pooled placebo effect size for all modalities was large (g = 1.05; 95% CI, 0.91-1.1); the placebo effect size in RCTs of specific treatment modalities did not significantly differ. Similarly, response and remission rates associated with placebo were comparable across modalities. Heterogeneity was large. Three variables were associated with a larger placebo effect size: open-label prospective treatment before double-blind placebo randomization (ß = 0.35; 95% CI, 0.11 to 0.59; P = .004), later year of publication (ß = 0.03; 95% CI, 0.003 to 0.05; P = .03), and industry-sponsored trials (ß = 0.34; 95% CI, 0.09 to 0.58; P = .007). The number of failed interventions was associated with the probability a smaller placebo effect size (ß = -0.12; 95% CI, -0.23 to -0.01, P = .03). The Egger test result was not significant for small studies' effects. Conclusions and Relevance: This analysis may provide a benchmark for past and future clinical RCTs that recruit patients with TRD standardizing an expected placebo effect size.