Dose increase of S-Adenosyl-Methionine and escitalopram in a randomized clinical trial for major depressive disorder

•A dose increase of S-adenosyl methionine (SAMe) in depression was examined.•Symptoms in non-responders improved after a dose increase from 1600 to 3200 mg/d.•No significant difference in efficacy was found between each SAMe dose.•No superiority was found between SAMe 3200 mg/d, escitalopram 20 mg/d, and placebo.•Abdominal discomfort was reported most frequently with SAMe 3200 mg/d treatment. The optimal dose of S-adenosyl methionine (SAMe) for major depressive disorder (MDD) remains unclear. The objective of this analysis was to address whether a dose increase provided further improvement in cases of insufficient response using data from an existing randomized clinical trial. Sixty-five patients with MDD who failed to respond to SAMe 1,600 mg/day, escitalopram 10 mg/day, or placebo for 6 weeks were treated with doubled doses of the allocated treatments for the following 6 weeks. Changes in 17-item Hamilton Depression Rating Scale, Inventory of Depressive Symptomatology-Self Rated, and Systematic Assessment for Treatment Emergent Events-Specific Inquiry were compared between the lower and higher dose treatments in each treatment group and among the higher dose treatments of SAMe, escitalopram, and placebo. Various depression severity scores decreased significantly for all three treatment arms during the higher dose treatment. No within-group and between-group differences were found in any of the efficacy measures when comparing the doses and treatments. There was a significant difference in reported abdominal discomfort among patients receiving the higher dose of SAMe (31.3%), compared to escitalopram (8.7%) and placebo (3.8%) (χ2=7.32, p = 0.026). The sample size was relatively small. The study duration for dose increase was relatively short. Patients with MDD failing to respond to 1,600 mg/day of SAMe may improve after increasing the dose to 3,200 mg/day, but we cannot rule out the contribution of a placebo effect and time-related improvement. The risk of abdominal discomfort may be increased with higher doses of SAMe.