Nutraceuticals for major depressive disorder : more is not merrier : an 8-week double-blind, randomised, controlled trial

Background: One of the most pressing questions in "Nutritional Psychiatry" is whether using combinations of different nutraceuticals with putative antidepressant activity may provide an enhanced synergistic antidepressant effect. Methods: A phase II/III, Australian multi-site, 8-week, double-blind, RCT involving 158 outpatients with a DSM-5 diagnosis of MDD. The intervention consisted of a nutraceutical combination: S-adenosyl methionine; Folinic acid; Omega-3 fatty acids; 5-HTP, Zinc picolinate, and relevant co-factors versus placebo. The primary outcome was change in MADRS score. Hypothesis-driven analyses of potential moderators of response involving key SNPs, and BDNF were also conducted. Results: Placebo was superior to the nutraceutical combination in reducing MADRS score (differential reduction -1.75 points), however a mixed linear model revealed a non-significant Group X Time interaction (p = 0.33). Response rates were 40% for the active intervention and 51% for the placebo; remission rates were 34% and 43% for active and placebo groups, respectively. No significant differences were found between groups on any other secondary depression, anxiety, psychosocial, or sleep outcome measures. Key SNPs and BDNF did not significantly moderate response. No significant differences occurred between groups for total adverse effects, aside from more nausea in the active group. Limitations: Very high placebo response rates suggest a placebo run-in design may have been valuable. Interpretation: The adoption of a nutraceutical 'shotgun' approach to treating MDD was not supported, and appeared to be less effective than adding placebo to treatment as usual.