Nutraceuticals and phytoceuticals in the treatment of bipolar disorder: A systematic review and network meta-analysis.
Michele Fornaro, Nicolas A Nunez, Chiara Di Lorenzo et al.
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In 30 seconds
This systematic review and network meta-analysis assessed randomized controlled trials of nutraceuticals and phytoceuticals for bipolar disorder. Twenty-eight trials involving 2,222 participants evaluated 22 treatments. No treatment outperformed placebo for depressive symptoms. For manic symptoms, palmitoylethanolamide and folic acid showed greater symptom reductions than placebo, but estimates were highly heterogeneous and evidence confidence was predominantly low or very low. The palmitoylethanolamide result relied on one trial. Overall, the review found insufficient evidence to support firm recommendations for these treatments in acute bipolar depression or mania.
Key findings
- Across 28 RCTs (n=2,222), no treatment outperformed placebo for depressive symptoms.
- For manic symptoms, palmitoylethanolamide (SMD=-4.58, 95% CI -6.24 to -2.92) and folic acid (SMD=-2.42, 95% CI -4.06 to -0.79) outperformed placebo.
- Mania estimates showed substantial heterogeneity (I²=91.3%); the palmitoylethanolamide finding relied on one RCT.
- Free-and-easy-wanderer-plus™ combined with carbamazepine outperformed placebo for response and acceptability.
Why it matters
Interest in adjunctive nutraceutical and phytoceutical approaches is growing, but this synthesis does not establish reliable benefits for acute bipolar symptoms. The contrast between positive estimates for some mania outcomes and generally low or very low confidence highlights the need to interpret apparent effects cautiously and to distinguish promising signals from evidence sufficient to guide treatment decisions.
What to keep in mind
Evidence confidence was predominantly low or very low, particularly for manic symptoms. Estimates were substantially heterogeneous, and the palmitoylethanolamide finding relied on one trial.