A few supplements post reproducible results
STUDY: Di Francesco A et al, Pharmacopsychiatry 2026
STUDY TYPE: Systematic review and meta-analysis
FUNDING: Independent
Background
Antipsychotics drive weight gain and metabolic syndrome through histamine, serotonin, and dopamine receptor effects. While GLP-1 agonists and metformin have good evidence, many patients don’t want to add another medication to treat a side effect.
The Study
- 21 randomized, placebo-controlled trials (1,426 patients with schizophrenia spectrum disorders) testing 16 different nutraceuticals or herbal agents, each added to ongoing antipsychotics.
- Trials ran at least 4 weeks (median 12 weeks, range 4-24).
Results
Berberine was tested in multiple weight-loss trials, but didn’t work: pooled weight change was essentially zero. It did lower systolic blood pressure by about 3 mmHg across two trials, a small but consistent effect. Alpha-lipoic acid was also tested repeatedly, and lowered triglycerides by about 23 mg/dL across two trials.
Omega-3 fatty acids, despite three trials, gave inconsistent results across every metabolic measure.
The biggest weight reductions came from single trials of Liuyu decoction (a Chinese herbal formula, reduced weight by 6 kg) and probiotics plus dietary fiber (by 4 kg). The probiotic study was replicated, although it appears the authors overlooked this, as they did not lump together the study of probiotic + fiber with a study of synbiotics (these are essentially the same thing) (Basafa-Roodi 2024, Huang 2022).
They analysis left out a few trials of melatonin, but when considering the data in full this well-tolerated hypnotic is a useful adjunct. Melatonin reduced antipsychotic weight gain with a small effect size (0.3) in one large and three small placebo-controlled trials. It also improved blood pressure, fasting glucose, triglycerides, and HDL cholesterol (dose 3-5 mg qhs, ideally 1.5-3 hours before bed for sleep).
Mechanistically, melatonin improves insulin sensitivity and shifts the body from fat storage (lipogenesis) toward fat breakdown (lipolysis).
Dropout rates didn’t differ from placebo for any agent.
Side Effects
Berberine caused GI upset, headache, and drowsiness in other studies, and it inhibits CYP3A4 and CYP2D6, so check for interactions with your patient’s antipsychotic. Alpha-lipoic acid was well tolerated.
Limitations
Small trials.
Practice Implications
- Start with melatonin, but use lab-tested products as quality control is problematic with this hormone.
- Next, consider probiotics. In the trials, they worked better with a prebiotic (eg, fiber), and the lab-tested products here have a prebiotic in them. These also have benefits in anxiety, cognition, and mood.
- Omega-3’s have mixed data for metabolic effects in this population, but more broad support in the general population, particularly for triglycerides.
- Diet and exercise are part of the plan, but research hasn’t found robust effects in this population, possibly because adherence is difficult.
- Here’s an update on pharmaceutical strategies.
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
