Adjunctive n-3 PUFA supplementation improves niacin skin flush response and shows biomarker-stratified signals in schizophrenia

BACKGROUND: Findings regarding the efficacy of n-3 polyunsaturated fatty acid (PUFA) supplementation as an adjunct treatment for schizophrenia (SZ) have been inconsistent. This study investigated whether n-3 PUFA supplementation was associated with changes in niacin skin flush response (NSFR) and clinical symptoms in patients with SZ, and explored the value of baseline NSFR for patient stratification. METHODS: A total of 99 patients with SZ and 30 healthy controls (HCs) were enrolled. Patients with SZ were randomized in a 1:2 ratio to standard pharmacotherapy alone or standard pharmacotherapy plus n-3 PUFA supplementation for 21 days. NSFR and Positive and Negative Syndrome Scale (PANSS) assessments were performed at baseline and post-intervention. Following intervention, total PANSS scores decreased in both groups, while significant NSFR improvement was observed only in the n-3 PUFA supplementation group. Adjusted linear mixed-effects models revealed a significant "group × time" interaction for NSFR (standardized β = 0.57, 95% CI: 0.08 to 1.06, P = 0.025). Exploratory stratified analysis showed that patients with blunted baseline NSFR who received n-3 PUFA supplementation exhibited the most favorable short-term response, reflected by the largest and statistically significant NSFR increase, with a directionally favorable change in PANSS total score. CONCLUSIONS: Baseline NSFR blunting may help identify a subgroup of SZ patients with greater short-term responsiveness to adjunctive n-3 PUFA supplementation. These findings support further investigation of NSFR as a candidate stratification marker for targeted adjunctive intervention in schizophrenia.