Tehran University of Medical Sciences Iranian Journal of Psychiatry 1735-4587 0 0 2026 06 07 1 12 EN Mahnaz Shah Ali Psychosis Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran. Omid Rezaei Psychosis Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran. Reza Momeni Shideh Islamic Azad University, Tehran Medical Sciences, Pharmaceutical Sciences, Medical Toxicology, Tehran, Iran. Gita Sadighi Psychosis Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran. 2025 11 02 2026 02 18 Objective: Persistent negative symptoms in chronic schizophrenia often show limited responsiveness to antipsychotic therapy. The present study evaluated whether supplementation with vitamin B12 and folic acid improves negative symptoms as the primary endpoint, while also examining effects on positive symptoms and global cognitive functioning as secondary outcomes. Method: In this randomized, double-blind, placebo-controlled trial, 88 inpatients with chronic schizophrenia receiving stable risperidone therapy were assigned to one of four groups: vitamin B12 (1 mg/day), folic acid (1 mg/day), combined vitamin B12 plus folic acid (1 mg/day each), and placebo for eight weeks. Negative symptoms were measured using the Scale for the Assessment of Negative Symptoms (SANS), positive symptoms using the Scale for the Assessment of Positive Symptoms (SAPS), and cognitive function using the Mini-Mental State Examination (MMSE). Serum concentrations of vitamin B12 and folate were assessed at baseline and after the intervention. Results: Supplementation with vitamin B12 and/or folic acid led to significant increases in serum concentrations of the corresponding vitamins (P < 0.001). All supplementation groups demonstrated significant and clinically meaningful reductions in negative symptom severity compared with placebo, with large effect sizes. In contrast, no significant changes were detected in positive symptoms or global cognitive performance. Conclusion: Adjunctive vitamin B12 and folic acid supplementation significantly reduced negative symptom severity in chronic schizophrenia, without affecting positive symptoms or global cognition. Targeted correction of vitamin deficiencies may represent a valuable adjunctive approach for persistent negative symptoms. https://ijps.tums.ac.ir/index.php/ijps/article/view/4465 https://ijps.tums.ac.ir/index.php/ijps/article/download/4465/1339