Background: Anxiety and depressive disorders account for a significant proportion of the global mental health burden. Treatment challenges in antidepressant therapy have stimulated interest in adjunctive nutritional interventions, such as B vitamins, due to their role in neurobiological processes relevant to mood regulation. However, existing systematic reviews have not focused specifically on adjunctive regimens combining multiple B vitamins with antidepressants. Consequently, this systematic review aimed to evaluate the efficacy and safety of combining a vitamin B complex (≥2 B vitamins) with antidepressant medication to improve symptom severity in depression and anxiety.

Method: A systematic literature search targeting clinical trials involving patients (≥18 years) with clinical diagnosis of depression or anxiety was performed. Eligible studies compared vitamin B complex supplementation plus antidepressant treatment with antidepressant monotherapy. The primary outcome was a change in symptom severity on validated scales; secondary outcomes included response rate, remission rate, cognitive outcomes, quality of life and safety outcomes. Study selection, data extraction, and risk-of-bias assessment were performed by one reviewer. Evidence was summarised narratively, and the certainty of evidence was not formally graded.

Results: The review included two double-blind randomised controlled trials (RCTs), two open-label RCTs, and one non-randomised controlled trial (NRCT), totalling 320 study participants. All included studies assessed depressive outcomes; no studies evaluating anxiety were identified. One open-label RCT and one NRCT reported significant improvements in depressive symptom severity with folic acid (vitamin B9) plus vitamin B12; however, the evidence is limited by small sample sizes and a high risk of bias. The remaining three trials assessing ≥3 B vitamins showed no significant benefits. The largest, lowest-risk-of-bias trial with the longest follow-up found no significant difference in depressive symptom severity but an improved response over 12 months. Cognitive outcomes and adverse events showed no significant differences, but evidence was scarce due to a small number of events. Trial comparability was limited by clinical and methodological heterogeneity.

Conclusions: Overall, evidence for adjunctive vitamin B complex supplementation with antidepressants remains very limited, warranting high-quality RCTs.