Efficacy and safety of adjunctive therapy to lamotrigine, lithium, or valproate monotherapy in bipolar depression: a systematic review and meta-analysis of randomized controlled trials.

Background: The efficacy and safety of adjunctive therapy are unclear in bipolar depression. In this systematic review and meta-analysis, we aimed to evaluate the efficacy and safety of second-generation antipsychotic, lamotrigine, lithium, or valproate therapy used in adjunction with lamotrigine, lithium, or valproate monotherapy in bipolar depression. A literature search of major electronic databases was conducted in February 2021, and all articles published until then were eligible. Two researchers independently screened relevant publications, extracted data, and evaluated methodological quality according to the Cochrane criteria.

Results: Five studies met the inclusion criteria. The meta-analysis revealed significant differences in the following outcomes: (i) remission rates from depressive episodes (risk ratio [RR]: 1.23, 95% confidence interval [CI] 1.01-1.50, p = 0.04), (ii) improvement in depressive symptoms (standardized mean difference [SMD]: 0.21, 95% CI 0.09-0.34, p = 0.001), (iii) improvement in quality of life (SMD: 0.22, 95% CI 0.06-0.37, p = 0.005), and (iv) rate of adverse events during the study period (RR: 1.12, 95% CI 1.03-1.22, p = 0.008). There was no significant difference between adjunctive therapy and monotherapy in the emergence of suicide-related behaviors, dropout rate during the study period, or rate of manic switching.

Conclusions: Our results suggest that adjunctive second-generation antipsychotics, lamotrigine, lithium, or valproate increase both the benefits and risks in patients with bipolar depression, although there is no significant difference in severe adverse events. Adjunctive therapy should be provided through shared decision-making while considering the patients' condition in clinical settings.