Efficacy of Lamotrigine in the Treatment of Unipolar and Bipolar Depression: Meta-Analysis of Acute and Maintenance Randomised Controlled Trials

<b>Background/Objectives:</b> Lamotrigine has been widely investigated in the treatment and prevention of the emergence of symptoms of depression in unipolar and bipolar depression. This work systematically appraises published and unpublished double-blind randomised controlled trials of lamotrigine to provide up-to-date guidance on the use of lamotrigine in the presence of depressive symptoms. <b>Methods:</b> Systematic searches identified 32 randomised controlled trials, of which 24 were included in the meta-analysis, involving 2257 patients and 2320 controls. <b>Results:</b> Evidence supports the use of lamotrigine in the acute phase of bipolar depression in monotherapy vs. placebo (SMD: 0.155; CI: 0.005-0.305) in the absence of significant heterogeneity and small study effects. In the prophylaxis of bipolar depression, lamotrigine reduced the risk of the emergence of depressive symptoms (RR: 0.78; CI: 0.63, 0.98) and prolonged the duration of symptoms survival (RR: 1.59; CI: 1.19, 2.11) compared to placebo, with no evidence of publication and small study bias. Lamotrigine was not found to be superior to lithium in the acute treatment and prophylaxis of bipolar depression. In the treatment of unipolar depressive episodes, with the inclusion in the analyses of three unpublished studies, lamotrigine was not superior to placebo in monotherapy and as adjunct treatment. There were no maintenance studies in unipolar depression. <b>Conclusions:</b> There is evidence supporting the use of lamotrigine in monotherapy as acute and prophylactic treatment of bipolar depression. Evidence of the use of lamotrigine in unipolar disorders is lacking. PROSPERO registration ID: CRD42025633709.