Antidepressant-associated Suicidality and Behavioural Activation in Adolescent Depression: the Role of Unrecognised Bipolar Spectrum Features: A Systematic Review and Meta-Analysis

Background and objectives Antidepressant treatment in adolescents with depressive episodes has been associated with an increased risk of suicidality and behavioural activation, particularly during the early phase of treatment. Emerging evidence suggests that underlying bipolar spectrum vulnerability may be associated with these adverse outcomes and could modify their risk. This study aimed to systematically evaluate the association between antidepressant exposure and early suicidality, behavioural activation, and treatment-emergent affective symptoms in adolescents, with a focus on unrecognised bipolar spectrum features as a potential moderator of risk. Methods A PRISMA 2020–compliant systematic review and meta-analysis was conducted using MEDLINE, Embase, PsycINFO, Web of Science, and CENTRAL. Randomised controlled trials and observational studies involving adolescents (≤18 years) with depressive episodes treated with antidepressants were included. Random-effects meta-analyses were performed where appropriate, with emphasis on early risk windows following treatment initiation. Results Twenty-two studies met inclusion criteria. Pooled analyses demonstrated an increased risk of suicidality and behavioural activation following antidepressant initiation, with the highest risk observed within the first 4–12 weeks. Effect sizes were consistently larger in samples characterised by mixed depressive features or indicators of bipolar spectrum vulnerability. Findings were broadly consistent across study designs, although heterogeneity varied across outcomes. Conclusion Antidepressant-associated suicidality and behavioural activation in adolescents appear to be temporally front-loaded and phenotype-sensitive. Unrecognised bipolar spectrum features may represent a clinically relevant vulnerability marker and a potential moderator of early adverse outcomes, although the available evidence does not establish a causal pathway.These findings underscore the importance of careful assessment for bipolar spectrum indicators, cautious dosing strategies, and close clinical monitoring during early treatment phases.