Stage 2 Registered Report: Clinical and Cognitive Mediators Underlying Subsequent Depression in Individuals With Attention-Deficit/Hyperactivity Disorder:A Developmental Approach

Objective: ADHD may lead to depression, but little is known about its underlying mechanisms. We examined whether clinical factors (irritability, anxiety), cognitive–affective processes (emotion recognition, response inhibition, working memory, sustained attention), and negative thought patterns (external locus of control, negative cognitive style), mediate ADHD-depression associations across development and whether these pathways differ by sex. Method: Analyses were performed in the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Twins Early Development Study (TEDS). In both samples, ADHD was assessed using the Strengths and Difficulties Questionnaire (SDQ) hyperactivity/inattention subscale at ages 7, 12/13, and 16/17. Depressive symptoms were assessed using the short Mood and Feelings Questionnaire at ages 12, 18/21, and 26/27. Mediators were assessed at ages 8-11, 16-17, and 21-25 with counterfactual mediation models. Results: Clinical factors were assessed and mediated the ADHD-depression effect in both cohorts across development. In ALSPAC, clinical mediators contributed most in childhood (30%) and young adulthood (25%), whereas in TEDS, they contributed most in adolescence (46%). In ALSPAC, negative thought patterns mostly contributed in adolescence (39%), while cognitive–affective factors did not show consistent evidence of mediating effects across development. All mediators combined explained 30%, 48% and 29% of the total effect of ADHD on depression in childhood, adolescence, and young adulthood, respectively. In sex-stratified models, the relative contribution of mediators varied by sex and developmental stage. In childhood, mediators accounted for a greater proportion of the total effect in males (37%) than in females (25%), while a similar proportion of mediated effects was observed across sexes during adolescence (48% in females and 45% in males). In young adulthood, the indirect effect via all mediators was evident only in females (36%). Conclusion: Mechanisms linking ADHD and depression are developmental stage- and sex-specific. Irritability and anxiety in childhood and young adulthood (particularly for females), and external locus of control and negative cognitive style in adolescence, might represent promising intervention targets for preventing depression in youth with ADHD. Study preregistration information: Study Preregistration: Clinical and Cognitive Mediators Underlying Subsequent Depression in Individuals With Attention-Deficit/Hyperactivity Disorder: A Developmental Approach; https://www.jaacap.org/article/S0890-8567(25)00171-6/fulltext