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Children of parents with depression, hereafter referred to as high-risk youth, are at elevated risk for mental illness, yet the mechanisms underlying this vulnerability remain unclear. Biased interpretation of ambiguous information and altered stress responses in this population have been proposed as potential pathways. As no previous study has examined these factors together, we investigated interpretation bias and endocrinological and affective stress responses as potential markers of depression vulnerability in high-risk children. We hypothesised that children of parents with depression would show more negative interpretation bias, altered cortisol stress responses and greater affective reactivity and prolonged recovery compared to children of parents with no mental illness. Across the sample, associations between interpretation bias and stress responses were expected.

Participants were 80 high-risk (parental depression) and 77 low-risk (no parental mental illness) youth aged 10 to 14 years. Mental health was assessed using structured clinical interviews. Interpretation bias was measured using the Scrambled Sentences Task, and stress reactivity and recovery were indexed by salivary cortisol and self-reported affect across six time points. Group differences were tested with t-tests and analyses of covariance. Regressions examined the unique contribution of familial risk status beyond other relevant factors, including depression, anxiety, childhood trauma, pubertal status, and sex. Correlations examined associations between interpretation bias and cortisol and affective stress indices.

Groups did not differ in interpretation bias, or cortisol or affective stress responses. Children's own symptoms of psychopathology (depression slightly more so than anxiety) positively predicted their interpretation bias but not their cortisol or affective stress responses. Exploratory moderation analyses showed that higher baseline cortisol strengthened the relationship between depression and interpretation bias. Interpretation bias correlated with cortisol reactivity and recovery within the high-risk but not the low-risk group.

Contrary to theoretical accounts, high-risk youth did not exhibit cognitive, affective, or endocrinological vulnerabilities relative to low-risk peers. Interpretation bias was found to be a promising target, robustly linked to clinical outcomes and tentatively to cortisol stress responses, though its absence in high-risk youth is in support of a more selective intervention approach.

The study was preregistered under the Deutsches Register Klinischer Studien DRKS00028842 on August 19, 2022.