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Although antidepressants are effective, around 50% of depressed patients are non-responsive. At the same time, some patients show alterations in the hypothalamic-pituitary-adrenal (HPA) axis. Due to interactions with central monoaminergic systems, these may profit less from antidepressants.To determine whether non-responders and responders differed in pre-treatment HPA axis functioning, the Cochrane Library, EMBASE, MEDLINE, and PsycINFO were searched. Studies using patients with depression being treated with antidepressants, and including both a pre-treatment HPA and a post-treatment response measure were included. Standardised mean differences were calculated for meta-analysis.Thirty-nine studies were included. Non-responders and responders did not differ in pre-treatment corticotropin-releasing hormone or adrenocorticotropic hormone. Meta-regression showed non-responders had comparably higher pre-treatment cortisol in studies measuring cortisol non-invasively, not reporting sample storage, failing to control for age, and excluding patients with comorbidities.Only studies with a specific methodological profile seem to be able to show that the more marked depressed patients’ alterations in the HPA axis, the less likely they are to profit from antidepressants.39 studies investigated HPA functioning as a predictor of antidepressant response.Non-responders did not differ from responders in pre-treatment CRH and ACTH.Non-responders had higher cortisol in studies with a specific methodological profile.