The role of the HPA axis in tailoring cognitive remediation therapy in patients with early psychosis: An exploratory randomized clinical trial.

BACKGROUND

Cognitive remediation therapy (CRT) improves cognition in psychosis, yet response variability remains high. The hypothalamic-pituitary-adrenal (HPA) axis may influence cognitive plasticity. This study examined whether the cortisol awakening response (CARi) and diurnal cortisol slope predict cognitive change during CRT in recent-onset psychosis (ROP).

METHODS

In a randomized, crossover pilot trial (first 12-week phase analyzed), 28 outpatients with ROP were assigned to CRT (n = 14) or treatment as usual (TAU; n = 14). The CRT program (NeuroPersonalTrainer®) consisted of twice-weekly, 90-minute computerized sessions targeting attention, memory, and executive functions. Cognitive performance was assessed with the CANTAB battery at baseline and 12 weeks. Salivary cortisol, collected on two consecutive days, was used to compute CARi (AUCi at awakening, +30, +60 min) and diurnal slope (awakening to 23:00 h). Linear mixed-effects models tested Time × Group × Biomarker interactions for z-scored cognitive outcomes, adjusting for sex and applying false discovery rate (FDR) correction.

RESULTS

Groups were comparable at baseline. No domain showed a significant Time × Group × CARi interaction after FDR correction (nominal: Spatial Working Memory - Between Errors, p = .023). In contrast, the diurnal slope significantly moderated change in Rapid Visual Processing Accuracy (RVPA; p = .002, FDR-adjusted p = .04): participants with a steeper (more negative) slope displayed greater gains in sustained attention with CRT versus TAU.

CONCLUSIONS

A steeper diurnal cortisol slope-but not CARi-predicted greater cognitive improvement following CRT, particularly in sustained attention. The slope may serve as a feasible biomarker to personalize CRT within precision psychiatry.