Sex-stratified cognitive response to transcranial direct current stimulation in schizophrenia: a randomized controlled trial

Cognitive impairment is a core feature of schizophrenia and a major determinant of functional outcome. Transcranial direct current stimulation (tDCS) shows potential for cognitive enhancement, yet response variability remains substantial. Biological sex may influence stimulation effects through neuroanatomical and pharmacological mechanisms, although evidence for sex-related moderation is limited. In this predefined secondary analysis of a randomized, double-blind, sham-controlled trial, 120 clinically stable outpatients with schizophrenia (80 men, 40 women) received active bifrontal tDCS (2 mA; anode F3/cathode F4; 20 min; 10 weekday sessions) or sham. Cognition was assessed pre–post using the MATRICS Consensus Cognitive Battery. Primary outcomes were change in Working Memory and Neurocognition composite scores (Δ post–pre, T-scores). Two-way ANCOVA models tested effects of intervention, sex, and their interaction, adjusting for baseline cognition, age, antipsychotic treatment, and chlorpromazine-equivalent dose. Associations between Subjective Cognitive Improvement (SCI) and objective change were examined using sex-stratified analyses, and screening validity for clinically meaningful improvement was explored. Active tDCS produced greater Working Memory improvement than sham (F = 17.79, p < 0.001; partial η²=0.14), with no sex effects or sex×intervention interaction. For Neurocognition, the adjusted intervention effect was not significant. SCI showed limited concordance with objective change, correlating modestly with Working Memory improvement in men only. Bifrontal tDCS selectively improved Working Memory in schizophrenia without evidence of sex-related moderation, supporting domain-targeted and precision-based neuromodulation strategies in clinical psychiatric rehabilitation.