Sex Differences in Cognitive Response to Transcranial Direct Current Stimulation in Schizophrenia: A Randomized Controlled Trial

Background Cognitive dysfunction is a central feature of schizophrenia and a major predictor of functional outcome. Transcranial direct current stimulation (tDCS) has been proposed as an adjunctive intervention to ameliorate these deficits, yet treatment response is highly variable. While sex-related neuroanatomical and pharmacological factors may modulate cortical excitability, their influence on clinical tDCS efficacy in schizophrenia remains poorly understood. Methods We conducted a predefined secondary analysis of a randomized, double-blind, sham-controlled trial including 120 clinically stable outpatients with schizophrenia (80 men, 40 women). Participants received either active bifrontal tDCS (2 mA, anode F3/cathode F4, 20 minutes, 10 weekday sessions) or sham stimulation. Cognitive performance was assessed pre- and post-intervention with the MATRICS Consensus Cognitive Battery (MCCB). Primary outcomes were changes in Working Memory (WM) and Neurocognition composite scores. Subjective cognitive improvement was also recorded. Results Active tDCS produced significant improvements in WM (F(1,116) = 19.041, p < 0.001, partial η² = 0.141) and Neurocognition (F(1,116) = 4.268, p = 0.041, partial η² = 0.035) relative to sham. Effect sizes for WM were large in both men (d = 0.80) and women (d = 0.82). No significant main effect of sex or group × sex interaction was detected. Descriptively, men exhibited greater differentiation between active and sham stimulation, whereas women showed modest but comparable gains across conditions. Subjective–objective concordance was modest, with slightly higher accuracy in women. Conclusions Sex did not significantly moderate tDCS-induced cognitive enhancement in schizophrenia, but subtle sex-related patterns emerged. These findings highlight the need to integrate sex and pharmacological factors into precision neuromodulation strategies for psychosis.