Optimizing tDCS cognitive outcomes in schizophrenia: the role of dopaminergic tone and antipsychotic load

Working memory deficits are a central cognitive impairment in schizophrenia and a key therapeutic target. Transcranial direct current stimulation (tDCS) has emerged as a potential cognitive enhancer, yet considerable interindividual variability limits its clinical utility. Pharmacological modulation of dopaminergic signaling, particularly through antipsychotic medications, may influence neuroplasticity and thereby alter responsiveness to tDCS. This study investigated whether antipsychotic dose or pharmacodynamic profile affects tDCS-related working memory improvements in schizophrenia. In a randomized, double-blind, placebo-controlled trial, 120 clinically stable outpatients received active or sham bifrontal tDCS delivered over 10 consecutive weekdays. Working memory performance was assessed using the MATRICS Consensus Cognitive Battery. Antipsychotic regimens were categorized as full D2 antagonists or partial D2 agonists, and all doses were converted to olanzapine equivalents. Results showed a significant negative correlation between antipsychotic dose and tDCS-induced working memory enhancement (r = -0.197, p = 0.031), indicating diminished cognitive gains at higher doses. In contrast, no significant differences in working memory outcomes emerged between patients receiving full antagonists versus partial agonists. These findings suggest that overall dopaminergic blockade, rather than specific receptor-binding profiles, modulates cognitive responsiveness to tDCS. High antipsychotic doses may reduce neuroplastic capacity, thereby limiting the therapeutic potential of neuromodulation. The results highlight the need to consider antipsychotic load in the design and interpretation of cognitive enhancement trials and support the use of pharmacological burden as a stratification variable in precision-psychiatry approaches.