Effectiveness of Exercise Alone and tDCS+Exercise on Cognitive Function Improvement in Patients With Treatment Resistant Schizophrenia

Randomised Control Trial of Effectiveness of Exercise Alone and tDCS+Exercise on Cognitive Function Improvement in Patients With Treatment Resistant Schizophrenia

Cognitive impairment is a major determinant of disability in schizophrenia. Aerobic exercise improves global cognition in schizophrenia, particularly working memory and attention/vigilance. Transcranial direct current stimulation (tDCS) targeting frontal regions has shown promise for cognitive deficits, including working memory improvements in some studies. This randomized 2×2 factorial trial will test the independent and combined effects of supervised aerobic exercise and prefrontal tDCS on cognition in treatment resistant schizophrenia, measured using the MATRICS Consensus Cognitive Battery (MCCB).

This is an individually randomized, sham controlled (tDCS), assessor blinded 2×2 factorial clinical trial comparing: (1) aerobic exercise vs stretching/education control and (2) active vs sham prefrontal tDCS. The factorial design enables estimation of the main effects of exercise and tDCS and their interaction (synergy/antagonism) in one trial.

Participants with treatment resistant schizophrenia (TRS) will complete 18 sessions over 6 weeks (3 sessions/week). Each session includes tDCS (active or sham) during the physical activity condition (aerobic exercise or stretching/education) to standardize timing and contact. Evidence suggests exercise associated cognitive gains relate to intervention dose and supervision. Noninvasive brain stimulation outcomes may vary with stimulation dose parameters, supporting a standardized protocol.

Cognition will be assessed using the MCCB, which evaluates seven cognitive domains relevant to schizophrenia and yields an Overall Composite T score. The primary endpoint is Week 6 (end of intervention), with durability assessed at 3 months post intervention (Week 18).

Inclusion Criteria:

• DSM 5 schizophrenia-spectrum disorders
• Treatment resistant schizophrenia: inadequate response to ≥2 antipsychotics of adequate dose/duration
• Clinically stable ≥4 weeks
• Able to provide informed consent

Exclusion Criteria:

• Neurological disorder (e.g., epilepsy, stroke) or significant head injury
• Implanted electronic devices / contraindications to tDCS; scalp lesions at electrode sites
• Medical contraindications to moderate aerobic exercise
• Substance dependence within 3 months (except nicotine)
• Pregnancy