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).
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
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)
Factorial
Aerobic Exercise
Behavioral* Dose: 18 sessions over 6 weeks (3/week) * Session duration: 45-60 minutes including warm up/cool down * Intensity: Moderate (target 60-75% HRR or RPE 12-15) * Mode: Aerobic dance * Delivery: Supervised by qualified staff; HR/RPE logged each session * Rationale: Exercise improves global cognition and domains such as working memory and attention/vigilance in schizophrenia; supervision/dose relate to effect size.
Stretching/Education Control
Behavioral* Dose: 18 sessions over 6 weeks (3/week) * Session duration: 45-60 minutes * Intensity: Low (HR \<40% HRR; RPE \<10) * Components: Stretching + standardized health education modules * Purpose: Attention matched control to reduce contact/expectancy bias in non pharmacological trials.
Active tDCS
Device* Montage: Anode F3 (left DLPFC), cathode Fp2 (right supraorbital) * Intensity: 2.0 mA * Duration: 20 minutes (30 s ramp up/down) * Schedule: 18 sessions (one per visit) * Rationale: Frontal tDCS protocols have shown promise for cognitive deficits and working memory in schizophrenia
Sham tDCS
Device• Same montage; ramp up then off (device standard sham) to mimic cutaneous sensations.
MCCB Overall Composite T score change from baseline (Week 0) to end of intervention (Week 6).
MCCB provides standardized domain and composite T scores for schizophrenia cognition research.
MCCB Working Memory Domain change (LNS + WMS III Spatial Span domain T score) baseline to Week 6.
Working memory is responsive to exercise in schizophrenia meta-analysis and frequently targeted in frontal tDCS studies.
MCCB Attention/Vigilance Domain change (CPT IP domain T score) baseline to Week 6.
Attention/vigilance improves with exercise in schizophrenia meta analysis; attention demanding performance may improve in some tDCS protocols.
Changes of negative symptoms measured with SANS from baseline to week 6
Studies have shown effectiveness of exercise and tDCS on improvement of negative symptoms in patients with schizophrenia
Durability of changes of negative symptoms relative to baseline and week 6
Evaluates the persistence of the improvement of negative symptoms
Durability: MCCB Overall Composite and key domains at 3 months post intervention (Week 18) relative to baseline and Week 6.
Evaluates persistence of cognitive gains.
Changes of social functioning measured with SOFAS from baseline to 18 weeks
Cognitive function and negative symptoms are closely related to social functioning. Improvement of these may contribute to the improvement of overall social functioning
Durability: MCCB Overall Composite and key domains at 6 months post intervention (Week 24) relative to baseline and Week 6 and week 18
Evaluates persistence of cognitive gains
Durability of improvement of negative symptoms at 6 months after intervention (week 24) relative to baseline, week 6 and week 18
Evaluates persistence of the improvement of negative symptoms
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Kit Wa Chan
Lead sponsor
The University of Hong Kong
Sponsor institution
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