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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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arm 1: Aerobic Exercise + Active tDCS | Experimental |
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| Arm 2: Aerobic Exercise + Sham tDCS | Active Comparator |
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| Arm 3: Stretching/Education + Active tDCS | Active Comparator |
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| Arm 4: Stretching/Education + Sham tDCS | Sham Comparator |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Aerobic Exercise | Behavioral |
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| Measure | Description | Time Frame |
|---|---|---|
| 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. | 6 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 6 weeks |
| MCCB Attention/Vigilance Domain change (CPT IP domain T score) baseline to Week 6. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 18 weeks total |
| Changes of social functioning measured with SOFAS from baseline to 18 weeks |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Kit Wa Chan, MD | Contact | 852-22554489 | kwsherry@hku.hk | |
| Yifan Chen, PhD | Contact | 852-22554486 | yifchen@hku.hk |
| Name | Affiliation | Role |
|---|---|---|
| Kit Wa Chan, MD | The University of Hong Kong | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The University of Hong Kong | Hong Kong | Hong Kong |
Sharing data will depend on funder. Further information will need to be checked and confirmed.
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| Stretching/Education Control | Behavioral |
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| Active tDCS | Device |
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| Sham tDCS | Device | • Same montage; ramp up then off (device standard sham) to mimic cutaneous sensations. |
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Attention/vigilance improves with exercise in schizophrenia meta analysis; attention demanding performance may improve in some tDCS protocols. |
| 6 weeks |
| 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 | 6 weeks |
| Durability of changes of negative symptoms relative to baseline and week 6 | Evaluates the persistence of the improvement of negative symptoms | 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 |
| 18 weeks |
| 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 | 24 |
| 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 | 24 weeks |
| Durability of the improvement of social functioning at 6 months post intervention (week 24) relative to baseline and week 18 | Evaluates the persistence or even further improvement of the social functioning | 24 weeks |
| ID | Term |
|---|---|
| D012559 | Schizophrenia |
| D000090663 | Schizophrenia, Treatment-Resistant |
| D060825 | Cognitive Dysfunction |
| ID | Term |
|---|---|
| D019967 | Schizophrenia Spectrum and Other Psychotic Disorders |
| D001523 | Mental Disorders |
| D003072 | Cognition Disorders |
| D019965 | Neurocognitive Disorders |
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| ID | Term |
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| D015444 | Exercise |
| ID | Term |
|---|---|
| D009043 | Motor Activity |
| D009068 | Movement |
| D009142 | Musculoskeletal Physiological Phenomena |
| D055687 | Musculoskeletal and Neural Physiological Phenomena |
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