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

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).

Study Overview

• Status: Not yet recruiting
• Conditions: Schizophrenia; Cognitive Impairment; Treatment Resistant Schizophrenia
• Intervention / Treatment: Behavioral: Aerobic Exercise; Device: Active tDCS; Device: Sham tDCS; Behavioral: Stretching/Education Control

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Estimated): 160
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Kit Wa Chan, MD; Phone Number: 852-22554489; Email: kwsherry@hku.hk
• Study Contact Backup: Name: Yifan Chen, PhD; Phone Number: 852-22554486; Email: yifchen@hku.hk

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong
    • The University of Hong Kong
    • Contact: Kit Wa Chan, MD; Phone Number: 852-22554489; Email: kwsherry@hku.hk
    • Contact: Yifan Chen, PhD; Phone Number: 852-22554486; Email: yifchen@hku.hk
    • Principal Investigator: Jessie Lin, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1: Aerobic Exercise + Active tDCS; Intervention 1 (Behavioral): Aerobic exercise; Intervention 2 (Device): Active tDCS	Behavioral: Aerobic Exercise; 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.; Device: Active tDCS; 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
Active Comparator: Arm 2: Aerobic Exercise + Sham tDCS; Intervention 1 (Behavioral): Aerobic exercise; Intervention 2 (Device): Sham tDCS	Behavioral: Aerobic Exercise; 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.; Device: Sham tDCS; • Same montage; ramp up then off (device standard sham) to mimic cutaneous sensations.
Active Comparator: Arm 3: Stretching/Education + Active tDCS; Intervention 1 (Behavioral): Stretching/education control; Intervention 2 (Device): Active tDCS	Device: Active tDCS; 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; Behavioral: Stretching/Education Control; 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.
Sham Comparator: Arm 4: Stretching/Education + Sham tDCS; Intervention 1 (Behavioral): Stretching/education control; Intervention 2 (Device): Sham tDCS	Device: Sham tDCS; • Same montage; ramp up then off (device standard sham) to mimic cutaneous sensations.; Behavioral: Stretching/Education Control; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	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.	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

Other Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Kit Wa Chan
• Investigators: Principal Investigator: Kit Wa Chan, MD, The University of Hong Kong

Study record dates

Study Major Dates

• Study Start (Estimated): February 23, 2026
• Primary Completion (Estimated): January 30, 2028
• Study Completion (Estimated): January 30, 2028

Study Registration Dates

• First Submitted: February 4, 2026
• First Submitted That Met QC Criteria: February 4, 2026
• First Posted (Actual): February 11, 2026

Study Record Updates

• Last Update Posted (Actual): February 11, 2026
• Last Update Submitted That Met QC Criteria: February 4, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: tDCS; cognitive function; aerobic exercise; treatment-resistant schizophrenia
• Additional Relevant MeSH Terms: Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Schizophrenia, Treatment-Resistant; Schizophrenia; Cognitive Dysfunction; Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena; Exercise
• Other Study ID Numbers: C7001-24Y

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Sharing data will depend on funder. Further information will need to be checked and confirmed.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No