Efficacy of Remote Ischemic Conditioning in Preventing Post-Stroke Depression

Efficacy of Remote Ischemic Conditioning in Preventing Post-Stroke Depression: A Multicenter, Randomized, Double-Blind, Sham-Controlled Clinical Trial

Post-stroke depression (PSD) is characterized primarily by low mood and loss of interest following a stroke. It is one of the most common and serious complications of stroke, with an incidence of 11% to 41% within two years post-stroke. PSD significantly impacts stroke prognosis, not only hindering neurological recovery but also increasing clinical disability and mortality rates, thereby imposing substantial economic and psychological burdens on families and society. Therefore, preventing PSD is crucial for stroke rehabilitation.

Clinical trials have demonstrated that preventive antidepressant treatment can reduce PSD incidence and improve clinical outcomes; however, controversies remain regarding the timing, methods, and safety. Meanwhile, preventive psychological therapy faces challenges in implementation due to effectiveness, accessibility, and cost-effectiveness.

Remote ischemic preconditioning (RIC) is a non-invasive, cost-effective, and non-pharmacological intervention. By modulating small molecules in the peripheral and central nervous systems through transient, periodic limb blood flow restriction and reperfusion, RIC reverses neurobiological changes and demonstrates neuroprotective potential in various neurological diseases. Recently, a study showed that RIC is safe and effective in preventing PSD; however, the sample size is small and the specific mechanisms remain unclear. Therefore, this study aims to further explore the role and mechanisms of RIC in PSD prevention.

Study Overview

• Status: Not yet recruiting
• Conditions: Post-stroke Depression; Remote Ischemic Conditioning
• Intervention / Treatment: Device: RIC; Device: Sham-RIC

Detailed Description

This multicenter, randomized, double-blind, sham controlled clinical study will enroll acute ischemic stroke patients within 48 hours of symptom onset. Eligible participants will be randomly allocated (1:1) to receive either remote ischemic conditioning (RIC) or sham-RIC treatment for 14 consecutive days. The primary outcome is the incidence of post-stroke depression at day 14 post-randomization.

• Study Type: Interventional
• Enrollment (Estimated): 240
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Lina Jia; Phone Number: +8615901588600; Email: lnjia@ccmu.edu.cn
• Study Contact Backup: Name: Shuling Wan; Phone Number: +8615901589718; Email: 15901589718@163.com

Study Locations

• China
  • Beijing, China, 100053
    • Xuanwu Hospital, Capital Medical University
    • Contact: Lina Jia; Phone Number: +8615901588600; Email: lnjia@ccmu.edu.cn
  • Guizhou
    • Tongren, Guizhou, China, 554399
      • Tongren City People's Hospital
      • Contact: Long Liao; Phone Number: +8615121644332
  • Hebei
    • Baoding, Hebei, China, 071030
      • Baoding People's Hospital
      • Contact: Lan Hou; Phone Number: +8613931239934
  • Jilin
    • Jilin, Jilin, China, 132001
      • Jilin People's Hospital
      • Contact: Zhifei Wang; Phone Number: +8618104421807
  • Shanxi
    • Jincheng, Shanxi, China, 048028
      • Jincheng People's Hospital
      • Contact: Lina Xu; Phone Number: +8613835628289

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Patient age≥18 years;
• No gender preference;
• Diagnosed with acute ischemic stroke;
• From onset to treatment ≤48 h;
• 6≤ NIHSS scores ≤25;
• Premorbid mRS ≤1;
• Signed informed consent.

Exclusion Criteria:

• Baseline HAMD-24 scores ≥8;
• Infarction area overlapped with the area where the DTI-ALPS index is calculated;
• A history of severe mental illness such as depression, bipolar disorder, and schizophrenia;
• A history of mental disorders caused by other organic diseases, such as post-Parkinson depression;
• Participants with cognitive impairment, disturbance of consciousness, severe hearing impairment, or aphasia who were unable to cooperate with the assessment;
• A history of autoimmune diseases (such as multiple sclerosis, neuromyelitis optica spectrum disorders, systemic lupus erythematosus, etc.), malignant tumors, or obstructive sleep apnea hypopnea syndrome;
• Intracranial tumor, arteriovenous malformation, or aneurysm;
• Uncontrolled severe hypertension (systolic pressure >180mmHg or diastolic pressure >110 mmHg after drug treatment) ;
• Subclavian artery stenosis≥50% or subclavian steal syndrome;
• Any contraindication for remote ischemic adaptation: the upper limb has serious soft tissue injury, fracture or vascular injury, distal upper limb perivascular lesions, etc.;
• Severe coagulation dysfunction, platelet count < 100×10^9/L, cardiac dysfunction (NYHA class Ⅲ or above), hepatic dysfunction (aspartate aminotransferase and/or alanine aminotransferase > 3 times the upper limit of normal), or renal dysfunction (serum creatinine > 265μmol/L);
• Any contraindication for magnetic resonance imaging: metal implants, claustrophobia, etc.;
• Women known to be pregnant or lactating, or have a positive pregnancy test;
• Participating in other clinical trials within three months;
• Participants not suitable for this clinical studies considered by researcher.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RIC group; Subjects in the RIC group receive standard therapy and RIC treatment.	Device: RIC; The ischemic preconditioning training device is applied to the subjects' upper arms to administer pressure (200 mmHg). The pressure is maintained for 5 minutes, followed by 5 minutes of release, completing one ischemia-reperfusion cycle. Each training session consists of 5 consecutive cycles, performed twice daily for 14 days.
Sham Comparator: Sham-RIC group; Subjects in the Sham-RIC group receive standard therapy and Sham-RIC treatment.	Device: Sham-RIC; The ischemic preconditioning training device is applied to the subjects' upper arms to administer pressure (60 mmHg). The pressure is maintained for 5 minutes, followed by 5 minutes of release, completing one ischemia-reperfusion cycle. Each training session consists of 5 consecutive cycles, performed twice daily for 14 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of post-stroke depression	The diagnosis of post-stroke depression is established according to the "Depressive Disorder Due to Another Medical Condition" criteria specified in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), using the Structured Clinical Interview for DSM-5 Disorders, Research Version (SCID-5-RV).	Day 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative incidence of post-stroke depression	The cumulative incidence of post-stroke depression is calculated as (number of post-stroke depression cases during follow-up / total enrolled participants) × 100%.	Day 28, Day 90, and Day 180
Incidence of post-stroke anxiety	The diagnosis of post-stroke anxiety is established according to the "Anxiety Disorder Due to Another Medical Condition" criteria specified in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), using the Structured Clinical Interview for DSM-5 Disorders, Research Version (SCID-5-RV).	Day 180
Cumulative incidence of post-stroke anxiety state	Post-stroke anxiety state is defined as a 14-item Hamilton Anxiety Rating Scale (HAMA-14) score ≥7 points.	Day 14, Day 28, Day 90, and Day 180
Change from baseline in enlarged perivascular spaces (EPVS) severity score (range 0-4)	EPVS in the basal ganglia (BG) and centrum semiovale (CSO) are visually scored as: 0 = none, 1 = 1-10, 2 = 11-20, 3 = 21-40, and 4 = >40 on the axial slice with the highest burden and hemicerebrum with higher burden. The higher the score, the worse the outcome.	Day 14
Change from baseline in Diffusion Tensor Imaging-Analysis along the Perivascular Space (DTI-ALPS) index.	The DTI-ALPS index is calculated as the ratio of projection-to-association fiber diffusivity in the lateral ventricular region.	Day 14
Change from baseline in Neurotransmitter levels in brain regions	Proton magnetic resonance spectroscopy (¹H-MRS) is performed to quantify the levels of N-acetylaspartate (NAA), glutamate/glutamine (Glx), choline (Cho), and creatine (Cr) in the following brain regions: thalamus, caudate nucleus, putamen, globus pallidus, amygdala, hippocampus, insular cortex, medial prefrontal cortex, and cingulate cortex.	Day 14
Change from baseline in peripheral blood neurotransmitter levels	Levels of γ-aminobutyric acid (GABA), glutamate (Glu), glutamine (Gln), serotonin (5-HT), norepinephrine (NE), and dopamine (DA) in peripheral blood are measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS).	Day 14
Change from baseline in peripheral blood cytokine levels	Levels of interleukin (IL)-1β, IL-6, IL-10, IL-15, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and transforming growth factor-β (TGF-β) in peripheral blood are measured using enzyme-linked immunosorbent assay (ELISA).	Day 14
Change from baseline in 24-item Hamilton Depression Rating Scale (HAMD-24) score (range 0-76)	The HAMD-24 is a standardized, clinician-rated instrument for quantifying depression severity, where elevated scores correlate with increased symptom burden.	Day 14, Day 28, Day 90, and Day 180
Change from baseline in 14-item Hamilton Anxiety Rating Scale (HAMA-14) score (range 0-56)	The HAMA-14 is a standardized, clinician-rated instrument for quantifying anxiety severity, with higher scores indicating greater severity.	Day 14, Day 28, Day 90, and Day 180
Change from baseline in Pittsburgh Sleep Quality Index (PSQI) score (range 0-21)	The PSQI is a validated self-reported questionnaire assessing sleep quality and disturbances over a 1-month period. Higher scores indicate worse sleep quality.	Day 14, Day 28, Day 90, and Day 180
Change from baseline in Fugl-Meyer Assessment (FMA) score (range 0-226)	The FMA is administered to evaluate sensorimotor recovery post-stroke. Higher total scores indicate better functional recovery.	Day 14
Change from baseline in National Institutes of Health Stroke Scale (NIHSS) score (range 0-42)	The NIHSS is assessed to quantify neurological deficit severity. Higher scores indicate more severe impairment.	Day 14
Change from baseline in Mini-Mental State Examination (MMSE) score (range 0-30)	The MMSE is administered to assess global cognitive function, with lower scores indicating greater impairment.	Day 90 and Day 180
Change from baseline in EuroQol 5-Dimension 5-Level questionnaire (EQ-5D-5L) score (range 5-25)	The EQ-5D-5L is administered to assess health-related quality of life. Higher scores indicate worse quality of life.	Day 90 and Day 180
Change from baseline in EuroQol 5-Dimension 5-Level questionnaire Visual Analogue Scale (EQ-5D-5L VAS) score (range 0-100)	The EQ-5D-5L VAS records self-rated overall health status on a vertical scale, with higher scores indicating better perceived health.	Day 90 and Day 180
The proportion of modified Rankin Scale (mRS) Score 0-2	The mRS is administered to evaluate global functional outcomes after stroke, with scores ranging from 0 (no symptoms) to 6 (death). For analysis, outcomes were dichotomized as favorable (mRS 0-2) or poor (mRS 3-6).	Day 90 and Day 180
The distribution of modified Rankin Scale (mRS) Score (range 0-6)	The mRS is administered to evaluate global functional outcomes after stroke, with higher scores indicating worse outcome.	Day 90 and Day 180
All-cause mortality	All-cause mortality is defined as death from any cause occurring during the study period.	Day 180
Total hospitalization time	Total hospitalization time is calculated by summing all inpatient days across neurology and rehabilitation departments within the follow-up period.	Day 180

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events	Adverse events include dizziness, headache, palpitation, and subcutaneous ecchymosis and swelling at the intervention site.	Day 14, Day 28, Day 90, and Day 180
Incidence of serious adverse events	Serious adverse events include death, life-threatening illness or injury, hospitalization or prolonged hospitalization, medical or surgical intervention required to prevent permanent injury, severe disability, or incompetence, and other serious medical events.	Day 14, Day 28, Day 90, and Day 180

Collaborators and Investigators

• Sponsor: Xuanwu Hospital, Beijing
• Investigators: Study Director: Lina Jia, Xuanwu Hospital, Beijing

Study record dates

Study Major Dates

• Study Start (Estimated): April 10, 2025
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: March 18, 2025
• First Submitted That Met QC Criteria: April 2, 2025
• First Posted (Actual): April 10, 2025

Study Record Updates

• Last Update Posted (Actual): April 10, 2025
• Last Update Submitted That Met QC Criteria: April 2, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Mental Disorders; Pathologic Processes; Behavioral Symptoms; Mood Disorders; Stroke; Ischemia; Depression; Depressive Disorder
• Other Study ID Numbers: LYS[2025]039-002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No