Hyperbaric Oxygen Therapy for Persistent Post Stroke Depression

Hyperbaric Oxygen Therapy for Persistent Post Stroke Depression: A Prospective, Randomized, Double Blind Study

The study evaluates the effect of HBOT on depression in patients suffering from persistent symptoms of post stroke depression (PSD) in an double blind sham control study.

Study Overview

• Status: Recruiting
• Conditions: Post Stroke Depression
• Intervention / Treatment: Device: hyperbaric oxygen therapy

Detailed Description

Post-stroke depression (PSD) is a prevalent mental health complication, affecting approximately 33% of stroke survivors. Its occurrence not only hinders rehabilitation and recovery from motor and cognitive deficits post-stroke but also escalates the risk of subsequent neurovascular events. Both biological and psychological factors are instrumental in the onset of PSD.

Ischemia plays a pivotal role in the development of long-term PSD due to its impact on specific brain regions, neurotransmitter systems, neural connectivity, inflammatory responses, and mitochondrial dysfunction.

brain ischemia can instigate a protracted cycle of inflammation, levels and functions of neurotransmitters, impaired mitochondrial function, that directly impinges on the brain's ability to undergo neuroplastic changes. This relationship underscores the importance of targeting the cure of brain ischemia in therapeutic strategies for PSD. Managing the brain ischemia could potentially salvage neuroplasticity and mitigate the mental and cognitive decline associated with PSD.

The new protocols of hyperbaric oxygen therapy (HBOT), using the hyperoxic-hypoxic paradox (HHP), is one of the first therapeutic intervention already in clinical use today for the specific goal of inducing regeneration of damaged brain tissue.

Cumulative data from recent years provide convincing evidence that HBOT can induce neuroplasticity leading to repair of chronically impaired brain functions and improved quality of life in post-stroke patients.

Both neurological and cognitive functions were improved even years after the stroke.

The observed restoration of neuronal activity in the metabolically dysfunctional stunned areas indicates that HBOT is a potent means of delivering sufficient oxygen needed for activation of neuroplasticty and restoration of impaired functions.

HBOT was found to be effective in small clinical trials for patients suffering from post-stroke depression. In a meta-analysis done by Liang et al. the efficacy and safety of HBOT for PSD was evaluated. A total of 27 RCTs involving 2250 participants were identified. Patients in HBOT group had a higher response rate than patients in control group (response rate: 69.4% vs 51.2%, odds ratio [OR] = 2.51, 95% confidence interval [CI] [1.83-3.43], P = 0.000). HBOT significantly reduced Hamilton Depression (HAMD).

The aim of the current study is to evaluate the effect of HBOT on depression in patients suffering from persistent symptoms of post stroke depression (PSD) in an double blind sham control study.

• Study Type: Interventional
• Enrollment (Estimated): 142
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Shai a Efrati, MD; Phone Number: 972549212866; Email: efratishai@outlook.com

Study Locations

• Israel
  • Zrifin, Israel, 70300
    • Recruiting
    • The Sagol Center for Hyperbaric Medicine and Research Shamir Medical Center (Assaf Harofeh)
    • Contact: Shai Efrati, Prof; Phone Number: 972-8-9779393; Email: efratishai@outlook.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Age between 50 -85
2. Suffered an ischemic stroke 6 months to 7 years prior to their inclusion
3. Treated or being treated by antidepressants for at least 3 months
4. Diagnosis of PSD based on HDRS-17 score of 17 and above.
5. Stable psychological and pharmacological treatment for more than three months prior to inclusion.
6. Subject willing and able to read, understand and sign an informed consent.

Exclusion Criteria:

1. Inability to attend scheduled clinic visits and/or comply with the study protocol
2. Diagnosis of a psychiatric disorder prior to the recent stroke including: major depression, schizophrenia or bipolar disease.
3. Diagnosis of aphasia or major cognitive decline
4. History of Deep brain stimulation (DBS)
5. History of traumatic brain injury, brain tumors, brain surgery, chronic subdural haemorrhages, Epilepsy
6. Active malignancy
7. Substance use at baseline.
8. History of other neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Lewy body dementia (LBD), Frontotemporal dementia (FTD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS), Creutzfeld Jacob disease (CJD), Multisystem atrophy (MSA), Pseudobulbar palsy (PSP), Corticobasal degeneration (CBD), Wernicke Korsakoff syndrome
9. Serious suicidal ideation
10. Renal or liver insufficiency, electrolyte imbalances
11. Chronic heart failure with ejection fraction of 30 or less
12. HBOT for any reason prior to study enrolment
13. Chest pathology incompatible with pressure changes (including active asthma or COPD)
14. Ear or Sinus pathology incompatible with pressure changes (above 3 otolaryngologist visits a year)
15. An inability to perform an awake brain MRI
16. No evidence of vascular related lesions in the brain MRI
17. Active smoking
18. Participation in another study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: hyperbaric oxygen therapy (HBOT) active treatment; The HBOT protocol consists of 60 daily sessions, five times per week, within a three months' period. Then there will be a follow-up period for 3 months without any investigated intervention. each session lasting 90 minutes, of 100% oxygen at 2 ATA and 5-minute air breaks every 20 minutes.	Device: hyperbaric oxygen therapy; The HBOT protocol consists of 60 daily sessions, five times per week, each session lasting 90 minutes. Investigational product: Multiplace hyperbaric oxygen chamber (Haux, Germany) located at the Sagol Center for Hyperbaric Medicine and Research, Shamir (Assaf-Harofeh) Medical Center, Israel.
Sham Comparator: Sham hyperbaric oxygen therapy (HBOT) Sham treatment; All the conditions provided in the HBOT intervention will be provided in the sham intervention. However, in contrast to the HBOT, each session includes breathing 21% oxygen by mask while in the same multiplace chamber. SHAM pressure will go up to 1.2 ATA during the first five minutes of the session (to simulate the pressure sensation in the ears), and then decrease during the next 5 minutes to 1.03 ATA for 90 minutes with 5-minute air breaks, every 20 minutes The initial 1.2 ATA level will provide a minimal pressure sensation in the ears, with the same nurse advice on pumping the ears. In the last five minutes of the session, the air will be circulated again with its related noises. Sham and HBOT sessions will never be adjacent, so subjects from the two groups cannot meet and discuss the session and its effects.	Device: hyperbaric oxygen therapy; The HBOT protocol consists of 60 daily sessions, five times per week, each session lasting 90 minutes. Investigational product: Multiplace hyperbaric oxygen chamber (Haux, Germany) located at the Sagol Center for Hyperbaric Medicine and Research, Shamir (Assaf-Harofeh) Medical Center, Israel.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PSD symptoms	Depression severity will be evaluated by structured interview based on the HDRS-17 guided structural questioner (Hamilton Depression Rating Scale from 0-53 ,Levels of depression is categorized according to the following accepted criteria: Not depressed: 0-7; Mild (subthreshold): 8-13; Moderate: 14-18; Severe: 19-22; Very severe: >23)	Change from Baseline immediately after the intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MRI Imaging	At each of the evaluations, patients will undergo structural and functional MRI scanning. Images will be acquired on Vida 3 Tesla Scanner, configured with a 64-channel receiver head coils (Siemens Healthcare, Erlangen, Germany) at Shamir medical center radiology department.	Change from Baseline immediately after the intervention
Short form health survey (sf-36)	Quality of life questionnaire, scale of 0-100, higher score means better outcome	at baseline, 3 months, 6 months
depression	Beck depression inventory II. Each answer is scored on a scale value of 0 to 3 . The score ranges between 0 and 63, with higher scores indicating more severe depression symptoms.	Change from Baseline immediately after the intervention
psychological distress	The Brief Symptom Inventory-18 (BSI-18). self-report questionnaire which generates a summary scale, the global stress index (GSI), and three subscales: depression, anxiety, and somatization. Each item is rated on a 5-point scale, with distress ratings ranging from 0 (not at all) to 4 (extremely) .	Change from Baseline immediately after the intervention
health status	Changes will be measured by The Stroke Impact Scale (SIS). The SIS version 3.0 includes 59 items, An extra question on stroke recovery asks that the client rate on a scale from 0 - 100 how much the client feels that he/she has recovered from his/her stroke.	Change from Baseline immediately after the intervention
independent living skills	Changes will be measured by Instrumental Activities of Daily Living (IADL) Scale. There are eight domains of function measured with the Lawton IADL scale. Clients are scored according to their highest level of functioning in that category. A summary score ranges from 0 (low function, dependent) to 8 (high function, independent) for women, and 0 through 5 for men.	Change from Baseline immediately after the intervention
NeuroTrax	computerized cognitive evaluation battery. each outcome parameter will be normalized and fit to an IQ-like scale (mean=100, STD=15), according to the participants' age and education.	at baseline, 3 months
MoCA	Montreal Cognitive Assessment (MoCA). The maximum MoCA score is 30 points, with a 1-point scoring correction for individuals with 12 years of education or less. A score of 26 or above is considered normal and a score lower than 26 has been considered to be the optimal cutoff point for diagnosis of cognitive impairment.	Change from Baseline immediately after the intervention
CANTAB Cambridge Neuropsychological Test Automated Battery	computerized cognitive evaluation battery test, divided into 2 tasks: 1- Multitasking test (MTT)- attention, reaction time and executive functions, Multitasking test Incongruency cost - A higher incongruency cost indicates that the subjects takes longer to process conflicting information. 2-Paired associated learning (PAL)- visual memory and new learning, PAL Number of Patterns Reached (0-8), PAL Total Errors (Adjusted) (0-64), PAL Total Attempts(0-64).	at baseline, 3 months
fMRI Imaging	Resting state fMRI(rsfMRI or R-fMRI)- a method of functional brain imaging that can be used to evaluate regional interactions that occur when a subject is not performing an explicit task. This resting brain activity is observed through changes in blood flow in the brain which creates what is referred to as a blood-oxygen-level dependent (BOLD) signal that can be measured using functional Magnetic Resonance Imaging (fMRI).	Change from Baseline immediately after the intervention
Physical, Neurological and functional evaluation	A general physical and neurological evaluation will be done. NIHSS - The National Institutes of Health Stroke Scale, or NIH Stroke Scale (NIHSS), will be used as part of the neurological evaluation to objectively quantify the impairment caused by the stroke. The NIHSS is composed of 11 items, each of which scores a specific ability between a 0 and 4 .For each item, a score of 0 typically indicates normal function in that specific ability, while a higher score is indicative of some level of impairment.	Change from Baseline immediately after the intervention
electrical brain activity	Quantitative EEG (qEEG) including task related EEG analysis. EEG analysis for each state within subject and between subjects will include frequency analysis (peak frequency and relative power), oscillations (proportions of the different bands alpha, beta, theta, delta activities) and power spectra distribution.	Change from Baseline immediately after the intervention
Inflammatory cytokines 1	blood tests will include Inflammatory markers: IL-1 (IL-1β): pg/mL	Change from Baseline immediately after the intervention
Inflammatory cytokines 2	blood tests will include Inflammatory markers: IL-6: pg/mL	Change from Baseline immediately after the intervention
Inflammatory cytokines 3	blood tests will include Inflammatory markers: Tumor necrosis factor-alpha (TNF-α): pg/mL	Change from Baseline immediately after the intervention
Inflammatory cytokines 4	blood tests will include Inflammatory markers: hsCRP (high-sensitivity C-reactive protein): mg/L	Change from Baseline immediately after the intervention
Inflammatory cytokines 5	blood tests will include Inflammatory markers: Exosomes: particles/mL (by NTA) or µg protein/mL (by protein assay)	Change from Baseline immediately after the intervention
Inflammatory cytokines 6	blood tests will include Inflammatory markers: Serum VEGF: pg/mL	Change from Baseline immediately after the intervention
Inflammatory cytokines 7	blood tests will include Inflammatory markers: Testosterone (serum): ng/dL or nmol/L	Change from Baseline immediately after the intervention
Inflammatory cytokines 8	blood tests will include Inflammatory markers: Estradiol (E2, serum): pg/mL or pmol/L	Change from Baseline immediately after the intervention
Inflammatory cytokines 9	blood tests will include Inflammatory markers: DHEA-S (serum): µg/dL (commonly) or µmol/L	Change from Baseline immediately after the intervention
Inflammatory cytokines 10	blood tests will include Inflammatory markers: Progesterone (serum): ng/mL or nmol/L	Change from Baseline immediately after the intervention
Inflammatory cytokines 11	blood tests will include Inflammatory markers: Cortisol (serum): µg/dL or nmol/L	Change from Baseline immediately after the intervention
Inflammatory cytokines 12	blood tests will include Inflammatory markers: Telomere length: kilobases (kb) or relative T/S ratio (qPCR, arbitrary units)	Change from Baseline immediately after the intervention

Collaborators and Investigators

• Sponsor: Assaf-Harofeh Medical Center
• Investigators: Principal Investigator: Shai a Efrati, MD, Asaf-Harofhe MC

Study record dates

Study Major Dates

• Study Start (Actual): November 8, 2023
• Primary Completion (Estimated): December 1, 2030
• Study Completion (Estimated): December 1, 2030

Study Registration Dates

• First Submitted: April 15, 2024
• First Submitted That Met QC Criteria: February 18, 2026
• First Posted (Actual): February 20, 2026

Study Record Updates

• Last Update Posted (Actual): April 17, 2026
• Last Update Submitted That Met QC Criteria: April 16, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: hyperbaric oxygen therapy
• Additional Relevant MeSH Terms: Therapeutics; Respiratory Therapy; Oxygen Inhalation Therapy; Hyperbaric Oxygenation
• Other Study ID Numbers: 0202-23

Drug and device information, study documents

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