FMRI of Patients Receiving IV Ketamine for Treatment Resistant Bipolar Depression

Phase 2

Recruiting

• Conditions: Bipolar Depression; Treatment Resistant Bipolar Depression
• Interventions: Drug: Ketamine; Other: Functional magnetic resonance imaging (fMRI)

• Registration Number: NCT06620042
• Lead Sponsor: Brian Barnett

Brief Summary

This is a prospective open-label observational study of patients with treatment resistant bipolar depression referred for intravenous ketamine, with an interventional component of fMRI.

Detailed Description

This is a prospective open-label observational study of patients with treatment resistant bipolar depression referred for intravenous ketamine. All participants will receive an acute series of ketamine consisting of twice weekly infusions over three weeks. Non-responders will have their End of Study visits within 5 days of the last ketamine infusion. Responders (participants who achieve a greater than or equal to 50% decrease on their QIDS-SR-16 score from Baseline) will return for three weeks of continuation treatment (weekly ketamine) and then have their End of Study visit within 5 days of the last continuation treatment. All participants will undergo fMRI the prior to their first ketamine infusion, and after completion of their acute series.

Study Timeline

• Study First Submitted: 2024-09-26
• Study First Submitted QC: 2024-09-26
• Study First Posted: 2024-10-01
• Study Start: 2024-11-12
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-17
• Last Update Posted: 2025-04-18
• Primary Completion: 2025-08-01
• Study Completion: 2025-12-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 20

Inclusion Criteria

1. Written informed consent before any study related procedures are performed

2. Males/females at least 18 years of age but no older than 75 years of age

3. Meet DSM-5 criteria for a current Major Depressive Episode and lifetime Bipolar I disorder or Bipolar II disorder as determined by both:

   A. a clinician's diagnostic evaluation and B. confirmed with the MINI International Neuropsychiatric Interview (MINI 7.0.2)

4. A current depressive episode that has lasted a minimum of 4 weeks as determined by both:

   A. a clinician's diagnostic evaluation and B. confirmed with the MINI International Neuropsychiatric Interview (MINI 7.0.2)

5. Meet all the following criteria on symptom rating scales at screening:

   A. Montgomery Asberg Depression Rating Scale (MADRS) score ≥20 B. Young Mania Rating Scale (YMRS) score of ≤ 5 C. QIDS-SR-16 score of ≥ 11

6. Have had ≥ 2 adequate trials of mood stabilizers, antipsychotics (only those FDA approved for bipolar depression), or antidepressants or augmentation strategies during their lifetime. An adequate trial is defined as 4 weeks of medication at the minimum FDA approved dose.

7. In the opinion of the investigator, the patient is willing and able to comply with scheduled visits, treatment plan, and other trial procedures for the duration of the study.

Exclusion Criteria

1. Meet DSM-5 criteria for schizophrenia, schizophreniform disorder, schizoaffective disorder, mental retardation, or pervasive developmental disorder

2. Meets any exclusion criteria for ketamine treatment (uncontrolled arterial hypertension, uncontrolled hyperthyroidism, severe ischemic heart disease or heart failure, severe liver or kidney disease, space occupying lesion in the brain or the spinal cord, and uncontrolled glaucoma)

3. The patient is pregnant or breast feeding

4. The patient has a severe medical illness or severe neurological disorder

5. The patient has a known ketamine allergy or is taking a medication that may significantly interact with ketamine (see Appendix)

6. Diagnosis of psychotic features during the current depressive episode or within the past 6 months

7. Was previously enrolled in the trial

8. Active moderate or severe substance use disorder within the last 3 months (no exclusion for tobacco use disorder of any severity)

9. Current episode of mania/hypomania or mixed episode according to MINI or study clinician

10. MRI contraindications

    • Severe head trauma
    • Claustrophobia incompatible with scanning
    • Cardiac pacemaker
    • Implanted cardiac defibrillator
    • Aneurysm brain clip
    • Inner ear implant
    • Prior history as a metal worker and/or certain metallic objects in the body -- must complete MRI screening form and be approved by MRI technologist before each scan
    • History of clinically significant vertigo middle ear disorder, or double vision

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Open-label Ketamine TRBD	Ketamine	Outpatients with treatment resistant bipolar depression referred by their clinical providers for intravenous ketamine treatment
Open-label Ketamine TRBD	Functional magnetic resonance imaging (fMRI)	Outpatients with treatment resistant bipolar depression referred by their clinical providers for intravenous ketamine treatment

Primary Outcome Measures

Name	Time	Method
Acute Response Changes in Subgenual Cingulate Functional Connectivity	Three weeks after treatment initiation	Seed-to-whole brain functional connectivity z-maps will be calculated from the left and right subgenual cingulate on the baseline and post-acute resting-state functional MRI (rs-fMRI) from each participant. After acute treatment, participants will be categorized as "responders" (≥50% decrease from baseline score of Quick Inventory of Depressive Symptomatology 16-item self-report, QIDS-SR-16) or "non-responders". Brain regions in responders that exhibit significantly different treatment-related change in functional connectivity compared to non-responders will be identified using general linear model methods.

Secondary Outcome Measures

Name	Time	Method
Acute Response Baseline Structural Connectivity	Three weeks after treatment initiation	Baseline structural connectivity will be assessed from baseline diffusion tensor imaging for each participant. White matter tracts in responders that exhibit significantly different mean transverse diffusivity compared to non-responders will be identified.
Sustained Response Changes in Subgenual Cingulate Functional Connectivity	Six weeks after treatment initiation	Acute "responders" will undergo a maintenance treatment phase (3 treatments over 3 weeks). After maintenance treatment, participants will be categorized as "sustained responders" (≥50% decrease from baseline QIDS-SR-16 score) or "relapsers" at the end of treatment. Brain regions in sustained responders that exhibit significantly different treatment-related change in subgenual cingulate brain functional connectivity maps compared to relapsers will be identified using general linear model methods.
Suicidal Ideation Changes in Subgenual Cingulate Functional Connectivity	Six weeks after treatment initiation	Brain regions in participants that experience suicidal ideation during treatment that exhibit significantly different treatment-related change in subgenual cingulate brain functional connectivity maps compared to participants who do not experience suicidal ideation will be identified using general linear model methods.

Trial Locations

Locations (1)

Cleveland Clinic Lutheran Hospital; 🇺🇸 Ohio City, Ohio, United States