miRNAs, Suicide, and Ketamine - Plasma Exosomal microRNAs as Novel Biomarkers for Suicidality and Treatment Outcome

• ClinicalTrials.gov Identifier: NCT02418195
• Recruitment Status: Active, not recruiting
• First Posted: April 16, 2015
• Last Update Posted: February 3, 2022
• Sponsor: University of Alabama at Birmingham
• Collaborator: National Institute of Mental Health (NIMH)
• Information provided by (Responsible Party): Yogesh Dwivedi, PhD, University of Alabama at Birmingham

Tracking Information

• First Submitted Date: April 13, 2015
• First Posted Date: April 16, 2015
• Last Update Posted Date: February 3, 2022
• Actual Study Start Date: April 20, 2015
• Actual Primary Completion Date: December 31, 2020 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: April 15, 2015): Beck Scale for Suicide Ideation (BSS) [ Time Frame: 180 minutes post dose ]
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 15, 2015)

• Montgomery Asberg Depression Rating Scale (MADRS) [ Time Frame: 180 minutes post dose ]
• Beck Depression Inventory (BDI) [ Time Frame: 180 minutes post dose ]
• Beck Anxiety Inventory (BAI) [ Time Frame: 180 minutes post dose ]
• Beck Hopelessness Scale (BHS) [ Time Frame: 180 minutes post dose ]
• 4-item Brief Psychiatric Rating Scale (BPRS) [ Time Frame: 180 minutes post dose ]
• Clinician-Administered Dissociative States Scale (CADSS) [ Time Frame: 180 minutes post dose ]
• Young Mania Rating Scale (YMRS) [ Time Frame: 180 minutes post dose ]
• Systematic Assessment for Treatment Emergent Events (SAFTEE) [ Time Frame: 180 minutes post dose ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: miRNAs, Suicide, and Ketamine - Plasma Exosomal microRNAs as Novel Biomarkers for Suicidality and Treatment Outcome
• Official Title: Plasma Exosomal MicroRNAs as Promising Novel Biomarkers for Suicidality and Treatment Outcome
• Brief Summary: The purpose of this study is to examine whether neural-derived exosomal miRNAs are differentially expressed that are specific to suicidal ideation or behavior, and which by affecting specific miRNA targets and pathways, are associated with suicidal behavior and response to ketamine. The following groups of subjects will be examined: 1) major depressive disorder (MDD) with a recent suicide attempt (in past 2 weeks), 2) MDD with serious ideation (in the past 7 days) without recent suicide attempt (in the past 6 months), 3) MDD without clinically significant suicidal ideation (in the past 7 days) or recent suicide attempt (in the past 6 months), and 4) healthy controls. Both suicidal and non-suicidal MDD will be given ketamine (0.5 mg/kg, IV) and blood will be drawn at predose, 30 min, 180 min, 24 hours, and 14 days post-infusion to measure changes in miRNAs.

Detailed Description

Neural miRNAs are responsive to environmental, synaptic, and pathological changes and can be actively secreted by cells such as exosomes from brain into blood. These exosomes bear cell-type specific surface markers. Using a neural specific surface marker, the investigators successfully isolated neural-derived exosomes and found that these exosomes are enriched with miRNAs/mRNAs that are expressed in brain. Using this novel approach the investigators aim to examine whether neural derived exosomal miRNAs are differentially expressed that are specific to suicidal ideation or behavior, and which by affecting specific mRNA targets and pathways, are associated with suicidal behavior and response to ketamine.

The following groups of subjects will be examined: 1) major depressive disorder (MDD) with a recent suicide attempt (in past 2 weeks), 2) MDD with serious ideation (in the past 7 days) without recent suicide attempt (in the past 6 months), 3) MDD without clinically significant suicidal ideation (in the past 7 days) or suicide attempt in the past 6 months, and 4) healthy controls. Both suicidal and non-suicidal MDD will be given ketamine (0.5 mg/kg, IV) and blood will be drawn at pre-infusion, 30 minutes and 180 minutes post-infusion to measure changes in miRNAs. Healthy controls will have a one-time blood draw. The investigators also propose a parallel human postmortem brain study to examine whether changes in miRNAs in suicidality correspond to miRNA changes in brain by comparing dlPFC and hippocampus from MDD suicide, MDD non-suicide, and control subjects.

With this the investigators attempt to discover 1) whether suicidal ideation or behavior is associated with differences in the expression of specific miRNAs, 2) whether anti-suicidal/antidepressant effects of ketamine is associated with miRNAs changes, and 3) whether miRNA/mRNA-regulatory pathways contribute to suicide pathogenesis and treatment response. Our study will provide a novel avenue for the development of miRNAs as ''molecular tool'' to identify suicidality and treatment response and in generating target based therapies to treat this devastating disorder.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Basic Science
• Condition: Major Depressive Disorder

Intervention

Drug: ketamine

IV infusion of ketamine 0.5mg/kg at a rate of 40mL over 40 minutes

Other Name: ketalar

Study Arms

• Active Comparator: MDD with recent Suicide Attempt
  All subjects with Major Depressive Disorder with a recent Suicide Attempt (in the past 2 weeks) will receive a one-time IV infusion of ketamine at a dose of 0.5mg/kg at a rate of 40mL over 40 minutes. Blood will be drawn at pre-dose, 30 minutes post dose, 180 minutes post dose, 24 hours post dose, and 14 days post dose to measure changes in miRNAs.
  Intervention: Drug: ketamine
• Active Comparator: MDD with Suicidal Ideation no attempt
  All subjects with Major Depressive Disorder with recent Suicidal Ideation (in the past 7 days) without a recent Suicide Attempt (in the past 6 months) will receive a one-time IV infusion of ketamine at a dose of 0.5mg/kg at a rate of 40mL over 40 minutes. Blood will be drawn at pre-dose, 30 minutes post dose, 180 minutes post dose, 24 hours post dose, and 14 days post dose to measure changes in miRNAs.
  Intervention: Drug: ketamine
• Active Comparator: MDD without Suicidal Ideation no attempt
  All subjects with Major Depressive Disorder without recent Suicidal Ideation (in the past 7 days) without a recent Suicide Attempt (in the past 6 months) will receive a one-time IV infusion of ketamine at a dose of 0.5mg/kg at a rate of 40mL over 40 minutes. Blood will be drawn at pre-dose, 30 minutes post dose, 180 minutes post dose, 24 hours post dose, and 14 days post dose to measure changes in miRNAs.
  Intervention: Drug: ketamine
• No Intervention: Healthy Controls
  Healthy Control subjects without a psychiatric diagnosis will have a one-time blood draw to examine miRNAs.

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: January 20, 2021): 247
• Original Estimated Enrollment (submitted: April 15, 2015): 240
• Estimated Study Completion Date: December 31, 2022
• Actual Primary Completion Date: December 31, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Age 18-65
2. Physically healthy and capable of undergoing ketamine infusion
3. Willing and able to provide informed consent
4. Diagnosis of MDE as determined by the MINI (MDD participants)
5. HAM-D 21 score ≥ 16 (MDD participants)
6. Suicide attempt occurred within past 2 weeks (MDD Participants with Suicide Attempt)
7. For the time frame of the past 7 days, C-SSRS score ≥ 3 (MDD Participants without Suicide Attempt, with Suicidal Ideation)
8. For the time frame of the past 7 days, C-SSRS score < 3 (MDD Participants without Suicide Attempt, without SUicidal Ideation)

Exclusion Criteria:

1. Pregnancy or lactation
2. Post-partum state (being within 2 months of delivery or miscarriage)
3. Homicide risk as determined by clinical interview
4. A lifetime history of psychotic disorder
5. Any history of dissociation or dissociative disorder
6. Bipolar disorder
7. Pervasive developmental disorder
8. Cognitive disorder
9. Cluster A personality disorder
10. Anorexia nervosa
11. Treatment with one of the following medications, known to affect the glutamate-NMDA receptor system (specifically: lamotrigine, acamprosate, memantine, riluzole, or lithium)
12. Alcohol or drug dependence (except nicotine and caffeine) within the last month or the use of any hallucinogen (except cannabis), including phencyclidine in the last month
13. Any known hypersensitivity or serious adverse effect associated with ketamine treatment
14. Any clinically-significant medication condition or therapy that would preclude treatment with ketamine, to include: Recent myocardial infarction
15. Unstable angina
16. Active neoplasm in the past 6 months
17. Immunosuppressive or corticosteroid therapy within the last month, with the following exceptions: any inhaled, intranasal, topical or vaginal corticosteroids are allowed.
18. Chemotherapy
19. Head injury of loss of consciousness in the past 6 months

20. If the subject reports any of the following disorders:

    • Rheumatoid arthritis
    • Lupus erythematosus
    • Autoimmune hepatitis
    • Autoimmune peripheral neuropathy
    • Autoimmune pancreatitis
    • Behcet's disease
    • Chrohn's disease
    • Autoimmune glomerulonephritis
    • Grave's disease
    • Guillain-Barre syndrome (if active)
    • Hashimoto's thyroiditis
    • Autoimmune polymyositis or polymyalgia (fibromyalgia is OK)
    • Myasthenia gravis
    • Narcolepsy
    • Polyarteritis nodosa
    • Scleroderma
    • Sjogren's syndrome
    • Transverse myelitis
    • Wegener's granulomatosis
    • HIstory of seizures (only childhood febrile seizures allowed)
    • (HIV and Hepatitis are OK if stable)
21. Systolic blood pressure > 150 and/or diastolic blood pressure >90 at screening
22. A QTc > 480 msec as determined by an ECG

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02418195
• Other Study ID Numbers: F141029007; 1R01MH107183-01 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Yogesh Dwivedi, PhD, University of Alabama at Birmingham
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Alabama at Birmingham
• Original Study Sponsor: Same as current
• Collaborators: National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Yogesh Dwivedi, Ph.D.; University of Alabama at Birmingham
• Principal Investigator: Richard C Shelton, M.D.; University of Alabama at Birmingham

• PRS Account: University of Alabama at Birmingham
• Verification Date: February 2022