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

NCT ID: NCT02418195

Last Updated: 2022-08-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 247 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-04-20
• Study Completion Date: 2020-12-30

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.

As of May 2022, study is in data analysis. Final outcomes will be known once analysis is complete.

As of July 2022, all data collection is complete. The primary and secondary data outcome measure results are complete.

The investigators are working on final analysis of the mRNA samples, to provide final responses to questions posed in the Detailed Description section below and listed here: 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.

Detailed Description

Neural MicroRNAs (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/Messenger RNA (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.

Conditions

Major Depressive Disorder

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

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 40 milliliters (mL) 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.

Group Type: ACTIVE_COMPARATOR

ketamine

Intervention Type: DRUG

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

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.

Group Type: ACTIVE_COMPARATOR

ketamine

Intervention Type: DRUG

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

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.

Group Type: ACTIVE_COMPARATOR

ketamine

Intervention Type: DRUG

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

Healthy Controls

Healthy Control subjects without a psychiatric diagnosis will have a one-time blood draw to examine miRNAs.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

ketamine

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

Intervention Type: DRUG

Other Intervention Names

ketalar

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 Major Depressive Episode (MDE) as determined by the Mini International Neuropsychiatric Interview (MINI) (MDD participants)

5. Hamilton Depression Rating Scale (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, Columbia-Suicide Severity Rating Scale (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-N-methyl-D-aspartate (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 Corrected QT Interval (QTc) > 480 msec as determined by an ECG

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute of Mental Health (NIMH)

NIH

Sponsor Role: collaborator

University of Alabama at Birmingham

OTHER

Sponsor Role: lead

Responsible Party

Yogesh Dwivedi, PhD

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Yogesh Dwivedi, Ph.D.

Role: PRINCIPAL_INVESTIGATOR

University of Alabama at Birmingham

Richard C Shelton, M.D.

Role: PRINCIPAL_INVESTIGATOR

University of Alabama at Birmingham

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

Countries

United States

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

1R01MH107183-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

F141029007

Identifier Type: -

Identifier Source: org_study_id