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

Primary Purpose

Major Depressive Disorder

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

ketamine

About this trial

This is an interventional basic science trial for Major Depressive Disorder focused on measuring Depression, Ketamine, Suicide Attempt, Suicidal Ideation, Suicidality

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Age 18-65
Physically healthy and capable of undergoing ketamine infusion
Willing and able to provide informed consent
Diagnosis of Major Depressive Episode (MDE) as determined by the Mini International Neuropsychiatric Interview (MINI) (MDD participants)
Hamilton Depression Rating Scale (HAM-D) 21 score ≥ 16 (MDD participants)
Suicide attempt occurred within past 2 weeks (MDD Participants with Suicide Attempt)
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)
For the time frame of the past 7 days, C-SSRS score < 3 (MDD Participants without Suicide Attempt, without SUicidal Ideation)

Exclusion Criteria:

Pregnancy or lactation
Post-partum state (being within 2 months of delivery or miscarriage)
Homicide risk as determined by clinical interview
A lifetime history of psychotic disorder
Any history of dissociation or dissociative disorder
Bipolar disorder
Pervasive developmental disorder
Cognitive disorder
Cluster A personality disorder
Anorexia nervosa
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)
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
Any known hypersensitivity or serious adverse effect associated with ketamine treatment
Any clinically-significant medication condition or therapy that would preclude treatment with ketamine, to include: Recent myocardial infarction
Unstable angina
Active neoplasm in the past 6 months
Immunosuppressive or corticosteroid therapy within the last month, with the following exceptions: any inhaled, intranasal, topical or vaginal corticosteroids are allowed.
Chemotherapy
Head injury of loss of consciousness in the past 6 months
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)
Systolic blood pressure > 150 and/or diastolic blood pressure >90 at screening
A Corrected QT Interval (QTc) > 480 msec as determined by an ECG

Sites / Locations

University of Alabama at Birmingham

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

No Intervention

Arm Label

MDD with recent Suicide Attempt

MDD with Suicidal Ideation no attempt

MDD without Suicidal Ideation no attempt

Healthy Controls

Arm Description

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.

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.

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.

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

Outcomes

Primary Outcome Measures

Beck Scale for Suicide Ideation (BSS)

The Beck Scale for Suicidal Ideation (BSSI) is a 21-item, self-report rating scale that measures the current intensity of specific attitudes, behaviors, and plans to commit suicide. Each item consists of 3 options graded according to intensity on a 3-point scale (0-2). Scores range from 0-42, with higher scores indicating more severe symptoms. The participant numbers below correlate to the number of usable lab samples. This is the reason for discrepancy in numbers.

Secondary Outcome Measures

Montgomery Asberg Depression Rating Scale (MADRS)

The Montgomery-Åsberg Depression Rating Scale revised to reflect shorter timeframes will be the primary measure of change in depression. The Montgomery-Asberg Depression Rating Scale is a ten-item diagnostic questionnaire which psychiatrists use to measure the severity of depressive episodes in patients with mood disorders. A total score ranging from 0 to 6 indicates that the patient is in the normal range (no depression), a score ranging from 7 to 19 indicates mild depression, 20 to 34 indicates moderate depression, a score of 35 and greater indicates severe depression, and a total score of 60 indicates very severe depression. Scores range form 0-60, with higher scores indicating more severe symptoms. The participant numbers below correlate to the number of usable lab samples. This is the reason for discrepancy in numbers

Beck Depression Inventory (BDI)

The Beck Depression Inventory is a 21-item, self-report rating inventory that measures characteristic attitudes and symptoms of depression. The inventory contains 21 items on a 4-point scale from 0 (symptom absent) to 3 (severe symptoms). Anxiety symptoms are not assessed but affective, cognitive, somatic and vegetative symptoms are covered. Scoring is achieved by adding the highest ratings for all 21 items. The minimum score is 0 and maximum score is 63. Higher scores indicate greater symptom severity. The participant numbers below correlate to the number of usable lab samples. This is the reason for discrepancy in numbers.

Beck Anxiety Inventory (BAI)

The scale is a 21-item self-report of anxiety. The total score is calculated by finding the sum of the 21 items. The scores range form 0-63, with higher scores indicating more severe symptoms. Score of 0 - 21 = low anxiety Score of 22 - 35 = moderate anxiety Score of 36 and above = potentially concerning levels of anxiety

Beck Hopelessness Scale (BHS)

The Beck Hopelessness Scale is a 20-item self-report index of pessimism about the future, loss of motivation, and negative expectations. Each optimistic response is scored as 0 and each pessimistic response is scored as 1. A total score is calculated by summing the pessimistic responses for each of the 20 items. Minimum possible score is 0. The participant numbers below correlate to the number of usable lab samples. This is the reason for discrepancy in numbers.

4-item Brief Psychiatric Rating Scale (BPRS)

The Brief Psychiatric Rating Scale is used to assess the presence of psychotic symptoms. This 4-item version assesses conceptual disorganization, suspiciousness/persecution, hallucinatory behavior, and unusual thought content. Each item is rated on a scale from 0 (not present) to 6 (extreme). The scores range from 0-24, with higher scores indicating more severe symptoms. The participant numbers below correlate to the number of usable lab samples. This is the reason for discrepancy in numbers.

Clinician-Administered Dissociative States Scale (CADSS)

The Clinician-Administered Dissociative States Scale, ascertains the presence or absence of dissociative symptoms. There are 23 clinician-administered items, each scored from 0 (not at all) to 4 (extreme). Scores range from 0-92, with higher scores indicating more severe symptoms. Items assess impairment in body sensation, perception of time and environment, memory impairment, and feelings of unreality. The participant numbers below correlate to the number of usable lab samples. This is the reason for discrepancy in numbers.

Young Mania Rating Scale (YMRS)

This scale assesses for manic symptoms. The scale has 11 items and is based on the patient's subjective report of his or her clinical condition over the previous 48 hours. 13-19=minimal symptoms; 20-25=mild mania, 26-37=moderate mania, 38-60=severe mania. The YMRS total score ranges from 0 to 60 where higher scores indicate more severe mania.

Systematic Assessment for Treatment Emergent Events (SAFTEE)

The Systematic Assessment for Treatment Emergent Events, is a 56 item, self-report inventory for adverse events. Each item is categorized by severity as: 0-none, 1-mild, 2-moderate, 3-severe. Score range is 0-168, with higher scores indicating more severe symptoms. It is designed to report adverse health events, regardless of whether or not they are suspected to be drug related, in order to reduce the under-reporting of unanticipated events compared with "known or expected" events. The participant numbers below correlate to the number of usable lab samples. This is the reason for discrepancy in numbers.

Full Information

NCT ID

NCT02418195

First Posted

April 13, 2015

Last Updated

August 3, 2022

Sponsor

University of Alabama at Birmingham

Collaborators

National Institute of Mental Health (NIMH)

1. Study Identification

Unique Protocol Identification Number

NCT02418195

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

Study Type

Interventional

2. Study Status

Record Verification Date

August 2022

Overall Recruitment Status

Completed

Study Start Date

April 20, 2015 (Actual)

Primary Completion Date

December 30, 2020 (Actual)

Study Completion Date

December 30, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Alabama at Birmingham

Collaborators

National Institute of Mental Health (NIMH)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Major Depressive Disorder

Keywords

Depression, Ketamine, Suicide Attempt, Suicidal Ideation, Suicidality

7. Study Design

Primary Purpose

Basic Science

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

247 (Actual)

8. Arms, Groups, and Interventions

Arm Title

MDD with recent Suicide Attempt

Arm Type

Active Comparator

Arm Description

Arm Title

MDD with Suicidal Ideation no attempt

Arm Type

Active Comparator

Arm Description

Arm Title

MDD without Suicidal Ideation no attempt

Arm Type

Active Comparator

Arm Description

Arm Title

Healthy Controls

Arm Type

No Intervention

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

ketamine

Other Intervention Name(s)

ketalar

Intervention Description

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

Primary Outcome Measure Information:

Title

Beck Scale for Suicide Ideation (BSS)

Description

Time Frame

180 minutes post dose

Secondary Outcome Measure Information:

Title

Montgomery Asberg Depression Rating Scale (MADRS)

Description

Time Frame

180 minutes post dose

Title

Beck Depression Inventory (BDI)

Description

Time Frame

180 minutes post dose

Title

Beck Anxiety Inventory (BAI)

Description

Time Frame

180 minutes post dose

Title

Beck Hopelessness Scale (BHS)

Description

Time Frame

180 minutes post dose

Title

4-item Brief Psychiatric Rating Scale (BPRS)

Description

Time Frame

180 minutes post dose

Title

Clinician-Administered Dissociative States Scale (CADSS)

Description

Time Frame

180 minutes post dose

Title

Young Mania Rating Scale (YMRS)

Description

Time Frame

180 minutes post dose

Title

Systematic Assessment for Treatment Emergent Events (SAFTEE)

Description

Time Frame

180 minutes post dose

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Age 18-65 Physically healthy and capable of undergoing ketamine infusion Willing and able to provide informed consent Diagnosis of Major Depressive Episode (MDE) as determined by the Mini International Neuropsychiatric Interview (MINI) (MDD participants) Hamilton Depression Rating Scale (HAM-D) 21 score ≥ 16 (MDD participants) Suicide attempt occurred within past 2 weeks (MDD Participants with Suicide Attempt) 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) For the time frame of the past 7 days, C-SSRS score < 3 (MDD Participants without Suicide Attempt, without SUicidal Ideation) Exclusion Criteria: Pregnancy or lactation Post-partum state (being within 2 months of delivery or miscarriage) Homicide risk as determined by clinical interview A lifetime history of psychotic disorder Any history of dissociation or dissociative disorder Bipolar disorder Pervasive developmental disorder Cognitive disorder Cluster A personality disorder Anorexia nervosa 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) 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 Any known hypersensitivity or serious adverse effect associated with ketamine treatment Any clinically-significant medication condition or therapy that would preclude treatment with ketamine, to include: Recent myocardial infarction Unstable angina Active neoplasm in the past 6 months Immunosuppressive or corticosteroid therapy within the last month, with the following exceptions: any inhaled, intranasal, topical or vaginal corticosteroids are allowed. Chemotherapy Head injury of loss of consciousness in the past 6 months 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) Systolic blood pressure > 150 and/or diastolic blood pressure >90 at screening A Corrected QT Interval (QTc) > 480 msec as determined by an ECG

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Yogesh Dwivedi, Ph.D.

Organizational Affiliation

University of Alabama at Birmingham

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Richard C Shelton, M.D.

Organizational Affiliation

University of Alabama at Birmingham

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Alabama at Birmingham

City

Birmingham

State/Province

Alabama

ZIP/Postal Code

35294

Country

United States

12. IPD Sharing Statement

Learn more about this trial

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

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