Clinical trial NCT02418195: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Major Depressive Disorder
Keywords: Depression
Ketamine
Suicide Attempt
Suicidal Ideation
Suicidality
Lead sponsor: University of Alabama at Birmingham
Sponsor class: OTHER
Collaborators: name: National Institute of Mental Health (NIMH)
First posted: 2015-04-16
Enrollment: 247
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

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

Primary outcomes:
measure: Beck Scale for Suicide Ideation (BSS)
timeFrame: 180 minutes post dose
Secondary outcomes:
measure: Montgomery Asberg Depression Rating Scale (MADRS)
timeFrame: 180 minutes post dose
measure: Beck Depression Inventory (BDI)
timeFrame: 180 minutes post dose
measure: Beck Anxiety Inventory (BAI)
timeFrame: 180 minutes post dose
measure: Beck Hopelessness Scale (BHS)
timeFrame: 180 minutes post dose
measure: 4-item Brief Psychiatric Rating Scale (BPRS)
timeFrame: 180 minutes post dose
measure: Clinician-Administered Dissociative States Scale (CADSS)
timeFrame: 180 minutes post dose
measure: Young Mania Rating Scale (YMRS)
timeFrame: 180 minutes post dose
measure: Systematic Assessment for Treatment Emergent Events (SAFTEE)
timeFrame: 180 minutes post dose
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
Study officials:
affiliation: University of Alabama at Birmingham
name: Yogesh Dwivedi, Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Alabama at Birmingham
name: Richard C Shelton, M.D.
role: PRINCIPAL_INVESTIGATOR
References: