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

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.

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