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