Neurobiology of Suicide

A. Objective

Suicide occurs across demographics and psychiatric disorders, killing at least one million
individuals worldwide each year. In contrast to other injury-related death such as homicide
or motor vehicle accidents, suicide rates have increased, particularly among middle-aged
adults. Clinicians have a limited ability to predict imminent suicidal behavior and few, if
any, efficacious treatments are available to treat suicidal patients. Advances in the
treatment of the suicidal patients have been hampered by an incomplete understanding of the
neurobiological underpinnings of the suicidal crisis, as suicidal thoughts and behaviors have
not been clearly linked with specific neural circuits.

The aim of this study is to evaluate possible biomarkers of suicidal thoughts and behaviors
in individuals currently experiencing a suicidal crisis. In taking a dimensional approach to
suicide research, we will be able to study phenomenology across Research Domain Criteria
(RDoC) units of analysis, from genes through circuits to self-report and experimental
paradigms. Through this approach, we can identify potential neurobiological risk factors for
both short and long-term suicide risk. As a secondary aim, we will use ketamine to identify
biomarkers of ketamine response in a sample at acute risk for suicide.

B. Study Population

Four participant populations will be recruited into this protocol in order to encompass the
continuum of suicide risk. A total of 170 individuals will be enrolled in the study.
Participant populations are individuals with the following conditions: 1.) recent suicidal
ideation with intent and/or suicide attempt (Group 1- active crisis , n= 50); 2) a past
history of suicide attempt, but no suicidal behavior in the last year (Group 2, n= 40); 3)
anxiety or mood symptoms, but no recent or past suicidal thoughts or behavior (Group 3, n=
40); and, 4) healthy controls with no psychiatric or suicide history (Group 4, n= 40).

C. Design

The research protocol will occur across three phases: baseline, ketamine response and
optional repeated infusions. All participants will first be consented into Phase I, which may
last up to seven days. This baseline phase will entail multimodal assessment, using
pathophysiological markers (blood draw, lumbar puncture), neuroimaging (fMRI, MEG),
polysomnography, clinical ratings and experimental paradigms (shock experiments).
Participants will receive their regularly scheduled daily medications, but will not receive
additional treatment (including new prn medications, such as benzodiazepines for management
of anxiety or agitation) during this brief baseline phase. After completion of Phase I,
eligible participants from Group 1 only (active crisis) will be offered participation in
Phase II, the ketamine response phase. This phase, which will last up to four days, consists
of a single, open-label trial of ketamine (0.5 mg/kg). The focus of this phase will be
identification of potential biomarkers of antisuicidal ketamine response. Participants who
complete Phase II will be offered Phase III, which will involve repeated ketamine infusions
over two weeks (2 times/ per week for 2 weeks). Psychiatric medication adjustment will be
permitted during Phase III.

After participation in Phases I-III, participants in Groups 1-3 will be offered standard
clinical treatment (excluding healthy controls), or participation in another protocol. In
standard clinical treatment, adjustment of psychiatric medications and commencement of
psychotherapeutic interventions will be permitted. Finally, participants in the first three
groups (excluding healthy controls) will receive follow-up evaluations at six months and
yearly evaluations for up to 5 years after study participation.

D. Outcome Measures

In Phase I, the outcome measures will be underlying psychiatric, psychological, neuroimaging,
sleep and biological differences between the participant groups. In Phase II, the outcome
measures will be reductions in suicidal thoughts and depressive and anxiety symptoms at 24
hours post-ketamine infusion.

- INCLUSION CRITERIA:

Phase I: Groups 1-3 (Patients)

1.18 to 70 years of age.

2.A level of understanding sufficient to agree to all required tests and examinations, sign
an informed consent document and verify understanding by a score greater than or equal to
90% on the Baseline consent quiz.

3.Additional Criteria for Group 1 (Active Crisis): Agree to be hospitalized

Phase I: Group 4 (Healthy Volunteers)

1.18 to 70 years of age.

2.A level of understanding sufficient to agree to all required tests and examinations, sign
an informed consent document.

3. Individuals who are able to get pregnant must be willing to remain sexually abstinent or
use at least one form of effective birth control during participation in Phase I.

Phase II: Group 1 (Active Crisis)

1. Patients must have completed Study Phase I as a participant in Group 1

2. Participants must verify understanding of the protocol by a score greater than or
equal to 80% on the Ketamine Response consent quiz.

3. Patients must report at least minimal suicidal ideation, depressive or anxiety
symptoms to be eligible for this phase (see Monitoring Suicide Risk section).

- MADRS score of over 10 (10 used as an outcome measure for remission)126

- OR HAMA score of over 7 (7 used as an outcome measure for remission)127

- OR SSI score of 2 or more (indicates any residual suicidal thoughts)

4. Individuals who are able to get pregnant must be willing to remain sexually abstinent
or use at least one form of effective birth control during participation in Phase II.

Phase III: Group 1 (Active Crisis)

1. Participants must have met all inclusion criteria for and completed Study Phase II as
a participant in Group 1 (active crisis)

2. Individuals who are able to get pregnant must be willing to remain sexually abstinent
or use at least one form of effective birth control during participation in Phase III.

EXCLUSION CRITERIA:

Phase I: Groups 1-3 (Patients)

1. Current psychotic features or cognitive impairment that would preclude understanding
of the consenting process or tests/examinations.

2. Current drug or alcohol dependence

3. Currently intoxicated or under the acute effects of an illicit substance will not be
consented into the study.

4. Pregnant or nursing individuals or those who plan to become pregnant.

5. Serious, unstable medical conditions/problems including hepatic, renal,
gastroenterologic, respiratory, cardiovascular (including blood pressure, ischemic
heart disease), endocrinologic, neurologic, immunologic, or hematologic disease.

6. Clinically significant abnormal laboratory tests.

7. Positive HIV test

8. Participants who, in the investigator s judgment, pose a current homicidal risk or
pose suicide risk that cannot be managed in a secure, voluntary inpatient setting.

9. Non-English speakers

10. Additional Criteria for Group 1(Active Crisis):

For participants who still experience the effects of their suicide attempt, i.e. someone
who overdosed is significantly drowsy or confused, the consenting process will occur after
the patient has improved from the effects. If there is a concern around a participant s
capacity to consent, the Human Subjects Protections Unit (HSPU) team member who is
monitoring the informed consent process will complete a capacity assessment. Participants
who are determined not to have capacity to consent to research will not be included in the
study.

Phase I: Group 4 (Healthy Volunteers)

1. Current or past Axis I diagnosis

2. Presence of medical illness likely to alter brain morphology and/or physiology (e.g.,
hypertension, diabetes) even if controlled by medications.

3. Current or past alcohol or substance abuse or dependence diagnosis (except for
nicotine or caffeine).

4. Presence of psychiatric disorders or a history of suicide attempt or death in
first-degree relatives.

5. Pregnant or nursing individuals or those who plan to become pregnant.

6. No lifetime suicide attempts or ideations

7. Non-English speakers

8. Positive HIV test

Exclusions for Imaging

1. Participants with metal objects implanted in the body, such as aneurysm clips, neural
stimulators, implanted cardiac pacemakers, or auto-defibrillator, cochlear implant, or
ocular foreign body which would make having an MRI scan unsafe

2. Participants who are uncomfortable in small closed spaces (have claustrophobia) and
would feel uncomfortable in the MRI machine

3. Participants with a brain abnormality on an initial MRI scan

Phase II: Group 1 (Active Crisis)

1. Treatment with a reversible MAOI within 2 weeks prior to study Phase II.

2. Treatment with any other concomitant medication not allowed within 5 (Omega)
half-lives prior to study Phase II.

3. Subjects with one or more seizures without a clear and resolved etiology

4. Participants with a positive urine for an illicit substance no more than 24 hours
prior to the ketamine infusion.

5. Presence of current psychotic features or a diagnosis of Schizophrenia or any other
psychotic disorder as defined in the DSM-IV

6. Pregnant or nursing individuals or those who plan to become pregnant

7. A medical finding or condition that in the clinical judgement of the investigator
increases the risk of adverse effects from the ketamine administration (for example:
findings suggesting difficulties with kidney or cardiac function that may be
contradictions for an experimental intervention)

Phase III: Repeated Administration (Group 1 only)

1. Intolerable or serious adverse reaction to ketamine during Phase II

2. Treatment with a reversible MAOI within 2 weeks prior to study Phase III.

3. Treatment with any other concomitant medication not allowed within 5 (Omega)
half-lives prior to study Phase III.

4. Subjects with one or more seizures without a clear and resolved etiology

5. Participants with a positive urine for an illicit substance no more than 24 hours
prior to the ketamine infusion.

6. Presence of current psychotic features or a diagnosis of Schizophrenia or any other
psychotic disorder as defined in the DSM-IV

7. Pregnant or nursing nursing individuals who plan to become pregnant.

Exclusions for Imaging:

1. Participants with metal objects implanted in the body, such as aneurysm clips, neural
stimulators, implanted cardiac pacemakers, or auto-defibrillator, cochlear implant, or
ocular foreign body which would make having an MRI scan unsafe

2. Participants who are uncomfortable in small closed spaces (have claustrophobia) and
would feel uncomfortable in the MRI machine

3. Participants with a brain abnormality on an initial MRI scan