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 Five participant populations will be recruited into this protocol in order to encompass the continuum of suicide risk. A total of 325 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= 65); 2) a past history of suicide attempt, but no suicidal behavior in the last year (Group 2, n= 65, "attempters"); 3) anxiety or mood symptoms, but no recent or past suicidal thoughts or behavior (Group 3, n= 65); 4) healthy controls with no psychiatric or suicide history (Group 4, n= 65); and lifetime suicidal thoughts with intent (Group 5, n=65, ideators ). 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 or 5 only (active crisis or ideators) 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 and 5 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 Groups 1-3 and 5 will receive follow-up evaluations at six months after completion of Study Phase I. 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.