Impact of Ketamine on Surrogate Markers of Suicide Risk

Close to a million Americans present to the emergency department each year for suicidal thoughts and behaviors.  As the week after psychiatric hospitalization is a high-risk time for suicidal behavior, there is a critical need for interventions to rapidly reduce suicide risk in the short term.  However, clinicians have few treatments with rapid effect and even more limited guidance on which treatments may be most effective for a specific patient.  For example, intravenous ketamine is associated with reduced depressive symptoms and suicidal thoughts within hours to days but has not been linked with either reduced risk of suicidal behavior or specific patient groups who are most likely to respond.  In order to identify the patients who may most benefit from ketamine, it is crucial to understand how ketamine impacts the desire to make a suicide attempt.

Therefore, my aim in this application to evaluate the impact of ketamine on brain response to tasks associated with suicide risk.  The Life-Death Implicit Association Task (LD-IAT) is a computerized, behavioral task associated with risk of suicide attempt that does not rely on self-report of suicidal thoughts.  I have developed a neuroimaging version of the LD-IAT which can be administered in functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG). I have demonstrated that this task is associated with neural activation in the anterior insula in a sample of healthy volunteers in both neuroimaging modalities; I have also shown that suicidal ideation after ketamine administration is associated with gamma power in anterior insula on MEG.  Therefore, I will evaluate the impact of ketamine on the LD-IAT in MEG.

Specifically, I hypothesize that ketamine will be associated with reduced gamma power in the anterior insula on the LD-IAT task.  To minimize variability and simulate a stressful event leading to a suicide attempt, I will take the following steps: 1.) Recruit participants who have attempted suicide in the last year but are not in active crisis; 2.) Implement a mood induction paradigm just before the LD-IAT.  For this study, I will enroll 20 individuals with suicide attempts in the last year, but not in the last two weeks to avoid enrolling participants in active crisis. Participants will be administered a negative mood induction and LD-IAT during a MEG before and after open-label ketamine administration.  The results of this pilot will aid me in designing a larger randomized clinical trial of the mechanisms of ketamine on neural markers of suicide risk.  Such an understanding of the brain response to ketamine will allow me to determine which patients may most benefit from ketamine administration.  I can also use this paradigm in the evaluation of other suicide-focused treatments, such as psychotherapy or other psychiatric medications, to improve the treatment of suicidal patients.