Long-Term Maintenance with Ketamine Infusions for Reduction of Suicide in High-Risk Patients with Depression

Despite the advancement in the understanding and treatment of mental health disorders, the incidence of suicide continues to rise. Major Depressive Disorder (MDD) is associated with a 20-fold increase in risk of suicide, and the period post-discharge from psychiatric hospitalization has been identified as a time of higher risk for suicide ideation (SI) and suicide attempts (SA). Although several treatments are available for depression and SI, they require weeks or months to be effective, and hence they are inadequate during this time window of increased SA risk. Within the past decade, numerous trials have shown that ketamine, a noncompetitive antagonist of NMDA glutamate receptors, has a rapid (within hours of administration) antisuicidal and antidepressant effect among depressed patients. Protocols for acute treatment consisting of 6 intravenous (IV) ketamine infusions over 2 to 3 weeks have been examined by our team and other groups and have shown beneficial effects on SI and depressive symptoms. Unfortunately, ketamine's effects are short-lived, with most patients relapsing within 2 to 4 weeks after stopping treatment. Long-term clinical trials on IV ketamine treatment have not been conducted, and the feasibility and efficacy of integrating IV ketamine treatment for SI in inpatient clinical settings has not been carefully studied. Finally, it is not clear which patients are those more likely to benefit from IV ketamine treatment. 

Our proposed trial aims to 1) systematically examine feasibility, and 2) efficacy of IV ketamine treatment for SI among 100 individuals with MDD recently admitted to a psychiatric inpatient unit due to SI or SA. Efficacy will be examined by evaluating trajectory of symptoms change (SI and depression) of the treatment group and by comparing healthcare utilization and rehospitalization between the IV ketamine treatment group and an historical control group. Given the variability of response rates among patients receiving IV ketamine treatment, we will also examine 3) predictors of treatment response. We hypothesize that the patients receiving IV ketamine will experience a significant decrease in SI and depression over the acute (week 1 to 3) as well as maintenance (week 4 to 24) phases of the trial and that they will exhibit significantly lower rates of hospital readmission rates and suicidal behaviors relative to historical controls. We also hypothesize that demographic and clinical variables will predict treatment response. 

To pursue the study's aims, 100 individuals with MDD from the Massachusetts General Hospital Inpatient Psychiatric Service will be enrolled. Participants will receive IV ketamine treatment at no cost for 6 months and will complete twelve research visits during which they will report SI and depression severity. They will also complete a daily survey on their SI and mood on their mobile phones. The study will employ advanced statistical methods including, latent growth analyses, machine learning, and time series analyses to examine outcome trajectory and to further our knowledge on optimal treatment protocols. 

Increasing knowledge on long-term efficacy, safety, and tolerability of ketamine treatment may support its dissemination and facilitate coverage from insurance carriers, potentially helping to prevent suicide and saving lives also among underserved populations.