Immune Mechanisms Underlying The Rapid Anti-suicidal Effects of Electroconvulsive Therapy and Ketamine

Suicide rates have continued to rise in the United States over the past two decades. Suicidal thoughts usually precede suicide attempts but the transition from suicidal thinking to action is difficult to predict. Therefore, rapid treatment of suicidal thoughts is crucial for suicide prevention. Electroconvulsive therapy (ECT) and intravenous ketamine are the two most effective treatments for individuals suffering from depression and acute suicidal crisis but their mechanisms of action are not well studied.

Studies by our group and others have found that abnormalities in the immune system are linked to elevated risk for suicide in depressed individuals. However, no studies have been conducted on whether targeting these immune abnormalities could result in reduction of suicide risk. ECT and ketamine result in changes in the concentrations of the immune factors circulating in the blood, which suggests that their well-known positive effects on depression and suicidal ideation may be due to their biological effects on the immune system.

In this study, we plan to use a novel, next-generation immune approach to study the relationship between the effects of ECT and ketamine on immune factors and their clinical effects on suicidal ideation. Our approach has been shown to capture abnormalities of the immune system that cannot be identified using conventional methods. We will collect blood samples from 30 individuals with major depression and acute suicidal ideation who are enrolled in a larger study that examines the effect of ECT and ketamine on acute suicidal crisis. We will isolate specific type of blood cells called peripheral blood mononuclear cells or PBMCs. We will use a bacterial toxin called lipopolysaccharide to stimulate PBMCs to secrete inflammatory biomarkers. We will then measure these biomarkers before, during and after treatment with ECT and ketamine, and examine if the changes of the concentration of these biomarkers are related to the changes of suicidal thoughts.

To date, research on the immune modulating mechanisms of ECT and ketamine is limited. This project will the first to directly examine these mechanisms in patients at a significant risk for suicidal behavior. ECT and ketamine are the only two available rapidly acting interventions for acute suicidal crisis. Understanding their mechanisms of action can help refine their use in this context.

This AFSP study will determine feasibility of this line of research. Success will guide a future larger project to further elucidate the individual mechanisms underlying the anti-suicidal properties of ECT and ketamine. Research in this area may also facilitate the development of new anti-suicidal treatments with immune modulating effects, providing relief for the significant percentage of patients who do not respond to currently available medications.