Association of Irritability and Suicide-Related Behaviors During Social Cognition

Suicide accounts for 1.5% of deaths worldwide and is the tenth leading cause of death in North America. Adults with major depressive disorder (M.D.D) are at an increased risk for suicide, although the clinical and biological correlates of suicidality are poorly understood or not yet validated. Recent evidence suggests that elevated irritability correlates with severe suicidal thoughts and behavior (STB). However, irritability is not a conventional diagnostic criterion for adult M.D.D and is rarely assessed in this population. Its relation to depressive symptoms is therefore unclear. Irritability is a diagnostic criterion for certain psychiatric disorders in children, however, and in children increased irritability is associated with alterations in frontolimbic structure and function. No studies exist that explore the neurobiological relationship of irritability and suicidality in adults with M.D.D. We need to understand this relationship in adults to set an evidence base for considering irritability when assessing STB and deciding on treatments. This study aims to quantify the behavioral and neurobiological relationship between irritability and past suicide attempts in adults with M.D.D. Among adults with M.D.D with suicidal ideation who have or who have not previously attempted suicide, we aim to quantify differences in irritability, and circuit activity during two decision-making tasks.

This cross-sectional study will investigate the behavioral and neurobiological relationship between irritability and suicidality in M.D.D participants with a history of suicide attempt relative to M.D.D participants without a history of suicide attempt and healthy controls (90 participants total). All participants will complete questionnaires evaluating irritability, depressive symptoms, and STB. Afterwards, we will measure frontolimbic activity with functional magnetic resonance imaging during two tasks that increase irritability and retaliatory behavior. First, the Cyberball Task, simulates social exclusion and negative social interactions. Next, the Dictator Task, in which participants will divide money between themselves and players from the Cyberball Task. We will use linear mixed-effects models to identify differences in irritability, task behavior and brain activity between the three groups; and interactions between irritability severity and history of suicide attempt. Compared to those who have not attempted suicide, we anticipate that people with M.D.D and a past suicide attempt will exhibit: more severe baseline irritability as well as elevated negative affect and irritability during the tasks; and altered frontolimbic activity during both behavioral tasks. We also hypothesize that frontolimbic activity during the tasks will mediate the association between irritability severity and retaliatory behavior in those with depression and a past suicide attempt.

This study aims to address the urgent need to understand how specific environmental or symptom factors impact neurobiological correlates of suicide risk. To our knowledge, our neuroimaging study represents the first to link irritability and previous suicide attempts among adults with M.D.D. This will represent a novel angle to our understanding of the behavioral and biological mechanisms of suicide to define prevention, treatments and stratify risk. Our results may also set a rationale for future explorations of non-invasive brain stimulation and/or other manipulations of the frontolimbic circuitry as new treatments for STB in the presence of irritability.