ABSTRACT One million people around the world die from suicide annually. Suicide is the tenth leading cause of death for all ages and the second leading cause of death among young people with mental disorders. More people under the age of 55 die by suicide than from HIV, stroke, influenza, respiratory diseases, chronic lung disease and homicide. There are at least 20 suicide attempts for every completed suicide. Better prevention strategies are urgently needed; yet, mechanisms that confer increased risk for suicidal behaviors (ranging from suicidal ideation to suicide attempts and completed suicide) remain largely unknown. Neurobiological alterations associated with a history of suicidal thoughts and behaviors may predict future risk and provide targets for interventions. Inquiry into the neurobiology of suicidal behaviors is hindered by a low base rate of occurrence and the heterogeneous nature of suicidal attempts, requiring large, inclusive samples from around the world to understand the underlying mechanisms. We propose a worldwide collaboration to study the neurobiological and transdiagnostic mechanisms underlying suicidal behaviors in people with mental disorders. Research to date has been performed in small (typically N<50) samples of suicidal ideators and attempters and examined neural markers of suicidal behaviors within a single mental illness. We will pool existing neuroimaging and clinical data from approximately 23,000 individuals with and without mental health disorders forming the “ENIGMA-Suicidal Thoughts and Behaviors (STB)” initiative. We will integrate and analyze datasets from 24 institutions worldwide in a cost-efficient manner to (1) identify transdiagnostic neural mechanisms that differentiate between suicidal ideators and suicide attempters through MRI, and how these vary with age, sex, and disease characteristics; (2) integrate differential explanatory levels and investigate interacting effects between brain mechanisms and sociodemographic, psychosocial, clinical and cognitive risk factors on suicidal behaviors. We will identify different biopsychosocial pathways that discriminate suicidal ideators from people with a history of suicide attempt, yielding novel suicide risk subtypes based on different configurations of biopsychosocial risk factors; (3) go beyond binary classifications of ideation or attempt and conduct an in-depth investigation of structural and functional brain circuitries underlying fine-grained dimensional phenotypes of suicidal behaviors in a subset of samples. Transdiagnostic brain mechanisms uniquely associated with suicidal ideation and suicide attempts, and with more in-depth dimensional suicidal behavior phenotypes, can inform the development of novel interventions directly or indirectly targeting alterations in these brain circuitries. The biopsychosocial suicide risk subtypes identified through this study may highlight distinct pathways to suicidal behaviors in different groups of people and have the potential for individualizing the selection of prevention and intervention strategies.

NARRATIVE Despite many efforts to prevent suicide, suicides and suicide attempts continue to increase in the US. Better prevention strategies are urgently needed; yet, mechanisms that confer increased risk for suicidal ideation and attempt remain largely unknown. The proposed study, with its large sample size and strong methodology, will allow us to investigate, systematically, mechanisms underlying suicidal behaviors, and the results from this study can inform the development of novel preventions.