Although there are many pathways to suicide, studies in the domains of neuropsychology, cognitive psychology, neurobiology, and clinical psychiatry provide increasing evidence in support of a stress–diathesis model of suicidal behavior. While depression is the common final pathway to suicidal behavior, the vast majority of depressed individuals neither attempt nor complete suicide. It appears that a diathesis to suicidal behavior differentiates depressed individuals who will kill themselves from other depressed patients. The diathesis may be due to (epi-)genetic effects and childhood adversity, and is reflected by a distinct biological, psychological and clinical profile. This chapter will first review stress-diathesis models of suicidal behavior, ranging from cognitive models such as the “cry of pain” model to a neurobiological model in which deficient decision-making and its neural basis are central issues. Second, implications for treatment and prevention will be discussed. The identification of diathetic traits can be expected to facilitate early recognition of suicide risk. Vulnerability traits are open to modification early in life, and interventions during sensitive periods of development may have durable effects on vulnerability and resilience. The antisuicidal effects of drugs such as lithium and clozapine may well exert such effects via neurobiological components of the diathesis such as the serotonergic neurotransmission system.

In addition to neurocognitive studies, neuroimaging techniques provide a unique opportunity to study brain characteristics. Structural imaging studies clearly demonstrate volumetric differences in particular brain areas between individuals with a history of nonfatal suicidal behavior and those without such a history. Functional imaging studies show a reduced prefrontal perfusion or metabolism and a blunted increase in activation when challenged in the brains of individuals with a history of suicide attempts. Moreover, impairment of the prefrontal serotonergic system in association with suicidal behavior is demonstrated in a number of studies. Recent structural and functional imaging studies show changes in cortical and subcortical areas and their connections in association with suicidal behavior and risk factors such as mental pain, hopelessness, and impulsivity. The global picture that emerges from these studies reflects the involvement of a particular circuit in the development of suicidal behavior, the so-called frontothalamic network.

In addition to suicide prediction, neuroscience can be expected to contribute in a unique and substantial way to the treatment of suicide risk. For psychotropic drugs such as lithium and clozapine a specific antisuicidal effect has been demonstrated, independent of effects on associated psychiatric disorders. The results from studies with ketamine are promising as they indicate a rapid and sustained relief of suicidal thoughts. Neurostimulation and neuromodulation provide new approaches to treatment, with a substantial impact on suicide risk. Novel pharmacological compounds targeting the vulnerability to suicidal behavior include drugs that affect the stress-response system and neuroprotective factors.

Limitations in our capacity to predict the occurrence of suicidal behavior constitute a major problem in the prevention of suicide. Due to their extremely limited predictive value, ratings scales and clinical measures are not available for practical use. This is an area in which neuroscience can be expected to contribute substantially via the identification of biomarkers using genetic and brain imaging techniques. Recent studies using genetic approachessuggest the existence of specific biomarkers that can be detected in the blood. In addition, findings from neuroimaging and neuropsychological studies indicate functional impairments with increasing specificity in association with suicidal behavior. Biomarkers can be expected to contribute substantially to the devlopment of accurate prediction in the context of personalized medicine.