The molecular bases of the suicidal brain

Abstract

Suicide ranks among the leading causes of death around the world and takes a heavy emotional and public health toll on most societies. Both distal and proximal factors contribute to suicidal behaviour. Distal factors - such as familial and genetic predisposition, as well as early-life adversity - increase the lifetime risk of suicide. They alter responses to stress and other processes through epigenetic modification of genes and associated changes in gene expression, and through the regulation of emotional and behavioural traits. Proximal factors are associated with the precipitation of a suicidal event and include alterations in key neurotransmitter systems, inflammatory changes and glial dysfunction in the brain. This Review explores the key molecular changes that are associated with suicidality and discusses some promising avenues for future research.

Figure 1. Overview of the contributors to suicidal behaviour

Suicidal behaviour is regulated by a number of different factors that can be broadly categorized as distal (predisposing), developmental (mediating) or proximal (precipitating) factors. The model proposed here takes into account the classic psychosocial and genetic risk factors for suicide, and integrates newer findings on epigenetic changes associated with suicidality. Predisposing factors include family history of suicide, and associated genetic predisposition; and early-life adversity and associated epigenetic changes. In both cases, predisposing factors lead to long-term effects on gene expression and regulation. Predisposing factors do not directly trigger suicidal events, but are linked to increased suicide risk through the effects of mediating factors. Mediating factors, which may directly result from the gene changes that occur as a consequence of predisposing factors, or may be associated with other factors such as chronic substance abuse, increase the risk of suicide by accentuating traits linked with suicidality. Specifically, family disposition and early-life events can shape behavioural and emotional traits such as impulsive-aggressive behaviour and anxiety traits, which increase the risk of acting on suicidal ideation, a common feature of depressive psychopathology and hopelessness. Proximal risk factors, such as depressive psychopathology and acute substance abuse, can also be associated with genetic and epigenetic factors and are often triggered by life events.