The neuroscience of suicidal behaviors: what can we expect from endophenotype strategies?

Abstract

Vulnerability to suicidal behavior (SB) is likely mediated by an underlying genetic predisposition interacting with environmental and probable epigenetic factors throughout the lifespan to modify the function of neuronal circuits, thus rendering an individual more likely to engage in a suicidal act. Improving our understanding of the neuroscience underlying SBs, both attempts and completions, at all developmental stages is crucial for more effective preventive treatments and for better identification of vulnerable individuals. Recent studies have characterized SB using an endophenotype strategy, which aims to identify quantitative measures that reflect genetically influenced stable changes in brain function. In addition to aiding in the functional characterization of susceptibility genes, endophenotypic research strategies may have a wider impact in determining vulnerability to SB, as well as the translation of human findings to animal models, and vice versa. Endophenotypes associated with vulnerability to SB include impulsive/aggressive personality traits and disadvantageous decision making. Deficits in realistic risk evaluation represent key processes in vulnerability to SB. Serotonin dysfunction, indicated by neuroendocrine responses and neuroimaging, is also strongly implicated as a potential endophenotype and is linked with impulsive aggression and disadvantageous decision making. Specific endophenotypes may represent heritable markers for the identification of vulnerable patients and may be relevant targets for successful suicide prevention and treatments.

Keywords: animal models; biomarker; decision making; emotions; orbitofrontal cortex; suicide.

Figure 1

Candidate gene regions, genes and endophenotypes implicated in suicide research. The upper portion of the figure indicates the dynamic interplay among genetic, epigenetic and environmental factors that produce cumulative liability to suicidal behaviors. Although attempted suicide does not always predate a completed suicide as suggested on the reaction surface, it is a significant risk factor. None of the sections of this figure can be definitive; many more gene loci, genes, candidate endophenotypes and links among the three remain to be discovered. Environment, protective and harmful, includes a substantial number of environmental events (for example, drug exposure) unmentioned here because of our focus on genetic and neurobiological correlates. Similarly, there are many gene loci, genes and candidate endophenotypes that were not included because of the conceptual limitations of this Figure. Modified from Kovacsics et al. See the following reviews for additional discussion: refs , , , , , , , . © II Gottesman and TD Gould and used with permission.