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The molecular bases of the suicidal brain

Key Points

  • Suicide takes a heavy toll on society but can often be avoided through adequate treatment. However, societal normalities and taboos often make it difficult for individuals who experience suicidal ideation or aspects of suicidal behaviour to seek help before it is too late.

  • Many factors contribute to suicidal behaviour and these can be globally classified as distal factors, which increase predisposition to suicide, and proximal factors, which precipitate a suicidal act.

  • Distal factors comprise a family history of suicide, indicating a genetic predisposition, genetic variation between individuals and experiences of early-life adversity. Early-life adversity can result in stable changes to gene expression, which results in increased lifetime susceptibility to suicidal behaviour.

  • Early-life adversity epigenetically regulates stress response systems and neuronal plasticity, which are associated with emotional and behavioural changes.

  • Behavioural and emotional traits are known mediators of suicide risk, with impulsive aggressive and anxiety traits being intimately linked to suicidal behaviour.

  • Proximal factors are associated with precipitation of the suicidal act and can be linked to changes in neurotransmitter levels, inflammation in the CNS and glial, notably astrocytic, dysfunction.

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.

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Figure 1: Overview of the contributors to suicidal behaviour.

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Acknowledgements

Preparation of this Review was supported by grants from the Canadian Institute of Health Research (CIHR), MOP119429 and MOP119430, and by the Fonds de Recherche du Québec – Santé (FRQS), through a Chercheur National salary award to the author and through support to the Réseau québécois sur le suicide, les troubles de l'humeur et les troubles associés (RQSHA). The author is indebted to S. Daniels for expert and essential help in the preparation of this Review.

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Association between methylation of the GR-encoding gene, early-life adversity and suicidal behaviour (PDF 200 kb)

Glossary

Suicidality

This broad term encompasses all forms of suicidal behaviour and suicidal ideation.

Suicidal ideation

This term describes the wish to die, including thoughts of actively ending one's life.

Suicidal behaviour

This term describes behaviours that result in self-injury and is generally used to refer to suicide attempts and suicide completion.

Self-harm

This broad term includes suicidal behaviour and non-suicidal self-injurious behaviours.

Non-suicidal self-injurious behaviours

Deliberate self-injury, often in the form of superficial skin cuts that are made with the intent to decrease emotional pain rather than to die.

Suicidal behaviour disorder

This disorder has recently been proposed as a condition for further study in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and is defined by the occurrence of at least one suicide attempt with some intent to die within the last 24 months. Conditions for further study in the DSM are disorders that should be investigated and considered for its future versions.

Suicidal crisis

Period when suicidal ideation becomes acute, which is often associated with emotional instability.

Distal risk factors

Predisposing factors that occur or are expressed temporally distant from the onset of the phenotype.

Early-life adversity

(ELA). Acts by a parent or caregiver that result in physical, sexual and/or psychological abuse of a child or that lead to neglect of essential physical or psychological needs of childhood.

Treatment-emergent suicidal events

This term describes suicidal ideation or suicidal behaviour that occurs in association with treatment and is a common term used in clinical trials of antidepressants.

Childhood sexual abuse

Any completed or attempted sexual act, or exposure to sexual interactions, with or without physical contact, with a child by a caregiver.

Childhood physical abuse

The intentional use of physical force against a child that results in, or has the potential to result in, physical injury.

Parental neglect

Failure to meet a child's basic physical, emotional, medical or dental, or educational needs, or a failure to ensure a child's safety.

Attachment styles

Stereotypical interpersonal styles that are rooted in early-life interactions with caregivers.

Biological embedding

The effects of early-life experiences on the differential regulation of biological systems and development.

Mediators

Variables that can fully or partially explain the relationship between a predictor and a dependent variable.

Endophenotypes

Traits that associate with an illness in the population, are heritable, state independent, and co-segregate with the condition investigated and are present in non-affected family members of affected individuals at a higher rate than in the general population.

Impulsive aggressive behaviours

The tendency to react with animosity or overt hostility without consideration of the possible consequences when piqued or under stress.

Proximal risk factors

Precipitating factors that occur or are expressed temporally close to the onset of the phenotype.

State markers

Biological, psychological, behavioural or clinical markers associated with a given phenotype.

Trait markers

Biological, psychological, behavioural or clinical markers that indicate a predisposition to or risk of a given phenotype.

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Turecki, G. The molecular bases of the suicidal brain. Nat Rev Neurosci 15, 802–816 (2014). https://doi.org/10.1038/nrn3839

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