ContextSuicide is a leading cause of death in the United States, but identifying
persons at risk is difficult. Thus, the US surgeon general has made suicide
prevention a national priority. An expanding body of research suggests that
childhood trauma and adverse experiences can lead to a variety of negative
health outcomes, including attempted suicide among adolescents and adults.ObjectiveTo examine the relationship between the risk of suicide attempts and
adverse childhood experiences and the number of such experiences (adverse
childhood experiences [ACE] score).Design, Setting, and ParticipantsA retrospective cohort study of 17 337 adult health maintenance
organization members (54% female; mean [SD] age, 57 [15.3] years) who attended
a primary care clinic in San Diego, Calif, within a 3-year period (1995-1997)
and completed a survey about childhood abuse and household dysfunction, suicide
attempts (including age at first attempt), and multiple other health-related
issues.Main Outcome MeasureSelf-reported suicide attempts, compared by number of adverse childhood
experiences, including emotional, physical, and sexual abuse; household substance
abuse, mental illness, and incarceration; and parental domestic violence,
separation, or divorce.ResultsThe lifetime prevalence of having at least 1 suicide attempt was 3.8%.
Adverse childhood experiences in any category increased the risk of attempted
suicide 2- to 5-fold. The ACE score had a strong, graded relationship to attempted
suicide during childhood/adolescence and adulthood (P<.001).
Compared with persons with no such experiences (prevalence of attempted suicide,
1.1%), the adjusted odds ratio of ever attempting suicide among persons with
7 or more experiences (35.2%) was 31.1 (95% confidence interval, 20.6-47.1).
Adjustment for illicit drug use, depressed affect, and self-reported alcoholism
reduced the strength of the relationship between the ACE score and suicide
attempts, suggesting partial mediation of the adverse childhood experience–suicide
attempt relationship by these factors. The population-attributable risk fractions
for 1 or more experiences were 67%, 64%, and 80% for lifetime, adult, and
childhood/adolescent suicide attempts, respectively.ConclusionsA powerful graded relationship exists between adverse childhood experiences
and risk of attempted suicide throughout the life span. Alcoholism, depressed
affect, and illicit drug use, which are strongly associated with such experiences,
appear to partially mediate this relationship. Because estimates of the attributable
risk fraction caused by these experiences were large, prevention of these
experiences and the treatment of persons affected by them may lead to progress
in suicide prevention.

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Childhood Abuse, Household Dysfunction, and the Risk of Attempted Suicide Throughout the Life Span Findings From the Adverse Childhood Experiences Study

About one million suicides and ten million suicide attempts occur worldwide each year. Suicide is not simply a response to stress, but generally a complication of a psychiatric disorder. A proposed stress–diathesis model is described in clinical and neurobiological terms. Neurobiological correlates of the diathesis for suicidal acts point to the involvement of the serotonergic and noradrenergic systems, and the ventromedial prefrontal cortex. Some treatments seem to reduce suicide risk independently of an effect on the primary psychiatric disorder, perhaps by reducing the diathesis.

Neurobiology of suicidal behaviour.

We report analyses from a study of gene-environment interaction in adolescent depression. The sample was selected from 1990 adolescents aged 10-20 years: those with depression symptoms in the top or bottom 15% were identified and divided into high or low environmental risk groups. DNA was obtained from 377 adolescents, representing the four quadrants of high or low depression and high or low environmental risk. Markers within, or close to, each of the serotonergic genes 5HTT, HTR2A, HTR2C, MAOA (monoamine oxidase type A) and tryptophan hydroxylase (TPH) were genotyped. Environmental risk group was a nonsignificant predictor and sex was a significant predictor of the depression group. HTR2A and TPH significantly predicted the depression group, independent of the effects of sex, environmental risk group and their interaction. In addition, there was a trend for an effect of 5HTTLPR, which was significant in female subjects. Furthermore, there was a significant genotype-environmental risk interaction for 5HTTLPR in female subjects only, with the effect being in the same direction as another recent study, reaffirming that an important source of genetic heterogeneity is exposure to environmental risk.

Gene-environment interaction analysis of serotonin system markers with adolescent depression.

Extensive studies showed that monoaminergic neurotransmission that involves serotonin (5-HT), norepinephrine (NE) and dopamine (DA) exerts major influence on brain circuits concerned by the regulation of mood, reactivity to psychological stress, self-control, motivation, drive, and cognitive performance. Antidepressants targeting monoamines directly affect the functional tone of these circuits, notably in limbic and frontocortical areas, and evidence has been provided that this action plays a key role in their therapeutic efficacy. Indeed, at least some of functional changes detected by functional magnetic resonance imaging in emotion- and cognitive-related circuits such as the one involving limbic-cortical-striatal-pallidal-thalamic connections in depressed patients can be reversed by monoamine-targeted antidepressants. However, antidepressants acting selectively on only one monoamine, such as selective inhibitors of 5-HT or NE reuptake, alleviate depression symptoms in a limited percentage of patients, and are poorly effective to prevent recurrence. Thorough investigations for the last 30 years allowed the demonstration of the existence of functional interactions between 5-HT, NE and DA systems, and the identification of the specific receptors involved. In particular, 5-HT systems were shown to exert negative influence on NE and DA systems through 5-HT2A and 5-HT2C receptor- mediated mechanisms, respectively. On the other hand, complex positive and negative influences of NE system on 5-HT neurotransmission are mediated through α1- and α2-adrenergic receptors, respectively. These data provided a rationale for the design of new, multimodal, therapeutic strategies involving drugs acting not only at the "historical" targets such as the 5-HT and/or the NE transporter, but also at other molecular targets to improve their efficacy and their tolerability.

Monoamine neurocircuitry in depression and strategies for new treatments.

The different serotonin (5-HT) receptors, including the serotonin transporter (5-HTT), are excellent candidate genes for suicide and suicidal behavior, and thus, they have been investigated in a large number of allelic association studies. The individual results of these studies have been inconsistent and definite conclusions are difficult to establish. A reliable method for assessing individual studies and generating combined results is provided by systematic reviews using meta-analytical techniques. In this study, we carried out a systematic review of studies investigating 5-HT receptors and the 5-HTT in suicidal behavior. Studies were identified by means of MEDLINE database searches and by scanning reference lists. More than 190 articles were reviewed and 26 met the inclusion criteria. In all, 14 studies investigated six different 5-HT receptor loci and 12 studies investigated the 5-HTT promoter 44 bp insertion/deletion polymorphism. Two specific meta-analyses were carried out, pooling studies investigating the 5-HT2A 102 T/C and the 5-HTT promoter loci that included, respectively, a total of 1599 and 2539 subjects. The combined evidence was significant for association with the 5-HTT locus (Mantel-Haenszel weighted odds ratio (M-H(w) OR)=1.17 CI : 1.04-1.32, P=0.009), but not for the 5-HT2A 102 T/C variant (M-H(w) OR)=1.09 CI : 0.93-1.27, P=0.319). The 5-HTT result was robust and remained significant following sensitivity analysis, suggesting that 5-HTT may play a role in the predisposition to suicide.

A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: II. Suicidal behavior.

OBJECTIVE: Postmortem studies have indicated that suicide victims have greater serotonin receptor 2A (5-HTR2A) binding in prefrontal brain regions. However, there remains some controversy regarding the biological specificity of these findings. The authors hypothesized that the variance observed in brain 5-HTR2A binding is genetically mediated, at least in part. METHOD: Postmortem data from 56 subjects who had committed suicide and 126 normal comparison subjects were studied; brain tissue was available from 11 subjects who committed suicide and 11 comparison subjects. Homogenate binding assays were carried out with [3H]ketanserin. Variation at the 5-HTR2A gene (HTR2A) was investigated by means of two polymorphisms: T102C and A-1438G. RESULTS: 5-HTR2A binding was greater in the prefrontal cortex of the subjects who committed suicide. In addition, the findings suggest that HTR2A variation significantly affects 5-HTR2A binding. However, no interaction between suicidal behavior and this locus was observed. CON...

https://ajp.psychiatryonline.org/doi/pdf/10.1176/ajp.156.9.1456

Prediction of level of serotonin 2A receptor binding by serotonin receptor 2A genetic variation in postmortem brain samples from subjects who did or did not commit suicide.

Richard Brière

Papers

Prediction of level of serotonin 2A receptor binding by serotonin receptor 2A genetic variation in postmortem brain samples from subjects who did or did not commit suicide.

Dr. Turecki and Colleagues Reply