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.

Background Major depression and suicide are associated with fewer serotonin transporter (5-HTT) sites. The 5′-flanking promoter region of the 5-HTT gene has a biallelic insertion/deletion (5-HTTLPR). We assayed prefrontal cortical (PFC) 5-HTT binding in major depression and suicide and examine the relationship to the 5-HTTLPR allele. Methods Postmortem brain samples from 220 individuals were genotyped for the 5-HTTLPR polymorphism. Binding of 5-HTT was assayed by quantitative autoradiography in the PFC of a subset of subjects (n = 159). Clinical information, including DSM-III-R Axis I diagnoses, was obtained by psychological autopsy and medical chart review. Results Binding to 5-HTT was lower in the ventral PFC of suicides compared with nonsuicides and was lower throughout the PFC of subjects with a history of major depression. The 5-HTTLPR genotype was associated with major depression but not with suicide or 5-HTT binding. Conclusions A diffuse reduction of 5-HTT binding in the PFC of individuals with major depression may reflect a widespread impairment of serotonergic function consistent with the range of psychopathologic features in major depression. The localized reduction in 5-HTT binding in the ventral PFC of suicides may reflect reduced serotonin input to that brain region, underlying the predisposition to act on suicidal thoughts. The 5-HTTLPR genotype was not related to the level of 5-HTT binding and does not explain why 5-HTT binding is lower in major depression or suicide.

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/481646/yoa9309.pdf

A serotonin transporter gene promoter polymorphism (5-HTTLPR) and prefrontal cortical binding in major depression and suicide.

The neurobiology of suicide

The Neurobiology and Genetics of Suicide and Attempted Suicide:: A Focus on the Serotonergic System

The concept that genetic factors contribute to the complex trait of suicidal behaviour has stimulated much work aimed at identifying susceptibility genes. So far molecular genetic studies focused on the serotonergic pathway as the intent to die and the lethality of suicide acts were related to the serotonergic system. Two genes have so far emerged as being involved in the vulnerability for suicidality: first, the intronic polymorphisms (A218C or A779C) of the tryptophan hydroxylase 1 (TPH1) gene, which was suggested as a quantitative risk factor for suicidal behaviour; second, the insertion/deletion polymorphism of the serotonin transporter gene (5-HTTLPR), which does not seem to be involved in general suicidal behaviour, but in violent and repeated suicide attempts. The data have further shown that the MAOA gene, which is consistently associated with impulsive-aggressive personality traits, is not related to suicide but might induce violent methods in subjects with other suicide risk factors. Predominantly negative were the findings with any type of the serotonin receptors and inconsistent with catecholamine-synthesizing and -metabolizing enzymes or with the dopaminergic receptors. This paper reviews the status of current knowledge in this area, points to the weakness of the investigations and presents new approaches beyond the serotonergic system.

Genetics of suicide

Suicide has been associated with decreased serotonin transmission Measurement of concentrations of serotonin, its precursors tryptophan (TRY) and 5-hydroxytryptophan (5-HTP) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), have been used as indices of serotonin activity, and with serotonin transporter binding, are indices of the integrity of serotonin nerve terminals Most previous studies have not distinguished high affinity transporter binding from a very similar nontransporter binding site, where binding is not dependent on Na+ or Cl- and that does not have a known functional role We therefore, assayed binding kinetics in prefrontal (PFC) and temporal cortex (TC) in matched pairs of suicide victims and controls using the selective ligand 3H-paroxetine, and employing 1 microM sertraline to define specific binding to the transporter and 10 microM sertraline which also displaces binding to the high affinity, nontransporter site In addition, we measured concentrations of TRY, 5-HTP, serotonin and 5-HIAA in the same brain areas The total number of 3H-paroxetine transporter and nontransporter binding sites (Bmax), was lower in the suicide group compared to controls in both Brodmann area 9 (prefrontal cortex; p = 002) and in Brodmann area 38 (temporal cortex, p = 001) In contrast, no differences were found in the number of high affinity transporter binding sites and concentrations of serotonin, 5-HIAA, 5-HTP or TRY (p > 005) We conclude that the number of serotonin transporter sites is not altered in Brodmann area 9 in suicide, and that fewer 3H-paroxetine and 3H-imipramine binding sites found in this region of cerebral cortex of suicides may be explained by a reduction in the nontransporter binding sites

T. F. Lagattuta

Papers

Lower 3H-paroxetine binding in cerebral cortex of suicide victims is partly due to fewer high affinity, non-transporter sites.