Statistical Methods for Health Care Research

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

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

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

Background: Endogenous opiates may reinforce self-injurious behavior in animal and human subjects. Higher postmortem μ-opioid receptor binding is reported in some brain regions in young compared with older suicide victims. The present study compared opioid receptor binding kinetics in postmortem brains of young suicide victims and matched controls in two brain areas. Methods: The density (Bmax) and affinity (KD) of the μ-opioid receptors were assayed postmortem using [3H] DAGO in prefrontal cortex (PFC) and pre-post central gyri (PPCG) in 9 suicide victims and 10 controls, matched for age and gender ratio. Results: Binding indices did not differ between suicide victims and controls in either brain area and did not correlate with age. PFC Bmax was higher than PPCG Bmax (F=8.030; df=1,16; p=.012) for the combined sample. There was no brain region difference in KD between PFC and PPCG, but the interaction between KD and group was significant (F = 5.890; df = 1,16; p = .027). The KD in the suicide victims was lower than controls in the PFC and higher than controls in the PPCG. Conclusion: Our study demonstrated more μ-opioid receptors in PFC compared with PPCG binding regardless of suicide status. The region-dependent differences in binding affinity in suicide victims may reflect regionally different opiate transmission.

Shuoqi Li

Papers

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

Postmortem μ-opioid receptor binding in suicide victims and controls