Original articleThe serotonin transporter in the midbrain of suicide victims with major depression
Introduction
Suicide is a major public health concern in the United States of America. In 1995, suicide was the ninth leading cause of death, with 31,284 people dying by suicide. Retrospective psychiatric assessments of suicide victims reveal that between 44% and 87% of these individuals meet the clinical criteria for a depressive disorder at the time of their death Arato et al 1988, Barraclough et al 1974, Cheng 1995, Modestin and Kopp 1988, Rich et al 1986. Based on epidemiological data, Isacsson et al (1997) suggest that successful strategies for suicide prevention should include significant efforts to recognize depressed individuals and treat them with antidepressant medications.
Research on the psychopharmacology, genetics, and postmortem neurochemistry of the brain suggests that alterations in serotonin-containing neurons, their transporter proteins, and related receptors are an integral part of the pathophysiology of major depression and suicide Charney 1998, Nemeroff 1998. For example, in most but not all studies, the content of serotonin or its metabolite, 5-hydroxyindoleacetic acid, is decreased in the brainstem of suicide victims (reviewed by Mann et al 1996b). The selective serotonin reuptake inhibitors (SSRIs), medications that block the serotonin transporter and prevent the reuptake of serotonin, are antidepressant and decrease the frequency of suicidal ideation or suicidal behavior Grimsley and Jann 1993, Montgomery 1995, Mourilhe and Stokes 1998, Verkes et al 1998. In addition, genetic variation in the serotonin transporter has been associated with bipolar disorder, major depression, and seasonal affective disorder Battersby et al 1996, Collier et al 1996a, Collier et al 1996b, Du et al 1999, Furlong et al 1998, Rees et al 1997, Rosenthal et al 1998.
It has been proposed that decreases in the monoamine transporters may be critical to the etiology of depression and suicide. In studies examining forebrain areas to which serotonin neurons project, there are several reports of decreases in the binding of radiolabeled inhibitors of serotonin reuptake in nonschizophrenic suicide victims or subjects with major depression or an affective disorder Arango et al 1995, Joyce et al 1993, Laruelle et al 1993, Leake et al 1991, Stanley et al 1982. Alternatively, several reports suggest that altered serotonin or norepinephine function in major depression and suicide may be detected at the sites of origin of these monoamine neurons in the brainstem Arango et al 1996, Malison et al 1998, Ordway et al 1994, Stockmeier et al 1998, Zhu et al 1999.
The dorsal raphe nucleus (DR) in the brainstem contains the cell bodies of many of the serotonergic neurons that project to the forebrain and these neurons appear to be involved in the pathophysiology of major depression and suicide. Evidence for involvement of the serotonergic brainstem in depression has emerged from reports of a significant decrease in radioligand binding to the serotonin transporter in major depression (Malison et al 1998), increased radioligand binding to the serotonin-1A autoreceptors in the DR in suicide victims with major depression (Stockmeier et al 1998), or decreased serotonin-1A receptor binding potential in patients in the depressed phase of familial mood disorder (Drevets et al 1999). Recently, morphological evidence has surfaced to suggest that the number and density of serotonin neurons is higher in the DR in suicide victims, most of whom had major depression (Underwood et al 1999).
In animal experiments, chronic treatment with antidepressant medications such as SSRIs or monoamine oxidase inhibitors appears to enhance net serotonergic neurotransmission via mechanisms in the midbrain DR Blier and de Montigny 1994, Invernizzi et al 1994. Therefore, the serotonergic system in the brainstem may be diminished in major depression and/or suicide, whereas conversely, antidepressant medications appear to enhance that system.
This study was designed to test the hypothesis that serotonin transporters are decreased in the midbrain DR of suicide victims with major depression. The midbrain was sampled at several rostral-to-caudal levels, and quantitative receptor autoradiography was used to measure the serotonin transporter. The suicide victims met clinical criteria for a current episode of major depression and the age-matched control subjects were determined to be without psychiatric illness.
Section snippets
Tissue collection and preparation
Brain tissue was obtained at autopsy at the Coroner’s Office of Cuyahoga County, Cleveland. The study was performed in accordance with an approved Institutional Review Board Protocol and written consent was obtained from the next-of-kin. As previously described (Stockmeier et al 1996), midbrains were collected and dissected from 10 suicide victims and 10 age-matched comparison subjects dying of natural or accidental causes. The causes of death were certified by the Coroner and are listed in
Results
The average age of the suicide group was 52 ± 6 years (mean ± SEM, range 25–83) and the average time between death and freezing of the tissue (PMI) was 17 ± 2 hours (mean ± SEM, range 5–23)(Table 1). The average age of the control group was 53 ± 5 years (range 27–82) with an average PMI of 17 ± 2 hours (range 6–26)(Table 1). There were no significant differences between groups for either age or PMI.
[3H]Paroxetine binding was examined within the DR of the human midbrain. A schematic diagram
Discussion
In the present study of psychiatrically characterized suicide victims with major depression and normal comparison subjects, there was no significant difference in the autoradiographic density of [3H]paroxetine binding to the serotonin transporters in either the entire midbrain DR or its subnuclei. In a companion study of sections taken adjacent to those for this study of serotonin transporters, radioligand binding of an agonist to serotonin-1A receptors was significantly increased in the DRd
Acknowledgements
This work was supported by grants from the National Institute of Mental Health (MH45488) and The American Foundation for Suicide Prevention.
The authors gratefully acknowledge the contributions of Herbert Y. Meltzer, M.D., and James C. Overholser, Ph.D., in the retrospective psychiatric diagnoses. The authors thank Jinrong Wei for assistance in determining rostral-to-caudal levels within the midbrains. The editorial assistance of Lisa M. Kempfer is also greatly appreciated.
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