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

Abstract

Neuro-receptors Major depression and suicidal behavior are independently related to altered serotonergic function (Mann and Stanley 1986). See Table 1 for a summary (Malone and Mann 1993;Owens and Nemeroff 1994;Stoff and Mann 1997;Mann 1998). In major depression there are fewer platelet serotonin transporters (5-HTT), lower CSF 5-HIAA (Mendels et al. 1972;Sjöström and Roos 1972; Ashcroft et al. 1973a Ashcroft et al. , 1973bPost and Goodwin 1974; Bowers 1974; Goodwin and Post 1977;van Praag and de Haan 1979;Koslow et al. 1983; Åsberg et al. 1984; Gerner et al. 1984;Roy et al. 1985;Redmond et al. 1986), as well as a reduced growth hormone (GH) response to 5-hydroxytryptophan (5-HTP) (Upadhyaya et al. 1991) and a blunted prolactin (PRL) response to oral fenfluramine (Siever et al. 1984; Coccaro et al. 1989;O'Keane and Dinan 1991;Mann et al. 1992) and to intravenous L-tryptophan (Heninger et al. 1984; Cowen et al. 1990;Price et al. 1991;Upadhyaya et al. 1991). The antidepressant efficacy of selective serotonin reuptake inhibitors (SSRIs) suggests the abnormality in depression probably includes impaired serotonergic function, because selective enhancement of serotonergic activity is therapeutic (Åsberg et al. 1986a). Depletion of serotonin by parachlorophenylalanine (PCPA) (Shopsin et al. 1976) or by reduction of brain tryptophan (Delgado et al. 1990), quickly reverses the antidepressant effect of serotonergic medication in patients (Åsberg et al. 1986a), suggesting that sustained enhancement of serotonergic function is a necessary requirement to sustain this SSRI-mediated antidepressant effect. It seems that the abnormality in serotonergic function may be a biochemical trait, because a blunted prolactin response to fenfluramine and a vulnerability to depression in response to tryptophan depletion are present during the 24 , NO . 5 period of remission between episodes (Flory et al. 1998). An intermorbid biological abnormality or trait implies a genetic or developmental origin, although enduring illness or treatment effects cannot be ruled out.Lower serotonergic activity is also independently associated with suicidal behavior. We have hypothesized that there is a serotonergic abnormality contributing to the diathesis or vulnerability for suicidal acts (Mann 1998). Lower levels of CSF 5-HIAA (Åsberg et al. 1986b) and a blunted prolactin response to fenfluramine (Mann et al. 1992) correlate with the presence and lethality of past suicide attempts in patients with major depression and can predict future suicide or suicide attempts (Roy et al. 1989;Träskman-Bendz et al. 1992;Nordström et al. 1994). The association between suicide attempts and low CSF 5-HIAA has also been reported in schizophrenia and personality disorders, indicating that this association is independent of diagnosis. Lower brainstem serotonin (5-HT) and/or 5-hydroxyindoleacetic acid (5-HIAA) levels, and alterations in binding kinetics of a number of serotonin receptor subtypes are reported postmortem in the brain of suicide victims compared...

Altered expression of genes involved in ATP biosynthesis and GABAergic neurotransmission in the ventral prefrontal cortex of suicides with and without major depression

“…1 There is also a large body of evidence suggesting that neurobiological factors increase the predisposition to suicide. 2 In spite of some overlap, this neurobiological predisposition seems to be, to a considerable extent, different from that mediating risk to major depression or other psychopathological processes commonly present in suicide completers. 3 A number of investigations have illustrated the importance of the prefrontal regions in depression and suicidal behavior.…”

Patterns of gene expression in the limbic system of suicides with and without major depression

“…36 Additionally, in a recent study, Rosel et al 37 observed altered levels of 5-HT2A and 5-HT4 receptors and their respective intracellular signaling systems IP 3 and cAMP in hippocampi of suicides when compared to controls. A number of recent investigations have highlighted the potential for identification of genetic predisposing factors for depression 38 and suicidal behavior, 39 including WFS1 [40][41][42] and p75NTR, 43 among others. However, these studies have focused on expression levels of one or several genes at a time and compared suicides with or without psychopathology to controls, not providing an idea of the overall changes taking place in relation to suicide versus the ones related to major depression.…”

The Effect of Citalopram Pretreatment on Neuronal Responses to Neuropsychological Tasks in Normal Volunteers: An fMRI Study

“…Findings common to some or all of these disorders include reduced cerebrospinal fluid concentrations of the 5-HT metabolite, 5-hydroxyindoleacetic acid, reduced hormonal responses to 5-HT drug challenge, and altered brain 5-HT receptor numbers (Mann et al, 1995;O'Keane et al, 1992;Coccaro et al, 1995;Dolan et al, 2001;Drevets et al, 1999;Stockmeier, 2003). In addition, selective serotonin reuptake inhibitors (SSRIs) have proved effective in their treatment, an action that is believed to be due to the enhancement of 5-HT neurotransmission (Bell and Nutt, 1998;Mann et al, 2001;Jetty et al, 2001;Nemeroff, 2002).…”