Reducing Suicide A National Imperative (2002) / Chapter Skim
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4 Biological Factors
4 Biological Factors
Pages 119-156
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From page 119... ...
Postmortem studies of suicide victims are complicated by other influences on the brain that must be taken into account such as prior medications, substances of abuse and/or self-poisoning, consequences of the suicide-related trauma and injury especially to the head, and postmortem delay prior to preservation of brain tissue samples. This chapter starts with the physiological stress system, a common pathway for response to acute and cumulative physical and psychological stressors.
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From page 120... ...
, another component of the HPA axis feedback loop, were noted to be lower than other psychiatric patients in cerebrospinal fluid (Brunner et al., 2001; TraskmanBendz et al., 1992) and in plasma (Westrin et al., 1999)
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From page 121... ...
A number of studies have indicated that abnormal DST results and changes in daily rhythms of stress hormone release correlate with recent suicide attempts independently of psychiatric diagnosis (Bank) et al., 1984; Lopez-Ibor et al., 1985; Pfeffer et al., 1991; Targum et al., 1983~.
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From page 122... ...
A wealth of evidence points to reduced serotonergic and altered noradrenergic function in the brains of suicide victims (both attempters and completers)
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, probably because most of the decline in indolamine levels occurs in the first 2 hours postmortem and all published studies of suicide victims have a longer postmortem delay. Low serotonin or serotonin turnover in suicide appears to be confined to some brain regions.
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From page 124... ...
are a strong correlate of current and future suicidal behavior. For those with a history of a suicide attempt, 5-HIAA levels are low across diagnoses of depression, schizophrenia, or personality disorders compared to psychiatrically matched control groups (16 of 22 studies, Table 4-2~.
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From page 125... ...
nonattempters but nonsignificant Low CSF 5-HIAA predicted future suicide Only high planned suicide attempters had lower CSF 5-HIAA Reduced in higher lethality attempters Negative correlation with most lethal lifetime attempt SOURCE: Adapted from Mann et al., 1996b with permission of Elsevier Science.
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From page 126... ...
Impulsive aggression but not planned or predatory aggression correlates with low CSF 5-HIAA (Lidberg et al., 1985; Linnoila et al., 1983; Virkkunen et al., 1989a; Virkkunen et al., 1989b; Virkkunen et al., 1987) suggesting that impulsivity plays a role in suicide attempters and predicting a negative correlation of impulsivity and CSF 5-HIAA.
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From page 127... ...
Earlier studies (Arato et al., 1987; Arato et al., 1991; Crow et al., 1984; Stanley et al., 1982) found low 3H-imipramine binding in the dorsal prefrontal cortex of suicide victims that may reflect fewer SERT sites.
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From page 128... ...
(1997) reported an increase in 5-HT~D binding in globus pallidus, but not in putamen, parietal or prefrontal cortex of violent suicide victims.
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From page 129... ...
Low urinary excretion of the metabolite MHPG in suicide attempters provides some further indirect evidence of low NE turnover (Agree, 1980; Agren, 1982~. High binding to p-adrenergic receptors in the cerebral cortex in suicide victims compared to controls has been reported by some investigators (Arango et al., 1990; Biegon and Israeli, 1988; Mann et al., 1986)
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From page 130... ...
(1994) reported low basal, GTP yS and forskolin-stimulated adenylyl cyclase activity in the cortex of suicide victims.
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From page 131... ...
For, while the majority of those who attempt and complete suicide have at least one mental illness, the converse is far from true a very low proportion of mentally ill persons eventually kill themselves, and the majority never make as much as one suicide attempt (e.g., Bostwick and Pankratz, 2000; Murphy and Wetzel, 1990; Pokorny, 1983~. One hypothesis, first advanced several decades ago, is that there are additional genetic factors relevant to suicide and suicidal behavior, perhaps related to a liability to impulsive behavior and aggression (Kety, 1986~.
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From page 132... ...
Two other studies examining familial concordance between suicide attempts, one looking at twin pairs of attempts, and the other at parent-child pairs has found wide variability in the timing of the pairs of attempts, not consistent with imitation (Brent et al., in press; Statham et al., 1998~. Family discord impacts suicidal behavior, particularly among adolescents (Brent et al., 1994; Kosky et al., 1986; Kosky et al., 1990; Taylor and Stansfeld, 1984)
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From page 133... ...
Genetic Assessments Several lines of evidence point to a link between genetic inheritance and risk of suicide. The following sections describe some of that evidence that derives from adoption studies, twin studies, family studies, candidate genes, and a new microarray approach.
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for dizygotic twins after controlling for other psychiatric risk factors. Family Studies Several family studies have compared the risk for suicide or suicide attempt in the first degree relatives of individuals who have completed suicide, compared to the rate among relatives of control probands.
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From page 135... ...
of specific genes in cases of suicide or suicidal behavior to controls. The choice of candidate genes to examine in studying the etiology of suicide is guided by findings described earlier in the chapter regarding changes in serotonin metabolites and receptors in suicide victims and attempters.
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From page 136... ...
Exposure to a serotonin agonist activates less transcription of the S than the L form (Greenberg et al., 1999~. Comparing suicide victims to controls revealed an association between the L allele and depressed suicides (Du et al., 2000b)
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From page 137... ...
The inconsistency is hard to explain it could be due to sex differences, diagnostic differences, or design differences, or it could be that both polarities of the allele, under different circumstances, predispose to a suicide attempt. The association of the S allele in the serotonin transporter promoter region to suicide attempt in alcoholics was strongly influenced by the presence or absence of a history of major depression (Gorwood et al., 2000~.
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From page 138... ...
A related issue is that there may be an "endophenotype" associated with suicidal behavior, namely impulsive aggression, yet most studies did not assess this, even though it appeared to be related to both TPH, polymorphisms of the serotonin transporter, and MAOA (Manuck et al., 1999; Manuck et al., 2000; New et al., 1998; Zalsman et al., 2001~. Sex differences.
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From page 139... ...
Possible experiments to attempt to identify a set of genes unique to suicide might involve scientists investigating brain tissue from a cohort of major depressive disorder patients with and without suicidal behavior, bipolar affective disorder patients with and without suicidal behavior, and schizo
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From page 140... ...
Low levels of serotonin and/or its metabolite have been found in the brains and cerebrospinal fluid of serious suicide attempters and/or those who complete suicide; abnormalities in serotonin receptors have also been found in those who complete suicide. Studies suggest that impaired serotonin function specifically influences suicidality via increased impulsive aggression.
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From page 141... ...
Genetic markers that have functional significance and correlate with impulsive aggression and suicidal behavior cross-sectionally may have the potential to identify individuals at risk and help pinpoint treatment. · Adoption studies, twin studies, and family studies are effective approaches to elucidate the genetic liability for suicide and to assess both genetic and non-genetic influences.
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From page 142... ...
2001. Suicide attempts and the tryptophan hydroxylase gene.
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1995. Localized alterations in pre- and postsynaptic serotonin binding sites in the ventrolateral prefrontal cortex of suicide victims.
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1998. Selective increase of alpha2A-adrenoceptor agonist binding sites in brains of depressed suicide victims.
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1988. Brain 5-HT2 receptor binding sites in depressed suicide victims.
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1994. Autoradiographic demonstration of increased alpha 2-adrenoceptor agonist binding sites in the hippocampus and frontal cortex of depressed suicide victims.
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1993. 5-HT uptake sites and 5-HT2 receptors in brain of antidepressant-free suicide victims/depressives: Increase in 5HT2 sites in cortex and amygdala.
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1993. Beta-adrenergic receptor binding in frontal cortex from suicide victims.
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From page 149... ...
Increased serotonin2 and beta-adrenergic receptor binding in the frontal cortices of suicide victims. Archives of General Psychiatry, 43~10~: 954-959.
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1991. Serotonergic measures in suicide brain: 5-HT1A binding sites in frontal cortex of suicide victims.
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receptor complex in the frontal cortex of suicide victims. Brain Research, 675~1-2~: 157164.
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From page 152... ...
receptors in the postmortem brains of teenage suicide victims. American Journal of Psychiatry, 159~3~: 419429.
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From page 153... ...
Cholinergic receptor binding in the frontal cortex of suicide victims. American Journal of Psychiatry, 141~11~: 1432-1436.
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From page 154... ...
1988. CSF monoamine metabolites in patients and controls: support for a bimodal distribution in major affective disorders.
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From page 155... ...
2001. Family-based association study of serotonin transporter promoter in suicidal adolescents: No association with suicidality but possible role in violence traits.
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From page 156... ...
In a Time In a time of secret wooing Today prepares tomorrow's ruin Led knows not what right is Joing MY heart is torn asunder. In a time of furtive sighs Sweet hellos and sad goodbyes Half-truths told and entire lies MY conscience echoes thunder In a time when kingdoms come Joy is brief as summer's fun Happiness, its race has run Then pain stalks in to plunder .
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