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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Psychiatr Clin North Am. Author manuscript; available in PMC 2009 July 15.
Published in final edited form as:
PMCID: PMC2710608
NIHMSID: NIHMS51312

Stress, Genes and the Biology of Suicidal Behavior

Abstract

Suicidal behavior is in part heritable. Studies seeking the responsible candidate genes have examined genes involved in neurotransmitter systems demonstrated to have altered function in suicide and attempted suicide. These neurotransmitter systems include the serotonergic, noradrenergic and dopaminergic systems and the HPA axis. With some exceptions, most notably the serotonin transporter promotor HTTLPR polymorphism, replication of candidate gene association studies findings has proven difficult. This chapter reviews what is known of specific gene effects and gene-environment interactions that influence risk for suicidal behavior. Effects of childhood stress on development and how that influences adult responses to current stress will be shown to be relevant for mood disorders, aggressive/impulsive traits and suicidal behavior.

Keywords: Suicide, Mood Disorders, Genetics, Stress, Serotonin, HPA axis

Suicidal Behavior and Genetics

Family, twin, and adoption studies provide evidence of the heritability of suicide and attempted suicide, in part independent of the familial transmission of major psychiatric disorders (see Brent & Mann for a review 1). From twin studies, based on case and register studies, estimates of heritability for suicide range between 21-50%, and 30-55% for a broader phenotype of suicidal behavior (attempts, thoughts, plans) based on general population studies.2 Identifying the relevant genes and the neurobiological pathways through which they contribute to the etiology of suicidal behavior is important for designing and implementing preventative strategies. The first wave of genetic studies sought to identify genes involved in suicide and/or attempted suicide by linkage studies or specific single nucleotide polymorphisms (SNPs) in association studies. Emerging approaches aim to investigate functional genomics using microarray technologies to profile expression of thousands of genes simultaneously (see Mirnics et al 3 for a review) or doing a genome wide array for hundreds of thousands of SNPs.

Candidate genes for association studies have been generally selected based on evidence from neurobiological studies in suicide. Consequently, the serotonergic system has been most extensively investigated, with other target systems including the dopaminergic and noradrenergic systems, neurotrophins such as brain derived neurotrophic factor (BDNF) and, more recently, genes related to the hypothalamic-pituitary-adrenal (HPA) axis. Association studies have been the commonest design but replication of findings has proven difficult for individual SNP association studies for a number of reasons, including differences in study sample size and composition with respect to diagnosis, different definitions of suicidality including suicide, nonfatal attempts or suicidal ideation, the effects of ethnicity/race-related stratification, and the effect of, or interactions with, environmental factors. Environment, particularly during childhood developmental periods, can influence the effect of genetic variants on neurobiological function. Another factor contributing to the disparity in results from association studies may be the complexity of the suicidal behavior phenotype, although this may be less of a problem as suicide, nonfatal suicide attempts and suicidal ideation are all partly heritable and perhaps involve many of the same genes. Nevertheless, there are probably many genes, as well as epigenetic factors, involved in the diathesis for suicidal behavior. Moreover, the rarity of completed suicide means that studies may be underpowered to detect the effect of a single SNP or gene. To address the matter of a low base rate for suicide, one approach is to focus on endophenotypes for suicidal behavior that are more prevalent and can often be more narrowly and specifically defined and measured. These may include clinical traits such as impulsive-aggression, cognitive function, or neurobiological functioning such as amygdala responsivity.

Much remains unknown regarding which genes have the most influence in suicidal behavior and the neurobiological mechanisms through which genetic variants act to affect the risk for suicidal behavior. Here we review published findings that together begin to elucidate a picture of the genes, their functional effects, and their involvement in endophenotypes that are putative pathways to suicidal acts.

Serotonergic System

About thirty years of research documents abnormalities in the serotonergic system in suicide and non-fatal suicidal behavior (see Mann 4 for a review). Thus, it is not surprising that the serotonergic system has been most scrutinized regarding genetic variants potentially contributing to serotonergic system dysfunction and thereby to suicidal behavior. Candidate genes from the serotonergic system that have been examined with respect to suicidal behavior include SNPs in genes for the serotonin transporter, serotonin receptors including 5-HT2A, 5-HT1A and 5-HT1B, tryptophan hydroxylases I and II (the rate limiting enzymes in serotonin synthesis), as well as monoamine oxidase A, which is involved in the breakdown of monoamines including serotonin.

Serotonin Transporter

Postmortem studies of depressed suicides report fewer serotonin transporters in prefrontal cortex (suicide or major depression), hypothalamus (suicide), occipital cortex (major depression) and brainstem (suicide and major depression) 5. Of relevance in identifying the responsible brain circuitry in suicides, this prefrontal cortex deficit appears localized to the ventromedial prefrontal cortex (a brain region involved in willed action and decision-making), whereas major depression is associated with lower binding throughout the prefrontal cortex.6

The cause of lower transporter binding has been the target of inquiry. The serotonin transporter gene is located on chromosome 17 and has a common, functional promotor polymorphism (5-HTTLPR). Initially a short variant (S allele) of the polymorphism was found to have lower transcriptional efficiency and less transporter expression, binding, and 5-HT uptake in lymphoblasts 7. The so-called long or L variant was subsequently found to comprise low-expressing (LG) and higher-expressing (LA) variants.8,9 In healthy volunteers, two PET studies, using the high affinity ligand [11C} DASB, resported altered serotonin transporter binding in midbrain10 and putamen 11 associated with 5-HTTLPR genotype, however, these and other imaging studies find no evidence of geneotype effect on serotonin transporter binding in the amygdala, thalamus, prefrontal cortex, or anterior cingulate6,12-14.

Multiple studies in healthy adults have reported that individuals with the lower expressing SS genotype show increased amygdala activity when exposed to angry or fearful faces, negative words, or aversive pictures (reviewed in Brown & Hariri 15). Two recent studies examine whether genotype has an effect on resting amygdalar activity, that is, when exposed to neutral rather than negative stimuli.16,17 These studies use spin labeled perfusion fMRI methods, which qualifies absolute cerebral blood flow rather than the BOLD method which is only informative in comparing changes in state. Both report that, compared with the l/l group, the s/s group or s/s & s/l combined group had significantly higher resting CBF in the amygdala.16,17 This suggests that the presence of the low-expressing allele may contribute to a more generalized alteration in amygdala function that may underlie the observed increased sensitivity to emotional stimuli. Canli et al also noted that life stress interacted with genotype with respect to amygdala function, whereby amygdala activation at rest correlated positively with life stress in short variant carriers, but correlated negatively with life stress in noncarriers.16 A similar effect was noted in the hippocampus. The amygdala is densely innervated by serotonergic neurons and 5-HT receptors are abundant 18-20 and thus the serotonergic abnormalities seen in suicides may indicate altered amygdala function.

5-HTTLPR and suicidal behavior

More than 20 studies have examined the 5-HTTLPR polymorphism with respect to suicidal behavior with both negative and positive findings. Meta-analyses of 12 studies comprising 1599 subjects found a significant association of the 5-HTTLPR low expressing S allele and suicidal behavior.21 Another meta-analysis found the S allele more frequent in suicide attempters within individual diagnostic categories, and that the S allele was associated with violent rather than non-violent suicide attempts.22

The 5-HTTLPR lower expressing alleles have been associated with violent behavior.23-25 The relationship between impaired serotonergic function and aggression is well established.26 One potential pathway by which the 5-HTTLPR gene is related to impulsivity and aggression is through observed alterations in amygdala function as the amygdala, along with the prefrontal cortex and orbital cortex, is thought to play a role in the emergence of violent behavior via faulty regulation of negative emotion.27

Serotonin Receptors

Greater postmortem 5-HT2A receptor binding was observed in the prefrontal cortex of suicides compared with non-suicides in some studies.28-32 Youths who died by suicide had increased protein levels and gene expression, which may partially explain observed higher binding.32 Higher 5-HT2A binding has also been reported in the amygdala in depressed suicides33, and in suicide victims with and without depressive diagnoses there is evidence that 5-HT2A receptors are up-regulated in the dorsal prefrontal cortex (areas 8 and 9) but unchanged in the rostral pole of the prefrontal cortex (area 10) (see Stockmeier 34 for a review). Not all studies concur, and several observe no difference in 5-HT2A receptors in the prefrontal cortex in depressed suicides compared to controls.35-42

In non-fatal suicide attempts, multiple platelet studies of 5-HT2A receptors, serotonin reuptake sites, and serotonin second messenger systems have reported higher platelet 5-HT2A receptor numbers in suicide attempters compared with nonattempters and healthy controls43, indications of impaired 5-HT2A receptor mediated signal transduction in the prefrontal cortex of suicides44, and blunted 5-HT2A receptor in major depression patients who made high-lethality suicide attempts compared to those who made low-lethality suicide attempts.45 The implications of such a defect in signal transduction, if present in the brain, would be that although there may be greater density of 5-HT2A receptors, the signal which is transduced by 5-HT2A receptor activation may be blunted, which would compound deficient serotonergic activity as seen in the lower levels of brainstem serotonin and/or 5-HIAA in suicide victims.35,36,46-50

5-HT receptor genes and suicidal behavior

Studies of 5-HT2A receptor gene and suicidal behavior have largely focused on the T102C SNP. The T102C SNP was not associated with suicide in post mortem studies but sample sizes are small.51-54 Positive association have been reported with suicide attempt in depressed individuals55 and with suicidal ideation56, however there are multiple negative studies in varied populations and diagnostic groups for both ideation and attempt.57-61 Metaanalysis of 9 studies found no association of the T102C polymorphism with suicide attempt or suicide21 and a recent expaned metaanalysis of 25 studies confirmed the lack of association.62

Huang et al reported decreased 5-HT1B binding in the prefrontal cortex of suicides and non-suicides associated with the C allele of C129T and G allele of G861C SNPs.63 Multiple studies of the common G861C SNP in the 5-HT1B receptor gene coding region report no association of genotype and suicide63-65 or suicide attempt.66-68 The observation that 5-HT1B knockout mice exhibit aggressive behavior69, suggested that this gene may be involved in the aggressive/impulsive endophenotype of suicidal behavior. Investigations of the two common SNPs in this gene have examined association with aggression and/or impulsive traits as well as with suicide directly. The G861C SNP was shown to be involved in aggression and impulsivity, with increased C allele frequency in antisocial alcoholics70, although a German study of alcoholics found lower C allele frequency in those with antisocial and conduct disorders.71

Other serotonin receptors have been less studied with respect to genetic involvement in suicidal behavior. An overrepresentation of 5-HT1A 1018G allele in suicides compared to controls has been reported by some72, but others find no association.73-75 Studies of the 5-HT2C 76, 5-HT6 receptor77 and a study of 7 other serotonin receptor genes78 all report no indication of association with suicidality.

The 5-HT1B receptor gene and aggression aside, there have been few other studies of 5-HT receptor polymorphisms for associations with endophenotypes. Giegling et al examined multiple 5-HT2A SNPs, and found that CC-homozygotes for the functional SNP rs6311 reported more anger and aggression related behavior, and that the C allele, as well as the G–C haplotype combination of rs594242–rs6311,. was related to nonviolent and impulsive suicidal acts.79 A study of multiple SNPs in the 5-HT2C and 5-HT1A genes found no effect of measures of state and trait anger or aggression in Caucasian suicides or in suicide attempters with various psychiatric diagnosis or in healthy volunteers.80

Tryptophan Hydroxylase

Tryptophan hydroxylase is the rate limiting enzyme in the synthesis of serotonin. Two isoforms of TPH have been identified, TPH1 and TPH2, the latter expressed primarily in the brain, and their genes are on different chromosomes. Postmortem studies comparing depressed suicides to controls, report greater density and number of TPH-immunoreactive (TPH-IR) neurons in the DRN81 and higher TPH IR in the dorsal raphe nucleus, but not in the median raphe nucleus, in depressed suicides82, although others find less TPH IR in the DRN of depressed alcoholics suggesting common mechanism in major depression.83 Depressed alcoholic suicides had 46% higher TPH immunoreactivity in the dorsal subnucleus, but no other dorsal raphe subregion, compared to controls.84 Higher levels of TPH2 mRNA and protein were found in the dorsal raphe nucleus of drug free suicides.85 This over-expression may be due to a stress response as it has been reported to occur in animal models of stress.

There are two common polymorphisms on intron 7 of TPH1: A218C and A779C (originally classified as U and L for upper and lower band) that are in very high linkage disequilibrium. A218C has been linked to altered 5-HT function. In a postmortem study, the AA genotype was associated with higher TPH immunoreactivity and lower 5-HT2A binding in the prefrontal cortex compared to other genotypes in both suicides and non-suicides while another TPH1 polymorphism, A-1438, had no effect on either serotonergic marker.86 Manuck et al found an attenuated prolactin response to fenfluramine in C allele of A779C relative to LL homozygotes in healthy volunteers87, but New et al observed no relationship between genotypes and prolactin response to fenfluramine in male personality disorder patients with respect to this polymorphism88. Jonnsen et al 89 reported a relationship to CSF 5-HIAA in male healthy volunteers but not females, however, we did not find such a relationship in mood disorder subjects (Galfalvy, in preparation). The differences in study population may account for the lack of replication

TPH genes and suicidal behavior

There have been multiple reports of both positive and negative associations with suicide and suicide attempt and the intron 7 A128C SNP. Initially meta-analysis, found no association with suicide or suicide attempt90, however subsequent expanded metaanalyses did find an association of this polymorphism with suicidal behavior in Caucasian91,92 and mixed populations.93 There have also been positive associations reported for the A779C SNP C allele and suicidal behavior in alcoholic offenders94 and surviving monozygotic twins of suicides95, however another study reported an opposite result, with the A allele more frequent in depressed suicide attempters than in non-attempters.96

The A allele of the TPH1 A779C polymorphism has been associated with higher scores for state and trait anger and angry temperament in suicide attempters, and suicide attempters and controls combined97, with higher aggressive hostility in healthy volunteers98, and aggression and outwardly expressed anger in healthy volunteers87 compared to CC homozygotes. Another study in schizophrenic males failed to replicate this finding. 99 Rujescu et al also found the TPH1 A allele of the 218C SNP associated with higher anger scores in a combined sample of suicide attempters and controls97, which is not surprising as the two SNPs are in strong linkage disequilibrium. A study of nonpsychotic inpatients and nonimpulsive controls found no difference in A218C genotype between the groups although the patient group had a number of behavioral tendencies associated with the C allele.100

Haplotype and association studies of different SNPs suggest the involvement of the TPH2 gene with suicide101 and suicide attempt102,103, however again not all studies agree.104-106 There are almost no reports of functional consequences of TPH2 gene variation. One recent study in healthy volunteers found evidence of a frequent functional cis-acting polymorphism in the TPH2 gene that affected mRNA expression. In that study, low levels of TPH2 mRNA expression in the pons were associated with the CTGTG combination of alleles and high levels of expression with the TAAGA combination of alleles for the SNPs re2171363, re4760815, rs7305115, rs6582076, and rs9325202.107 This specific haplotype has yet to be investigated with respect to suicidal behavior.

TPH2 has been little studied with respect to endophenotypes of suicidal behavior, although studies in healthy volunteers found an effect of the TPH2 -703 G/T SNP on amygdala responses to emotional stimuli108, and the TT genotype of this SNP was associated with more errors in the attention network test, a possible indicator of impaired impulse control, and decreased performance in executive control, explaining more than 10% of the variance in these two indicators of attention.109

Monoamine Oxidase A

Monoamine oxidase (MAO) A plays a key role in metabolism of amines. Low MAO A activity (about 80% reduced in activity is required to get a detectable effect) results in elevated levels of serotonin, norepinephrine and dopamine in the brain. The MAO A gene has a 13 −30bp uVNTR (variable number tandem repeat) in the promoter region, in which alleles with 3.5 or 4 repeats (referred to alleles 2 and 3) transcribed 2-10 times more efficiently than those with 3 or 5 repeats (referred to alleles 1 and 4).110 The 2 and 3 alleles were associated lower prolactin responses to fenfluramine challenge in males111 and higher levels of CSF 5-HIAA in healthy females112, and healthy males.113 Meyer-Lindenberg et al, in an fMRI study in healthy volunteers, showed the low expression variant was associated with limbic volume reductions and hyper-responsive amygdala during emotional arousal, as well as diminished reactivity of the regulatory prefrontal regions compared with the higher expressing alleles. 114 Thus a potential pathway for genetic involvement in suicidal behavior is through altered affect and behavioral regulation in part resulting from partially genetically related alterations in serotonergic system function.

MAO genes and suicidal behavior

MAOA uVNTR is mostly found to be unassociated with suicide or suicide attempt.115,116,116-118 One study did find an association with history of suicide attempt, particularly in women with bipolar disorder119, but not in major depressive disorder. Courtet et al, in a sample of European Caucasian suicide attempters with mixed psychiatric diagnoses and controls, found no association with suicidality, although they did observe a higher frequency of higher expressing alleles in males who made a violent suicide attempt compared to males who made a non-violent attempt.120

Human and rodent studies provide evidence of the involvement of MAO A in aggression.121,122 The MAO A uVNTR has been examined for associations with aggression and violence. In a study of multiple domains of aggressive and disruptive behavior in personality disorder patients, aggression and other domains of disruptive, outward-bound behavior traits were associated with MAOA u-VNTR.123 Meyer-Lindenberg et al 114 used fMRI study and found the low expressing alleles to be associated with increased risk of violent behavior, and alterations in the corticolimbic circuitry involved in affect regulation, emotional memory, and impulsivity, and thought to be involved in the emergence of aggressive behavior.27 Moreover, two fMRI studies observed an effect of MAOA genotype during response tasks indicative of impulsivity.124,125

Stress, Genes and Serotonin

Caspi et al observed that life events predicted onset of depressive episode only in individuals with the low expressing 5-HTTLPR S allele. This finding has been replicated multiple times, although not in every case (see Uher & McGuffin126 for a review). Moreover, Caspi et al found that childhood maltreatment predicted adult depression that appeared to be triggered by stress but more so in individuals with the S allele127, a finding which has also been replicated in some and not others126. With respect to suicidal behavior, Caspi et al found the same relationship between life events, the S allele, and suicide attempt and ideation, however did not report on suicidality with respect to childhood maltreatment/genotype interaction. Childhood adversity-genotype interactions and suicidal behavior are reported in mixed diagnosis inpatients128 and abstinent African American substance dependent patients.129

Gene*environment interactions for the 5-HTTLPR have been investigated with respect to behavioral and putative biological endophenotypes for suicidal behavior, including aggression, amygdala responsivity. Reif et al found that an interaction effect of childhood environment and 5-HTTLPR genotype on violent behavior, whereby high adversity in childhood was associated with later-life violence if the short promoter alleles were present.130 Gene and early-life environment effects on later life aggressive/violent traits have also been sought for the MAOA uVNTR. Adverse child-rearing in combination with a lower expressing variant of the MAO A gene was also found to contribute, in males only, to the development of antisocial behavior and more impulsivity, both of which may contribute to suicidal behavior.115,131 In other studies of the MAOA uVNTR, Foley et al found the low expressing alleles more frequent in conduct disorder in the presence of an adverse childhood environment132, and Nilsson et al found that the short allele interacted with adverse psychosocial risk factors, including adverse living environment and violent victimization, in adolescent boys to increase violent behaviors.133 Another study reported that for women with a history of childhood sexual abuse, the low-expressing allele was associated with alcoholism and particularly antisocial alcoholism, while in non-abused women there was no relation between genotype and antisocial personality disorder or alcoholism.134 Not all studies observed a moderating effect of MAOA genotype on childhood/adolescent maltreatment and antisocial or violent behavior.135,136

Elucidating the neurobiological underpinnings of this type of gene*early-life environment interactions is a complex task. Both animal and human studies show that early-life stress has an effect on the development and functioning of the serotonergic system in adulthood. Adult rats exposed to maternal separation in early life show evidence of autoreceptor super-sensitivity indicative of enduring alteration in 5-HT transporter and 5-HT1A autoreceptors.137 In humans, a history of childhood abuse has been associated with blunted prolactin response to different serotonergic agonists in depressed children138, boys in juvenile detention139, and adult borderline personality women.140 Prolactin release is mediated via 5-HT1A and 5-HT2A receptors, and these findings suggest sensitization of these receptors due to early-life stress.

The detrimental effect of early-life stress on the development and function of the serotonergic system may in and of itself confer increased risk for suicidal behavior, for example thorough increased aggression and impulsivity. Moreover, given that there may be underlying genetic differences in level of serotonergic system function, as described earlier, those with low function genotypes may be more vulnerable to the detrimental effects of early-life stress on 5-HT function. Animal studies have observed such effects. Monkeys exposed to maternal deprivation in infancy and having the 5-HTTLPR lower expressing S allele manifest a lowering of CSF 5-HIAA that persists into adulthood, while monkeys exposed to maternal deprivation in infancy with the higher expressing alleles do not show any such alterations.141 It would be instructive to undertake similar studies in human samples.

Another pathway between genes, stress, and suicidal behaviors may be via the effects of impaired serotonergic function on stress response regulation later in life. Studies in animals and humans demonstrate that the serotonergic system is involved in the regulation of stress response via the HPA axis, and that impairments in the serotonergic system may deteriorate HPA function (for a review see Firk142). Thus individuals with lower 5-HT function, due to genes and/or early environment effects, would demonstrate altered HPA axis function. A recent study reports that the low expressing S allele was associated with higher levels of waking cortisol in non-depressed older adults143, however others found no association of 5-HTTLPR genotype and plasma cortisol.144,145 Early life experience is likely to mediate this relationship, and animal studies have examined this. In, six month old macaque monkeys exposed to social stress, peer-reared animals with the S allele had a higher ACTH response, an HPA axis hormone related to stress response, compared with peer-reared animals without that allele and to S allele animals who were maternally-reared.146 Thus, studies of the serotonergic system suggest that elucidating the genetics of suicidal behavior involves examing not justgenes, but also early-life environment, biologic and behavioral endophenotypes, and interactions between biologic systems.

Other Systems

Noradrenergic system

The noradrenergic system has been investigated with respect to suicidal behavior as it is involved in the regulation of stress response. Post mortem studies of suicides have reported ewer noradrenergic neuron in the locus coeruleus of suicide victims with major depression147 increased brainstem levels of tyrosine hydroxylase.148 Binding to alpha2 adrenergic receptors in brains of suicides have been reported variously as increased, decreased, or unchanged (see Pandeyand Dwivedi 149 for a review).

There have been few studies of genes related to the noradrenergic system. α2Aadrenoceptors located in the locus coeruleus exert a tonic inhibitory modulation on the firing activity of noradrenergic cells and the release of norepinephrine in projecting areas.150 Sequiera, et al examining the α2-adrenergic receptor gene in Canadian suicides, found the rare allele of N251K functional SNP that results in an asparagines to lysine amino acid change, present only in suicide victims, but only in 3 cases.151 A subsequent study could not replicate this finding, failing to detect the polymorphism is a large sample of 214 suicides and 176 controls.152

Tyrosine hydroxylase is the rate limiting step for catecholamine synthesis and Persson et al observed a non-significant tendency for low incidence TH-KI allele among suicides compared to controls, although there was a significant association of the K3 allele in subgroup adjustment disorders and suicide attempt.153 Other studies report a trend for association154 or no association.155

Catechol-O-methyltransferase (COMT) enzyme metabolizes the noradrenaline that diffuses in synaptic cleft. COMT has a common functional polymorphism, val158met, that results in the substitution of valine by methionine. The Val allele has relatively high COMT activity compared to the Met allele.156,157 Recent metaanalysis of 6 studies with 519 cases and 933 controls found suggestive evidence of an association between COMT val158met polymorphism and suicidal behavior, perhaps related to the lethality of suicide attempt.158 Supporting this, are reports of association in schizophrenia between the low functioning met allele and impulsive aggression159-161, violent suicide attempts162, and of the Met/Met genotype and outward directed aggression in suicide attempters of varied psychiatric diagnosis.163 Other studies find no relationship between aggression and the Met allele164-167 or the opposite direction.168-170 A post mortem study found the Val allele less prevalent and the heterozygote Val/Met more prevalent in male suicides than in controls.171

There have been no studies of the effect of early-life environment gene interaction on suicidal behavior with respect to genes related to the noradrenergic system. Given that early life stress has been shown to modify noradrenergic system function in adulthood172, examining possible genetic factors that play a role in this would be of interest.

Dopaminergic system

Abnormality of the dopaminergic systems has been reported in depressive disorders (see Dailly 173 for a review) however the role of the dopaminergic system in suicidal behavior is unclear. Reduced dopamine turnover was observed in the caudate, putamen and nucleus accumbens in a postmortem study of depressed suicides.174 However, no differences in number or affinity of the dopamine transporters was found in depressed suicides compared to controls.175 Depressed suicide attempters had lower CSF homovanillic acid (HVA), a dopamine metabolite176, and lower urinary HVA, DOPAC and dopamine177, however other studies find no evidence that CSF HVA levels predict suicide or correlate with clinical factors related to suicide, such as aggression or impulsive traits.178-180 In studies of violent offenders significant correlations between CSF HVA/5-HIAA ratio and psychopathic traits of aggression and violence are reported, suggesting dysfunction in the relative activity of the two systems rather than in dopaminergic system alone may be important.181,182

There have been few studies of dopaminergic system genes with respect to suicidal behavior. In studies of dopamine receptor genes, the del allele of the of 141C Ins/Del polymorphism the D2 receptor gene was not associated with suicide attempt, but was found in excess in alcoholics with suicidality.183 An A-G polymorphism in the 3′utr of exon 8 of the D2 receptor gene was associated with increased number of suicide attempts in alcoholics.184 No differences between Swedish suicide attempters of mixed psychiatric diagnoses and controls185 or between Israeli adolescent suicide attempters and controls186 was found in the dopamine receptor subtype 4 (DRD4) gene exon III 48 bp repeat polymorphism.

HPA Axis

HPA axis function may be involved in suicidal behavior in the context of acute stress response to life events preceding a suicidal act in which impaired stress response mechanisms contribute to risk. It may also be involved in suicidal behavior if increased activity of stress response to adversity during development has deleterious effects on the development of other systems and brain structures implicated in suicidal behavior.

One measure of abnormal HPA axis function in non-suppression of cortisol in response to dexamethasone administration (DST). Over a 15 year follow-up period, DST cortisol nonsuppressors had an approximately 14 fold higher risk of suicide compared to suppressors187, and our recent meta-analysis found that for mood disorder individuals, DST nonsuppressors had a 4.5 fold risk of dying by suicide.188 There have been fewer neuroanatomical studies of HPA axis with respect to suicide, however reported anomalies include larger pituitary and larger adrenal gland volumes found post mortem and using MRI in vivo in depressed suicide victims189-192, and fewer CRH binding sites in the prefrontal cortex of depressed suicide victims.193

For non-fatal suicidal behavior the DST results are inconclusive194-200, however there are reports that DST nonsuppression may be characteristic of more serious attempts that result in high medical damage199,201 or the use of violent method in the suicide attempt.198 In other indices of HPA axis function, depressed adolescents who attempted suicide during a 10 year follow-up period had elevated pre-sleep cortisol compared to depressed non-attempters and healthy controls.202 Depressed suicide attempters have attenuated plasma cortisol responses to fenfluramine203-205, and CSF CRH is lower in previous attempters compared to non-attempters206,207, though not all studies agree177

HPA axis gene and suicidal behavior

There have been comparatively few genetic studies of the HPA axis function, and fewer still in relation to suicidal behavior. In studies of healthy volunteers, there is some evidence that genes play a role in basal HPA axis function, and limited and conflicting reports on the genetic role in HPA axis activity in response to various challenges or stressors (see Wust et al208 for a review). There have been almost no studies of HPA axis genes with regards to suicidal behavior. Recently the CRH receptor has been examined. One study reported linkage and association between SNP rs4792887 and suicide attempt among depressed males exposed to low lifetime levels of stress, but not in males exposed to high-stress levels.209 The authors suggest this may indicate increase in risk for suicidal behavior resulting from an overactive stress response system. Another recent study found the I allele of the ACE I/D polymorphism to be more frequent in completed suicides than in controls.210

Studies in animals211-214, and humans215-218 have demonstrated that early-life stress results in abnormal HPA axis function in adulthood. There have, as yet, been no studies published examining early-life stress, genes and suicidal behavior with respect to the HPA axis, however preliminary data show an early-life stress gene interaction of the CRH R1 gene and early life stress on severity of depression.219 Another study reported an interaction effect of a CRH R1 polymorphism and negative life stress on alcohol use behavior in adolescents.220 Clearly studies investigating the genetic and gene/environment influences on basal HPA axis function and to response to stressors are necessary for elucidating the genetic contributions to suicidal behavior.

Conclusion

With respect to the genes and biology of suicidal behavior, stress can be considered from two perspectives. Firstly, exposure to stress in early life has lasting detrimental effects on the development and function of neurobiological systems thought to be involved in suicides including those that regulate behavior, affect, and cognitive function. Secondly, impairments in stress response systems may be directly involved in suicidal behavior. In both contexts genes may contribute to altered neurobiological function. Increasingly sophisticated association studies that include an examination of early-life stress, markers of biological function, and/or intermediate phenotypes of suicidal behavior will shed further light on the complexities of the relationship between stress, genes, and suicidal behavior.

Footnotes

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Reference List

1. Brent DA, Mann JJ. Family genetic studies, suicide, and suicidal behavior. Am J Med Genet C Semin Med Genet. 2005;133:13–24. [PubMed]
2. Voracek M, Loibl LM. Genetics of suicide: a systematic review of twin studies. Wien Klin Wochenschr. 2007;119:463–475. [PubMed]
3. Mirnics K, Levitt P, Lewis DA. Critical appraisal of DNA microarrays in psychiatric genomics. Biol Psychiatry. 2006;60:163–176. [PubMed]
4. Mann JJ. Neurobiology of suicidal behaviour. Nat Rev Neurosci. 2003;4:819–828. [PubMed]
5. Purselle DC, Nemeroff CB. Serotonin transporter: a potential substrate in the biology of suicide. Neuropsychopharmacology. 2003;28:613–619. [PubMed]
6. Mann JJ, Huang YY, Underwood MD, et al. A serotonin transporter gene promoter polymorphism (5-HTTLPR) and prefrontal cortical binding in major depression and suicide. Arch Gen Psychiatry. 2000;57:729–738. [PubMed]
7. Heils A, Teufel A, Petri S, et al. Allelic variation of human serotonin transporter gene expression. J Neurochem. 1996;66:2621–2624. [PubMed]
8. Nakamura M, Ueno S, Sano A, Tanabe H. The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants. Mol Psychiatry. 2000;5:32–38. [PubMed]
9. Hu XZ, Lipsky RH, Zhu G, et al. Serotonin Transporter Promoter Gain-of-Function Genotypes Are Linked to Obsessive-Compulsive Disorder. Am J Hum Genet. 2006;78:815–826. [PubMed]
10. Reimold M, Smolka MN, Schumann G, et al. Midbrain serotonin transporter binding potential measured with [11C]DASB is affected by serotonin transporter genotype. J Neural Transm. 2007;114:635–639. [PubMed]
11. Praschak-Rieder N, Kennedy J, Wilson AA, et al. Novel 5-HTTLPR allele associates with higher serotonin transporter binding in putamen: a [(11)C] DASB positron emission tomography study. Biol Psychiatry. 2007;62:327–331. [PubMed]
12. Willeit M, Stastny J, Pirker W, et al. No evidence for in vivo regulation of midbrain serotonin transporter availability by serotonin transporter promoter gene polymorphism. Biol Psychiatry. 2001;50:8–12. [PubMed]
13. Shioe K, Ichimiya T, Suhara T, et al. No association between genotype of the promoter region of serotonin transporter gene and serotonin transporter binding in human brain measured by PET. Synapse. 2003;48:184–188. [PubMed]
14. Parsey RV, Hastings RS, Oquendo MA, et al. Effect of a triallelic functional polymorphism of the serotonin-transporter-linked promoter region on expression of serotonin transporter in the human brain. Am J Psychiatry. 2006;163:48–51. [PubMed]
15. Brown SM, Hariri AR. Neuroimaging studies of serotonin gene polymorphisms: exploring the interplay of genes, brain, and behavior. Cogn Affect Behav Neurosci. 2006;6:44–52. [PubMed]
16. Canli T, Qiu M, Omura K, et al. Neural correlates of epigenesis. Proc Natl Acad Sci U S A. 2006;103:16033–16038. [PubMed]
17. Rao H, Gillihan SJ, Wang J, et al. Genetic variation in serotonin transporter alters resting brain function in healthy individuals. Biol Psychiatry. 2007;62:600–606. [PubMed]
18. Azmitia EC, Gannon PJ. The primate serotonergic system: a review of human and animal studies and a report on Macaca fascicularis. Adv Neurol. 1986;43:407–468. [PubMed]
19. Sadikot AF, Parent A. The monoaminergic innervation of the amygdala in the squirrel monkey: an immunohistochemical study. Neuroscience. 1990;36:431–447. [PubMed]
20. Smith HR, Daunais JB, Nader MA, Porrino LJ. Distribution of [3H]citalopram binding sites in the nonhuman primate brain. Ann N Y Acad Sci. 1999;877:700–702. [PubMed]
21. Anguelova M, Benkelfat C, Turecki G. A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: II. Suicidal behavior. Mol Psychiatry. 2003;8:646–653. [PubMed]
22. Lin PY, Tsai G. Association between serotonin transporter gene promoter polymorphism and suicide: results of a meta-analysis. Biol Psychiatry. 2004;55:1023–1030. [PubMed]
23. Gerra G, Garofano L, Santoro G, et al. Association between low-activity serotonin transporter genotype and heroin dependence: behavioral and personality correlates. Am J Med Genet B Neuropsychiatr Genet. 2004;126:37–42. [PubMed]
24. Retz W, Retz-Junginger P, Supprian T, Thome J, Rosler M. Association of serotonin transporter promoter gene polymorphism with violence: relation with personality disorders, impulsivity, and childhood ADHD psychopathology. Behav Sci Law. 2004;22:415–425. [PubMed]
25. Hallikainen T, Saito T, Lachman HM, et al. Association between low activity serotonin transporter promoter genotype and early onset alcoholism with habitual impulsive violent behavior. Mol Psychiatry. 1999;4:385–388. [PubMed]
26. Olivier B, van OR. 5-HT1B receptors and aggression: a review. Eur J Pharmacol. 2005;526:207–217. [PubMed]
27. Davidson RJ, Putnam KM, Larson CL. Dysfunction in the neural circuitry of emotion regulation--a possible prelude to violence. Sci. 2000;289:591–594. [PubMed]
28. Stanley M, Mann JJ. Increased serotonin-2 binding sites in frontal cortex of suicide victims. Lancet. 1983;i:214–216. [PubMed]
29. Arora RC, Meltzer HY. Serotonergic measures in the brains of suicide victims: 5-HT2 binding sites in the frontal cortex of suicide victims and control subjects. Am J Psychiatry. 1989;146:730–736. [PubMed]
30. Mann JJ, Stanley M, McBride PA, McEwen BS. Increased serotonin2 and β-adrenergic receptor binding in the frontal cortices of suicide victims. Arch Gen Psychiatry. 1986;43:954–959. [PubMed]
31. Arango V, Ernsberger P, Marzuk PM, et al. Autoradiographic demonstration of increased serotonin 5-HT2 and beta-adrenergic receptor binding sites in the brain of suicide victims. Arch Gen Psychiatry. 1990;47:1038–1047. [PubMed]
32. Pandey GN, Dwivedi Y, Rizavi HS, et al. Higher expression of serotonin 5-HT(2A) receptors in the postmortem brains of teenage suicide victims. Am J Psychiatry. 2002;159:419–429. [PubMed]
33. Hrdina PD, Demeter E, Vu TB, Sótónyi P, Palkovits M. 5-HT uptake sites and 5-HT2 receptors in brain of antidepressant- free suicide victims/depressives: Increase in 5- HT2 sites in cortex and amygdala. Brain Res. 1993;614:37–44. [PubMed]
34. Stockmeier CA. Involvement of serotonin in depression: evidence from postmortem and imaging studies of serotonin receptors and the serotonin transporter. J Psychiatr Res. 2003;37:357–373. [PubMed]
35. Owen F, Cross AJ, Crow TJ, et al. Brain 5-HT2 receptors and suicide. Lancet. 1983;ii:1256. [PubMed]
36. Crow TJ, Cross AJ, Cooper SJ, et al. Neurotransmitter receptors and monoamine metabolites in the brains of patients with Alzheimer-type dementia and depression, and suicides. Neuropharmacology. 1984;23:1561–1569. [PubMed]
37. Owen F, Chambers DR, Cooper SJ, et al. Serotonergic mechanisms in brains of suicide victims. Brain Res. 1986;362:185–188. [PubMed]
38. Cheetham SC, Crompton MR, Katona CLE, Horton RW. Brain 5-HT2 receptor binding sites in depressed suicide victims. Brain Res. 1988;443:272–280. [PubMed]
39. Lowther S, De Paermentier F, Crompton MR, Katona CLE, Horton RW. Brain 5-HT2 receptors in suicide victims: Violence of death, depression and effects of antidepressant treatment. Brain Res. 1994;642:281–289. [PubMed]
40. Arranz B, Eriksson A, Mellerup E, Plenge P, Marcusson J. Brain 5-HT1A, 5-HT1D, and 5-HT2 receptors in suicide victims. Biol Psychiatry. 1994;35:457–463. [PubMed]
41. Stockmeier CA, Dilley GE, Shapiro LA, Overholser JC, Thompson PA, Meltzer HY. Serotonin receptors in suicide victims with major depression. Neuropsychopharmacology. 1997;16:162–173. [PubMed]
42. Rosel P, Arranz B, San L, et al. Altered 5-HT2A binding sites and second messenger inositol trisphosphate (IP3) levels in hippocampus but not in frontal cortex from depressed suicide victims. Psychiat Res Neuroimag. 2000;99:173–181. [PubMed]
43. Pandey GN. Altered serotonin function in suicide. Evidence from platelet and neuroendocrine studies. Ann N Y Acad Sci. 1997;836:182–200. [PubMed]
44. Pandey GN, Dwivedi Y, Pandey SC, et al. Low phosphoinositide-specific phospholipase C activity and expression of phospholipase C beta1 protein in the prefrontal cortex of teenage suicide subjects. Am J Psychiatry. 1999;156:1895–1901. [PubMed]
45. Malone KM, Ellis SP, Currier D, John MJ. Platelet 5-HT2A receptor subresponsivity and lethality of attempted suicide in depressed in-patients. Int J Neuropsychopharmacol. 2007;10(3):335–43. [PubMed]
46. Beskow J, Gottfries CG, Roos BE, Winblad B. Determination of monoamine and monoamine metabolites in the human brain: Post mortem studies in a group of suicides and in a control group. Acta Psychiatr Scand. 1976;53:7–20. [PubMed]
47. Lloyd KG, Farley IJ, Deck JHN, Hornykiewicz O. Serotonin and 5-hydroxyindoleacetic acid in discrete areas of the brainstem of suicide victims and control patients. Adv Biochem Psychopharmacol. 1974;11:387–397. [PubMed]
48. Pare CMB, Yeung DPH, Price K, Stacey RS. 5-Hydroxytryptamine, noradrenaline, and dopamine in brainstem, hypothalamus, and caudate nucleus of controls and of patients committing suicide by coal-gas poisoning. Lancet. 1969;ii:133–135. [PubMed]
49. Bourne HR, Bunney WE, Jr, Colburn RW, Davis JM, Shaw DM, Coppen AJ. Noradrenaline, 5-hydroxytryptamine, and 5-hydroxyindoleacetic acid in hindbrains of suicidal patients. Lancet. 1968;ii:805–808. [PubMed]
50. Shaw DM, Camps FE, Eccleston EG. 5-Hydroxytryptamine in the hind-brain of depressive suicides. Br J Psychiatry. 1967;113:1407–1411. [PubMed]
51. Du L, Faludi G, Palkovits M, et al. Frequency of long allele in serotonin transporter gene is increased in depressed suicide victims. Biol Psychiatry. 1999;46:196–201. [PubMed]
52. Ono H, Shirakawa O, Nishiguchi N, et al. Serotonin 2A receptor gene polymorphism is not associated with completed suicide. J Psychiatr Res. 2001;35:173–176. [PubMed]
53. Crawford J, Sutherland GR, Goldney RD. No evidence for association of 5-HT2A receptor polymorphism with suicide. Am J Med Genet. 2000;96:879–880. [PubMed]
54. Bondy B, Kuznik J, Baghai T, et al. Lack of association of serotonin-2A receptor gene polymorphism (T102C) with suicidal ideation and suicide. Am J Med Genet. 2000;96:831–835. [PubMed]
55. Arias B, Gasto C, Catalan R, Gutierrez B, Pintor L, Fananas L. The 5-HT(2A) receptor gene 102T/C polymorphism is associated with suicidal behavior in depressed patients. Am J Med Genet. 2001;105:801–804. [PubMed]
56. Du L, Bakish D, Lapierre YD, Ravindran AV, Hrdina PD. Association of polymorphism of serotonin 2A receptor gene with suicidal ideation in major depressive disorder. Am J Med Genet. 2000;96:56–60. [PubMed]
57. Tan EC, Chong SA, Chan AO, Tan CH. No evidence for association of the T102C polymorphism in the serotonin type 2A receptor with suicidal behavior in schizophrenia. Am J Med Genet. 2002;114:321–322. [PubMed]
58. Ertugrul A, Kennedy JL, Masellis M, Basile VS, Jayathilake K, Meltzer HY. No association of the T102C polymorphism of the serotonin 2A receptor gene (HTR2A) with suicidality in schizophrenia. Schizophr Res. 2004;69:301–305. [PubMed]
59. Khait VD, Huang YY, Zalsman G, et al. Association of serotonin 5-HT2A receptor binding and the T102C polymorphism in depressed and healthy Caucasian subjects. Neuropsychopharmacology. 2005;30:166–172. [PubMed]
60. Correa H, De Marco L, Boson W, et al. Analysis of T102C 5HT2A polymorphism in Brazilian psychiatric inpatients: relationship with suicidal behavior. Cell Mol Neurobiol. 2002;22:813–817. [PubMed]
61. Zalsman G, Frisch A, Bromberg M, et al. Family-based association study of serotonin transporter promoter in suicidal adolescents: no association with suicidality but possible role in violence traits. Am J Med Genet. 2001;105:239–245. [PubMed]
62. Li D, Duan Y, He L. Association study of serotonin 2A receptor (5-HT2A) gene with schizophrenia and suicidal behavior using systematic meta-analysis. Biochem Biophys Res Commun. 2006;340:1006–1015. [PubMed]
63. Huang Y, Grailhe R, Arango V, Hen R, Mann JJ. Relationship of psychopathology to the human serotonin1B genotype and receptor binding kinetics in postmortem brain tissue. Neuropsychopharmacology. 1999;21:238–246. [PubMed]
64. Stefulj J, Buttner A, Skavic J, et al. Serotonin 1B (5HT-1B) receptor polymorphism (G861C) in suicide victims: association studies in German and Slavic population. Am J Med Genet B Neuropsychiatr Genet. 2004;127:48–50. [PubMed]
65. Nishiguchi N, Shirakawa O, Ono H, et al. No evidence of an association between 5HT1B receptor gene polymorphism and suicide victims in a Japanese population. Am J Med Genet. 2001;105:343–345. [PubMed]
66. Rujescu D, Giegling I, Sato T, Moller HJ. Lack of association between serotonin 5-HT1B receptor gene polymorphism and suicidal behavior. Am J Med Genet B Neuropsychiatr Genet. 2003;116:69–71. [PubMed]
67. Hong CJ, Pan GM, Tsai SJ. Association study of onset age, attempted suicide, aggressive behavior, and schizophrenia with a serotonin 1B receptor (A-161T) genetic polymorphism. Neuropsychobiology. 2004;49:1–4. [PubMed]
68. Tsai SJ, Hong CJ, Yu YW, Chen TJ, Wang YC, Lin WK. Association study of serotonin 1B receptor (A-161T) genetic polymorphism and suicidal behaviors and response to fluoxetine in major depressive disorder. Neuropsychobiology. 2004;50:235–238. [PubMed]
69. Bouwknecht JA, Hijzen TH, van der GJ, Maes RA, Hen R, Olivier B. Absence of 5-HT(1B) receptors is associated with impaired impulse control in male 5-HT(1B) knockout mice. Biol Psychiatry. 2001;49:557–568. [PubMed]
70. Lappalainen J, Long JC, Eggert M, et al. Linkage of antisocial alcoholism to the serotonin 5-HT1B receptor gene in 2 population. Arch Gen Psychiatry. 1998;55:989–994. [PubMed]
71. Soyka M, Preuss UW, Koller G, Zill P, Bondy B. Association of 5-HT1B receptor gene and antisocial behavior in alcoholism. J Neural Transm. 2004;111:101–109. [PubMed]
72. Lemonde S, Turecki G, Bakish D, et al. Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide. J Neurosci. 2003;23:8788–8799. [PubMed]
73. Huang YY, Battistuzzi C, Oquendo MA, et al. Human 5-HT1A receptor C(-1019)G polymorphism and psychopathology. Int J Neuropsychopharmacol. 2004;7:441–451. [PubMed]
74. Ohtani M, Shindo S, Yoshioka N. Polymorphisms of the tryptophan hydroxylase gene and serotonin 1A receptor gene in suicide victims among Japanese. Tohoku J Exp Med. 2004;202:123–133. [PubMed]
75. Nishiguchi N, Shirakawa O, Ono H, et al. Lack of an association between 5-HT1A receptor gene structural polymorphisms and suicide victims. Am J Med Genet. 2002;114:423–425. [PubMed]
76. Stefulj J, Buttner A, Kubat M, et al. 5HT-2C receptor polymorphism in suicide victims. Association studies in German and Slavic populations. Eur Arch Psychiatry Clin Neurosci. 2004;254:224–227. [PubMed]
77. Okamura K, Shirakawa O, Nishiguchi N, et al. Lack of an association between 5-HT receptor gene polymorphisms and suicide victims. Psychiatry Clin Neurosci. 2005;59:345–349. [PubMed]
78. Turecki G, Sequeira A, Gingras Y, et al. Suicide and serotonin: study of variation at seven serotonin receptor genes in suicide completers. Am J Med Genet B Neuropsychiatr Genet. 2003;118:36–40. [PubMed]
79. Giegling I, Hartmann AM, Moller HJ, Rujescu D. Anger- and aggression-related traits are associated with polymorphisms in the 5-HT-2A gene. J Affect Disord. 2006;96:75–81. [PubMed]
80. Serretti A, Mandelli L, Giegling I, et al. HTR2C and HTR1A gene variants in German and Italian suicide attempters and completers. Am J Med Genet B Neuropsychiatr Genet. 2007;144:291–299. [PubMed]
81. Underwood MD, Khaibulina AA, Ellis SP, et al. Morphometry of the dorsal raphe nucleus serotonergic neurons in suicide victims. Biol Psychiatry. 1999;46:473–483. [PubMed]
82. Boldrini M, Underwood MD, Mann JJ, Arango V. More tryptophan hydroxylase in the brainstem dorsal raphe nucleus in depressed suicides. Brain Res. 2005;1041:19–28. [PubMed]
83. Bonkale WL, Murdock S, Janosky JE, Austin MC. Normal levels of tryptophan hydroxylase immunoreactivity in the dorsal raphe of depressed suicide victims. J Neurochem. 2004;88:958–964. [PubMed]
84. Bonkale WL, Turecki G, Austin MC. Increased tryptophan hydroxylase immunoreactivity in the dorsal raphe nucleus of alcohol-dependent, depressed suicide subjects is restricted to the dorsal subnucleus. Synapse. 2006;60:81–85. [PMC free article] [PubMed]
85. Bach-Mizrachi H, Underwood MD, Kassir SA, et al. Neuronal tryptophan hydroxylase mRNA expression in the human dorsal and median raphe nuclei: major depression and suicide. Neuropsychopharmacology. 2006;31:814–824. [PubMed]
86. Ono H, Shirakawa O, Kitamura N, et al. Tryptophan hydroxylase immunoreactivity is altered by the genetic variation in postmortem brain samples of both suicide victims and controls. Mol Psychiatry. 2002;7:1127–1132. [PubMed]
87. Manuck SB, Flory JD, Ferrell RE, Dent KM, Mann JJ, Muldoon MF. Aggression and anger-related traits associated with a polymorphism of the tryptophan hydroxylase gene. Biol Psychiatry. 1999;45:603–614. [PubMed]
88. New AS, Gelernter J, Yovell Y, et al. Trytophan hydroxylase genotype is associated with impulsive-aggerssion measures: A preliminary study. Am J Med Genet. 1998;81:13–17. [PubMed]
89. Jönsson EG, Goldman D, Spurlock G, et al. Tryptophan hydroxylase and catechol-O-methyltransferase gene polymorphisms: Relationships to monoamine metabolite concentrations in CSF of healthy volunteers. Eur Arch Psychiatry Clin Neurosci. 1997;247:297–302. [PubMed]
90. Lalovic A, Turecki G. Meta-analysis of the association between tryptophan hydroxylase and suicidal behavior. Am J Med Genet. 2002;114:533–540. [PubMed]
91. Rujescu D, Giegling I, Sato T, Hartmann AM, Moller HJ. Genetic variations in tryptophan hydroxylase in suicidal behavior: analysis and meta-analysis. Biol Psychiatry. 2003;54:465–473. [PubMed]
92. Bellivier F, Chaste P, Malafosse A. Association between the TPH gene A218C polymorphism and suicidal behavior: a meta-analysis. Am J Med Genet. 2004;124B:87–91. [PubMed]
93. Li D, He L. Further clarification of the contribution of the tryptophan hydroxylase (TPH) gene to suicidal behavior using systematic allelic and genotypic meta-analyses. Hum Genet. 2006;119:233–240. [PubMed]
94. Nielsen DA, Virkkunen M, Lappalainen J, et al. A tryptophan hydroxylase gene marker for suicidality and alcoholism. Arch Gen Psychiatry. 1998;55:593–602. [PubMed]
95. Roy A, Rylander G, Forslund K, et al. Excess tryptophan hydroxylase 17 779C allele in surviving cotwins of monozygotic twin suicide victims. Neuropsychobiology. 2001;43:233–236. [PubMed]
96. Mann JJ, Malone KM, Nielsen DA, Goldman D, Erdos J, Gelernter J. Possible association of a polymorphism of the tryptophan hydroxylase gene with suicidal behavior in depressed patients. Am J Psychiatry. 1997;154:1451–1453. [PubMed]
97. Rujescu D, Giegling I, Bondy B, Gietl A, Zill P, Moller HJ. Association of anger-related traits with SNPs in the TPH gene. Mol Psychiatry. 2002;7:1023–1029. [PubMed]
98. Hennig J, Reuter M, Netter P, Burk C, Landt O. Two types of aggression are differentially related to serotonergic activity and the A779C TPH polymorphism. Behav Neurosci. 2005;119:16–25. [PubMed]
99. Nolan KA, Volavka J, Lachman HM, Saito T. An association between a polymorphism of the tryptophan hydroxylase gene and aggression in schizophrenia and schizoaffective disorder. Psychiatr Genet. 2000;10:109–115. [PubMed]
100. Staner L, Uyanik G, Correa H, et al. A dimensional impulsive-aggressive phenotype is associated with the A218C polymorphism of the tryptophan hydroxylase gene: a pilot study in well-characterized impulsive inpatients. Am J Med Genet. 2002;114:553–557. [PubMed]
101. Zill P, Buttner A, Eisenmenger W, Moller HJ, Bondy B, Ackenheil M. Single nucleotide polymorphism and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene in suicide victims. Biol Psychiatry. 2004;56:581–586. [PubMed]
102. Zhou Z, Roy A, Lipsky R, et al. Haplotype-based linkage of tryptophan hydroxylase 2 to suicide attempt, major depression, and cerebrospinal fluid 5-hydroxyindoleacetic acid in 4 populations. Arch Gen Psychiatry. 2005;62:1109–1118. [PubMed]
103. Lopez de Lara C, Brezo J, Rouleau G, et al. Effect of tryptophan hydroxylase-2 gene variants on suicide risk in major depression. Biol Psychiatry. 2007;62:72–80. [PubMed]
104. De Luca V, Hlousek D, Likhodi O, Van Tol HH, Kennedy JL, Wong AH. The interaction between TPH2 promoter haplotypes and clinical-demographic risk factors in suicide victims with major psychoses. Genes Brain Behav. 2006;5:107–110. [PubMed]
105. De Luca V, Voineskos D, Wong GW, et al. Promoter polymorphism of second tryptophan hydroxylase isoform (TPH2) in schizophrenia and suicidality. Psychiatry Res. 2005;134:195–198. [PubMed]
106. Mann JJ, Currier D, Murphy L, et al. No association between a TPH2 promoter polymorphism and mood disorders or monoamine turnover. J Affect Disord. 2008;106:117–21. [PMC free article] [PubMed]
107. Lim JE, Pinsonneault J, Sadee W, Saffen D. Tryptophan hydroxylase 2 (TPH2) haplotypes predict levels of TPH2 mRNA expression in human pons. Mol Psychiatry. 2007;12:491–501. [PubMed]
108. Canli T, Congdon E, Gutknecht L, Constable RT, Lesch KP. Amygdala responsiveness is modulated by tryptophan hydroxylase-2 gene variation. J Neural Transm. 2005;112:1479–1485. [PubMed]
109. Reuter M, Ott U, Vaitl D, Hennig J. Impaired executive control is associated with a variation in the promoter region of the tryptophan hydroxylase 2 gene. J Cogn Neurosci. 2007;19:401–408. [PubMed]
110. Sabol SZ, Hu S, Hamer D. A functional polymorphism in the monoamine oxidase A gene promoter. Hum Genet. 1998;103:273–279. [PubMed]
111. Manuck SB, Flory JD, Ferrell RE, Mann JJ, Muldoon MF. A regulatory polymorphism of the monoamine oxidase-A gene may be associated with variability in aggression, impulsivity, and central nervous system serotonergic responsivity. Psychiatry Res. 2000;95:9–23. [PubMed]
112. Jonsson EG, Norton N, Gustavsson JP, Oreland L, Owen MJ, Sedvall GC. A promoter polymorphism in the monoamine oxidase A gene and its relationships to monoamine metabolite concentrations in CSF of healthy volunteers. J Psychiatr Res. 2000;34:239–244. [PubMed]
113. Williams RB, Marchuk DA, Gadde KM, et al. Serotonin-related gene polymorphisms and central nervous system serotonin function. Neuropsychopharmacology. 2003;28:533–541. [PubMed]
114. Meyer-Lindenberg A, Buckholtz JW, Kolachana B, et al. Neural mechanisms of genetic risk for impulsivity and violence in humans. Proc Natl Acad Sci U S A. 2006;103:6269–6274. [PubMed]
115. Huang YY, Cate SP, Battistuzzi C, Oquendo MA, Brent D, Mann JJ. An association between a functional polymorphism in the monoamine oxidase a gene promoter, impulsive traits and early abuse experiences. Neuropsychopharmacology. 2004;29:1498–1505. [PubMed]
116. Kunugi H, Ishida S, Kato T, et al. A functional polymorphism in the promoter region of monoamine oxidase-A gene and mood disorders. Mol Psychiatry. 1999;4:393–395. [PubMed]
117. Ono H, Shirakawa O, Nishiguchi N, et al. No evidence of an association between a functional monoamine oxidase a gene polymorphism and completed suicides. Am J Med Genet. 2002;114:340–342. [PubMed]
118. Gerra G, Garofano L, Bosari S, et al. Analysis of monoamine oxidase A (MAO-A) promoter polymorphism in male heroin-dependent subjects: behavioural and personality correlates. J Neural Transm. 2004;111:611–621. [PubMed]
119. Ho LW, Furlong RA, Rubinsztein JS, Walsh C, Paykel ES, Rubinsztein DC. Genetic associations with clinical characteristics in bipolar affective disorder and recurrent unipolar depressive disorder. Am J Med Genet. 2000;96:36–42. [PubMed]
120. Courtet P, Jollant F, Castelnau D, Buresi C, Malafosse A. Suicidal behavior: relationship between phenotype and serotonergic genotype. Am J Med Genet C Semin Med Genet. 2005;133:25–33. [PubMed]
121. Brunner HG, Nelen M, Breakefield XO, Ropers HH, van Oost BA. Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. Sci. 1993;262:578–580. [PubMed]
122. Cases O, Seif I, Grimsby J, et al. Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA. Sci. 1995;268:1763–1766. [PMC free article] [PubMed]
123. Jacob CP, Muller J, Schmidt M, et al. Cluster B personality disorders are associated with allelic variation of monoamine oxidase A activity. Neuropsychopharmacology. 2005;30:1711–1718. [PubMed]
124. Passamonti L, Fera F, Magariello A, et al. Monoamine oxidase-a genetic variations influence brain activity associated with inhibitory control: new insight into the neural correlates of impulsivity. Biol Psychiatry. 2006;59:334–340. [PubMed]
125. Fan J, Fossella J, Sommer T, Wu Y, Posner MI. Mapping the genetic variation of executive attention onto brain activity. Proc Natl Acad Sci U S A. 2003;100:7406–7411. [PubMed]
126. Uher R, McGuffin P. The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis. Mol Psychiatry. In Press. [PubMed]
127. Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Sci. 2003;301:386–389. [PubMed]
128. Gibb BE, McGeary JE, Beevers CG, Miller IW. Serotonin transporter (5-HTTLPR) genotype, childhood abuse, and suicide attempts in adult psychiatric inpatients. Suicide Life Threat Behav. 2006;36:687–693. [PubMed]
129. Roy A, Hu XZ, Janal MN, Goldman D. Interaction between childhood trauma and serotonin transporter gene variation in suicide. Neuropsychopharmacology. 2007;32:2046–2052. [PubMed]
130. Reif A, Rosler M, Freitag CM, et al. Nature and nurture predispose to violent behavior: serotonergic genes and adverse childhood environment. Neuropsychopharmacology. 2007;32:2375–2383. [PubMed]
131. Caspi A, McClay J, Moffitt TE, et al. Role of genotype in the cycle of violence in maltreated children. Sci. 2002;297:851–854. [PubMed]
132. Foley DL, Eaves LJ, Wormley B, et al. Childhood adversity, monoamine oxidase a genotype, and risk for conduct disorder. Arch Gen Psychiatry. 2004;61:738–744. [PubMed]
133. Nilsson KW, Sjoberg RL, Damberg M, et al. Role of monoamine oxidase A genotype and psychosocial factors in male adolescent criminal activity. Biol Psychiatry. 2006;59:121–127. [PubMed]
134. Ducci F, Enoch MA, Hodgkinson C, et al. Interaction between a functional MAOA locus and childhood sexual abuse predicts alcoholism and antisocial personality disorder in adult women. Mol Psychiatry. In Press. [PubMed]
135. Haberstick BC, Lessem JM, Hopfer CJ, et al. Monoamine oxidase A (MAOA) and antisocial behaviors in the presence of childhood and adolescent maltreatment. Am J Med Genet B Neuropsychiatr Genet. 2005;135:59–64. [PubMed]
136. Huizinga D, Haberstick BC, Smolen A, et al. Childhood maltreatment, subsequent antisocial behavior, and the role of monoamine oxidase A genotype. Biol Psychiatry. 2006;60:677–683. [PubMed]
137. Arborelius L, Hawks BW, Owens MJ, Plotsky PM, Nemeroff CB. Increased responsiveness of presumed 5-HT cells to citalopram in adult rats subjected to prolonged maternal separation relative to brief separation. Psychopharmacology (Berl) 2004;176:248–255. [PubMed]
138. Kaufman J, Birmaher B, Perel J, et al. Serotonergic functioning in depressed abused children: clinical and familial correlates. Biol Psychiatry. 1998;44:973–981. [PubMed]
139. Pine DS, Coplan JD, Wasserman GA, et al. Neuroendocrine response to fenfluramine challenge in boys: Associations with aggressive behavior and adverse rearing. Arch Gen Psychiatry. 1997;54:839–846. [PubMed]
140. Rinne T, Westenberg HG, Den Boer JA, van den BW. Serotonergic blunting to meta-chlorophenylpiperazine (m-CPP) highly correlates with sustained childhood abuse in impulsive and autoaggressive female borderline patients. Biol Psychiatry. 2000;47:548–556. [PubMed]
141. Bennett AJ, Lesch KP, Heils A, et al. Early experience and serotonin transporter gene variation interact to influence primate CNS function. Mol Psychiatry. 2002;7:118–122. [PubMed]
142. Firk C, Markus CR. Review: Serotonin by stress interaction: a susceptibility factor for the development of depression? J Psychopharmacol. 2007;21:538–544. [PubMed]
143. O'Hara R, Schroder CM, Mahadevan R, et al. Serotonin transporter polymorphism, memory and hippocampal volume in the elderly: association and interaction with cortisol. Mol Psychiatry. 2007;12:544–555. [PMC free article] [PubMed]
144. Wand GS, McCaul M, Yang X, et al. The mu-opioid receptor gene polymorphism (A118G) alters HPA axis activation induced by opioid receptor blockade. Neuropsychopharmacology. 2002;26:106–114. [PubMed]
145. Smith GS, Lotrich FE, Malhotra AK, et al. Effects of serotonin transporter promoter polymorphisms on serotonin function. Neuropsychopharmacology. 2004;29:2226–2234. [PubMed]
146. Barr CS, Newman TK, Shannon C, et al. Rearing condition and rh5-HTTLPR interact to influence limbic-hypothalamic-pituitary-adrenal axis response to stress in infant macaques. Biol Psychiatry. 2004;55:733–738. [PubMed]
147. Arango V, Underwood MD, Mann JJ. Fewer pigmented locus coeruleus neurons in suicide victims: Preliminary results. Biol Psychiatry. 1996;39:112–120. [PubMed]
148. Ordway GA, Smith KS, Haycock JW. Elevated tyrosine hydroxylase in the locus coeruleus of suicide victims. J Neurochem. 1994;62:680–685. [PubMed]
149. Pandey GN, Dwivedi Y. Noradrenergic function in suicide. Arch Suicide Res. 2007;11:235–246. [PubMed]
150. Fernandez-Pastor B, Mateo Y, Gomez-Urquijo S, Javier MJ. Characterization of noradrenaline release in the locus coeruleus of freely moving awake rats by in vivo microdialysis. Psychopharmacology (Berl) 2005;180:570–579. [PubMed]
151. Sequeira A, Mamdani F, Lalovic A, et al. Alpha 2A adrenergic receptor gene and suicide. Psychiatry Res. 2004;125:87–93. [PubMed]
152. Martin-Guerrero I, Callado LF, Saitua K, Rivero G, Garcia-Orad A, Meana JJ. The N251K functional polymorphism in the alpha(2A)-adrenoceptor gene is not associated with depression: a study in suicide completers. Psychopharmacology (Berl) 2006;184:82–86. [PubMed]
153. Persson ML, Wasserman D, Geijer T, Jönsson EG, Terenius L. Tyrosine hydroxylase allelic distribution in suicide attempters. Psychiatry Res. 1997;72:73–80. [PubMed]
154. DeLuca V, Strauss J, Kennedy JL. Power based association analysis (PBAT) of serotonergic and noradrenergic polymorphisms in bipolar patients with suicidal behaviour. Prog Neuropsychopharmacol Biol Psychiatry. 2007 [PubMed]
155. Hattori H, Shirakawa O, Nishiguchi N, Nushida H, Ueno Y, Maeda K. No evidence of an association between tyrosine hydroxylase gene polymorphisms and suicide victims. Kobe J Med Sci. 2006;52:195–200. [PubMed]
156. Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshilboum RM. Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics. 1996;6:243–250. [PubMed]
157. Chen J, Lipska BK, Halim N, et al. Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet. 2004;75:807–821. [PubMed]
158. Kia-Keating BM, Glatt SJ, Tsuang MT. Meta-analyses suggest association between COMT, but not HTR1B, alleles, and suicidal behavior. Am J Med Genet B Neuropsychiatr Genet. 2007 [PubMed]
159. Lachman HM, Nolan KA, Mohr P, Saito T, Volavka J. Association between catechol O-methyltransferase genotype and violence in schizophrenia and schizoaffective disorders. Am J Psychiatry. 1998;155:835–837. [PubMed]
160. Kotler M, Barak P, Cohen H, et al. Homicidal behavior in schizophrenia associated with a genetic polymorphism determining low catechol O-methyltransferase (COMT) activity. Am J Med Genet. 1999;88:628–633. [PubMed]
161. Strous RD, Bark N, Parsia SS, Volavka J, Lachman HM. Analysis of a functional catechol-O-methyltransferase gene polymorphism in schizophrenia: evidence for association with aggressive and antisocial behavior. Psychiatry Res. 1997;69:71–77. [PubMed]
162. Nolan KA, Volavka J, Czobor P, et al. Suicidal behavior in patients with schizophrenia is related to COMT polymorphism. Psychiatr Genet. 2000;10:117–124. [PubMed]
163. Rujescu D, Giegling I, Gietl A, Hartmann AM, Moller HJ. A functional single nucleotide polymorphism (V158M) in the COMT gene is associated with aggressive personality traits. Biol Psychiatry. 2003;54:34–39. [PubMed]
164. Zammit S, Jones G, Jones SJ, et al. Polymorphisms in the MAOA, MAOB, and COMT genes and aggressive behavior in schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 2004;128:19–20. [PubMed]
165. Wei J, Hemmings GP. Lack of evidence for association between the COMT locus and schizophrenia. Psychiatr Genet. 1999;9:183–186. [PubMed]
166. Liou YJ, Tsai SJ, Hong CJ, Wang YC, Lai IC. Association analysis of a functional catechol-o-methyltransferase gene polymorphism in schizophrenic patients in Taiwan. Neuropsychobiology. 2001;43:11–14. [PubMed]
167. Russ MJ, Lachman HM, Kashdan T, Saito T, Bajmakovic-Kacila S. Analysis of catechol-O-methyltransferase and 5-hydroxytryptamine transporter polymorphisms in patients at risk for suicide. Psychiatry Res. 2000;93:73–78. [PubMed]
168. Jones G, Zammit S, Norton N, et al. Aggressive behaviour in patients with schizophrenia is associated with catechol-O-methyltransferase genotype. Br J Psychiatry. 2001;179:351–355. [PubMed]
169. Hallikainen T, Lachman H, Saito T, et al. Lack of association between the functional variant of the catechol-o-methyltransferase (COMT) gene and early-onset alcoholism associated with severe antisocial behavior. Am J Med Genet. 2000;96:348–352. [PubMed]
170. Baud P, Courtet P, Perroud N, Jollant F, Buresi C, Malafosse A. Catechol-O-methyltransferase polymorphism (COMT) in suicide attempters: A possible gender effect on anger traits. Am J Med Genet B Neuropsychiatr Genet. 2007 [PubMed]
171. Ono H, Shirakawa O, Nushida H, Ueno Y, Maeda K. Association between catechol-O-methyltransferase functional polymorphism and male suicide completers. Neuropsychopharmacology. 2004;29:1374–1377. [PubMed]
172. Heim C, Nemeroff CB. The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biol Psychiatry. 2001;49:1023–1039. [PubMed]
173. Dailly E, Chenu F, Renard CE, Bourin M. Dopamine, depression and antidepressants. Fundam Clin Pharmacol. 2004;18:601–607. [PubMed]
174. Bowden C, Cheetham SC, Lowther S, Katona CL, Crompton MR, Horton RW. Reduced dopamine turnover in the basal ganglia of depressed suicides. Brain Res. 1997;769:135–140. [PubMed]
175. Bowden C, Theodorou AE, Cheetham SC, et al. Dopamine D1 and D2 receptor binding sites in brain samples from depressed suicides and controls. Brain Res. 1997;752:227–233. [PubMed]
176. Roy A, Ågren H, Pickar D, et al. Reduced CSF concentrations of homovanillic acid and homovanillic acid to 5-Hydroxyindoleacetic acid ratios in depressed patients: Relationship to suicidal behavior and dexamethasone nonsuppression. Am J Psychiatry. 1986;143:1539–1545. [PubMed]
177. Roy A, Karoum F, Pollack S. Marked reduction in indexes of dopamine metabolism among patients with depression who attempt suicide. Arch Gen Psychiatry. 1992;49:447–450. [PubMed]
178. Engstrom G, Alling C, Blennow K, Regnell G, Traskman-Bendz L. Reduced cerebrospinal HVA concentrations and HVA/5-HIAA ratios in suicide attempters. Monoamine metabolites in 120 suicide attempters and 47 controls. Eur Neuropsychopharmacol. 1999;9:399–405. [PubMed]
179. Nordström P, Samuelsson M, Åsberg M, et al. CSF 5-HIAA predicts suicide risk after attempted suicide. Suicide Life Threat Behav. 1994;24:1–9. [PubMed]
180. Placidi GP, Oquendo MA, Malone KM, Huang YY, Ellis SP, Mann JJ. Aggressivity, suicide attempts, and depression: relationship to cerebrospinal fluid monoamine metabolite levels. Biol Psychiatry. 2001;50:783–791. [PubMed]
181. Soderstrom H, Blennov K, Manhem A, Forsman A. CSF studies in violent offenders. 1. 5-HIAA as a negative and HVA as a positive predictor of psychopathy. J Neural Transm. 2001;108:869–878. [PubMed]
182. Soderstrom H, Blennow K, Sjodin AK, Forsman A. New evidence for an association between the CSF HVA:5-HIAA ratio and psychopathic traits. J Neurol Neurosurg Psychiatry. 2003;74:918–921. [PMC free article] [PubMed]
183. Johann M, Putzhammer A, Eichhammer P, Wodarz N. Association of the -141C Del variant of the dopamine D2 receptor (DRD2) with positive family history and suicidality in German alcoholics. Am J Med Genet B Neuropsychiatr Genet. 2005;132:46–49. [PubMed]
184. Finckh U, Rommelspacher H, Kuhn S, et al. Influence of the dopamine D2 receptor (DRD2) genotype on neuroadaptive effects of alcohol and the clinical outcome of alcoholism. Pharmacogenetics. 1997;7:271–281. [PubMed]
185. Persson ML, Geijer T, Wasserman D, et al. Lack of association between suicide attempt and a polymorphism at the dopamine receptor D4 locus. Psychiatr Genet. 1999;9:97–100. [PubMed]
186. Zalsman G, Frisch A, Lev-Ran S, et al. DRD4 exon III polymorphism and response to risperidone in Israeli adolescents with schizophrenia: a pilot pharmacogenetic study. Eur Neuropsychopharmacol. 2003;13:183–185. [PubMed]
187. Coryell W, Schlesser M. The dexamethasone suppression test and suicide prediction. Am J Psychiatry. 2001;158:748–753. [PubMed]
188. Mann JJ, Currier D, Stanley B, Oquendo MA, Amsel LV, Ellis SP. Can biological tests assist prediction of suicide in mood disorders? Int J Neuropsychopharmacol. 2006;9:465–474. [PubMed]
189. Szigethy E, Conwell Y, Forbes NT, Cox C, Caine ED. Adrenal weight and morphology in victims of completed suicide. Biol Psychiatry. 1994;36:374–380. [PubMed]
190. Dorovini-Zis K, Zis AP. Increased adrenal weight in victims of violent suicide. Am J Psychiatry. 1987;144:1214–1215. [PubMed]
191. Dumser T, Barocka A, Schubert E. Weight of adrenal glands may be increased in persons who commit suicide. Am J Forensic Med Pathol. 1998;19:72–76. [PubMed]
192. Nemeroff CB, Krishnan KR, Reed D, Leder R, Beam C, Dunnick NR. Adrenal gland enlargement in major depression. A computed tomographic study. Arch Gen Psychiatry. 1992;49:384–387. [PubMed]
193. Nemeroff CB, Owens MJ, Bissette G, Andorn AC, Stanley M. Reduced corticotropin releasing factor binding sites in the frontal cortex of suicide victims. Arch Gen Psychiatry. 1988;45:577–579. [PubMed]
194. Secunda SK, Cross CK, Koslow S, et al. Biochemistry and suicidal behavior in depressed patients. Biol Psychiatry. 1986;21:756–767. [PubMed]
195. Brown RP, Mason B, Stoll P, et al. Adrenocortical function and suicidal behavior in depressive disorders. Psychiatry Res. 1986;17:317–323. [PubMed]
196. Modestin J, Ruef C. Dexamethasone suppression test (DST) in relation to depressive somatic and suicidal manifestations. Acta Psychiatr Scand. 1987;75:491–494. [PubMed]
197. Roy A, Pickar D, Linnoila M, Doran AR, Paul SM. Cerebrospinal fluid monoamine and monoamine metabolite levels and the dexamethasone suppression test in depression. Relationship to life events. Arch Gen Psychiatry. 1986;43:356–360. [PubMed]
198. Roy A. Hypothalamic-pituitary-adrenal axis function and suicidal behavior in depression. Biol Psychiatry. 1992;32:812–816. [PubMed]
199. Norman WH, Brown WA, Miller IW, Keitner GI, Overholser JC. The dexamethasone suppression test and completed suicide. Acta Psychiatr Scand. 1990;81:120–125. [PubMed]
200. Black DW, Monahan PO, Winokur G. The relationship between DST results and suicidal behavior. Ann Clin Psychiatry. 2002;14:83–88. [PubMed]
201. Targum SD, Rosen L, Capodanno AE. The dexamethasone suppression test in suicidal patients with unipolar depression. Am J Psychiatry. 1983;140:877–879. [PubMed]
202. Mathew SJ, Coplan JD, Goetz RR, et al. Differentiating depressed adolescent 24 h cortisol secretion in light of their adult clinical outcome. Neuropsychopharmacology. 2003;28:1336–1343. [PubMed]
203. Cleare AJ, Murray RM, O'Keane V. Reduced prolactin and cortisol responses to d-fenfluramine in depressed compared to healthy matched control subjects. Neuropsychopharmacology. 1996;14:349–354. [PubMed]
204. Duval F, Mokrani MC, Correa H, et al. Lack of effect of HPA axis hyperactivity on hormonal responses to d- fenfluramine in major depressed patients: implications for pathogenesis of suicidal behaviour. Psychoneuroendocrinology. 2001;26:521–537. [PubMed]
205. Malone KM, Corbitt EM, Li S, Mann JJ. Prolactin response to fenfluramine and suicide attempt lethality in major depression. Br J Psychiatry. 1996;168:324–329. [PubMed]
206. Brunner J, Stalla GK, Stalla J, et al. Decreased corticotropin-releasing hormone (CRH) concentrations in the cerebrospinal fluid of eucortisolemic suicide attempters. J Psychiatr Res. 2001;35:1–9. [PubMed]
207. Träskman-Bendz L, Ekman R, Regnell G, Öhman R. HPA-related CSF neuropeptides in suicide attempters. Eur Neuropsychopharmacol. 1992;2:99–106. [PubMed]
208. Wust S, Van Rossum EF, Federenko IS, Koper JW, Kumsta R, Hellhammer DH. Common polymorphisms in the glucocorticoid receptor gene are associated with adrenocortical responses to psychosocial stress. J Clin Endocrinol Metab. 2004;89:565–573. [PubMed]
209. Wasserman D, Sokolowski M, Rozanov V, Wasserman J. The CRHR1 gene: a marker for suicidality in depressed males exposed to low stress. Genes Brain Behav. 2007 [PubMed]
210. Hishimoto A, Shirakawa O, Nishiguchi N, et al. Association between a functional polymorphism in the renin-angiotensin system and completed suicide. J Neural Transm. 2006;113:1915–1920. [PubMed]
211. Liu D, Diorio J, Tannenbaum B, et al. Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Sci. 1997;277:1659–1662. [PubMed]
212. Meaney MJ, Diorio J, Francis D, et al. Early environmental regulation of forebrain glucocorticoid receptor gene expression: implications for adrenocortical responses to stress. Dev Neurosci. 1996;18:49–72. [PubMed]
213. Plotsky PM, Meaney MJ. Early, postnatal experience alters hypothalamic corticotropin-releasing factor (CRF) mRNA, median eminence CRF content and stress-induced release in adult rats. Brain Res Mol Brain Res. 1993;18:195–200. [PubMed]
214. Avishai-Eliner S, Eghbal-Ahmadi M, Tabachnik E, Brunson KL, Baram TZ. Down-regulation of hypothalamic corticotropin-releasing hormone messenger ribonucleic acid (mRNA) precedes early-life experience-induced changes in hippocampal glucocorticoid receptor mRNA. Endocrinology. 2001;142:89–97. [PMC free article] [PubMed]
215. Breier A. A.E. Bennett award paper. Experimental approaches to human stress research: assessment of neurobiological mechanisms of stress in volunteers and psychiatric patients. Biol Psychiatry. 1989;26:438–462. [PubMed]
216. Stein MB, Yehuda R, Koverola C, Hanna C. Enhanced dexamethasone suppression of plasma cortisol in adult women traumatized by childhood sexual abuse. Biol Psychiatry. 1997;42:680–686. [PubMed]
217. Heim C, Newport DJ, Bonsall R, Miller AH, Nemeroff CB. Altered pituitary-adrenal axis responses to provocative challenge tests in adult survivors of childhood abuse. Am J Psychiatry. 2001;158:575–581. [PubMed]
218. Heim C, Newport DJ, Heit S, et al. Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood. J Am Med Assoc. 2000;284:592–597. [PubMed]
219. Ressler KJ, Binder EB, Bradley RG, Tang Y, Liu W, Gillespie CF, Heim CM, Schwartz A, Nemeroff CB, Cubells JF. CRHR1 Haplotypes Moderate Effects of Early Life Stress (ELS) on Adult Depression. Soc of Biological Psy San Diego. 2007 Ref Type: Abstract.
220. Blomeyer D, Treutlein J, Esser G, Schmidt MH, Schumann G, Laucht M. Interaction between CRHR1 Gene and Stressful Life Events Predicts Adolescent Heavy Alcohol Use. Biol Psychiatry. 2008;63:146–151. [PubMed]