Suicidal behavior is a complex and multi-factorial phenomenon for which epidemiological genetics suggests a genetic basis that may be specific and independent from those implicated in the vulnerability to the psychiatric disorders associated with SB. Recently, new molecular biology tools have been designed to identify predisposition factors to complex disorders. One of the main goals of current studies is to specify the suicidal phenotype, as well as the intermediate phenotypes associated with these genes.
Suicide persists as a major public health problem in all industrialized countries. More than 90% of people who commit suicide suffered from a psychiatric disorder, mostly a mood disorder (Mann, 2003). Nevertheless, even in psychiatric groups with the highest risk, most individuals never attempt suicide. It has been suggested that stress factors may trigger a suicidal act only in vulnerable individuals (Mann et al., 1999). Clinical vulnerability factors include impulsive aggression, pessimism and a previous history of suicide attempt (Oquendo et al., 2004). Despite the existence of comprehensive models of suicidal behavior (SB), national prevention strategies have yielded variable results and psychiatric assessment is usually insufficient to predict suicide on the basis of risk factors (Work Group on Suicidal Behaviors, 2003). Progress in the field of genomics should improve our understanding of the complex mechanisms involved in the development of SB. Psychiatrists could also benefit from genetic tools to characterize and define suicidal phenotypes (Merikangas and Risch, 2003).
A Genetic Contribution to Suicide?
Results of family studies indicate that SB aggregates within families (for review, see Brent and Mann, 2005). Moreover, these studies support the view of a shared familial transmission for both suicide attempt and completion. However, the existence of a familial transmission does not mean that suicidal behavior is under a genetic influence. Thus, the examination of concordance rates for SB in monozygotic (MZ) and dizygotic (DZ) twins provides arguments for the existence of genetic factors. In a review of all the published twin case reports for suicide, Roy and Segal (2001) reported an increased concordance for suicide in MZ versus DZ twins (18% versus 0.7%). Furthermore, this difference in concordance rates does not seem to be due to greater bereavement reactions in MZ twins (Segal and Roy, 2001), and the higher concordance rate for suicide attempts in the surviving MZ twin suggested that the clinical phenotype for concordance included both completed suicide and suicide attempts (Roy et al., 1995). Lastly, the strongest evidence for the presence of genetic factors comes from Danish adoption studies. Indeed, Schulsinger et al. (1979) reported a sixfold higher rate of suicide in the biological relatives of adoptees who committed suicide and the absence of suicide among the adoptive relatives of the person who committed suicide versus control adoptees.
Overall, these studies provide evidence for a genetic vulnerability to SB that is shared by people who either attempt or complete suicide.
A Specific Genetic Vulnerability?
Does the genetic vulnerability to suicidal behavior simply reflect the genetic vulnerability to psychiatric disorders related to SB? In the Old Order Amish study, while over 90% of the suicide victims had a mood disorder, some pedigrees were both loaded for mood disorder and suicide, whereas others were equally laden for mood disorder but not for suicide (Egeland and Sussex, 1985). This supports the notion that the familial liability for SB could be independent or additive from the genetic vulnerability to psychiatric disorders. Using sophisticated methodologies, several recent studies showed that the familial transmission of SB cannot be explained by the transmission of psychiatric disorder (Brent and Mann, 2005). Moreover, the familial transmission of suicidal ideation is related to the transmission of psychiatric disorder, whereas the familial transmission of SB may be mediated by the transmission of personality traits like impulsive aggression (Brent et al., 2003, 1996). Interestingly, these recent data tend to confirm the initial assumption by Kety (1986), who suggested that genetic predisposition to SB results from an inability to control impulsive behavior, which can be expressed in the presence or absence of psychiatric disorders.
Studies also emphasize the role for unshared environment and, to a lesser extent, shared environment in the etiology of SB. Adverse childhood experiences are particular life events that influence the vulnerability to SB. Sexual abuse in parent and child seems to increase the risk for transmission of SB through several possible mechanisms, suggesting complex interactions between genes, environment and personality factors (Brent and Mann, 2005).
In conclusion, the vulnerability to SB may involve interactions between genetic factors, acting via the transmission of personality traits like impulsive aggression and environmental factors. At the clinical level, a psychiatric patient carrying a familial/genetic vulnerability to SB should be considered at high risk for suicidal acts. Keeping the elements of this vulnerability in mind may help clinicians to accurately assess their patients.
'Gene Hunting': Serotonin-Related Genes
Suicidal behavior, like other psychiatric disorders, is probably a complex hereditary disorder determined by the action of several genes interacting with environmental factors. Thus, molecular biology studies have been performed since the mid-90s with the aim of identifying the genes involved in susceptibility to SB (Table).
At the neurobiological level, it has been hypothesized that the serotonergic input in the orbitofrontal cortex modulates the risk of SB (Mann, 2003). Given that the serotonergic activity is stable over time and largely under genetic control, it is assumed that the genetic factors conferring a vulnerability to SB act at this level (Higley et al., 1996). There is growing evidence from candidate gene association studies that serotonin-related genes influence the vulnerability to SB (for review, see Courtet et al., 2005). Data concerning the two most studied genes in SB are discussed below.
Tryptophan hydroxylase (TPH), an enzyme involved in the first and limiting step of the synthesis of serotonin, is encoded by two genes: TPH1, the most studied candidate gene, and TPH2, which was identified more recently (Walther et al., 2003). Although no functional marker has been identified in TPH1, allele A of intron 7 has been found to be associated with low levels of 5-hydroxyindole acetic acid (5-HIAA) in the cerebrospinal fluid (CSF) and with a blunted prolactin response to fenfluramine, two indicators of the serotonergic dysfunction (Jonsson et al., 1997; Manuck et al., 1999).
My group reported an association between TPH1 and SB independent of psychiatric diagnoses (Abbar et al., 2001). Moreover, the implication of TPH1 in vulnerability to SB has been found in different psychiatric populations: patients with depression, bipolar disorder, schizophrenia and alcoholic violent offenders (Courtet et al., 2005). Two recent meta-analyses have concluded that there is an association between TPH1 and a history of suicide attempts in whites (Bellivier et al., 2004; Rujescu et al., 2003). Two other studies reported an association between TPH1 and completed suicides (Roy et al., 2001; Turecki et al., 2001). Interestingly, as observed previously with biochemical serotonergic markers, the association is stronger in violent SB (Abbar et al., 2001; Turecki et al., 2001).
As stated before, Mann et al. (1999) proposed that the vulnerability to SB depends on personality traits like impulsive aggression. This model is convincing given its coherence with biological studies that suggest the existence of a psychobiological trait linking serotonergic dysfunction to traits related to failure to control impulsions. Impulsive aggressive dimensions may be considered intermediate phenotypes, in other words, intermediate between suicidal behavior and genetic factors (Leboyer et al., 1998). Rujescu et al. (2002) and Manuck et al. (1999) reported an association between TPH1 and anger-related traits.
The study of TPH1 has provided numerous concordant results suggesting that the intron 7 A218 allele is associated with vulnerability to SB, independently from psychiatric diagnoses, via a serotonergic dysfunction and anger-related traits.
Postmortem examination of suicide victims showed decreased binding of the serotonin transporter in the ventral prefrontal cortex independently of depression (Mann et al., 2000). The serotonin transporter plays a major role in the regulation of the synaptic concentration of serotonin. A functional polymorphism has been identified in the promoter region of this gene (5-HTTLPR), and in vitro studies have shown that the S allele is associated with a lower expression of the gene and a decrease in serotonin uptake (Lesch et al., 1996). Two recent meta-analyses concluded that 5-HTTLPR is involved in the susceptibility to SB (Anguelova et al., 2003; Lin and Tsai, 2004). For suicide attempts, the S allele was significantly more frequent in suicidal patients than in patients with the same psychiatric diagnosis but with no history of suicide attempts (Lin and Tsai, 2004).
However, questions have been raised about the associated suicidal phenotype, as this polymorphism seems to be preferentially related to repeated and violent suicide attempts. First, as suggested by Forman et al. (2004), multiple suicide attempters "should be considered as a unique subgroup of suicide attempters." Moreover, serotonergic dysfunction has been considered a predictive factor of further SB (Roy et al., 1989). In a prospective genetic study, it was found that the risk of repeated attempts at one year is significantly associated with the SS genotype of 5-HTTLPR, but not with TPH1 (Courtet et al., 2004). Second, after the seminal observation by Asberg et al. (1976) who reported lower CSF levels of 5-HIAA in individuals who used violent means to commit suicide, several genetic studies have focused on the violent suicidal phenotype. The results obtained with the serotonin transporter gene are striking in this sense. Indeed, Lin and Tsai (2004) found that the probability of harboring the S allele is 4.67-fold higher (95% CI 1.60-13.63) in participants who have made violent suicide attempts than in those who only made nonviolent attempts. These findings do not allow for a conclusion on whether the trait associated with vulnerability to SB is quantitative (the more it is marked, the more severe and/or violent the suicidal act) or qualitative (only individuals who made the most severe and/or violent attempts are carriers). Further studies will have to constitute homogeneous groups of patients by determining several dimensions of suicidal acts such as means, intentionality, degree of planning and lethality.
5-HTT has been also associated with mood disorders and their responses during treatments (Bellivier et al., 2002; Malhotra et al., 2004). These observations led Bellivier et al. (2002) to suggest that this gene could be associated with a shared trait such as affective instability. Moreover, the data showing the involvement of 5-HTT in vulnerability to violent SB should be considered in the light of the results of several studies in which the S allele was shown to be associated with violent behavior or impulsive aggression in individuals with type II alcoholism, heroin addicts, suicide attempters and adolescent prisoners (Courtet et al., 2004; Gerra et al., 2004; Hallikainen et al., 1999; Lee et al., 2003; Sander et al., 1998). Lastly, a large number of studies on personality revealed an association between 5-HTT and anxiety-related traits (Hariri et al., 2002; Van Gestel and Van Broeckhoven, 2003).
The functional S polymorphism is associated with serotonergic dysfunction and may be involved in vulnerability to SB, notably violent and repeated attempts, by affecting a psychobiological trait involving affective instability, impulsiveness and anxiety. These conclusions should be considered only as hypotheses that warrant specific studies; genetic studies may make it possible to define suicidal phenotypes more precisely, thus helping clinicians to detect patients at risk of particularly harmful progression.
Over the last 10 years, molecular genetic studies have confirmed the results of epidemiological genetics studies and neurobiological studies suggesting that genes of the serotonergic system are involved in the susceptibility to SB independently of psychiatric diagnosis. This may suggest that SB constitutes an autonomous entity within psychiatric nosology. Therefore, SB deserves to be better individualized as more rigorous definition would improve identification and care.
It is likely that several genes of small effect size contribute to the genetic vulnerability of such a complex phenomenon as SB. The recently published human genome map should enable us to search for functional polymorphisms in candidate genes of various neurotransmitters and neuropeptides systems.
The clinical basis of the susceptibility to SB involves personality traits such as impulsive aggression, neuroticism and hopelessness. The implication of different SB susceptibility genes in different dimensions should also help us to understand the physiopathology of the suicidal process. It is possible that TPH1 acts on anger and 5-HTT acts on a complex process of emotional regulation involving affective instability, impulsivity and anxiety as a function of particular contexts. The presence of these psychobiological traits, measured roughly as global serotonergic dysfunction, may depend on pleiotrophic effects and affect the suicidal process at specific levels. Thus, in a certain context (when interacting with particular genetic or environmental factors), 5-HTT may induce emotional dysregulation responsible for negative thoughts, one of the steps preceding suicidal thoughts, whereas in another context, this emotional dysregulation may be associated with impulsiveness and increase the risk of repeated suicide attempts. In their recent cohort study, Caspi et al. (2003) showed that environmental stress increases the risk of depression and SB only in individuals with certain 5-HTT genotypes. These important results show that the role of early and late environmental factors is modulated by specific genetic factors.
Antidepressant drugs represent a particular environmental factor in patients with depression. Pharmacogenomics data could provide a helpful tool to clinicians in daily clinical decision making. For instance, even if this needs to be replicated, recent data suggest that patients carrying a specific 5-HTT genotype may develop agitation and insomnia shortly after the initiation of a selective serotonin reuptake inhibitor treatment (Perlis et al., 2003). Furthermore, the same genotype has been associated with a poorer response to SSRI in depression (for review, see Malhotra et al., 2004). It is not known yet if these observations account for the increased suicidal risk during the first days following the treatment's initiation described in some patients (Jick et al., 2004). However, further studies are needed to examine this interplay between genes and this specific environment. As stated by Wong and Licinio (2004), "There is an overall perception that evidence is accumulating to indicate that prospective testing of genetic variations could be of benefit to many patients."
Dr. Courtet has received funding from the Unite de Recherche Clinique of Montpellier University Hospital (PHRC UF 7653) and the Fondation pour la Recherche Medicale.
Dr. Courtet is psychiatrist in the department of psychological medicine and psychiatry at the University Hospital of Montpellier, France.
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