Genetics of Suicidal Behavior in Children and Adolescents

Gil Zalsman

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Dwivedi Y, editor. The Neurobiological Basis of Suicide. Boca Raton (FL): CRC Press/Taylor & Francis; 2012.

The Neurobiological Basis of Suicide.

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Chapter 14Genetics of Suicidal Behavior in Children and Adolescents

Gil Zalsman.

14.1. INTRODUCTION

14.1.1. Suicidal Behavior among Children and Adolescents

Suicide is the third leading cause of death in adolescence in the United States. In addition, nonfatal forms of suicidal behavior are the most common reasons for the psychiatric hospitalization of adolescents in many countries (Center for Disease Control 1994). About 1600 youngsters, age 15–19, committed suicide in the United States in 2001; 3.4 million youngsters in this age group seriously considered suicide; 1.7 million made a suicide attempt; and 590,000 made a suicide attempt sufficiently serious to require medical attention (Grunbaum et al. 2004). It is of note that not all suicidal ideation or behavior in pediatric population is directly attributable to depression (Zalsman et al. 2006c). One major survey, the biennial Youth Risk Behavior Survey (YRBS) data for adolescents (Grunbaum et al. 2004), found that during the preceding 12 months, 28.6% of high school students nationwide had felt so sad or hopeless almost every day for ∼2 weeks in a row that they stopped doing some usual activities; 16.9% of students had seriously considered attempting suicide; 16.5% of students nationwide had made a plan to attempt suicide; 8.5% of students had actually attempted suicide one or more times; and 2.9% of students nationwide had made a suicide attempt that had to be treated by a doctor or nurse. Understanding the precursors of suicidal behavior in youths is important for the treatment and prevention of suicidal behavior in this population (Grunbaum et al. 2004).

Despite suicidal behavior being a major public health problem in the youth, relevant genetic studies are still sparse. Adoption studies suggest that there is a genetic susceptibility to suicide that is partially independent of the presence of a psychiatric disorder (Roy 1983). Roy et al. (1983) found suicide rates for monozygotic and dizygotic twins as 11.3% and 1.8%, respectively. When considered together with results from earlier twin studies, even greater differences were noted: 13.2% in monozygotic pairs versus 0.7% in dizygotic pairs.

These findings are supported by the study of Brent et al. (1996) who screened 58 adolescent suicide probands and concluded that suicidal behavior may be transmitted as a familial trait, regardless of the presence of Axis I or II diagnosis.

Suicidal behavior in adolescents has been found to have biochemical, genetic, and psychological correlates (Apter et al. 1990; Brent et al. 2003; Mann 2003). Suicidal behavior refers to the occurrence of suicide attempts and ranges from fatal acts (completed suicide) and high-lethality and failed suicide attempts (where serious intention and careful planning are evident, and survival is fortuitous) to low-lethality attempts.

Usually impulsive attempts that are triggered by social crisis seem to be ambivalent and contain a strong element of appeal for help (Beck et al. 1976; Stengel 1973). Intent and lethality are positively correlated and related to biological abnormalities that mostly involve the serotonergic system. The clinical and neurobiological study of failed suicides can provide information about completed suicide because the two populations are clinically and demographically similar (Mann 2003).

Among adolescents, the annual rate of suicide attempts that require medical attention is 2.6%, while suicide is much less prevalent. Among 15–19 year olds, the rates in 1998 were 14.6 per 100,000 in boys and 2.9 per 100,000 in girls (Brent 2002). There is a strong relationship between attempted suicide in adolescent psychiatric patients and eventual death from suicide (Garrison et al. 1991). Predisposition to suicidal behavior might be genetically transmitted as a trait independent of Axis I or II diagnosis (Brent et al. 1996). Suicide and suicidal behavior of adolescents are linked to a wide variety of psychiatric disorders, including affective illness, alcohol and substance abuse, conduct disorder, and schizophrenia (Shaffer 1998). Over 90% of adolescent and adult suicide victims appear to have at least one Axis I disorder (Brent 1995).

Several neurobiological systems were linked to suicide and suicidal behavior; mainly from neuroendocrine studies of the hypothalamic axes and studies of the serotonergic system (5-HT). Data were collected utilizing several methodologies such as hormonal suppression tests, sleep studies, postmortem studies, and genetic factor analysis. Currently, it is believed that the most plausible biological system related to suicidality, impulsive violence, and anxiety is the serotonergic system (Apter et al. 1990, 1993b; Mann 2003; Zalsman et al. 2006c).

14.2. RISK FACTORS FOR SUICIDE IN PEDIATRIC AGE GROUP

Risk factors for suicidality are discussed elsewhere in this clinical book and are not specific for children and adolescents. Suicide and suicidal behavior of adolescents are linked to a wide variety of psychiatric disorders, including affective illness, alcohol and substance abuse, conduct disorder, and schizophrenia (Shaffer 1998). Over 90% of adolescent and adult suicide victims appear to have at least one Axis I disorder (Brent 1995).

Since the majority of psychiatric patients do not attempt or commit suicide, it appears that psychiatric disorder may be necessary but not a sufficient cause for suicide. In addition to other investigators (for a review, see Mann 2002, 2003), we have found evidence to suggest that certain psychopathological dimensions, namely, a tendency to impulsive aggression and anxiety, may predispose to suicidal behaviors and suicide in this age group (Apter et al. 1991, 1993a,b, 1995) independently from or interactively with psychiatric disorder and that the risk for suicide is substantially increased when psychiatric disorder and certain personality traits occur together.

Currently, the most common biological correlated system related to suicidality, impulsive violence, and anxiety is the serotonergic system (Apter et al. 1993b; Mann 2003; Zalsman et al. 2006b). Suicide attempters have been shown to have lower responsivity and sensitivity of their platelet 5-HT₂ receptors than nonattempters. There appears to be a high correlation between the medical damage resulting from a suicide attempt and the number of 5-HT receptors (Apter et al. 1993b; Mann 2003; Zalsman et al. 2006b). Following the finding of higher B_max in the 5-HT_2A receptors in suicidal patients independent of diagnosis (Pandey et al. 1995, 2002a, 2004), postmortem studies have demonstrated higher 5-HT_2A receptor binding in postmortem brains of adolescent suicide victims (Pandey et al. 2002a), hence replicating the abnormalities observed in adults.

Low platelets, low serum, and low cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) levels were found to be related with suicidal behavior, especially more lethal suicide attempts, regardless of psychiatric diagnosis (Tyano et al. 2006; Zalsman et al. 2005a, 2006b).

14.3. INVOLVEMENT OF THE NEUROENDOCRINE SYSTEM

14.3.1. Hypothalamic–Pituitary–Adrenal Axis

Administration of dexamethasone in healthy adults suppresses the release of cortisol (dexamethasone suppression test [DST]). Nonsuppression or early escape from dexamethasone suppression is considered partly the result of corticosteroid receptor downregulation at the level of the hippocampus, hypothalamus, or pituitary and contributes to hypothalamic–pituitary–adrenal (HPA) axis hyperactivity in depressed adults. Some evidence in adults indicates DST nonsuppression as a predictor of suicide, but not nonfatal suicidal behavior (Coryell and Schlesser 2001). Dahl et al. (1992a) found no difference between suicidal and non-suicidal depressed children on the DST. In another study (Pfeffer et al. 1991), it was found that although there was no association between suicidal behavior and DST nonsuppression in prepubertal children, the patients with persistent suicidal behavior had significantly higher pre-dexamethasone 4 p.m. cortisol levels. In a comparison of depressed adolescents and healthy controls, it was found that both had similar cortisol secretion patterns with the exception of sleep onset when the cortisol secretion in the depressed group was higher. Most of this difference has contributed to suicidal or inpatient depressed adolescents (Dahl et al. 1991). Interestingly, sexually abused girls had significantly lower basal, net, and total corticotropin-releasing-hormone-stimulated ACTH response in comparison to non-abused subjects, but higher rates of suicidal ideation, suicide attempts, and dysthymia (De Bellis et al. 1994). Because the results from adult studies have shown that, in general, the HPA function is altered more frequently in older patients and dexamethasone resistance becomes more common with age, age-related difference may explain some of the discrepancies found in studies of children and adolescents (Zalsman et al. 2006c).

14.3.2. Growth Hormone

Growth hormone (GH) secretion, from the anterior pituitary, is stimulated by GH-releasing hormones (GHRH) and inhibited by somatostatin. Other stimulants of GH release are the α₂-adrenoreceptors, muscarinic cholinergic receptors, and activation of dopamine receptors. In depressed children and adolescents, increased nocturnal secretion of GH was reported (Kutcher et al. 1991; Puig-Antich et al. 1984). It may be that muscarinic hypersensitivity at sleep onset leads to excessive somatostatin inhibition and increased release of GH. Muscarinic hypersensitivity could be the consequence of serotonin deficit, since under normal conditions serotonin modulates the cholinergic surge that accompanies sleep onset (Zalsman et al. 2006c).

Ryan et al. (1988) suggested that lower GH secretion in the response to desmethylimipramine in depressed adolescents may be related to the presence of a suicide plan or attempt during the depressive episode. Dahl et al. (1992b) found no difference between the adolescents with major depression and controls on GH measures. However, the group with depression and suicidal behavior (definite plan or attempt) showed a blunting of sleep GH secretion compared with the non-suicidal group. In a follow-up of the subjects, 10 years after the original study, 13 (38.2%) of the control group adolescents developed some form of depressive disorder, whereas 21 remained depression free. Thirteen subjects (23%) from the depressive group (n = 56) made suicide attempts during the follow-up period. The original data from the sleep studies and GH examination were compared again, reclassifying subjects based on the updated data. During the follow-up period, suicide attempters secreted more GH during the first 4 h of sleep and during the whole 24 h period compared to the other three groups. The depressive non-suicidal group had demonstrated an earlier, steeper GH release curve when compared with depression-free controls, whereas the depressed, suicide-attempting subjects did not differ from controls. The role of GH on adolescents’ suicidality remains unclear and needs further investigation.

14.3.3. Serotonergic System

There is accumulating evidence of serotonergic system disruption in suicidality in adults as well as in children and adolescents (Pfeffer et al. 1998; Tyano et al. 2006). There appears to be a high correlation between the medical damage resulting from a suicide attempt and the number of 5-HT receptors in a given individual (Mann et al. 1992). Tyano et al. (2006) compared relationship of measured plasma serotonin and psychometric measures between depressed suicidal adolescents and controls (n = 211). A significant negative correlation was found between plasma serotonin levels and the severity of suicidal behavior among the suicidal inpatients; however, there was no difference in serotonin levels among psychiatric diagnostic categories. The biology of adolescent suicide attempters is understudied and seems to be somewhat different in terms of their response to serotonin-related medication (Brent and Birmaher 2002). Higher levels of B_max were found in the 5-HT_2A receptors in suicidal patients, independent of diagnosis (Pandey et al. 1995). Postmortem studies have demonstrated higher 5-HT_2A receptor binding in postmortem brains of adolescent suicide victims (Pandey et al. 2002b), hence replicating the abnormalities observed in adults.

In adults, low CSF 5-HIAA levels have been found to be related to suicidal behavior, especially more lethal suicide attempts regardless of psychiatric diagnosis (Mann et al. 1992). Moreover, low CSF 5-HIAA has been shown to be predictive of violent suicide attempts and suicide, suggesting that those measures represent trait rather than state measures (Traskman and Asberg 1986). A 2 year follow-up of a group of children and adolescents with disruptive behavior disorders showed that CSF 5-HIAA level predicted severity of physical aggression during follow-up but did not predict suicide attempters (Kruesi et al. 1992). It may be that these results are still preliminary since this group is at risk for suicidality.

14.3.4. Neuroendocrine Challenge Studies

The prolactin response to fenfluramine is an important index of serotonergic function (Malone et al. 1996; Sher et al. 2003). Fenfluramine causes the release of serotonin and inhibits serotonin reuptake. In adults, a history of highly lethal suicide attempts is associated with blunted prolactin response to fenfluramine (Malone et al. 1996). Patients with a history of a very lethal suicide attempts have a blunted prolactin response compared with individuals with major depression but no history of a very lethal suicide attempts, and like low CSF 5-HIAA, a blunted prolactin response to fenfluramine may be a biochemical trait.

In a study (Kaufman et al. 1998) where groups of depressed abused children, depressed non-abused children, and nondepressed, non-abused children were given l-5-hydroxytryptophan challenge in order to examine the measure of prolactin release, it was found that children with a positive family history for suicide attempts, from all three groups, had a more robust prolactin release after the challenge, in comparison to children without a family history of suicide attempts. These results suggested that suicidal behavior in youth is associated with a different pattern of serotonergic abnormality compared with adults, a pattern that may include greater 5-HT_1A or 5-HT_2A receptor responsiveness (the serotonin affecting prolactin release) (Zalsman et al. 2005b, 2006c).

14.3.5. Platelet Studies

Platelets have been used as a less invasive approach to model brain serotonin neurons, since they share many properties—that is, both are derived from the embryonic neural crest and contain serotonin, 5-HT_2A receptors, MAO-B, and serotonin transporters—an approach that is more suitable for the pediatric age group. Yet, this method raised questions regarding its validity, mainly since platelets are not part of the neural circuit that can be modulated by other neurotransmitter systems. A study (Ambrosini et al. 1992) that examined platelet serotonin transporter binding (B_max) using ³H-imipramine in depressed children found inverse relationship between ³H-imipramine binding and presence of suicidal behavior. In contrast, Pine et al. (1995) compared ³H-imipramine binding in platelets of adolescents with conduct disorder who had attempted suicide with those of non-suicidal controls with conduct disorder. They found no difference between the two groups; however, the suicidal group showed significant seasonal variations of ³H-imipramine binding with the lowest amount in late winter/early spring.

Serotonin uptake by platelets may represent a number of serotonin transporter binding sites on the membranes of platelets. Suicidality was not found as a factor affecting the lower V_max values of depressed adolescents (Modai et al. 1989). The serotonin amplified aggregation of children with mood disorders although lower tryptophan levels were found in the blood of children who had recently attempted suicide as compared to the levels found in the blood of normal controls (Pffefer et al. 1998). Various measures of serotonin receptor contents of precursors in platelets have not yielded a consistent picture (Zalsman et al. 2005a). A significant positive correlation between platelet serotonin transporter density and anger scores and a negative correlation between platelet count and trait anxiety were observed in a suicidal versus a non-suicidal group of adolescent inpatients, although the serotonin transporter promoter (5-HTTLPR) polymorphism was not associated with transporter binding and suicidality (Zalsman et al. 2005).

14.3.6. Postmortem Studies

Pandey et al. (2002b) examined the right prefrontal cortex (Broadmann area 8/9) in 15 teenage suicide victims compared with 15 matched normal subjects. They found that 5-HT_2A receptor protein and mRNA levels were higher in the prefrontal cortex and hippocampus but not in the nucleus accumbens of adolescent suicide victims; these higher levels were restricted to the pyramidal cells of layer V. In adults, most autopsy studies of suicide victims reveal various abnormalities in serotonin function in the brain stem and prefrontal cortex, where more 5-HT_1A and 5-HT_2A binding and lower serotonin transporter bindings are reported, mostly in the ventral prefrontal cortex (Arango et al. 1995). Serotonergic function may be a mechanism whereby genetic factors influence the suicide threshold. Its stability as shown by genetic studies of CSF 5-HIAA over time suggests that serotonergic function is a trait and may contribute to its potential use as a predictor of suicide and suicide attempts (Traskman-Bendz et al. 1992).

14.3.7. Sleep-Related Studies

In addition to disturbances in the quality of sleep reported by adult suicidal patients, some studies have also shown sleep polysomnography abnormalities when comparing to non-suicidal patients, including increased rapid eye movement (REM) time and REM activity (Sabo et al. 1991). In children and adolescents, the findings have not been consistent. Some studies have shown no difference between suicidal and non-suicidal depressed adolescents (Rao et al. 1996), while others show higher sleep latency in suicidal adolescents (Khan and Todd 1990) and possibly shorter REM latency compared with other depressive adolescents (Armitage et al. 2001) as well as significantly higher REM density among suicidal depressives (Goetz et al. 1991). Considering the relationship between sleep and the serotonin system, further studies are needed to clarify the relationship between sleep abnormalities and suicidal behavior.

14.4. FAMILIAL TRANSMISSION OF SUICIDAL BEHAVIOR

Suicidal behavior runs in families (Brent et al. 1996; Egeland and Sussex 1985; Zalsman et al. 2008). Despite great variability in the methodology of the studies, results consistently demonstrate the familial aggregation of suicidal ideation and behavior. Longitudinal community studies show that family history of suicidal behavior is one among other precursors of youthful suicidal behavior such as depression, suicidal ideation, behavioral symptoms, and child maltreatment (Shaffer 1998).

Family studies cannot distinguish between genetic and environmental causes of transmission. Findings of family-based aggregation of suicidal ideation and behavior can be attributed to unique diathesis, genetic transmission, mediated by transmission of psychiatric disorder, imitation, or shared environmental effect (Brent and Mann 2005). The literature provides clues as to the mechanisms and precursors of familial transmission of suicidal behavior (Zalsman 2010). The transmission of suicidal behavior may be through pure genetic transmission (specific genes and loci), pure environmental transmission (modeling, abuse, etc.), or interaction of these two factors (gene–environment interaction [GXE]) (Brent et al. 1996; Brent and Mann 2005; Mann et al. 2001; Zalsman 2010). The next paragraphs will review the evidence for each of these models.

14.5. GENETIC FACTORS LINKED TO SUICIDALITY

Suicidal behavior runs in families, probably as a factor independent from major depression. Adults who commit suicide or attempt suicide have a higher rate of familial suicidal acts (Roy 1983). Rates for suicide (Roy et al. 1991) and suicide attempts (Roy et al. 1995) are higher in monozygotic versus dizygotic twins. Adoption studies (Schulsinger et al. 1979) have shown a higher reported rate of suicide in the biological parents of adoptees who commit suicide compared with biological relatives of control adoptees, even after controlling for rates of psychosis and mood disorders. Heritability of suicide and suicide attempts is comparable to the heritability of other psychiatric disorders, such as bipolar disorder and schizophrenia (Statham et al. 1998). Several studies have shown a higher rate of suicidal behavior in families of children and adolescents who have attempted or completed suicide, compared with controls, independent of the diagnosis of depression (Pfeffer et al. 1994; Shafii et al. 1985).

These results could be caused by the genetic transmission of underlying psychiatric illnesses or nongenetic family influences, such as imitation or exposure to violence in the family. Brent et al. (1996) conducted a family study of adolescent suicide victims and 55 demographically similar controls. The rate of suicide attempts in first-degree relatives of suicide victims was higher than the controls, even after adjusting for differences in rates of Axis I and II diagnoses in the families, including depression, which suggested that suicidal behavior may be transmitted as an independent factor from Axis I and II disorders. Several studies have attempted to locate genetic markers for suicide, and interest focused on genes for serotonergic systems.

Although genetic factors account for ∼45% of the variance in suicidal thoughts and behavior, the specific genes that contribute to vulnerability for suicidal behavior are unknown despite numerous candidate genes association studies, especially relating to the serotonergic system (Mann 2003; Zalsman et al. 2002).

The family-based study design, collecting case-parent triads and other available first-degree relatives, will enrich genetic loading of the sample population and guard against potential population substructure (Zalsman et al. 2001a).

Another strategy that is wildly used in adults is the postmortem studies of suicide victims. This allows a combination of the most serious form of suicidal behavior, genotyping, and use of tissue analyses to determine biological intermediate phenotypes such as the gene transcription and proteins. Postmortem studies in adolescent suicide are still rare (Pandey et al. 2002b). Studies in adolescent population using such combined opportunities may add to our understanding of this fatal behavior in youth.

14.5.1. Candidate Genes

The promoter region of the serotonin transporter gene (5-HTTLPR) polymorphism was the center of investigation in relation to depression and suicidality.

Caspi et al. (2003) were the first to demonstrate a gene by environment interaction of this polymorphism with suicidality in young people. The short form of the allele (SL/SS) indicates lower expression of the serotonin transporter, while the opposite is true for the long form (LL). It seems that the long form comes in two varieties: LA express as the short form and LG as the long form (known as “triallelic polymorphism,” see Zalsman et al. 2006a). No association was found between the different alleles and depression or suicidality in adolescents. Possible association with aggressive traits was reported (Zalsman et al. 2001a). In the pediatric age group, the candidate genes 5-HT2A, COMT, TPH1, and DRD4III were also investigated to be associated with depression or suicidality (Zalsman et al. 2001a,b).

14.5.2. Family-Based Studies of Suicidal Behavior

For the child psychiatrist who works with families, the family-based studies are a popular genetic research strategy that have demonstrated advantages over case-control association studies (Schaid and Sommer 1994), particularly its low false-positive and false-negative results in the event of population stratification. The haplotype relative risk (HRR) method (Ott 1989) assesses “trios” of the patient and both biological parents. The alleles transmitted to the patient from the parents are compared with the alleles that were not transmitted. The non-transmitted parental alleles serve as controls. If only one parent is available, parent–child duos may be used in some cases. HRR also enables smaller samples than the case-control method (Ott 1989). The transmission disequilibrium test (TDT) (Spielman and Ewens 1996) analyzes transmitted versus non-transmitted alleles from heterozygote parents as another indicator of linkage disequilibrium. Our group and others have conducted a number of family-based studies on the genetics of suicide in adolescents with contradictory results. No one locus has yet been identified as significantly associated with suicidality, even when family-based methods are used.

14.6. GENE–ENVIRONMENT INTERACTION

Stressful life events (SLE) seem to have an etiologic influence on the vulnerability to depression and suicide. This vulnerability may be caused by genetic factors. The 5-HTTLPR polymorphism was found to moderate the influence of SLE on depression (Caspi et al. 2003); young adults with one or two copies of the short allele exhibited more depressive symptoms and suicidality in response to SLE than individuals who are homozygous for the long allele. This finding was replicated recently in children, adolescents, and young adults (Zalsman et al. 2006a).

14.6.1. Gene–Environment Interactions in Youth Suicidality

A GXE may explain some of the variance in the relationship between SLE and the development and severity of an episode of major depression and suicidal behavior in young people. Caspi et al. (2003) demonstrated that depressive symptoms increased between age 21 and 26 in individuals carrying at least one copy of the S allele of the 5-HTTLPR polymorphism who experienced SLEs after age 21. Furthermore, life events occurring after age 21 predicted depression and suicide ideation or attempt at age 26 among carriers of the S allele who did not have a prior history of depression (P = 0.02).

Nonhuman primates having the S allele experience a persistent decline in serotonin activity after maternal separation as measured by CSF 5-hydroxyindoleacetic acid (Suomi 2003). In humans, a decline in serotonin function results in greater aggression, impulsiveness, and risk-taking as an adult. Childhood separation from parents, sexual and physical abuse, and adult losses may precede the onset of major depression and suicidality (Kaufman et al. 2004; Kendler and Prescott 1999; Paykel 1983). Childhood adversity may produce a biological and clinical diathesis for mood disorder that endures into adulthood. SLEs associate with onset of major depression, modulated, at least in part, via an interaction with genetic predisposition (Kaufman et al. 2004; Kendler and Prescott 1999; Moffitt et al. 2005).

Life events predict depression and suicidal ideation or a suicide attempt in children, adolescents, and young adults who carry the S allele of the 5-HTTLPR polymorphism (Caspi et al. 2003; Eley et al. 2004; Kaufman et al. 2004). Analyzing strictly at severe levels of maltreatment requiring separation from parents, Kaufman et al. (2004) found only a potentiating effect of the S allele on the severity of depression. They also showed that therapy ameliorates the effect of the S allele. This relationship needs further study.

We replicated Kaufman et al.’s findings (Zalsman et al. 2006a) using a third functional allele that was originally described by Nakamura et al. (2000). This allele, L_G, is equivalent in expression to the S allele. The allelic frequency of L_G is 0.09–0.14 in Caucasians and 0.24 in African-Americans. Combined with the observation that the three alleles, S, L_A, and L_G, appear to act codominantly, this may partly explain discordant findings in the literature.

The complexity of the GXEs needs to be considered in both directions. For example, Merikangas and Spiker (1982) found that depressed persons tend to select mates with psychiatric illness and therefore increase the genetic risk for depression and suicide in their offspring.

Despite the aforementioned, recent meta-analysis has not yielded evidence that the serotonin transporter genotype alone or in interaction with SLE is associated with an elevated risk of depression in men alone, women alone, or in both sexes combined (Risch et al. 2009). In contrary, a larger meta-analysis has shown a strong interaction and association (Karg et al. 2011), while other replications and nonreplications emphasize the debate (Carli et al. 2011; Lesch 2011; Uher et al. 2011). Thus, the question, whether another interaction is playing a role, especially in the developing brain, arises.

14.7. GENE–ENVIRONMENT AND TIMING

The child psychiatrist who studies behaviors generally uses the developmental psychopathology paradigm. One concept in this paradigm, the equifinality approach, conceptualizes behavior as an outcome of many etiologies, including genetics, SLE, nonadaptive cognitions, abnormal affect regulation, low self-esteem, neuroendocrine dysregulation, and defects in brain development.

The recent studies of Giedd et al. (1999) and others show how the adolescent brain develops. Evidence of increased white matter volume with accelerated myelination and synaptic pruning in the cerebral cortex elucidates our understanding of the changes in the developing brain. Studies using magnetic resonance imaging (MRI) and functional MRI (fMRI) demonstrate both age-related changes and gender-related differences in gray and white matter during adolescents. These findings may explain in part why many psychiatric disorders emerge during adolescence including depression, bipolar disorders, and risk-taking behavior. Suicidal behavior is strongly related to all of these (Giedd et al. 1999; Paus et al. 1999). Such findings may also explain the gender differences observed in adolescent suicidal behavior: females tend more to attempt suicide, while males tend more to commit suicide. Gender differences are found in GXE studies in the young. Examining children of both sexes, Eley et al. (2004) found a significant GXE interaction in depression for females only.

Suicidality has been associated with novelty seeking and risk-taking behaviors in adolescents. Recent fMRI studies have demonstrated age-related differences in the nucleus accumbens reaction to sensation and reward during anticipation of monetary gain (Giedd et al. 1999; Paus et al. 1999).

I suggest that limiting the study of suicidal behavior in adolescents to the GXE may miss another factor in the complex interplay, that being timing. One may speculate that only when a specific genotype (e.g., S and maybe the L_G allele of the 5-HTTLPR polymorphism) is exposed to a specific environmental risk (e.g., child adversity) during a critical window of brain development (e.g., specific stage in pruning) will the outcome be suicidality. Surely, this speculation needs evidence-based investigation. Meanwhile, we should keep our depressed adolescents away from means of suicide and keep educating gatekeepers to watch for distress and hopelessness in youngsters in their immediate environment (Table 14.1).

TABLE 14.1

Published Studies on Genetics of Adolescent Suicide.

14.8. CONCLUSIONS AND FUTURE DIRECTIONS

It appears that suicidal behavior in children and adolescents correlates with several neurobiological evidences, independent of underlying psychiatric disorders. These include disturbances of the HPA axis as well as GH secretion irregularities. However, the serotonergic system disturbances, as manifested by postmortem findings, serotonin receptor abnormalities on platelets, and metabolite levels as well as genetic studies seem to be the clues for the mechanisms underlying suicidality that are most investigated and considered most critical.

In the future, it is hoped that utilizing a combination of neurobiological tools such as genetic vulnerability, environmental factors, and maybe levels of 5-HIAA in the CSF will help recognizing populations at high risk for suicide.

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