Suicidal Behavior in Pediatric Population Neurobiology and the Missing Links in Assessing Risk among Patients with Bipolar Disorder

Sonali Nanayakkara; Kiran Pullagurla; Mani Pavuluri

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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 16Suicidal Behavior in Pediatric Population Neurobiology and the Missing Links in Assessing Risk among Patients with Bipolar Disorder

Sonali Nanayakkara, Kiran Pullagurla, and Mani Pavuluri.

Suicidal behavior, in most of the people, is the result of conglomeration of recent negative events in their life. In some there is a planning for the final day, but most of the times, it is a rapid-onset act to relieve oneself from the mental agony (Kessler et al., 1999). Suicidal ideation refers to the thoughts of harming or killing oneself, wishing to be dead. Suicide intent conveys the seriousness or intensity of the person’s desire or wish to die at the time of a suicide attempt. Suicide attempt is an act undertaken with the goal of committing suicide. Parasuicide is a nonfatal, self-destructive act with the intention of ceasing one’s own life. Self-injury refers to a range of behaviors that may include cutting, scratching, head banging, self-mutilation with or without specific suicidal ideation or intent. Suicidality refers to all the suicidal behavior/acts and suicidal thinking/thoughts referring to an intention to end life (O’Carroll et al., 1996; Posner et al., 2007; Silverman et al., 2007a,b). This term must not be equated with prevalence of completed suicide or imply high correlation between suicidal thoughts, behavior, and death given that there is no adequate scientific data to quantify.

16.1. TRENDS IN SUICIDE IN PEDIATRIC POPULATION IN GENERAL AND BIPOLAR DISORDER IN SPECIFIC

Suicide, the act of deliberately taking one’s own life, is the fourth leading cause of death among children between ages 10 and 14 and third leading cause of death among young adults aged 15–24, with an annual loss of life due to suicide at 2000 per year (Degmecić and Filaković, 2008). Nearly 2 million U.S. adolescents attempt suicide and 700,000 receive medical attention as a result of their attempt. According to Centers for Disease Control and Prevention (CDC) youth behavior survey for 2007, 14.5% of high school students reported that they wanted to end their life in the past year (Eaton et al., 2008). Suicidal ideation is often reported in pediatric bipolar disorder (BD), but the number progressing to attempt is around 20% (Klimes-Dougan et al., 1999). Patients with BD who have a past history of suicide attempt are over four times (odds ratio = 4.52, p < 0.0001) more prone to repeat the attempt or complete suicide, and 50% of the events (repeat attempt or completed suicide) occurred by 6 months of the first attempt (Marangell et al., 2006). In 2001, after accidents (46%) and homicide (15%), suicide was the third leading cause of death among children aged 10–19 years (CDC, 2004), accounting for 13% of total deaths in this age group.

The three most common methods of suicide, firearms, hanging, and poisoning, account for 92.3% of all completed suicides in the United States, with firearms being the most common method for completed suicide at 55%. Hanging (or suffocation) was reported in one out of five completed suicides, using electric cords, belts, or bed sheets. Overdose, especially along with alcohol, is the most commonly used method in females (Doshi et al., 2005). Pediatric BD has the highest mortality risk (Simpson and Jamison, 1999).

16.2. RISK FACTORS POTENTIALLY APPLICABLE TO SUICIDAL RISK IN BIPOLAR DISORDER

16.2.1. Number of Suicide Attempts

Past history of a suicide attempt is considered the best predictor of a future attempt, regardless of the type of illness. In a prospective naturalistic study on 180 adolescents, the number of prior attempts strongly predicted a suicide attempt in the post-hospitalization period. The highest risk was in the first 6 months to 1 year (Goldston et al., 1999). A longitudinal European multisite follow-up study concluded that among a sample of 1264, 24% had a past history of suicide attempt within the previous year of index attempt. The repeated attempters are at 3.2 times greater risk in future attempt compared to those who attempted once (Hulten et al., 2001). The increased risk conferred by multiple attempts could be due to the persistence of mood disorder (Esposito et al., 2003). Another study on adolescents admitted to an inpatient psychiatric unit concluded that multiple attempters are more likely to be diagnosed with substance abuse and they would have more than one comorbid diagnosis than adolescents with a past history of single attempt or suicidal ideation alone (D’Eramo et al., 2004). Miranda and colleagues studied future suicide attempt outcomes of 228 teenagers who reported recent suicidal ideation or had a past history of suicide attempt (Miranda et al., 2008). With specificity to BD patients, 52 subjects between the ages 21 and 74 years were compared on the basis of single and multiple suicide attempts (Michaelis et al., 2003). Results indicated that single attempters were potentially fatal and serious in their first attempt (odd ratio = 0.65, 95%; confidence interval = 0.43–0.99). Otherwise, there was no other clinical or demographic difference in single and multiple suicide attempters. Two-third of their study sample had multiple suicide attempts indicating that multiple attempts are common in BD.

16.2.2. Age as Moderator

Though many patients with pediatric BD harbor suicidal thoughts, it is the adolescent age group that is more prone for both an attempt and a completion of suicide. Most of the suicides are reported in postpubertal period because of the increased prevalence of psychopathology in adolescents, particularly the combination of mood disorder and substance abuse in them (Brent et al., 1999), or simply because of the increased chronological age (Zubrick et al., 1987). There are various reasons given for this postpubertal increased risk of suicide. The adolescents are cognitively more developed, and plan and execute the plan in a more concrete way (Brent et al., 1999; Shaffer, 1974). A Norwegian study showed that romantic disappointment is one of the factors responsible for increased number of suicide attempts and deaths in older adolescents (Groholt et al., 1998), whereas in children, relatively minor family arguments or disciplinary events have been shown to precipitate a suicide attempt (Beautrais, 2001).

16.2.3. Gender as Moderator

Generally across disorders, girls outnumber boys in having both suicidal ideation and attempt. They are twice as likely to think of suicide and four times as likely to attempt than the boys (Dilsaver et al., 2005). Gender difference for completed suicide does not manifest till mid-adolescence, that is, 15–19 years (Nock et al., 2008). Girls attempt suicide at a much younger age than boys. This gender difference is explained in part by the proneness of female sex to sexual exploitation (Wunderlich et al., 2001).

16.2.4. Hopelessness as Mediator

One of the most important affective state in which young patients commit suicide is hopelessness. Other affective states that are also associated with increased suicide risk are rage, despair, and guilt (Hendin, 1991). The level of hopelessness correlates with the level of suicidal ideation (r = 0.45, p = 0.004) and is a key indicator of suicide in patients with BD (Valtonen et al., 2006). Though hopelessness, to some degree, will be present in almost all patients in depressed phase, the severity is more predictive of the suicide risk. Additionally, hopelessness is linked to poor problem-solving abilities (Cannon et al., 1999). In contrast, it has also been shown that hopelessness becomes less of a predictive factor when overall severity of depression is controlled (Goldston et al., 2001).

16.2.5. Comorbid Disorders

Mood, impulse control, alcohol and substance abuse, psychotic, and cluster B personality disorders are found to convey the higher risk for suicide and suicidal behavior, with the rate increasing with multiple disorders (Nock et al., 2008). Comorbid panic disorder was significantly associated with suicide attempts in the pediatric BD (Goldstein et al., 2005).

16.2.6. Impulsive Aggression as Mediator

The gap between suicide ideation and an attempt is explained in part by the personality traits of that patient. Impulsive aggression is noted to be strongly associated with suicide in both pediatric age group and adults (Brent et al., 2003). Presence of impulsivity also contributes for the earlier age of suicide at first attempt. There are studies that have implicated impulsivity as one of the precipitating factors in the biology of suicide attempt and behavior (Mann et al., 2001). Mann et al. (1999) draw a relationship between impulsivity driven by stress where stress leads to suicidal ideation and impulsivity mediates action. Cyclothymic-hypersensitive temperament (CHT) corresponds to irritability, aggressiveness, and explosive anger strongly linked to both suicidal ideations and attempts. CHT increases the risk of suicidal ideation by an odds ratio of 7.4, and attempt by 10.5 (Kochman et al., 2005).

16.2.7. Relationship between Affect Regulation and Impulsivity

A disturbingly high percentage of 20%–47% among BD youth attempt suicide at least once before age 18 (Bhangoo et al., 2003; Goldstein et al., 2005; Lewinsohn et al., 2005; Strober et al., 1995). The high rate of attempts suggests that suicide may be the most common cause of death among adolescent BD patients.

Pediatric BD patients characteristically presents with emotional dysregulation, severe frustration tolerance, rejection sensitivity, aggressive rages, impulsivity, high comorbidity with disruptive behavior disorders, substance abuse and anxiety, mixed episodes with mania and depression, and chronic illness and poor executive functions (Birmaher et al., 2002; Dickstein et al., 2004; Pavuluri et al., 2005, 2006, 2007; Rich et al., 2005). All of these are factors associated with completed suicides (Shaffer et al., 1996; Spirito et al., 2006). Given the prevalence of high risk for suicide in adolescent BD, with several trait characteristics increasing the vulnerability to suicide, understanding the underlying biological mechanisms becomes a top priority.

While suicidal symptoms in Diagnostic and Statistical Manual of Mental Disorders (DSM) IV describe the various gradients of severity (Figure 16.1), we do not yet know whether or if there are unique biological factors that propel distressed patients to complete suicide. The role of self-harm such as “cutting” in suicide is also unknown. Some researchers have suggested that overt suicidal acts may represent a way to reduce “intolerable emotional states” (Zlotnick et al., 1997), with an extreme variant being the completed suicide. In fact, the highly maladaptive phenomenon of repeated suicide attempts has been shown to be highly associated with completed suicide (Brent et al., 2003; Inoue et al., 2006). We depict our clinical model of the spectrum of suicidality in Figure 16.1. This model accommodates behaviors ranging from suicidal ideation and attempts to completed suicides. The degree of affect dysregulation and impulsivity may predict why some patients go on to complete suicides without a lag period of rumination and morbidity (Brent et al., 2003).

FIGURE 16.1

Model of affect dysregulation and impulsivity.

Therefore, two factors appear to be critical in increasing the risk for suicide in pediatric BD youth. First, severe affect dysregulation, especially in the context of negative emotions, leads to suicide attempts (Davidson et al., 2002; Thompson, 1994). We showed that pediatric BD patients have poor affect regulation, with greater amygdala response to negative emotions, associated with the shutdown of emotional and cognitive control systems, that is, ventrolateral and dorsolateral prefrontal cortex (Pavuluri et al., 2007, 2009). Those who complete suicide are also highly impulsive (Brent et al., 2003). Leibenluft et al. (2007) have also shown poor response inhibition in youth with bipolar diathesis, illustrating the decreased activation in frontostriatal system. There appears to be unexplored relationship between affect dysregulation and impulsivity that drives the youth with BD to be at increased risk for suicidal behavior.

16.2.8. Neurochemistry

Understanding chemical imbalance in neural systems helps encipher the pathophysiology behind increased risk for completed suicide. Many studies have been done on postmortem brain tissue to examine the serotonergic, noradrenergic, and dopaminergic neurotransmitter systems; signal transduction; and cellular morphology in suicide victims. Studies have shown that there are fewer presynaptic serotonin transporter sites in the prefrontal cortex, hypothalamus, occipital cortex, and brain stem (Mann, 2003). In addition, autoradiographic studies localize the abnormality to the ventromedial prefrontal cortex of suicide victims and this effect is independent of a history of major depression (Mann, 2003). Low serotonergic input to the ventral prefrontal cortex might contribute to impaired inhibition. This may create a greater propensity to act on suicidal or aggressive feelings. This also accounts for part of the stress–diathesis model of suicidal behavior proposed by Mann (2003), where decreased serotonin contributes to impulsivity and decreased noradrenaline plays a role in feelings of hopelessness or pessimism. Therefore, brain neurochemistry may modulate whether a person will act on suicidal ideation. Mann et al. (1986) found that β-adrenergic receptor binding in the prefrontal cortex is generally higher in suicide victims.

16.2.9. Genetics

Family, twin, and adoption studies demonstrate evidence that there is an underlying genetic predisposition to suicidal behavior (Ernst et al., 2009). Some studies have demonstrated evidence for familial transition of suicidal behavior even after controlling for mood and psychotic disorders (Nock, 2008). Although the specific genes that contribute to suicide risk independent of other associated psychiatric disorders are unknown, the serotonin transporter gene (SERT) and the three serotonin receptors (HTR1A, HTR2A, and HTR1B) and the monoamine oxidase promoter (MAOA) have been studied. The SERT promoter region has long and short allelic variants. Associations have been documented between the short form and violent suicide attempts in mood disorders, alcoholism, and suicide attempts (Bellivier et al., 2000; Bondy et al., 2000; Gorwood et al., 2000). The HTR1A gene is implicated because there is altered 5-HT1A binding in the midbrain and ventral prefrontal cortex of depressed suicide victims (Arango et al., 1995; Stockmeier et al., 1998). HTR1B has some involvement as 5-HT1B knockout mice are impulsive, aggressive, and more susceptible to self-administer substances of abuse such as cocaine and possibly alcohol (Ramboz et al., 1996; Rocha et al., 1998). The MAO gene has four or more variants based on the number of tandem repeats in the promoter region. Alleles with two to three tandem repeats have been associated with impulsive aggression in males as well as with lower levels of MAO expression (Manuck et al., 2000).

16.2.10. Substance Abuse as Mediator

A strong relation between suicide attempt and alcohol abuse has been shown to exist in children and adolescents (Wu et al., 2004). Cigarette smoking is also linked to suicide attempt. The association between suicidal ideation and substance abuse is insignificant after controlling for depression. The association of alcohol and the risk of suicide attempt is explained by the disinhibition and impaired serotonin system (Audenaert et al., 2001). Chronic use of alcohol can lead to lower levels of serotonin among nondependents (Weiss et al., 1996). Cigarette was worse in BD (Ostacher et al., 2006). Also, smoking was found to be associated with suicidality even after controlling for comorbid conditions and illness severity. This fact can be used to conclude that probably there may be another factor in smokers, like impulsive aggression, that leads to increased suicidality, but this needs further exploration. Somewhat different result was drawn from a case–control, psychological autopsy study, which showed that substance abuse was a risk factor for suicide in males only (Shaffer et al., 1996).

16.2.11. Pharmacotherapy: Implications

16.2.11.1. Selective Serotonin Reuptake Inhibitors:Risk of Suicide

Given the black box warnings from Food and Drug Administration (FDA) to increase awareness of potential suicide due to selective serotonin reuptake inhibitors (SSRIs), a careful appraisal of such risk is warranted. Treating depressed youth with SSRIs may be associated with a small increased risk of suicidality and therefore should only be considered if judicious clinical monitoring is possible. Specific treatment should be based on the individual’s needs and mental health treatment guidelines (Williams et al., 2009). The treatment with antidepressants has shown varied results. One study shows inverse relationship of antidepressant use and suicide risk (Olfson et al., 2003), while another one shows increase in the number suicide attempts and suicide deaths in children and adolescents (Olfson et al., 2006). While SSRIs modestly increase the risk of occurrence of suicidal ideation and behavior, several studies also show that their use is associated with a significant decrease in the suicide rates in children and adolescents, probably because of their efficacy, compliance, and low toxicity in overdose (Bailly, 2009). The use of a long-term antidepressant treatment should be adapted to each individual, being cautious of its potential benefits and risks (Sechter, 1995). It is generally agreed that antidepressants are prescribed with caution in the presence of BD or related symptoms, where likelihood of agitation is greater after the first week of taking SSRIs among those that are likely to deteriorate.

Among the treatment options available for BD, lithium has been shown to be most effective in decreasing the risk of suicide attempt as well as suicide death in comparison to other pharmacological agents (Goodwin et al., 2003). Not only this, lithium has been shown to act as an anti-aggressive drug in children and adolescents (Campbell et al., 1984). More studies are needed to show the effectiveness of lithium in suicidal BD. But surprisingly, the discontinuation of lithium in bipolar patients can lead to increase in the number of suicidal acts in the first year of discontinuation in comparison to the later years or the time before the start of lithium treatment (Tondo et al., 1998). The risk of suicide was also affected by a change in the place of treatment. It was noticed that risk of suicide was high immediately after admission to hospital and immediately following discharge from hospital (Hoyer et al., 2004). These findings suggest that the changes introduced with respect to the medical interventions can affect the suicidality in BD.

16.2.12. Heritability

Many studies have been done in the past to demonstrate the link between factors governing suicide in proband and the family. Familial loading of suicidal behavior is directly proportional to the risk of suicide attempt in the offspring (Brent et al., 2003). Risk is further increased with a concordant twin with suicidal behavior. Studies have shown that there may be other factors that regulate the genetics of both suicides and affective disorders (Egeland and Sussex, 1985). It has been hypothesized that the heritability is due to the familial transmission of impulsive aggression. Another study concluded that the relatives of psychiatric patients with suicide attempt had higher risk of suicide attempts, the males being more prone for the risk than the females (Tsuang, 1983).

16.2.13. Phases of Bipolar Disorder

Different phases of the BD and the timing of the disease onset influence suicidality in different ways. Early onset BD increases the risk of suicide in children and adolescents (Jolin et al., 2007). In similar fashion, not all phases of the disorder are associated with suicide. Mixed and depressive phases are shown to increase suicide attempts in pediatric bipolar patients, whereas no suicide attempts were seen in manic/hypomanic phases (Valtonen et al., 2006). The different phases have different factors responsible for the risk of suicide. Hopelessness was related to suicidal behavior during the depressive phase, but during the mixed phase, subjective rating of severity of depression (on Beck Depression Inventory) and younger age were the predictors. In another prospective study, it was shown that the number of days for which the patient was depressed was directly related to the risk of suicide (Marangell et al., 2006). They concluded that an increase of 10% in number of days depressed increased the odds of a suicide attempt by 22%. The type of BD also plays a role in predicting the severity of suicidality. The diagnosis of BD I carries higher risk for suicide attempts over BD not otherwise specified, but no significant difference was noted with respect to the BD II subtype (Goldstein et al., 2005).

16.2.14. Trauma

Physical and sexual abuse in children and adolescents has an escalating effect in suicidal attempts in their future course of illness (Goldstein et al., 2005). It was found that BD has an earlier onset among those who had past history of abuse (physical/sexual), and it is accompanied with other comorbid Axis I, II, and III disorders, including drug and alcohol abuse (Leverich et al., 2002). Sexual abuse alone, from rare to frequent, is shown to increase the risk of suicide attempts. The combination of both physical and sexual abuse has an even greater impact in increasing the risk of suicide attempts as compared to any one alone (Leverich et al., 2003). Family history of abuse has also been shown to act indirectly in increasing suicidality in children. The presence of a history of sexual abuse in a parent increases the likelihood that their children will also be sexually abused, and consequently, the chances of suicide attempt will be increased in them (Brent et al., 2002). Again, it is hypothesized that impulsive–aggressive trait has a role to play in cases of physical and sexual abuse, with consequent increase in suicidality (Brodsky et al., 2001).

16.3. CONCLUSION

Because the causes of suicidal behavior in pediatric BD are multifactorial, the aim to prevent it should be multidimensional. Prevention and intervention must be based on assessing risk factors including further research in neurobiology, affect dysregulation, depression, mixed episode, aggression, and impulsivity. Especially given that adolescents carry higher risk for suicide, patients with BD should be given extra attention and support in transitional phases of their life.

ACKNOWLEDGMENTS

This work is supported by NIMH 1R01MH85639-01A1, NIMH 5R01MH081019, NIMH 1RC1MH088462.

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