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Reducing Suicide: A National Imperative (2002)

Chapter: 4 Biological Factors

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Suggested Citation:"4 Biological Factors." Institute of Medicine. 2002. Reducing Suicide: A National Imperative. Washington, DC: The National Academies Press. doi: 10.17226/10398.
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4
Biological Factors

Suicide is the outcome of a complex set of factors that are reflected in the neurobiology of the suicidal individual. As discussed in more detail in Chapter 3, current data indicate that mental disorders are present in over 90 percent of suicides in Western society, and many of these disorders are associated with biological changes. Many other factors correlated with suicidality also have well-described biological aspects, including predisposing personality traits such as aggression and impulsivity, effects of acute and chronic stress, impact of trauma, gender, substance or alcohol abuse, and age, as discussed in Chapters 3 and 5.

The biological correlates of suicidality are studied in attempt survivors and in postmortem tissue from those who have completed suicide. Postmortem studies of suicide victims are complicated by other influences on the brain that must be taken into account such as prior medications, substances of abuse and/or self-poisoning, consequences of the suicide-related trauma and injury especially to the head, and postmortem delay prior to preservation of brain tissue samples.

This chapter starts with the physiological stress system, a common pathway for response to acute and cumulative physical and psychological stressors. This is followed by discussion of neurochemical findings in suicide. The chapter concludes with a discussion of what is known about the genetics of suicidal behaviors.

Suggested Citation:"4 Biological Factors." Institute of Medicine. 2002. Reducing Suicide: A National Imperative. Washington, DC: The National Academies Press. doi: 10.17226/10398.
×

THE PHYSIOLOGICAL STRESS SYSTEM

The hypothalamic-pituitary-adrenal (HPA) axis is one of the body’s major systems modulating physiological responses to actual, anticipated, or perceived harm, and is a major component of adaptation to stresses of all types. The HPA axis functioning reflects acute, chronic, and developmental stressors and trauma. The influence of long-term stressors on the HPA axis is reviewed in a recent IOM report on the links between health and behavior (IOM, 2001). Briefly, acute stress activates the HPA axis and increases levels of glucocorticoids—a family of hormones that mediates stress. Adaptation to chronic stress activates a negative feedback loop that causes: (1) decreased resting glucocorticoid levels, (2) decreased glucocorticoid secretion in response to subsequent stress, (3) increased density of glucocorticoid receptors in the hippocampus (Sapolsky et al., 1984; Yehuda et al., 1991). Chapter 5 provides a detailed description of the role early adverse experiences play in HPA axis functioning and how this may reflect a physiological mechanism for socioenvironmental influences on psychopathology. Dysregulation of the HPA axis has been found to be significantly associated with severe affective disorders (e.g., Plotsky et al., 1998) and with post-traumatic stress disorder (e.g., van der Kolk, 1996), although findings suggest that this dysregulation may take different forms for specific disorders (Yehuda et al., 1991). Irregularities in HPA axis function also appear to correlate with suicide regardless of psychiatric diagnosis, as described below.

Links between corticosteroids and suicide have been proposed for many years. In the late 1960s it was first noted that urinary 17-hydroxy-corticosteroids were elevated in patients who completed suicide (Bunney et al., 1969; Fawcett and Bunney, 1967). Subsequently, several other cases were published (Krieger, 1970), although not all reports were in concurrence (Levy and Hansen, 1969). Other postmortem findings implicated an overactive HPA axis with suicide: individuals who died from suicide were reported to have enlarged adrenal glands compared to controls who died from other violence (Dorovini-Zis and Zis, 1987; Szigethy et al., 1994). Increased levels of corticotropin-releasing factor (CRF) in the cerebrospinal fluid (Arató et al., 1989; Brunner and Bronisch, 1999) and fewer binding sites for CRF in the frontal cortex (Nemeroff et al., 1988) in victims of suicide suggested HPA axis hyperactivity. In patients who had attempted suicide, levels of corticotropin-releasing hormone (CRH), another component of the HPA axis feedback loop, were noted to be lower than other psychiatric patients in cerebrospinal fluid (Brunner et al., 2001; Träskman-Bendz et al., 1992) and in plasma (Westrin et al., 1999), a pattern associated with chronic stress.

A depressed cortisol release following challenge with a corticosteroid, dexamethasone, represents a normal HPA axis response. Non-sup-

Suggested Citation:"4 Biological Factors." Institute of Medicine. 2002. Reducing Suicide: A National Imperative. Washington, DC: The National Academies Press. doi: 10.17226/10398.
×

pression of cortisol after dexamethasone is interpreted as a consequence of hyperactive HPA axis. This “dexamethasone suppression test” (DST) has been evaluated with suicidal patients. The results have been mixed and subject of some controversy. A number of studies have indicated that abnormal DST results and changes in daily rhythms of stress hormone release correlate with recent suicide attempts independently of psychiatric diagnosis (Banki et al., 1984; Lopez-Ibor et al., 1985; Pfeffer et al., 1991; Targum et al., 1983). Other studies, however, have failed to demonstrate this relationship between DST non-suppression and suicide attempt (Brown et al., 1986). In contrast, strikingly more consistent results have been obtained for the association of an abnormal DST response with completed suicide. Several studies have suggested that non-suppression of cortisol in the DST is a good predictor of future suicide. Carroll et al. (1980) evaluated 250 patients with melancholy. Only about half of them were nonsuppressors but all of the 5 subsequent patients who completed suicide were in this group. Similarly, Coryell and Schlesser (1981) tested 205 patients with unipolar depression and found that 45.8 percent had abnormal DST results but all four suicides were nonsuppressors. Norman et al. (1990) compared 13 depressed inpatients who subsequently completed suicide with 25 attemptors of suicide and 28 non-attemptors from the same inpatient population. While the DST nonsuppression rate was similar for the latter two groups, it was significantly higher for those who competed suicide. A meta-analysis by Lester (1992) supported the conclusion that the DST nonsuppression was more prevalent among those who completed suicide. A more recent study by Coryell and Schlesser (2001) demonstrated dramatic predictive ability of the DST. Seventy-eight inpatients with major depressive disorder or schizoaffective disorder were under assessment between 1978 and 1981 and followed for up to 15 years. Of the 78 patients, 32 had abnormal DST results upon admission to the hospital. Of the 32 patients, 26.8 percent eventually completed suicide; in comparison, only 2.9 percent of those with normal DST responses completed suicide.

The mechanism by which the HPA axis influences suicidal behavior is not yet established. Various researchers investigating the pathophysiology of suicide have summarized findings that integrate HPA hyperfunction with disturbances in serotonin function (Lopez et al., 1997; Yehuda et al., 1988). As described below, serotonin function also appears associated with suicide. Evidence suggests a reciprocal relationship between the serotonergic system and the HPA axis. Activation of serotonergic pathways or administration of agents that increase the activation of serotonin receptors elicit increases in plasma cortisol (Calogero et al., 1990; Dinan, 1996; Fuller, 1990; Matheson et al., 1997a; 1997b; Meltzer et al., 1984; Owens et al., 1990). Conversely, serotonin receptors are inhibited by glucocorti-

Suggested Citation:"4 Biological Factors." Institute of Medicine. 2002. Reducing Suicide: A National Imperative. Washington, DC: The National Academies Press. doi: 10.17226/10398.
×

coids (Chaouloff, 1995). The link between the two systems is supported in part by the observation that chronic administration of antidepressants can reverse the overactivity of the HPA axis in animal pre-clinical models (Lopez et al., 1997). Van Praag (1996; 2001) proposes that a subtype of depression, anxiety/aggression-driven depression, is correlated with a sustained overproduction of cortisol, resulting in impaired 5-HT synthesis, and reduced 5-HT1a receptor sensitivity leading to susceptibility to stress induction of depression. He proposed that CRH antagonists would be helpful in such cases. On the other hand, Duval et al. (2001) found that the effectiveness of d-fenfluramine, a specific serotonin reuptake inhibitor, did not correlate with the basal or post-DST cortisol levels, suggesting limited functional links between the two systems in suicidal patients. Evidence does suggest that chronic stress of adverse rearing can lead to both low central serotonin responsivity in primates and in humans (Pine et al., 1997) and to HPA axis dysregulation (see Chapter 5) (Higley and Linnoila, 1997).

NEUROCHEMISTRY

The monoamines, particularly dopamine, norepinephrine, and serotonin, have been the focus of much of the research on mental disorders. Changes in these neurotransmitters appear to mediate the effect of the currently utilized psychotropic medications. These neurochemicals show significant changes in various neuropsychiatric disorders. While observable changes in these systems do not necessarily imply causality, they can offer opportunities for developing or improving interventions. A recently developed class of anti-depressants and anti-anxiety drugs, namely, selective serotonin reuptake inhibitors or SSRIs, work through the serotonin system. A wealth of evidence points to reduced serotonergic and altered noradrenergic function in the brains of suicide victims (both attempters and completers). This section summarizes studies on the serotonergic and noradrenergic systems associated with suicide and touches on the limited data on opiate, GABA, and other systems. Although for clarity, this chapter describes these neurochemical systems separately, the reader is reminded that the various systems are interactive and specific changes must be integrated to understand the comprehensive neurobiological effects.

The Serotonergic System

The serotonergic system is complex. Serotonergic pathways are profuse with major projections arising in the median and dorsal raphe nuclei and contacting thousands of cortical neurons. There are more than one

Suggested Citation:"4 Biological Factors." Institute of Medicine. 2002. Reducing Suicide: A National Imperative. Washington, DC: The National Academies Press. doi: 10.17226/10398.
×

dozen types of serotonin receptors, including at least two auto receptor1 populations. This section will review the evidence concerning changes in brain and cerebrospinal fluid levels of serotonin and its metabolites, and changes in a few of the serotonin receptors.

Brain Levels

Initial studies of the serotonergic system in suicide victims reported modestly low levels of brainstem serotonin and/or its metabolite 5-hydroxyindoleacetic acid (5-HIAA). The original assessments were methodologically limited. First, postmortem assays do not distinguish where the neurotransmitter was localized at the time of death and consequently, its functional importance. Second, serotonin and 5-HIAA levels drop rapidly after death. About a 70 percent loss of serotonin occurs after death and removal of the brain to the freezer prior to assay. This means that group differences must be detected in the residual 30 percent of the serotonin or metabolite. Nevertheless, most studies found low serotonin or 5-HIAA in the brainstem of suicides (Table 4-1). Only three of nine studies found low 5-HIAA levels, and no studies found low 5-HT in the prefrontal cortex (Table 4-1). Four of six studies of other brain regions also reported low serotonin or 5-HIAA (not shown). Postmortem interval differences do not appear to explain discrepancies in the literature (Arango and Mann, 1992), probably because most of the decline in indolamine levels occurs in the first 2 hours postmortem and all published studies of suicide victims have a longer postmortem delay.

Low serotonin or serotonin turnover in suicide appears to be confined to some brain regions. This may reflect the limitations of the assay methodology, which might not be sufficiently sensitive to measure the lower concentrations of serotonin and 5-HIAA in areas that contain less than the brainstem. Alternatively, there may be a regional localization of changes in serotonin levels or turnover, such that serotonin and 5-HIAA in the terminal fields are altered in some areas and not others. That conclusion is consistent with receptor mapping studies by Arango et al. (1995) and Mann et al. (2000).

The reduction in serotonin or 5-HIAA in the brainstem of suicide victims is independent of diagnostic category (Mann et al., 1989),with a similar degree of reduction seen in patients with depression, schizophre-

1  

Auto receptors are found on the cells releasing the chemical, and are involved in regulating further release.

Suggested Citation:"4 Biological Factors." Institute of Medicine. 2002. Reducing Suicide: A National Imperative. Washington, DC: The National Academies Press. doi: 10.17226/10398.
×

TABLE 4-1 Serotonin and 5-HIAA in the Brainstem and Cerebral Cortex of Suicide Victims versus Controls

 

Brainstem

Cerebral Cortex

Study

Serotonin

5-HIAA

Serotonin

5-HIAA

Shaw, Camps, and Eccleston (1967)

↓ 19%a

Bourne et al. (1968)

NC

↓ 28%a

Paré, Yeung, Price, and Stacey (1969)

↓ 11%a

NC

Lloyd, Farley, Deck, and Hornykiewicz (1974)

↓ 30%a

NC

Beskow, Gottfries, Roos, and Winblad NC (1976)

NC

↓ 30%a

↓ 43%a

Cochran, Robins, and Grote (1976)

NC

NC

Owen et al. (1983)

↓ 71%

Crow et al. (1984)

↓ 25%

Korpi et al. (1986)

NC

NC

NC

NC

Owen et al. (1986)

Arató et al. (1987)

NC

NC

Cheetham et al. (1989)

NC

NC

Ohmori, Arora, and Meltzer (1992)

NC

Mann et al. (1996a)

NC

NC

Arranz et al. (1997)

NC

NC

aIndicates a statistically significant difference.

NC No change was detected between groups.

SOURCE: Adapted from Mann et al., 1996c with permission of American Psychiatric Publishing, Inc.

nia, personality disorders, and alcoholism. Thus, serotonergic impairment appears related to suicide independently of psychiatric diagnosis.

CSF Levels

Serotonin metabolite (5-HIAA) levels in cerebrospinal fluid (CSF) are a strong correlate of current and future suicidal behavior. For those with a history of a suicide attempt, 5-HIAA levels are low across diagnoses of depression, schizophrenia, or personality disorders compared to psychiatrically matched control groups (16 of 22 studies, Table 4-2). Careful analyses of the studies that did not find low CSF 5-HIAA levels in association with suicidal behavior suggest that certain types of mood disorders (e.g., bipolar disorder) may be exceptions to the correlation (Roy-Byrne et al., 1983; Secunda et al., 1986; Vestergaard et al., 1978). One study, for example, found low CSF 5-HIAA levels in association with suicidal behavior in unipolar but not in bipolar depressed patients (Ågren, 1980).

Suggested Citation:"4 Biological Factors." Institute of Medicine. 2002. Reducing Suicide: A National Imperative. Washington, DC: The National Academies Press. doi: 10.17226/10398.
×

However, another study in which the depressed group was comprised of about 50 percent bipolar cases observed low CSF 5-HIAA in the attempters across diagnostic groups (Banki and Arató, 1983). Distinctions based on diagnosis still require additional evaluations.

Low CSF 5-HIAA is not just a correlate of suicidal behavior, but also

TABLE 4-2 CSF 5-HIAA and Suicidal Behavior in Major Depression

Study

Findings in CSF 5-HIAA Attempters vs. Nonattempters

Åsberg, Träskman, and Thoren (1976b)

Low CSF 5-HIAA predicted 22% suicide rate in 1 year

Åsberg, Thoren, Träskman, Bertilsson, and Ringberger (1976a)

↓ 40% of attempters had low CSF 5-HIAA vs. 15% of nonattempters

Vestergaard et al. (1978)

No difference

Ågren (1980)

Seriousness of intent of worst suicide attempt; negative correlation with CSF 5-HIAA in unipolar but not bipolar depression

Träskman, Åsberg, Bertilsson, and Sjostrand (1981)

CSF 5-HIAA ↓ in violent attempters and ↓ in nonviolent attempters

Banki and Arató (1983)

↓ in attempters; ↓ 37% in violent vs. nonviolent attempters and violent attempters vs. nonattempters

Palaniappan, Ramachandran, and Somasundaram (1983)

CSF 5-HIAA ↓ in attempters

Roy-Byrne et al. (1983)

No difference

Ågren and Niklasson (1986)

CSF 5-HIAA ↓ 12% in attempters (p=0.07)

Edman, Åsberg, Levander, and Schalling (1986)

CSF 5-HIAA ↓ in attempters

Secunda et al. (1986)

No difference

van Praag (1986)

CSF 5-HIAA ↓ (probenecid) in attempters

Peabody et al. (1987)

CSF 5-HIAA correlated with HAM-D

Nordin (1988)

No correlation with suicidal thoughts

Westenberg and Verhoeven (1988)

No difference

Jones et al. (1990)

CSF 5-HIAA ↓ in attempters

Lopez-Ibor, Lana, and Saiz-Ruiz (1990)

Low CSF 5-HIAA group had more attempters

Roy et al. (1990)

CSF 5-HIAA 22% ↓ in attempters vs. nonattempters but nonsignificant

Nordström et al. (1994)

Low CSF 5-HIAA predicted future suicide

Mann et al. (1992)

Only high planned suicide attempters had lower CSF 5-HIAA

Mann et al. (1996b)

Reduced in higher lethality attempters

Mann and Malone (1997)

Negative correlation with most lethal lifetime attempt

 

SOURCE: Adapted from Mann et al., 1996b with permission of Elsevier Science.

Suggested Citation:"4 Biological Factors." Institute of Medicine. 2002. Reducing Suicide: A National Imperative. Washington, DC: The National Academies Press. doi: 10.17226/10398.
×

a predictor. Low CSF 5-HIAA predicts a higher rate of future suicidal acts, as well as the maximal seriousness of suicidal acts in the lifetime of the individual. More lethal suicide attempts are associated with low CSF 5-HIAA (Malone et al., 1996).

The evidence suggests that serotonin mediates inhibition of impulsive action. Low function of the serotonergic systems may predispose individuals to suicidal and other potentially harmful impulsive acts. Animal and human studies link low serotonin function to impulsive aggression. Impulsive aggression but not planned or predatory aggression correlates with low CSF 5-HIAA (Lidberg et al., 1985; Linnoila et al., 1983; Virkkunen et al., 1989a; Virkkunen et al., 1989b; Virkkunen et al., 1987) suggesting that impulsivity plays a role in suicide attempters and predicting a negative correlation of impulsivity and CSF 5-HIAA. Non-human primate studies find such a relationship between impulsivity and CSF 5-HIAA (Higley et al., 1996). On the other hand, no link has been consistently demonstrated between CSF 5-HIAA and depressed mood or hopelessness.

Serotonergic Assessment in Suicide Attempters

To assess the role of the serotonergic system in suicide attempters, researchers can measure the release of prolactin following administration of fenfluramine (see previous section in this chapter). This works because fenfluramine causes the release of serotonin and inhibits its reuptake. Serotonin in turn evokes the release of prolactin into the blood stream. One caveat with this measurement is that endogenous dopaminergic activity may also modulate the prolactin responses to fenfluramine and dopamine has been associated with depression (Kapur and Mann, 1992).

A blunted prolactin response appears to be associated with a history of suicide attempt (Coccaro et al., 1989; Correa et al., 2000; Malone et al., 1996; Mann et al., 1995; see Newman et al., 1998 for review). Coccaro et al. (1989) found a blunted prolactin response in patients with a personality disorder or major depression characterized by suicidal acts compared to similar patients without a history of suicide attempt. Lopez-lbor et al. (1988), however, did not find this correlation of reduced prolactin response with suicide attempts in patients with major depression, though they did find a relationship with severity of the diagnosis. Similarly Mann et al. (1995) found that significantly more (78 percent) of the younger depression cases had a blunted prolactin response compared to only 29 percent of the older group. These younger depressed people were also distinguished from the older group in clinical characteristics including higher frequency of comorbid borderline personality disorder, younger age at onset of the depression, greater lethal intentions for recent suicide

Suggested Citation:"4 Biological Factors." Institute of Medicine. 2002. Reducing Suicide: A National Imperative. Washington, DC: The National Academies Press. doi: 10.17226/10398.
×

attempts, and twice the level of hopelessness. Other factors may impact these findings: O’Keane et al. (1992) found blunted prolactin responses compared to placebo in antisocial personality disorder.

Serotonin Receptors: SERT

The most studied serotonin receptor in suicidal behavior is the serotonin transporter (SERT). Many studies have suggested that the number of serotonin transporter binding sites is low in suicide victims. Methodological complexities such as the ligand used in the experiments have created some uncertainty about the interpretation of the data.

Furthermore, the changes in binding may be specific to certain brain regions. Gross-Isseroff et al. (1989) found strong regional differences in the binding of the 5-HT receptor ligand 3H-imipramine in suicide victims. Suicide-related decreases in SERT binding may be localized to the ventrolateral prefrontal cortex (Arango et al., 1995; Mann et al., 2000) as evidenced by studies on the binding of 3H-cyanoimipramine, another 5-HT receptor ligand. Earlier studies (Arató et al., 1987; Arató et al., 1991; Crow et al., 1984; Stanley et al., 1982) found low 3H-imipramine binding in the dorsal prefrontal cortex of suicide victims that may reflect fewer SERT sites. Studies of other brain regions are limited, but one preliminary report indicates low brainstem SERT binding (Lloyd et al., 1974).

Serotonin Receptors: 5-HT2A

Binding to the 5-HT2A receptor, a major postsynaptic receptor for serotonin may be greater in suicide victims. Several studies (Arango et al., 1990; Arora and Meltzer, 1989; Hrdina et al., 1993; Laruelle et al., 1993; Mann et al., 1986; Stanley and Mann, 1983) have demonstrated high ligand (either 3H-spiroperidol or 3H-ketanserin) binding to the 5-HT2A receptor in prefrontal cortex of suicide victims. Pandey and colleagues (2002) reported that there was greater 5-HT2A receptor protein and mRNA gene expression in the brains of teenage suicide victims than in matched normal controls. It should be noted, however, that the field is not in consensus on these findings; seven published studies have found no alteration in 5-HT2A binding (Arranz et al., 1994; Cheetham et al., 1988; Crow et al., 1984; Gross-Isseroff et al., 1990a; Lowther et al., 1994; Owen et al., 1983; 1986).

The changes in binding to the 5-HT2A receptor are found to be greater in prefrontal cortex than in temporal cortex (Arango et al., 1990). Like SERT, regional differences are evident for this postsynaptic receptor’s change with suicide. Further work is needed to map the distribution of change in 5-HT2A receptors in suicide victims throughout the prefrontal

Suggested Citation:"4 Biological Factors." Institute of Medicine. 2002. Reducing Suicide: A National Imperative. Washington, DC: The National Academies Press. doi: 10.17226/10398.
×

cortex as well as in other cortical brain regions. 5-HT2A receptor binding in suicide victims may be linked to more violent methods of suicide since the studies reporting increases (Arango et al., 1990; Arora and Meltzer, 1989; Hrdina et al., 1993; Laruelle et al., 1993; Mann et al., 1986; Stanley and Mann, 1983) had greater representation of violent deaths than the others (Arranz et al., 1994; Cheetham et al., 1988; Crow et al., 1984; GrossIsseroff et al., 1990a; Lowther et al., 1994; Owen et al., 1983; 1986).

Several other factors may influence the outcomes of these analyses. Psychotropic medication may down-regulate 5-HT2A receptors (Yates et al., 1990), and potentially obscure or reverse the up-regulation related to suicide. The presence or absence of a depressive illness may also be relevant (Yates et al., 1990); high 5-HT2A receptor number may be associated with the presence of a depressive illness independent of suicide risk.

Serotonin Receptors: 5HT1A

Another major cortical postsynaptic serotonin receptor is the 5-HT1A receptor. Two studies reported an increase in 5-HT1A binding in suicide victims (Arango et al., 1995; Joyce et al., 1993) and four did not (Brodsky et al., 1997; Dillon et al., 1991; Matsubara et al., 1991; Stockmeier et al., 1997). Arango et al. (1995) and Joyce et al. (1993) found the increase in 5-HT1A binding to be confined to discrete brain regions. Corticosteroids can mediate stress effects via mineralocorticoid (MR) and glucocorticoid (GR) receptors on hippocampal 5-HT1A receptors (Lopez et al., 1998). Stress elevates glucocorticoid levels and downregulates hippocampal 5-HT1A receptors in rodents. Suicide victims have low levels of MR and 5-HT1A mRNA in the hippocampus, an effect consistent with stress (Lopez et al., 1998).

Serotonin Receptors: Others

Few studies are published of 5-HT1B, 5-HT2C, and 5-HT1D receptors in suicide victims (Arranz et al., 1994). Lowther et al. (1997) reported an increase in 5-HT1D binding in globus pallidus, but not in putamen, parietal or prefrontal cortex of violent suicide victims. Huang et al. (1999) did not find any alteration in 5-HT1B binding in prefrontal cortex. More work needs to be done mapping these receptor changes.

The Noradrenergic System

Altered brain noradrenergic transmission also appears to be associated with suicidal behavior. Postmortem studies performed to date have sought to examine the noradrenergic system in brain by: measuring the

Suggested Citation:"4 Biological Factors." Institute of Medicine. 2002. Reducing Suicide: A National Imperative. Washington, DC: The National Academies Press. doi: 10.17226/10398.
×

concentration of norepinephrine (NE) or its metabolites in brain tissue, morphometric studies of noradrenergic neurons, measurement of tyrosine hydroxylase (the rate-limiting enzyme for NE synthesis), and assaying NE receptor subtypes. Alterations in noradrenergic neurotransmission in suicide are suggested based on a variety of findings, including changes in neurotransmitter indices in postmortem brain tissue and comparable findings in vivo.

Arango and colleagues (1996) found 23 percent fewer noradrenergic locus ceruleus2 neurons in the brain of completed suicides. Klimek et al. (1997) found fewer NE transporter sites in the LC. Ordway and colleagues reported high binding to a2-adrenergic receptors (1994b) and more tyrosine hydroxylase protein (1994a) in the LC of suicide victims, and a low concentration of NE in the LC (1994b). The latter two observations are consistent with animal studies of stress-induced reductions in NE levels in the LC due to release and compensatory increases in tyrosine hydroxylase activity. Arango and colleagues’ finding of fewer noradrenergic neurons may reflect low functional reserve and a greater susceptibility to depletion of NE by stress-induced release. Arango et al. (1993) and Manchon et al. (1987) found more NE in cortex and hippocampus, respectively.

Evidence from neurotransmitter or metabolite concentrations in the cerebrospinal fluid (CSF) is less convincing, with a minority (Ågren, 1980; Ågren, 1982) of studies finding low concentrations of the norepinephrine metabolite 3-methoxy, 4-hydroxyphenyl glycol (MHPG) in suicide attempters (Brown et al., 1982; Pickar et al., 1986; Roy et al., 1985; Roy et al., 1989; Secunda et al., 1986; Träskman et al., 1981). Low urinary excretion of the metabolite MHPG in suicide attempters provides some further indirect evidence of low NE turnover (Ågren, 1980; Ågren, 1982). High binding to ß-adrenergic receptors in the cerebral cortex in suicide victims compared to controls has been reported by some investigators (Arango et al., 1990; Biegon and Israeli, 1988; Mann et al., 1986) but not by others (De Paermentier et al., 1990; Little et al., 1993; Stockmeier and Meltzer, 1991). a1-Adrenergic and/or a2-adrenergic receptor binding in suicide victims in cerebral cortex have been reported to be increased (Arango et al., 1993; Callado et al., 1998; Gonzalez et al., 1994; Meana and Garcia-Sevilla, 1987) or decreased (Gross-Isseroff et al., 1990b). Taken together, these studies suggest altered noradrenergic neurotransmission is associated with suicidal behavior, perhaps reflecting a stress response that exhausts the noradrenergic system.

2  

Norepinephrine-producing cells originate in the locus ceruleus.

Suggested Citation:"4 Biological Factors." Institute of Medicine. 2002. Reducing Suicide: A National Imperative. Washington, DC: The National Academies Press. doi: 10.17226/10398.
×

Other Neurochemical Pathways

Other neurotransmitter systems may or may not be modified in suicide. Cholinergic receptor binding (ligand: 3H-ZNB) appears unaltered (Stanley, 1984). μ-Opioid receptor binding appears increased in prefrontal cortex and caudate but not thalamus (Gabilondo et al., 1995). CRH binding to prefrontal cortex is reduced (Nemeroff et al., 1988). GABAB sites in the prefrontal cortex, temporal cortex, and hippocampus are reported to be unchanged (Cross et al., 1988), whereas benzodiazepine binding is increased in suicides (Manchon et al., 1987). Palmer et al. (1994) report no change in the NMDA receptor, but Nowak et al. (1995) found altered NMDA binding in the prefrontal cortex as indicated by a decrease in high affinity binding of the ligand 3H-CGP-39653.

Several studies have found changes in postsynaptic signal transduction pathways in suicide. The phosphoinositide and protein kinase C signaling systems are second messenger systems for serotonin as well as other neurotransmitters. Cowburn et al. (1994) reported low basal, GTPγS and forskolin-stimulated adenylyl cyclase activity in the cortex of suicide victims. Levels of one isoform of the α-subunit of the G-protein (Gsα-s) were reduced in suicides. Pacheco et al. (1996) reported that GTPγS stimulation of phosphoinositide hydrolysis was reduced by 30 percent in suicides. Pandey et al. (1997) found reduced protein kinase C binding of 3H-phorbol dibutyrate in prefrontal cortex of teen suicides. Furthermore, the phosphoinositide-specific enzyme phospholipase C (PLC) was found to be abnormal in adolescent suicide victims (Pandey et al., 1999) but not in adults (Pandey, 2001). The contribution of these biological pathways deserved further analysis for their contribution to the pathophysiology of suicide.

GENETIC FACTORS

Similar to most complex conditions, such as obesity (Boutin and Froguel, 2001), hypertension (Higaki et al., 2001), and coronary artery disease (Winkelmann and Hager, 2000), there is growing evidence that genetic factors are related to liability for suicidal behavior. A clinical phenotype of suicide and suicidal behavior shows genetic liability from two sources. One is a genetic liability to mental illness, and the second to impulsive aggression. When both liabilities converge, the risk for suicidal behavior is particularly high. Candidate gene studies suggest that polymorphisms in serotonergic genes may be related to both alterations in serotonin function and to suicidal behavior, although the effects of individual candidate genes are small and may vary depending on psychiatric disorder, sex, and ethnicity. Since the heritability of liability to suicidal

Suggested Citation:"4 Biological Factors." Institute of Medicine. 2002. Reducing Suicide: A National Imperative. Washington, DC: The National Academies Press. doi: 10.17226/10398.
×

behavior appears to be on the order of 30–50 percent, family-environmental causes for suicidal behavior, such as abuse, must also be considered, as both independent factors and those that may interact with genetic vulnerability. Environmental influences are evidenced by the large shifts in rates of youth suicide in the United States and other Westernized countries over the last 20 years although the genetic makeup of the population has not changed appreciably over this short period of time.

The majority of those who complete and attempt suicide have evidence of at least one, and often more, major mental illness (see Chapter 3). The most common disorders associated with suicide and suicidal behavior are mood disorders, alcohol and substance abuse, and schizophrenia, all of which are familial disorders, which, on the basis of adoption and twin studies, have a strong genetic component (Cooper, 2001; McGuffin and Katz, 1989; McGuffin et al., 1991). Therefore, one set of genetic factors influencing suicide comprises those that predispose to the mental disorders that are associated with suicide (e.g., McGuffin and Katz, 1989).

However, the liability to mental disorder is not synonymous with the liability to suicide. For, while the majority of those who attempt and complete suicide have at least one mental illness, the converse is far from true—a very low proportion of mentally ill persons eventually kill themselves, and the majority never make as much as one suicide attempt (e.g., Bostwick and Pankratz, 2000; Murphy and Wetzel, 1990; Pokorny, 1983). One hypothesis, first advanced several decades ago, is that there are additional genetic factors relevant to suicide and suicidal behavior, perhaps related to a liability to impulsive behavior and aggression (Kety, 1986). The convergence of a mental disorder and aggression is associated with the greatest risk for suicidal behavior. Several studies have shown that mood disordered individuals with impulsive aggression are at much greater risk for suicidal behavior than are those without this trait (Mann et al., 1999). Furthermore, impulsive aggression contributes more to suicide and suicidal behavior in younger individuals (Conwell and Brent, 1995; Rich et al., 1986) than more mature adults.

Familial Aggregation of Suicidal Behavior

Even when suicidal behavior is familial, non genetic explanations must be considered. First, suicidal behavior in a relative can serve as a behavioral model for a family member, making imitation more likely to occur in subsequent generations. Second, there may be other familial factors that increase the liability to suicide such as parental psychopathology, lack of support, discord, and even frank abuse.

As discussed in Chapter 8, media presentation of suicide and suicidal behavior can result in imitation and contagion. This effect is most promi-

Suggested Citation:"4 Biological Factors." Institute of Medicine. 2002. Reducing Suicide: A National Imperative. Washington, DC: The National Academies Press. doi: 10.17226/10398.
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nent in adolescents and young adults (Gould and Shaffer, 1986; Phillips, 1974; Phillips and Carstensen, 1986; Schmidtke and Hafner, 1988). However, some evidence from adoption studies suggests that imitation is unlikely to explain all familial transmission because suicides in biological relatives unknown to the adoptee increase his or her risk (Schulsinger et al., 1979). Two other studies examining familial concordance between suicide attempts, one looking at twin pairs of attempts, and the other at parent–child pairs has found wide variability in the timing of the pairs of attempts, not consistent with imitation (Brent et al., in press; Statham et al., 1998).

Family discord impacts suicidal behavior, particularly among adolescents (Brent et al., 1994; Kosky et al., 1986; Kosky et al., 1990; Taylor and Stansfeld, 1984) (see Chapters 5 and 6). However, it is unclear to what extent family discord is the cause or consequence of other difficulties that may lead to suicide. Both sexual and physical abuse (see Chapter 5) have been associated with suicidal behavior (Brent et al., 1999; Brown et al., 1999; Fergusson et al., 1996; Kaplan et al., 1997; Renaud et al., 1999) as well as changes in central serotonin metabolism.

I see now that I had been incubating this death far longer than I recognized at the time. When I was a child, both my parents had half-heartedly put their heads in the gas oven. Or so they claimed. It seemed to me then a rather splendid gesture, though shrouded in mystery, a little area of veiled intensity, revealed only by hints and unexplained, swiftly suppressed outbursts. It was something hidden, attractive and not for the children, like sex. But it was also something that undoubtedly did happen to grownups. However hysterical or comic the behavior involved—and to a child it seemed more ludicrous than tragic to place your head in the greasy gas oven, like the Sunday roast joint— suicide was a fact, a subject that couldn’t be denied; it was something, however awful, that people did. When my own time came, I did not have to discover it for myself (Alvarez, The Savage God: A Study of Suicide, 1971/ 1990:291-292).

It is difficult to know how genetics and abuse interact in their influence on suicide. First, abuse is more likely to occur in the presence of parental depression and substance abuse (Chaffin et al., 1996). Second, abusing parents have a greater rate of impulsive control disorders, including suicide attempt (Roberts and Hawton, 1980). Third, abuse may bring about conditions that interact with pre-existing genetic vulnerablities for other risk factors such as depression or substance abuse (c.f., Silberg et al., 1999). Finally, there is evidence that some effects of sexual

Suggested Citation:"4 Biological Factors." Institute of Medicine. 2002. Reducing Suicide: A National Imperative. Washington, DC: The National Academies Press. doi: 10.17226/10398.
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abuse may be transmitted across generations, since non-abused children of sexually abused parents have increased suicidal behaviors (Brent et al., in press). Additional research is needed to sort out these issues.

Genetic Assessments

Several lines of evidence point to a link between genetic inheritance and risk of suicide. The following sections describe some of that evidence that derives from adoption studies, twin studies, family studies, candidate genes, and a new microarray approach.

Adoption Studies

Schulsinger et al. (1979) conducted a record linkage study among Danish adoptees, and found that the rate of suicide in the biological relatives of adoptees who had completed suicide was 6-fold higher than the rate in the biological relatives of living adoptees. There was no elevation of the rate of suicide in the adoptive relatives. This study strongly supports a genetic component to suicide, although it is less informative on exactly what is being transmitted—psychopathology or some other liability. It also argues against imitation.

A second adoption study examined the risk of suicide in the biological and adoptive relatives of adoptee probands who had a mood disorder (Wender et al., 1986). Interestingly, the highest rate of suicide was in the biological relatives of those probands with a diagnosis of “affect reaction,” which roughly corresponds to borderline personality disorder. This rate (7.6 percent) was almost 3 times higher than the rate of suicide in the biological relatives of those with unipolar depression (2.2 percent), suggesting that the familial transmission of suicidal behavior might be more closely related to the transmission of difficulty with regulation of affect and impulses than mood disorder per se. An analysis of this study (Abbar et al., 1996) concluded that the genetic susceptibility to suicide was transmitted independently of the transmission of personality disorder.

Twin Studies

Juel-Nielsen and Videbech (1970) showed that monozygotic (identical) twins showed greater concordance for suicide than did dizygotic (fraternal) twins. Roy and colleagues (1991) updated these results, reviewed the world literature of case reports of twin suicides, and again found a much higher concordance for suicide among monozygotic than dizygotic twins (11.3 percent vs. 1.8 percent), consistent with a genetic etiology, most likely polygenic. In a subsequent study, Roy et al. (1995)

Suggested Citation:"4 Biological Factors." Institute of Medicine. 2002. Reducing Suicide: A National Imperative. Washington, DC: The National Academies Press. doi: 10.17226/10398.
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showed a high concordance of attempted suicide in a surviving twin with suicide in monozygotic twins (38 percent), but not in dizygotic co-twins (0 percent3). A large Australian study of almost 3000 twin pairs confirmed these findings (Statham et al., 1998). If a monozygotic twin attempted suicide, his/her co-twin had a 17.5-fold increased risk of having made an attempt. In controlling for other risk factors for suicide, such as mood disorder, substance abuse, trauma, personality problems, and life events, a family history of a suicide attempt still conveyed a 4-fold increased risk for the co-twin making an attempt. All studies of suicide in twins discussed here were carried out in twins who were raised together, with ostensibly a shared environment, thereby controlling for environmental effects. To date, there are no published findings for suicide for twins raised apart, which is another way to examine this issue. The attempts among twins did not cluster in time, making imitation a less likely explanation.

In this study, genetic modeling showed that 45 percent of the variance for suicidal thoughts and behavior was genetic, which suggests a continuity between ideation and attempt (Statham et al., 1998). Glowinski et al. (2001) studied 3416 Missouri female adolescent twins and found that genetic and shared environmental influences together accounted for 35 percent to 75 percent of the variance in risk. The twin/cotwin suicide attempt odds ratio was 5.6 (95 percent confidence interval [CI] 1.75–17.8) for monozygotic twins and 4.0 (95 percent CI 1.1–14.7) for dizygotic twins after controlling for other psychiatric risk factors.

Family Studies

Several family studies have compared the risk for suicide or suicide attempt in the first degree relatives of individuals who have completed suicide, compared to the rate among relatives of control probands. Although the methodology varies to some degree, the results consistently point to a 4-fold increase in risk among relatives of suicide probands compared to the relatives of controls. Tsuang (1983) reported that the rates of suicide in the relatives of patients who completed suicide were higher than the rates among the relatives of patients who did not complete suicide. This suggests that something other than mental disorder is being transmitted to increase the familial transmission of suicide. Similarly, Egeland and Sussex (1985) found that the rate of suicide in the pedigrees of the Old Order Amish showed a marked degree of clustering

3  

This very low rate may be due to reporting bias.

Suggested Citation:"4 Biological Factors." Institute of Medicine. 2002. Reducing Suicide: A National Imperative. Washington, DC: The National Academies Press. doi: 10.17226/10398.
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of suicide that could not be explained by the clustering of mood disorder alone (see also Chapter 6).

Several studies also show that the families of suicide attempters display an increased risk of suicidal behavior. The methodology varies significantly in this set of studies from chart review (Garfinkel et al., 1982; Roy, 1983; Roy, 2000) to family history (Linkowski et al., 1985; Malone et al., 1995), to formal family history study with direct interview of several first degree relatives (Bridge et al., 1997; Johnson et al., 1998; Pfeffer et al., 1994). The median odds ratio of these studies was around 4. Some report that the greater the lethality of the attempt, the greater the familial incidence of suicide (Garfinkel et al., 1982; but see Johnson et al., 1998; Linkowski et al., 1985; Mitterauer, 1990; Papadimitriou et al., 1991).

Candidate Gene Studies

Candidate gene studies compare the prevalence of different genetic variants (polymorphisms) of specific genes in cases of suicide or suicidal behavior to controls. The choice of candidate genes to examine in studying the etiology of suicide is guided by findings described earlier in the chapter regarding changes in serotonin metabolites and receptors in suicide victims and attempters. It is becoming evident, for example, that levels of 5-HIAA in CSF are under genetic control (about 40 percent of the variance is genetic; Clarke et al., 1995; Higley et al., 1994). Consequently, variation in genes related to the serotonergic system are important candidates. Those relating to the responsivity to serotonin include tryptophan hydroxylase (Manuck et al., 1999), the serotonin transporter promoter regions (Lesch et al., 1996), or the monoamine oxidase-A promoter regions (Manuck et al., 2000). Genes related to the serotonin transporter, 5HT1A, 5HT2A, and 5HT1B are also candidates. These candidate genes will be reviewed in the following sections.

TPH. Trytophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin. Most of the studies consider one of two polymorphisms, A779C and A218C, which have been reported to be in tight disequilibrium (i.e., tightly linked genetically). Several studies linked low CSF 5-HIAA to the 779C allele especially in males (Jonsson et al., 1997; Nielsen et al., 1998) but not to A218C (Mann et al., 1997; Nielsen et al., 1998). The A218C allele has been linked to changes in serotonin functioning in a study done by Mannuc and colleagues (1999). Studies comparing suicide completers to controls found no association between the A218C polymorphism and suicide (Bennett et al., 2000; Du et al., 2000b; Ono et al., 2000; Turecki et al., 2001), but suggested a relationship between the A779C allele and suicide (Bennett et al., 2000; Roy et al., 2001). The current

Suggested Citation:"4 Biological Factors." Institute of Medicine. 2002. Reducing Suicide: A National Imperative. Washington, DC: The National Academies Press. doi: 10.17226/10398.
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research does not support a stronger relationship for either of these alleles compared to the other, and overall differences in research findings are likely more indicative of differences in the populations studied.

In alcoholic offenders an association between the 779C allele and suicide attempt was reported, with multiple attempts related to the number of C alleles (Nielsen et al., 1994). In addition, several studies report an association between the 218C allele and suicide attempt in non-mood-disordered individuals (Nielsen et al., 1998; Paik et al., 2000; Rotondo et al., 1999). In mood-disordered patients compared to healthy controls (Abbar et al., 2001; Bellivier et al., 1998; Tsai et al., 1999) and attempters compared to mood-disordered controls (Mann et al., 1997; Tsai et al., 1999), the A218 Allele was associated significantly with suicide attempt. The association was stronger for violent suicide attempt, especially if there was a history of depression (Abbar et al., 2001), with a dose response of the number of A alleles in one study (Abbar et al., 2001; Mann et al., 1997).

In a study of community volunteers, an association between impulsive aggressive traits and the A218 form of the TPH allele was reported, particularly in men (Manuck et al., 1999). Mann et al. (1997) reported an association between borderline personality disorder and the A218 polymorphism. In a small series of males with personality disorders, New et al. (1998) reported an association between the 218C allele and impulsive aggression.

Serotonin transporter studies. The serotonin transporter has two allelic variants in the promoter regions, a short (S) form and a long (L) form. Exposure to a serotonin agonist activates less transcription of the S than the L form (Greenberg et al., 1999). Comparing suicide victims to controls revealed an association between the L allele and depressed suicides (Du et al., 2000b), between the L allele and depression but not suicide (Mann et al., 2000), and between the S allele and violent suicide (Bondy et al., 2000). Others found no associations (Roy et al., 2001; Turecki et al., 1999). Family based studies on attempts demonstrated a relationship with the S allele, particularly for violent attempts in mood disordered (Bellivier et al., 2000) and alcoholic samples (Gorwood et al., 2000). There was a dose response between the number of S alleles and suicide attempt in those alcoholics with comorbid depression, with no relationship between the number of S alleles and attempts in those alcoholics without depression. On the other hand, Zalsman et al. (2001) reported that the L allele was associated with high measures of aggression. However, Geijer et al. (2000), in a comparison of a diagnostically mixed sample of attempters to healthy controls, found no association.

Suggested Citation:"4 Biological Factors." Institute of Medicine. 2002. Reducing Suicide: A National Imperative. Washington, DC: The National Academies Press. doi: 10.17226/10398.
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HT2A studies. Studies of suicidal behavior and the HTR2A receptor have examined three polymorphisms—T102C, His 452Tyr, and A1438G. Comparisons of suicide victims to controls (Du et al., 1999; Turecki et al., 1999) revealed no relationship between HTR2A polymorphisms (His452Tyr for Du et al., 1999; T102C in both studies, A1438G for Turecki et al., 1999). Turecki et al. (1999) found some functional significance of the 102T/1438A haplotype, which was associated with increased 5HT2A receptor binding. Most studies comparing suicide attempters to controls also demonstrated no effect (Geijer et al., 2000; Kunugi et al., 1999; Tsai et al., 1999). One study did report an association between suicide attempt and the 102C form of the allele (Zhang et al., 1997).

MAOA studies. In a study of community volunteers, Manuck et al. (2000) identified 4 haplotypes of monoamine oxidase-A (MAOA) and found an association between the 2-3 haplotype4 and impulsive aggression in men. This haplotype was also associated with an altered response to the fenfluramine challenge test. The relationship of these genetic variants to suicide attempt has not yet been studied.

Methodological issues. To date, while some trends are evident in the results for candidate genes, inconsistencies in the literature exist. Differences in diagnostic makeup may have accounted for differences in results. For example, many of the TPH studies that examined attempts in non-affectively-disordered samples found associations with the 779C or 218C allele, where studies in mood disordered samples tended to find associations with the A218 allele. In this linked set of polymorphisms, some studies find an association with the A and some with the C allele. The inconsistency is hard to explain—it could be due to sex differences, diagnostic differences, or design differences, or it could be that both polarities of the allele, under different circumstances, predispose to a suicide attempt. The association of the S allele in the serotonin transporter promoter region to suicide attempt in alcoholics was strongly influenced by the presence or absence of a history of major depression (Gorwood et al., 2000). Some studies used “healthy” controls, although screening for “healthy” ranged from an extensive psychiatric interview to asking subjects whether they had ever had any psychiatric difficulties. Other studies used diagnostically matched controls. By controlling for diagnosis, one can detect genes above and beyond those related to disorder that may account for suicidal behavior.

4  

A haplotype is a combination of alleles that tend to be inherited together.

Suggested Citation:"4 Biological Factors." Institute of Medicine. 2002. Reducing Suicide: A National Imperative. Washington, DC: The National Academies Press. doi: 10.17226/10398.
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Characterization of the sample by other behavioral characteristics may have a critical impact on results. For example, in the study of Nielsen et al. (1998), a differentiation was made on the basis of whether an offender was “impulsive” or “non-impulsive.” This turned out to be a critical differentiation since the associations were found to be much stronger in the impulsive sub-group. This differentiation was made on the basis of the most recent crime, so that a person could actually be reclassified from impulsive to non-impulsive, which goes against the view that impulsivity is a trait characteristic. Most studies did not ascertain Axis II conditions, except Mann et al. (1997) who did find a significant association between borderline personality disorder and TPH.

A related issue is that there may be an “endophenotype” associated with suicidal behavior, namely impulsive aggression, yet most studies did not assess this, even though it appeared to be related to both TPH, polymorphisms of the serotonin transporter, and MAOA (Manuck et al., 1999; Manuck et al., 2000; New et al., 1998; Zalsman et al., 2001).

Sex differences. It would be surprising if genetic effects were not moderated by gender. In fact, the functional significance of TPH polymorphisms appears to be different in males and females, with a more profound effect on central serotonin metabolism in men (Jonsson et al., 1997; Manuck et al., 1999). The relationship between impulsive aggression and TPH A218C appears to be moderated by sex (Manuck et al., 1999), as do relationships between other personality measures and polymorphisms of the serotonin transporter (Du et al., 2000a). Inconsistencies between studies of suicide and suicide attempt could be explained in part by differences in the sex composition of the groups. Sex effects need to be considered in these analyses.

Ethnic differences. Ethnic differences are also an important consideration, and may explain how studies in clinically similar samples might differ (e.g., a positive study in depressed Caucasians [Mann et al., 1997] versus a negative one in Japanese mood-disordered patients [Kunugi et al., 1999]). Particularly when studying haplotypes, there are likely to be significant ethnic differences, with a finding that allelles are tightly linked in a Caucasian sample, but not in a Japanese one (Ono et al., 2000; Turecki et al., 2001).

Screening Expressed Genes

It has been hypothesized that a separate unique set of expressed genes could be associated with suicidal behavior and that the interaction of these genes with depressive or schizophrenic genes may be necessary for

Suggested Citation:"4 Biological Factors." Institute of Medicine. 2002. Reducing Suicide: A National Imperative. Washington, DC: The National Academies Press. doi: 10.17226/10398.
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the expression of the suicidal phenotype. Whole genome scans of depressed and schizophrenic patients have revealed areas on the human genome containing genes that contribute to the depressive and/or schizophrenic phenotype. In the past for example, candidate genes implicated by our understanding of the pathophysiology of these diseased states or by their location in regions identified by whole genome scans have been investigated. So far, this has been a tedious and relatively unproductive approach in that researchers have only been able to evaluate one gene at a time. Previous technical limitations have severely hindered efforts to study the level and pattern of expression of many brain genes simultaneously in different regions. However, recent technological developments have dramatically altered the scientific landscape and made it possible, for the first time, to use microarray technology in postmortem brain tissue to screen 10,000 to 15,000 genes in one experiment.

The microarray technology involves the extraction of mRNA from brain regions of interest, construction of mRNA expression arrays following PCR amplification and purification of DNA clones, hybridization of labeled cDNA tissue to the array, and the quantification of the arrays. The arrays, which are an inch or so square and contain elements identifying up to 15,000 genes, can be robotically printed or obtained commercially. These arrays can be labeled with fluor dyes and the differential expression of the genes between patient and control tissue can be detected with lasers. A large number of genes can be screened for differential expressions between patient and control tissue, thus identifying new candidate genes.

A research strategy involves (1) identifying regions of interest in postmortem brain tissue and individually matched controls, (2) performing high density microarray analysis comparing the relative levels of gene transcripts in patients and controls, (3) analyzing gene expression profiling with cluster analysis and data mining tools, (4) evaluating selected mRNAs with real time quantitative polymerase chain reaction (PCR) and in situ hybridization mapping, and (5) repeating analyses of additional cohorts for each disease or condition. In the future, evidence from three bodies of data may converge to signal the relevance of specific identified genes. A gene of major interest could have (1) been identified as over- or underexpressed in suicidal patients versus controls, (2) occurred in a region of the genome identified as a “hotspot” in suicidal patients by whole genome scans; (3) occurred in brain regions and cell types compatible with our understanding of the pathophysiology of suicide. Possible experiments to attempt to identify a set of genes unique to suicide might involve scientists investigating brain tissue from a cohort of major depressive disorder patients with and without suicidal behavior, bipolar affective disorder patients with and without suicidal behavior, and schizo-

Suggested Citation:"4 Biological Factors." Institute of Medicine. 2002. Reducing Suicide: A National Imperative. Washington, DC: The National Academies Press. doi: 10.17226/10398.
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phrenic patients with and without suicidal behavior. In this design, diseased states remain constant while suicidal behavior varies. It should be emphasized that identified genes associated with suicide may or may not be causative, but may be vulnerability genes, or downstream modulating genes. Nevertheless, this technology will provide important candidate genes for future interaction with the pharmaceutical industry in the development of novel therapeutic compounds and could make important contributions to our understanding of the pathophysiology of suicide.

FINDINGS

  • Dysregulation of one of the body’s primary stress response systems, the hypothalamic-pituitary-adrenal (HPA) axis, appears associated with suicidality across psychiatric diagnoses. Such HPA axis dysfunction often develops following adverse developmental experiences and traumatic or chronic stress; HPA axis dysregulation is also implicated in the development of some mental disorders. Although screening for abnormal HPA axis function seems promising for predicting eventual suicide, it does not consistently predict acute suicidal behavior.

The utility of assessing HPA axis function as a physiological screening tool for suicide risk should be explored. Longitudinal, prospective studies of the influence of HPA axis function on suicidality are needed. Medical and psychosocial treatments that attenuate HPA dysregulation should be further developed and tested for their efficacy in reducing suicide.

  • Neurobiological research on suicide has revealed significant changes in the serotonergic systems. Low levels of serotonin and/or its metabolite have been found in the brains and cerebrospinal fluid of serious suicide attempters and/or those who complete suicide; abnormalities in serotonin receptors have also been found in those who complete suicide. Studies suggest that impaired serotonin function specifically influences suicidality via increased impulsive aggression. Other neurotransmitter systems, especially noradrenergic function, also show alterations with suicidal behavior. Neurochemical changes appear to be specific to certain brain regions. Brain mapping techniques provide a valuable tool for determining biological markers for suicide.

  • Studies find evidence of genetic influences on suicidality via familial aggregation of suicide, high suicide rates among adoptees whose biological families have elevated rates, and high concordance of suicide among identical vs. fraternal twins. This line of research represents a still-developing area of suicidology; no studies of suicide in identical twins

Suggested Citation:"4 Biological Factors." Institute of Medicine. 2002. Reducing Suicide: A National Imperative. Washington, DC: The National Academies Press. doi: 10.17226/10398.
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raised apart has been conducted, for example, and much remains unknown about non-genetic familial transmission of suicide.

Biological predictors of suicidal behavior should be sought through brain mapping studies. Prospective, rather than cross-sectional studies, are crucial. Analyses in vivo would allow the examination of changes over time to elucidate response to treatment and remission from episodes of mental illness. Moreover, brain mapping studies may help to identify individuals at risk for suicidal behavior.

  • Genetic factors are strongly related to liability for suicidal behavior, accounting for 30–50 percent of the variance. The genetic liability may be linked to the heritability of mental illness and/or impulsive aggression. However, family, cultural, and other environmental factors must be considered as independent factors. Family studies have shown that offspring of suicide attempters are much more likely to engage in suicidal behavior. Factors that increase the likelihood of transmission of suicidal behavior include the transmission of impulsive aggression and sexual abuse from parent to child. Therefore, offspring of parents who have made suicide attempts are at high risk for suicidal behavior and may inform us about the mechanisms of familial transmission, both genetic and non-genetic.

    Prospective studies of populations at high risk for the onset of suicidal behavior, such as the offspring of suicide completers or attempters, can allow for studies of neurobiologic, genetic, and non-genetic factors that predict the onset of suicidal behavior.

    Genetic markers that have functional significance and correlate with impulsive aggression and suicidal behavior cross-sectionally may have the potential to identify individuals at risk and help pinpoint treatment.

  • Adoption studies, twin studies, and family studies are effective approaches to elucidate the genetic liability for suicide and to assess both genetic and non-genetic influences. Candidate gene analyses suggest the genetic targets that influence suicidal behavior. New microarray technology can aid researchers in identifying genetic variations between suicidal and non-suicidal individuals. These approaches hold great promise for elucidating the risk factors for suicide and providing tools for its assessment, treatment and prevention.

Future research using these approaches should be pursued. Twin studies of suicidal behavior should examine familial transmission through genetic and non-genetic pathways and explore associations

Suggested Citation:"4 Biological Factors." Institute of Medicine. 2002. Reducing Suicide: A National Imperative. Washington, DC: The National Academies Press. doi: 10.17226/10398.
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with both mental disorders and impulsive aggression to shed light on the genetic antecedents of suicidal behavior.

Candidate gene approaches should be used to (a) study multiple genes, e.g., along the serotonin pathway; (b) examine candidate genes in greater depth, through direct sequencing and haplotype analyses; (c) examine candidate gene associations with related quantitative traits (endophenotypes) and should (d) use statistical approaches that fully exploit case control designs, and at the same time control for overdispersion (genetically related subjects), using, for example, the methods of genomic control or excess haplotype sharing extension.5

Genetic samples from psychiatric populations can provide valuable information. To get the most from genetic analyses, all psychiatric genetic studies should also gather information about suicidal behavior, including lethality, intent, and age of onset of first attempt. Existing samples of DNA on psychiatric populations should be studied to examine the relationship between genetic markers and suicidal behavior. Genetic isolates (i.e., populations that have had few or no new genes added from outsiders for many generations) with a high rate of suicide and suicidal behavior should be identified for linkage studies.

5  

Genomic control is a type of analysis of candidate gene data where one can control for the amount of overdispersion by genotypic “null genes” that are thought not to be involved with the disorder. If those null genes show a relationship to the disorder, that suggests overdispersion rather than a true relationship to the disease. Excess haplotype sharing means that a great extent of genetic material is shared in common. This would be rare and unlikely to be due to chance.

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×

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Suggested Citation:"4 Biological Factors." Institute of Medicine. 2002. Reducing Suicide: A National Imperative. Washington, DC: The National Academies Press. doi: 10.17226/10398.
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In a Time

In a time of secret wooing

Today prepares tomorrow’s ruin

Left knows not what right is doing

My heart is torn asunder.

In a time of furtive sighs

Sweet hellos and sad goodbyes

Half-truths told and entire lies

My conscience echoes thunder

In a time when kingdoms come

Joy is brief as summer’s fun

Happiness, its race has run

Then pain stalks in to plunder.

—MAYA ANGELOU

From Just Give Me A Cool Drink of Water Fore I Die by Maya Angelou, copyright © 1971 by Maya Angelou. Used by permission of Random House, Inc.

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Every year, about 30,000 people die by suicide in the U.S., and some 650,000 receive emergency treatment after a suicide attempt. Often, those most at risk are the least able to access professional help.

Reducing Suicide provides a blueprint for addressing this tragic and costly problem: how we can build an appropriate infrastructure, conduct needed research, and improve our ability to recognize suicide risk and effectively intervene. Rich in data, the book also strikes an intensely personal chord, featuring compelling quotes about people’s experience with suicide. The book explores the factors that raise a person’s risk of suicide: psychological and biological factors including substance abuse, the link between childhood trauma and later suicide, and the impact of family life, economic status, religion, and other social and cultural conditions. The authors review the effectiveness of existing interventions, including mental health practitioners’ ability to assess suicide risk among patients. They present lessons learned from the Air Force suicide prevention program and other prevention initiatives. And they identify barriers to effective research and treatment.

This new volume will be of special interest to policy makers, administrators, researchers, practitioners, and journalists working in the field of mental health.

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