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.



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Reducing Suicide: A National Imperative 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.

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Reducing Suicide: A National Imperative 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-

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Reducing Suicide: A National Imperative 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-

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Reducing Suicide: A National Imperative 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

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Reducing Suicide: A National Imperative 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.

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Reducing Suicide: A National Imperative 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).

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Reducing Suicide: A National Imperative 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.

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Reducing Suicide: A National Imperative 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

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Reducing Suicide: A National Imperative 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

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Reducing Suicide: A National Imperative 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

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Reducing Suicide: A National Imperative 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.

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Reducing Suicide: A National Imperative 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.