Neurobiological Factors Associated with Suicidal Behavior

SPECIAL ARTICLES

Neurobiological Factors Associated with Suicidal Behavior Bun-Hee Lee, M.D., Ph.D., Yong-Ku Kim, M.D., Ph.D. Department of Psychiatry and Division of Brain Korea 21 Biomedical Science, College of Medicine Korea University, Korea

Introduction

Abstract Suicide is a major public health issue and a signifi-

Suicide is a major public health issue, and constitutes

cant cause of death worldwide. Many animal, post-

a significant cause of death worldwide. The WHO esti-

mortem, clinical, and genetic studies have produced

mates that suicide accounts for almost 2% of all world-

results implicating at least 3 neurobiological systems in

wide deaths.1 In a consistent finding across cultures,

the pathogenesis of suicidal behavior: a deficiency in

the rates of completed suicides are higher in males than

the serotonergic system, hyperactivity of the hypothala-

in females.2 Attempted suicide occurs with greater fre-

mic-pituitary-adrenal axis, and excess of norepineph-

quency than completed suicide, with a lifetime preva-

rine release followed by norepinephrine deficiency. In

lence of approximately 3.5%, and it has been estimated

addition, several studies have pointed to the involve-

that up to 10% of suicide attempters will commit sui-

ment of the dopaminergic system, neurotrophic factors,

cide within 10 years.3

cholesterol, and cytokines in the pathogenesis of suici-

Defining suicidal behavior

dal behavior. However, more research will be required in order to confirm these associations. In the future, a greater understanding of suicidal behavior and its neu-

Suicidal behavior includes a wide spectrum of behav-

robiology may facilitate the detection of at-risk indi-

iors. On one end of this spectrum are fatal acts (com-

viduals, and contribute to the development of more

pleted suicide) and highly lethal, but failed suicide

effective interventions.

attempts (in which high degrees of intention and planning are evident and survival is fortuitous). At the other end of the spectrum are low-lethality attempts, which

Key words: Suicide, Neurobiology, Serotonin, Hypothalamic-pituitary-adrenal, Norepinephrine.

tend to be impulsive acts, which are frequently triggered by a social crisis.4 Suicidal ideation, which often

[ Psychiatry Invest 2006; 3 (2):23-35]

includes suicidal thoughts or threats without action, is more commonly encountered than either suicide attempts or completed suicide, with a wide variance in Correspondence: Yong-Ku Kim, M.D., Ph.D., Director and Professor, Department of Psychiatry, Korea University Ansan Hospital, College of Medicine, 516, GoJan-dong, Ansan, Kyunggi-do, Korea (425-020) Tel: +82-31-412-5140, Fax: +82-31-412-5144, E-mail: [email protected]

prevalence. Suicidal ideation has been reported in females with almost twice the frequency observed in males. It has also been determined that suicidal ideations are almost always associated with a psychi-

23

Neurobiology and suicide

FIGURE 1. A stress-diathesis model of suicidal behavior.

atric disorder.5,6 Although the precise clinical definition

tance of a diathesis or predisposition to suicidal behav-

of suicidal behavior remains less than satisfactory, the

ior which may be independent of the principal psychi-

phenomenon of suicidality is frequently viewed as

atric disorder.14 Other clinical features which increase

occurring on a continuum of increasing severity from

the risk of suicidal behavior include aggressive/impul-

ideation, to attempts, to completed suicide, and can be

sive traits, hopelessness or pessimism, substance abuse

classified in terms of the degree of actual intent to die,

or alcoholism, a history of physical or sexual abuse

the method employed, the lethality of the method (vio-

during childhood, a history of head injury or neurologi-

lent or non-violent), the degree of cognitive impairment

cal disorder, and cigarette smoking.14 The fact that this

involved (impulsivity, aggressiveness), and the mitigat-

list includes several strictly biological factors, includ-

ing circumstances inherent to the subject’s situation.

ing head injury, underlines the importance of neurobio-

7

8

logical correlates with regard to our current understanding of suicide.

Clinical correlates of suicidal behavior

In the stress–diathesis model of suicide behavior proposed by Mann,15 a typical stressor can acutely worsen

Over 90% of suicide victims and suicide attempters

a pre-existing psychiatric disorder, but the most proxi-

evidence some psychiatric illness. Approximately

mal stressor is frequently an acute psychosocial crisis,

60% of all suicides occur within the context of mood

which then elicits suicidal behavior. Pessimism and

disorders, and the remainder are associated with a

aggression/impulsivity are components of the diathesis

variety of other psychiatric conditions, including schiz-

for suicidal behavior, and sex, religion, familial/genetic

11

ophrenia, alcoholism, substance abuse, and diverse

factors, childhood experiences, and various other fac-

Even in the psychiatric

tors influence the diathesis (Figure 1).15 Among these

groups at the highest risk, the majority of patients

other factors are serotonin and cholesterol levels, as

never attempt suicide, thereby indicating the impor-

well as other biological correlates.

9

9

10

personality disorders.

12,13

24

Lee BH & Kim YK

The neurobiology of suicidal behavior

sistent, and have been discussed as being associated more with major depression than with suicide. 22 Several studies of the platelets of suicide attempters

The serotonergic system

revealed an upregulation of 5-HT2A receptors as a peripheral marker for suicidality.23,24

Serotonergic abnormalities, which are associated with a variety of psychopathological dimensions

Although plenty of investigations have been con-

including anxiety, depressed mood, impulsivity, and

ducted regarding serotonergic genes, only two

aggression, have been the focus of many previous

genes, one coding for tryptophan hydroxylase 1

investigations.

(TPH1) and the other for the serotonin transporter

Postmortem studies of the brains of suicide victims

5-HTTLPR, have been consistently suggestive of

have revealed evidence for reduced numbers of sero-

involvement in vulnerability to suicidal behavior

tonin transporter sites within the prefrontal cortex,

(Table 1). The TPH1 gene exhibits the less common

hypothalamus, occipital cortex, and brainstem.16 In an

A218 and A779 alleles, which have been associated

autoradiographic study, this abnormality was found to

with a blunted prolactin response to fenfluramine,25

be localized in the ventromedial prefrontal cortex.17

as well as low levels of CSF 5-HIAA in healthy

Alterations were also observed on the receptor level, as

volunteers.26 Courtet et al.7 suggested that TPH may

postsynaptic 5-HT1A and 5-HT2A receptors were

be a quantitative risk factor, in which a greater

determined to be upregulated in the prefrontal cortex,

effect of the gene results in an intensification of

and this increase was tentatively implicated as a com-

serotonergic dysfunction, associated with higher

pensatory mechanism for the low activity of the sero-

levels of anger and more severe suicidal acts. The

tonergic neurons.14 It is worthy of note that this sero-

5-HTTLPR serotonin transporter gene exhibits two

tonin dysfunction appears to be localized in the ventral

allelic variants, a long (L-allele) and a short allele

prefrontal cortex, a region known to be involved in

(S-allele). In studies concerning mood disorders,

behavioral and cognitive inhibition.17 Low serotonergic

alcoholism, and suicide attempts, associations have

input may contribute to impaired inhibition, thereby

been reported between the S-allele and violent sui-

producing a greater propensity to act upon suicidal or

cide attempts. 27-29 Mann et al. associated the S-

aggressive feelings.14

allele with major depression, but not with suicide.30

The finding that low concentrations of cerebrospinal

Du et al.31 discovered an association between the L-

fluid (CSF) 5-HIAA may be related to the incidence of

allele and suicide in people evidencing major

violent suicidal acts has been reported in several stud-

depression, but the association could be with either

ies of higher-lethality attempted suicides, within the

depression or suicide, as the controls evidenced neither of these conditions. Studies of gene polymor-

context of major depression, schizophrenia, and per-

phisms of the 5-HT1A, 5-HT2A, and 5-HT1B

sonality disorders.18-20 Low concentrations of CSF 5-

receptors have generated predominantly negative

HIAA are predictive of both future suicide attempts

findings (Table 1).

and suicide completions20,21 In a challenge investigation using fenfluramine, the

The noradrenergic system

increase in prolactin secretion elicited by fenfluramine was found to be more blunted in suicide attempters evi-

Only a few postmortem studies have concerned

dencing a higher degree of lethality, which may suggest

themselves with alterations in the noradrenergic or

that serotonergic activity tends to be lower in suicide

dopaminergic systems. The primary findings of these

attempters.21 However, some of these results are incon-

studies included reduced noradrenalin (NA) levels in

25

Neurobiology and suicide

TABLE 1. Candidate genes and polymorphisms associated with suicidal behavior Candidate gene

Methods

Findings

Tryptophan hydroxylase (TPH) gene TPH1 gene: A779C

A218C

promoter

a) 56 impulsive and 14 nonimpulsive alcoholic, violent offenders and 20 healthy controls

a) Only two of the 36 suicide attempters had the UU genotype in contrast to 10 out of 34 probands who never attempted suicide, independent of impulsivity status and cerebrospinal fluid 5-HIAA concentration.71

b) 804 Finnish alcoholic offenders, controls, and their relatives, altogether a sample that included 369 sib pairs

b) The L-allele showed significant linkage to suicidality in affected sib pairs, severe suicide attempts in unaffected sib pairs, alcoholism in unaffected sib pairs, and to the Karolinska Scales of Personality socialization score.72

c) 24 surviving monozygotic twins whose cotwins had committed suicide, compared to 158 Swedish controls

c) The living monozygotic cotwins of suicide victims had a significantly higher TPH 17 779C allele (L-allele) frequency than controls73

d) 41 Caucasian inpatients with major depression, with or without a history of suicidal acts

d) The less common TPH U allele occurred with greater frequency in the depressed patients with attempted suicide.19

a) 28 postmortem brains of suicide victims

a) AA genotype of the TPH1 A218C polymorphism showed TPH immunoreactivity in suicide victims.74

b) 927 patients (527 bipolar affective disorders and 400 unipolar affective disorders) and their matched healthy controls collected within the European Collaborative Project on Affective Disorders

b) No statistically significant difference was observed for allele frequency or genotypes. The C-C genotype (homozygosity for the short allele) was significantly less frequent in a subgroup of unipolar patients with a history of suicide attempt than in control subjects.75

c) Two meta-analyses of data from 17 studies: one compared suicide attempters or completers (n=1290) with 2295 healthy controls; the other compared suicide attempters (n= 625) with non-attempters (n=1475)

c) None of these analyses provided evidence for association. The combined results from both analyses showed no overall association between suicidal behavior and the intron 7 A218C polymorphism of the TPH gene.76

d) A meta-analysis of data from seven studies

d) The meta-analysis showed a significant increase in the frequency of the A218 allele and an over-representation of A-carriers in Caucasians with suicidal behaviors.77

e) A meta-analysis of data from 9 association studies between the A218C TPH polymorphism and suicidal behavior.

e) The meta-analysis showed a significant association between the TPH A218C polymorphism and suicidal behavior. The analysis suggested that the A allele has a dose-dependent effect on the risk of suicidal behavior.78

101 suicide completers with the most severe methods and 129 normal controls

Based on the genotypes at 3 TPH loci (the A6526G and G5806T polymorphisms in the promoter region, and A218C in intron 7), haplotype analysis revealed that one haplotype (6526G 5806T 218C) was significantly more frequent among suicide cases than among normal controls.79

Serotonin transporter gene a) 58 Caucasian suicide victims

a) An association of the S-allele of 5-HTTLPR and completed, mainly violent, suicide29

26

Lee BH & Kim YK

Candidate gene

Methods

Findings

b) 51 Caucasians who had made violent suicide attempts and 139 controls of the same ethnic origin, with no history of suicidal behavior

b) The frequencies of the S allele and the SS genotype were significantly higher in the violent suicide attempters than in the controls.80

c) 95 suicide completers recruited at the Montreal Central Morgue and 120 healthy controls of similar ethnic origin (French Canadians)

c) This study found no increased frequency of the short allele or of genotypes containing one or two copies of the short allele among suicide completers.81

d) Postmortem brain samples from 220 individuals: genotype 5-HTTLPR and assay binding of 5-HTT

d) The 5-HTTLPR genotype was associated with major depression but not with suicide or 5-HTT binding.30

e) A one-year follow-up study of 103 patients hospitalized after a suicide attempt

e) Patients who reattempted suicide during a 1-year follow-up period had a significantly higher frequency of the S-allele and the SS genotype.82

f ) Three meta-analyses: One compared suicidal subjects and normal control subjects; another compared suicide attempters with nonattempters of the same psychiatric diagnoses; the last one compared either violent or nonviolent suicidal subjects with normal control subjects

f ) This study found no association between 5-HTTLPR polymorphism and suicidal behavior. Comparing subjects with the same psychiatric diagnoses, the genotypes carrying the S allele were significantly more frequent in suicide attempters than in nonattempters. The S allele was associated with violent suicide, but not with nonviolent suicide.83

Serotonin 2A receptor gene T102C

a) 78 Canadian patients with major depression

a) This study reported an association of the 5-HT2A receptor 102C allele with suicidal ideation and that patients with the CC genotype had significantly higher scores of suicidal ideation in HAMD than TC or TT genotypes.84

b) 159 patients with major depression and 164 unrelated and healthy controls that were of Spanish origin

b) Significant differences in allele and genotype distributions were found between non-suicide attempters and suicide attempters. Those patients carrying 5HT(2A)-C allele had more than five times the risk for attempting suicide than noncarriers.85

c) 131 suicide victims, 84 patients with major depression, and 125 healthy controls

c) No association of 5-HT2A-T102C polymorphism with depression, suicidal ideation, or suicide.86

d) A meta-analysis of data from 6 association studies

d) No association with the 5-HT2A T102C variants.87

Serotonin 1A receptor gene C1019G

a) 700 psychiatric subjects

a) Positive associations in genotypes and allele frequencies were observed for substance abuse disorder, schizophrenia and panic attacks, but not for suicidal behavior.88

b) Investigated suicide completers and patients with major depression in separate cohorts (all Canadian Caucasian)

b) An association of the C-1019G 5-HT1A promoter polymorphism with major depression and suicide in separate cohorts. In depressed patients, the homozygous -1019G allele was enriched twofold versus controls, and in completed suicide cases the -1019G allele was enriched fourfold.89

27

Neurobiology and suicide

Candidate gene

Pro161Leu/ Gly272Asp

Methods

Findings

Examined the association with suicide victims

No significant difference in genotype distribution or allele frequencies between suicide victims and controls90

Monoamine oxidase A uVNTR & a dinucleotide repeat in intron 2

Genotyped 738 West European Caucasians, who had made suicide attempts, and 222 controls of the same ethnic origin with no history of suicidal behavior

No association between the two MAOA gene variants and suicidal behavior. However, the frequency of the uVNTR 2-3 alleles was significantly higher in men who had attempted suicide by violent means than in men who had used non-violent means.91

Catechol-O-methyltransferase (COMT) 158Val/Met (H/L)

a) Retrospectively investigated in a Finnish sample (n = 94) and a US sample (n = 54) with history of suicide attempts

a) The COMT L allele was more frequent in subjects who had attempted suicide by violent means. This association was significant in males but not females.92

b) 163 suicide completers (112 males and 51 females) and controls

b) This study found that the genotype distribution of the COMT 158Val/Met polymorphism was significantly different between male suicide completers and male controls, while the frequency of the Val/Val genotype, a high-activity COMT genotype, was significantly less in male suicide completers than in male controls.93

the brainstem and increased 2-adrenergic receptor densities in suicide victims, which were suggested to

of the D1 and D2 receptor or of D4 receptor binding

be upregulated secondary to NA deficits.32 Levels of

tims.35,36 A recent investigation of homovanillinic acid

tyrosine hydroxylase (TH), the rate-limiting enzyme in

(HVA) in the CSF of depressed suicide attempters has

NA and dopamine (DA) synthesis, were reported to be

demonstrated reduced levels of HVA in attempters, but

higher in one study, but were found to be reduced in

not in depressed non-attempters,37 and the dopamine

Increased TH and 2-adrenergic receptor densities may be indicative of noradrenergic depletion

system appears to function at a lower level in cases of

have been detected in the caudate nuclei of suicide vic-

33

another.

34

major depression.38

compensatory to increased NA release. Increased NA release might be attributed to the hypothesized rela-

The hypothalamic-pituitary-adrenal (HPA)

tionship between the noradrenergic system and stress

axis and cortisol

response, because severe anxiety or agitation are asso-

Cortisol and the HPA axis constitute an important

ciated with noradrenergic overactivity, higher risk of

stress-response system, and suicide may be associated

suicide, and overactivity of the hypothalamic-pituitary-

with hyperactivity of the HPA axis. Corticotropin-

adrenal (HPA) axis.14

releasing hormone (CRH) levels in the CSF have been reported to be increased in suicide victims, thereby

The dopaminergic system

revealing that increased HPA axis activity is associat-

Thus far, there have been few studies of the dopamin-

ed with suicidal behavior.39 However, not all studies

ergic system. Overall, no alterations of mRNA levels

have demonstrated a similar association, and patients

28

Lee BH & Kim YK

who made repeated suicide attempts have been found

acutely suicidal patients with affective disorder were

with CSF CRH levels even lower than those observed

also determined to be lower than those of nonsuicidal

in nonrepeaters. 40 No differences in CSF arginine

inpatients with affective disorder, or those of healthy

vasopressine concentrations have been demonstrated

subjects.51

between depression patients who have attempted sui-

A study comparing serum cholesterol levels

cide and depression patients who did not attempt sui-

among drug-free patients who had made a violent

Elevated 24-hour urinary cortisol and 17-

suicide attempt, patients who had made a nonvio-

hydroxycorticosteroid levels have been detected in

lent suicide attempt, and healthy subjects, deter-

patients who had recently attempted suicide, as com-

mined that serum cholesterol levels were 30%

pared with patients with no history of suicidal behav-

lower in the violent suicide attempters than in the

ior.

Studies comparing the results of the dexam-

other groups. 52 Our studies of Korean subjects

ethasone suppression test (DST) in suicidal and non-

have demonstrated that total serum cholesterol and

suicidal individuals have proven contradictory.

low density lipoprotein levels tend to be lower in

However, Coryell and Schlesser demonstrated that

the parasuicidal population, and that serum

HPA axis hyperactivity at baseline DST is associated

triglyceride levels tended to be lower in suicide

with a 14-fold increase in the likelihood of suicide

attempters with major depression than in non-sui-

during 15 years of follow-up. 44 Yerevanian et al.

cidal depressed patients. 53,54 We evaluated serum

reported that DST non-suppression can be used as an

cholesterol levels in 149 major depressive disorder

identifier for unipolar depressed patients with a higher

patients who had recently attempted suicide, 149

risk of future suicide completion or hospitalization for

non-suicidal depressive patients, and 251 normal

suicidality.

HPA axis hyperactivity may influence

controls. Our results suggested 2 serum choles-

adrenergic system overactivity and alterations of the

terol level cutoff points that could be employed in

serotonergic system.

the categorization of depressive patients: 180

cide.

41

42,43

45

14,46

mg/dl of cholesterol is a point associated with Plasma cholesterol

high sensitivity for possible suicide risk, and 150 mg/dl is a point with a high specificity for proba-

Examinations of clinical trials of cholesterol-lower-

ble suicide risk.55

ing drugs have revealed an associated increase in mortality due to accidents, violence, and suicide. 47,48

However, some studies have reported that treatment

Kaplan et al. suggested that serum cholesterol reduc-

with the cholesterol lowering agent, lovastatin, as well

tion, which is produced as the result of changes in

as diets that lowered serum cholesterol levels, affected

serum composition or lipoprotein concentrations, might

neither psychological distress nor adverse effects in a

affect brain levels of fat-soluble micronutrients, struc-

healthy population.56,57

48

tural lipids, cellular communication molecules, or neuMiscellaneous results

rotransmitters, including serotonin.49 Clinical studies have indicated the existence of a

Some postmortem studies have demonstrated signifi-

relationship between suicidal behavior and lower

cant decreases in brain-derived neurotrophic factor

total cholesterol levels. Suicide attempters evidenced

(BDNF) and neurotrophin-3 (NT-3) levels within the

significantly lower cholesterol levels than were

prefrontal cortices and hippocampi of suicide victims.58

detected in nonsuicidal psychiatric inpatients and

A study also reported that BDNF mRNA levels were

psychiatrically normal individuals who had sustained

significantly reduced in both the prefrontal cortices and

accidental injuries.50 Plasma cholesterol levels in

hippocampi of suicide subjects as compared with those

29

Neurobiology and suicide

detected in control subjects, regardless of psychiatric

The results of clinical, postmortem, genetic, and ani-

diagnosis.59 The results of our study, which compared

mal studies have suggested that at least 3 neurobiolog-

plasma BDNF levels among psychiatric patients who

ical systems may be involved in the pathogenesis of

had recently attempted suicide, psychiatric patients

suicidal behavior. First, a large number of studies

without suicide attempts, and normal controls, demon-

involving blood platelets, CSF, postmortem brains,

strated that plasma BDNF levels were significantly

functional neuroimaging, and genetics have convinc-

lower in recent suicide attempters than in others, par-

ingly demonstrated an association between a deficient

However, the find-

serotonergic system and suicidal behavior. Second,

ings of studies concerning the Val66Met polymorphism

urinary cortisol production, CSF studies, DST non-

of the BDNF gene demonstrated no relationship

suppression, and postmortem brain studies suggest an

between this polymorphism and a history of suicide

association between HPA axis hyperactivity and suici-

attempts in Chinese unipolar and bipolar patients.62 A

dal behavior.

ticularly the depressive patients.

60,61

study of the Ser205Leu polymorphism of the NT

Third, evidence has been found for a relationship

receptor gene reported a positive result in Japanese sui-

between excess norepinephrine release and associated

cide attempters.63 Our data also revealed that plasma -

changes in the noradrenergic neurotransmission sys-

nerve growth factor levels did not significantly differ

tem. In addition, the results of several studies appear to

between suicide-attempting and non-attempting depres-

point to the involvement of the dopaminergic system, neurotrophic factors, cholesterol, and cytokines.

sive patients.64

However, more research will be required in order to

Nitric oxide (NO) has also been suggested to play a

verify these associations. In the future, it is essential

role in the modulation of the release of other neuro-

that we identify the psychiatric, social, and environ-

transmitters in the HPA axis or in stress response.65-67

mental predictors of suicide, in order to improve our

We evaluated plasma NO metabolite levels in patients

ability to predict and prevent suicide. A better under-

who had recently attempted suicide, nonsuicidal psy-

standing of the neurobiology of suicide may facilitate

chiatric patients, and normal controls. Our data indi-

the detection of at-risk individuals, and may also con-

cated that increased NO generation in plasma was

tribute to the development of more effective treatments

associated with suicide attempts, particularly in

and interventions.

depressive patients.68 Our findings appear to suggest a Th1 and Th2 cytokine imbalance occurring in a subpopulation of depressed patients. 69 We also deter-

Acknowledgements

mined that the levels of Th1 cytokines (IL-2 and IL-6)

This study was supported by a grant of the Korean

were significantly lower in suicidal depressed patients

Health 21 R & D Project, Ministry of Health & Welfare,

than in non-suicidal depressive patients and normal

Republic of Korea (A040042).

controls.70

Conclusions

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