This document summarizes research on the neurobiological factors related to suicide. Key findings include: 1) Alterations in neurotransmitter systems like serotonin and norepinephrine are associated with suicidal behavior; 2) Imaging studies show differences in brain regions involved in mood regulation, decision-making, and stress response in suicide attempters; 3) Family, twin, and adoption studies provide evidence that genetic factors contribute to suicidal behavior independent of psychopathology. Specific genes like those related to serotonin transporters and MAO-A have been linked to suicide risk.

1. Neurobiology of Suicide
Dr. Challa S V Krishna Vasan
Senior Resident
Department of Psychiatry
Rangaraya Medical College

2. Overview
• Introduction
• Alterations in the neurotransmitter systems in suicidal behaviour
• Imaging studies in suicidal behaviour
• Genes and suicidal behaviour
• Genes and early environmental interaction
• Developmental factors related to neurobiology of suicide
• Cholesterol and lipid metabolism
• Conclusion
• References

3. Introduction
• Suicide accounts for about one million deaths world wide each year.
• Over 90% of suicide attempters or suicide victims have a psychiatric illness
with 60% of all suicides occurring in relation to mood disorders.
• Most people with major psychiatric disorders never manifest suicidal
behaviour, indicating the importance of diathesis in addition to a disorder.
• Only 1 in 20 persons who wish to end their life really try to do so.
• Only 1 in 5 or 10 who attempt will die of suicide.

4. Alterations in the neurotransmitter systems in
suicidal behaviour
• These include
a. Serotonin system
b. Catecholamine system
c. Other systems
i. GABAergic system
ii. Glutaminergic system
iii. Cholinergic system

5. Serotonin system
• Postmortem studies of the brain in suicide identified alterations in
serotonin transporter binding.
• Lower concentration of CSF 5-HIAA has also been reported in patients
who use violent methods to complete suicide or make non-fatal
attempts of higher lethality.
• Lower C-α-methyl-L-tryptophan trapping in the orbital and
ventromedial prefrontal cortex was found in suicide attempters who
made high-intent attempts.
• Abnormal serotonergic function is a biochemical trait of suicide.

6. Catecholamine system
• Dopamine
a. Inconsistent findings have been obtained when assessing the
relationship between CSF and urine levels of Dopamine metabolites
homovanillic acid (HVA) and dihydroxyphenylacetic acid
(DOPAC) and suicidal behaviour.
b. One study examined the basal ganglia of depressed suicide
completers and found no differences in numbers or affinities of
DRD1 and DRD2.

7. • Norepinephrine:
• Abnormalities in the noradrenergic system in suicide attempts include
fewer norepinephrine (NE) neurons in the locus ceruleus in depressed
suicides, greater prefrontal β-adrenergic cortical receptor binding and
lower alpha2 α-adrenergic binding.
• Lower baseline CSF 3-methoxy-4-hydroxphenylglycol (MHPG) was
associated with increased risk of suicidal behaviour (fatal or non-
fatal).
• The lower the CSF MHPG, the more lethal the suicide attempt at
follow-up.

8. • Higher NE concentrations have been associated with higher levels of
aggression and higher CSF MHPG with greater hostility.
• In remitted depressed individuals treated with norepinephrine
reuptake inhibitors, acute catecholamine depletion resulted in an
increase in hopelessness or depression.
• A selective serotonin reuptake inhibitor (SSRI) was more effective at
reducing suicidal ideation than a noradrenergic drug (TCA or SNRI).
• Perhaps an increase in noradrenergic function is less directly helpful
for suicidal ideation than an increase in serotonergic transmission.

9. Other systems
• Alteration of NMDA receptor functioning is seen in hippocampus.
• Increased GABA concentrations was found in the CSF of suicide
attempters with personality disorders which were highly related to
impulsivity in these individuals.
• Increased GABA-A receptor density in the prefrontal cortex is noted
particularly in violent suicide completers.
• Increased mAChR densities in the cerebral cortex of suicide
completers.

10. Stress-diathesis model of suicidal behaviour

11. Imaging studies in suicidal behaviour
• Structural imaging findings include mainly right-sided deficits in
volumes of grey matter in cortical areas orbitofrontal(aggression and
impulsivity), dorsolateral prefrontal (mood regulation and top down
control of decision making) and basal ganglia.
• The volumes of thalamus and right amygdala (stress response and
emotional memory) seem to be greater in suicide attempters.
• Functional neuroimaging findings include changed reactivity to
several stimuli, noted mainly in bilateral orbitofrontal, right
ventromedial and anterior cingulate (decision making).
• Functional connectivity is decreased between anterior cingulate and
posterior insula.

12. Genes and suicidal behaviour
• The idea that hereditary factors played a role in suicidal behavior has
been noted by as early as 1790.
• Both suicidal attempts and deaths due to suicide are found to be
hereditary.
• Inheritance of the risk for suicide is independent of transmission of
the psychopathology in the families.

13. Family studies
• The seminal psychological autopsy study conducted by Eli Robin
et al. in 1959, which found suicidal behavior between 6% and
31% of first-degree and second-degree relatives of suicide
probands.
• Probands with high levels of Cluster B traits had higher familial
loadings of suicide than other probands. A part of the familial
aggregation of suicidal behavior could be attributed to
cosegregation with impulsive-aggressive traits.
• Relatives of suicide completers were over 10 times more likely
than relatives of comparison subjects to attempt or complete
suicide after controlling for psychopathology.

14. Twin studies
• A higher concordance of suicidal behavior among MZ twins compared
to DZ twins and concordance for suicide completion was 11.3% in the
MZ twins and 1.8% in the DZ twins.
• The largest study was performed by Statham et al. (1998) found that
the history of suicidal behavior in one twin was a predictor for suicidal
behavior in MZ twin but not in DZ twins.
• Fu et al. examined suicidal ideation and suicide attempts in men and
found that after controlling for psychiatric disorders, the heritability
for ideation was 36%, and the heritability for suicide attempts was
17%.

15. Adoption studies
• Schulsinger et al. reported increase in suicides in biological relatives
and no incidents of suicide among the adoptive families of the suicide
completers or controls.
• Wender et al. identifed increase in both attempted and completed
suicides among biological relatives of adoptees with a 15-fold higher
prevalence in the biological relatives of the cases.
• Affect regulation was a greater indicator than depression for suicidal
behavior, and impulse control play an important role in suicide.
• Psychiatric morbidity in the biological parents accounted for a third of
the increased risk.

16. Association and linkage studies
• Chromosomal regions linked with suicide attempts, including 2p, 5q,
6q, 8p, 10q, 11q, and Xq. Regions linked with suicide completions
include 2q, 4p, 6q.
• The human serotonin transporter gene is located on chromosome 17
and a polymorphism in this transporter (5-HTTLPR) results in
differential expression of the gene product leading to suicidal
behavior.
• The MAO-A gene has been mapped to the short arm of the X
chromosomes higher rate of suicides among males could be due to
greater impulsivity and aggression, secondary to MAO-A
polymorphisms.

17. • The cathecol-O-methyl transferase (COMT) enzyme is a major enzyme
in norepinephrine inactivation.
• A Val158Met polymorphism in the COMT gene results in the allele
encoding valine having relatively high activity compared to that
encoding methionine.
• The methionine allele (Met allele) is reportedly associated with
violent suicide attempt, specifically in male schizophrenics.
• The Val/Val (high activity) genotype of the COMT 158Val/Met
polymorphism was reported to have a protective role against suicide.

18. Genes and early environmental interaction
• Maternal deprivation in rodents resulted in less expression of the
glucocorticoid gene due to DNA methylation of CpG sites in the
promoter or regulatory region of the gene. This would favor greater
cortisol levels under stress.
• Adverse experiences such as physical or sexual abuse, have been
shown to be transmitted intergenerationally may alter gene
expression and behavior through DNA methylation and other
epigenetic effects in key genes like HPA axis related genes.
• Altered gene expression within the brain, leads to permanent
modifications in HPA axis function that later in life result in abnormal
molecular and hormonal responses to further stressful stimuli.

19. Developmental factors related to
neurobiology of suicide
• Adversity in infancy have lower levels of CSF 5‐HIAA and lower
serotonin transporter binding.
• Rhesus monkeys exposed to maternal separation in infancy have
altered noradrenergic response to stress in adulthood, elevated CSF
NE showing evidence of overactivity and subsequent depletion.
• The excessive NE release when stressed in adulthood can result from
sensitization of the system as a result of childhood adversity leading
to increase in anxiety.
• Sexual and physical abuse independently contribute to repeated
suicide attempts (risk over 10 times) after controlling for a range of
childhood adversities such as parental loss and neglect.

20. Cholesterol and lipid metabolism
• There is a small increase in the rate of suicide, and perhaps suicide
attempts and ideation, in people with very low cholesterol levels and
after lowering of cholesterol through the diet.
• Muldoon et al. concluded that there was a significant increase in non-
illness-related mortality (i.e., deaths from accidents, suicide, or
violence) in groups receiving treatment to lower cholesterol
concentrations compared with controls.
• Although non-significant results have been observed among more
recent meta-analyses, the overall evidence strongly supports the
involvement of cholesterol in suicidal behavior.

21. • Lower serum cholesterol levels have been observed in violent
compared to nonviolent suicide attempters as well as in the brain
tissues of violent suicide completers.
• Gender-specific differences have sometimes been observed, with
greater effects being found in male compared to female suicide
attempters.
• There is a relationship between cholesterol and 5-HT
neurotransmission resulting from alterations in membrane fluidity.
• Altered immune response that the role of lipid metabolism in suicide
may be due to a relationship between increased levels of pro-
inflammatory cytokines and the levels of cholesterol and fatty acids.

22. Antisuicidal action of lithium and clozapine
• Lithium – serotonin 5HT2A receptor upregulation, enhancement of
brain glutamine levels and augmentataion of GABA-B receptors and
increased hippocampal volume.
• Clozapine - simultaneous modulation of dopamine, norepinephrine,
and serotonin, regulation of the hormone system (pregnenolone,
cortisol) and brain-derived neurotrophic factor up-regulation and
intracellular systems – dependent modulation of N-methyl-D-
aspartate (NMDA) receptor expression.

23. Conclusion
• Both completed and attempted suicide are heritable.
• Abnormal serotonergic function is a biochemical trait of suicide.
• Inheritance of the risk for suicide is independent of transmission of
the psychopathology in the families.

24. Suggested books to refer in Suicidology

25. References
• O'Connor RC, Pirkis J, editors. The international handbook of suicide
prevention. John Wiley & Sons; 2016.
• Nock MK, editor. The Oxford handbook of suicide and self-injury. Oxford
University Press; 2014.
• Van Heeringen K, Mann JJ. The neurobiology of suicide. The Lancet
Psychiatry. 2014 Jun 1;1(1):63-72.
• Carballo JJ, Akamnonu CP, Oquendo MA. Neurobiology of suicidal behavior.
An integration of biological and clinical findings. Archives of suicide
research. 2008 Feb 29;12(2):93-110.
• Mann JJ. Neurobiology of suicidal behaviour. Nature Reviews Neuroscience.
2003 Oct;4(10):819-28.

26. Thank you