The Neurobiology of Suicide Student name Date

Background What we’ve studied so far this semester This week: the neurobiological and genetic aspects of suicidal behavior This presentation will cover the neurobiological topics

Wake Up! Everybody stand up and stretch- I know this topic has a lot of jargon, so please bear with me!

Main Topics of Discussion The Serotonergic System The Noradrenergic System The Dopaminergic System The HPA Axis Abnormalities of Signal Transduction Genes, Environment, and Stress Responses

The Serotonergic System Fewer presynaptic serotonin transmitter sites in the prefrontal cortex, hypothalamus, occipital cortex, and brainstem of suicide victims. What does this mean?

The Serotonergic System Serotonin: a neurotransmitter which aids inhibition Prefrontal cortex: involved in personality, decision- making, appropriate social behavior Hypothalamus: releases hormones for homeostatic control RESULT: there is less serotonin reaching these areas of the brain, and so they are becoming disinhibited. Question: Why do you think these areas of the brain are involved?

The Serotonergic System Ono et al. found no alteration in TPH (the rate-limiting enzyme in the synthesis of serotonin) or in 5-HT binding in suicide victims, “indirectly indicating that impaired serotonin input… affects the ventromedial prefrontal cortex.” Ok, what does THAT mean?

The Serotonergic System The ventromedial prefrontal cortex is involved in behavioral & cognitive inhibition. Injury to this area leads to disinhibition, and low serotonergic input might lead to impaired inhibition as well. In other words, the previous slide meant that the processes (TPH and 5-HT binding) which could be buffering the effect of the low serotonergic input are not doing so- and so the low input is indeed affecting the brain, and perhaps causing disinhibition.

The Serotonergic System 5-HIAA is the main metabolite of serotonin “modestly lower” amounts are found in suicide victims Low CSF 5-HIAA predicts suicide attempts and completions The more lethal the suicide attempt, the lower the CSF 5-HIAA Why would low levels of the serotonin metabolite predict suicidal behavior?

The Serotonergic System The more lethal the suicide attempt, the lower the prolactin response to fenfluramine (a serotonin reuptake inhibitor). Similar blunted responses are seen in impulsive and aggressive individuals. Why would the hypoactive prolactin response to fenfluramine predict suicidal behavior?

The Noradrenergic System What is noradrenaline? Also known as norepinephrine, it is the “fight or flight” chemical responsible for the body’s reactions to stressful situations, and prevents distraction from irrelevant stimuli.

The Noradrenergic System Noradrenaline levels are lower in the brainstems of suicide victims, whereas alpha-2- adrenergic receptor numbers are higher. One study also showed higher TH (the rate-limiting enzyme in the biosynthesis of noradrenaline). TH increases as a compensatory mechanism under conditions in which increased noradrenaline release leads to transmitter depletion. So, increased TH and alpha-2-adrenergic binding could indicate noradrenic depletion.

The Noradrenergic System Depression increases noradrenergic and cortisol-dependant stress responses. So, TH unpregulation in the locus coeruleus of suicide victims could be in response to too much noradrenaline release in response to pre-suicide stress. Severe anxiety or agitation can lead to noradrenergic overactivity, higher suicide risk, and overactivity of the HPA axis.

The Dopaminergic System So far, there is little research in this area, and so there is not enough evidence to determine whether there are changes in dopamine or HVA (its main metabolite) in either the prefrontal cortex or the brainstem of victims. However, during major depression, the dopamine system is hypofuctional, and suicide attempters with major depression have low CSF HVA.

The Dopaminergic System Cholecystokinin mRNA levels (associated with anxiety and psychosis) are elevated in the prefrontal cortex of suicide victims. However, there have been too few studies conducted to fully understand this phenomenon.

The HPA Axis Using the DST test (and measuring cortisol response), studies suggest that hyperactivity of the HPA system may be involved in suicidal behavior, but much more research is needed.

Abnormalities of Signal Transduction The effects of receptor upregulation might be offset by impaired signal transduction. This impairment might be due to a loss of cortical target neurons during depression, but again more research is necessary.

Genes, Environment, & Stress “Adverse rearing” (i.e. abuse) might “set” the serotonergic function at a lower level, which could persist into adulthood. How do you think this might inform our understanding of “blame” in suicide?

Concluding Note Although the results found by the studies of the neurobiology of suicide may be interesting, Baldessarini and Hennen doubt their usefulness at this time.

Summary We discussed five different systems in the brain and how they might relate to suicidal behavior. We also mentioned the significance of impaired signal transduction and adverse rearing in suicidal behavior.

Questions for Discussion What do you think about the comparative relevance and usefulness of the biological studies? Which of the points did you find most compelling, and why? Can you think of any other systems in the brain that might be worth investigating, in terms of the links to suicide?

Thanks for listening! The End