Now moving on to the neurochemicals endophenotypes, we first begin with serotonin, which has long been known to be involved in emotional and cognitive functions including suicidal behavior. Cerebrospinal fluid (CSF) concentrations of major serotonin metabolite 5 hydroxyindoleacetic acid (or 5-HIAA) are reported to reflect central nervous system serotonergic function. Of note, low CSF 5-HIAA has been associated with impulsive, externally directed aggression which has been observed in impulsive murderers and arsonists compared to non-impulsive murderers and control subjects. The relationship between impulsivity and reduced serotonergic function has led to the hypothesis that this function supports a restraint mechanism and a deficiency in serotonergic function results in greater impulsivity and aggression including self-directed aggression of suicidal behavior.
Another endophenotype is Norepinephrine. The catecolaminergic dysfunction has been hypothesized to play a role in suicide based the observation of a high concentration of norepinephrine (or NE) with decreased alpha2-adrenergic bindings which has been observed in the prefrontal cortex of suicide victims.
The last neurochemical endophenotype is Dopamine. The dopaminergic system is abnormal in depression; increased concentrations of dopamine have been associated with aggressive behavior and suggest that increased dopamine concentrations may be related to violent suicide attempts or completions. In terms of neuroticism, studies have shown associations between the dopaminergic system and neuroticism. Striatal dopamine D2 receptor may be a significant predictor of neuroticism scores.
Finally in the last endophenotype of Carballo’s model, which are neuroendocrine endophenotypes. We focus more on the Hypothalamic-Pituitary-Adrenal Axis, or the HPA axis, now, this is a neuroendocrine system that regulates the body’s response to stress and has complex interactions with brain serotonergic, noradrenergic, and dopaminergic systems. Stress results in the release of the corticotrophin releasing hormone (CRH). Now, some studies indicate that suicidal behavior may be associated with hyperactivity of the HPA axis. These studies indicate higher cortisol levels after dexamethasone suppression (this is a clinical measure of HPA axis hyperactivity) and this hyperactivity at baseline levels may increase the risk of eventual suicide by as much as 14-fold. This according to two studies conducted in 1988 and 2001. The 1988 study was Brown, Ebert, Goyer et al., and the 2001 study, Coryell & Schlesser.
Continuing with neurobiological correlates of suicide risk-related diathesis traits, as found in Mann & Rizk’s article, which tells us that neuroimaging studies have found five main features of dysfunctional neural circuitry, starting with a relationship of enhanced negative affective and self-referential processing networks to suicidal ideation that may also underlie excessive subjective distress (these include the ventromedial prefrontal cortex, the medial orbitofrontal cortex , rostral anterior cingulate cortex, the insula, and the ventral striatum); two, structural and functional deficits in the dorsomedial prefrontal cortex, dorsolateral prefrontal cortex, the ventrolateral prefrontal cortex, and the dorsal anterior cingulate cortex that correlate with severity of subjective depression and contribute to less top-down control over ventromedial prefrontal cortex regions, which results in impaired decision making and, in turn, suicidal behavior; three, differential activation of the medial orbitofrontal cortex to pleasant versus negative facial expressions, which could be related to excessive distress and social distortions; four, serotonergic release deficits in the ventral prefrontal cortex and anterior cingulate cortex are more prominent in high-lethality suicidal behavior and suicide death; and finally, abnormalities of glutamate and opioid systems may affect memory, learning, and reward mechanisms.
In terms of Neurotrophic and Apoptotic Pathways, brain-derived neurotrophic factor (or BDNF) regulates neuron survival, plasticity, and synaptic function as well as plays an integral role in differentiation during development and is affected by stress as well as associated with major depression and suicidal behavior. With expression of BDNF and BDNF receptor tyrosine kinase B genes being lower in suicide decedents, and plasma BDNF levels being low in suicide attempters which could be reflecting a systemic genomic effect on BDNF expression.
Neuroinflammation can also be found to be related to suicide risk, with peripheral inflammatory biomarkers linked to this risk including elevated C-reactive protein, neutrophil-to-lymphocyte ratio, proinflammatory interleukins, cytokines that regulate the immune response, tumor necrosis factor-alfa, tissue growth factor b1 , and vascular endothelial growth factor as well as low levels of the anti-inflammatory Interleukin-2, Interleukin-4, and interferon-gamma in suicidal individuals (generally suicide attempters). Mann & Rizk’s article also refers that activated microglia, which is the primary immune response cells in the brain, and brain translocator protein found in mitochondria of activated glial cells are linked to suicide risk, independently of the presence of psychiatric disorders. Finally, greater suicidal ideation severity has been found to be associated with higher C-reactive protein, Interleukin-6, and Interleukin-10 levels and with activated microglia-related alterations of the tryptophan-kynurenine pathway. This suggests that regulation of inflammatory pathways may change with level of suicidal ideation and therefore risk. However, more longitudinal studies are needed to determine whether fluctuating suicide risk correlates with severity of inflammation, this is due to a recent study that reports no association between suicidal ideation severity and cytokine pathway marker mRNA expression.
Now to conclude this talk about the neurobiology of suicide, I will give a clinical description of Depression. Forbes (2020) tells us that depression is a developmental disorder that can occur as early as the preschool years, with adolescence being a vulnerability period for it.
In the article, Forbes references Rappaport et al. (2020) whose study showed that cumulative and current depression were associated with different patterns of frontostriatal response during adolescence. In addition, the developmental point at which depression was experienced appeared to influence the regions exhibiting disruption: while depression during early childhood was related to low responding in the dorsal striatum, ventral striatum, and rostral anterior cingulate cortex, depression during adolescence was related to low responding in the nucleus accumbens.
Nemeroff (2020) identifies the risk of major depressive disorder being characterized by a combination of ill-defined genetic and environmental factors, including a higher prevalence in the female gender, a history of childhood mistreatment, and family history of the illness, as well as more recent stressors.
There are remarkably high levels of a bidirectional comorbidity of major depression with other psychiatric illnesses including PTSD, syndromal anxiety disorders, OCD, and substance abuse disorders and even medical illnesses, where there is a documented relatively low treatment response in depressed patients with comorbid medical disorders, which coupled with suicide, is the primary cause of premature mortality in patients with major depression.
Depression is a uniquely human con
dition. It does not occur naturally in any other species in the same longitudinal nature, including its recurrent course.
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