Gutiérrez-García AG, Contreras CM

Language: Spanish
References: 0
Page: 321-329
PDF size: 133.85 Kb.

ABSTRACT

Suicidal behavior is a complex and multifactorial phenomenon. At present, growing evidence shows the participation of biological traits in suicidality. Some findings suggest the dysfunction of the serotonin system, since serotonin and some of its receptor subtypes are involved in the modulation of such as affective behavior and cognition, among other behavioral processes. The content of 5-hydroxyindoleacetic acid, the major serotonin metabolite, is reduced in the cerebrospinal fluid of violent suicide attempters, independently of any other previous psychiatric diagnosis. In fact, this reduction may predict future suicide attempts and suicide completion. Post-mortem studies of ventromedial prefrontal cortex from suicide victims show decreased density of the 5-HT_1A presynaptic serotonergic receptor subtype, and a compensatory upregulation of the 5-HT_2A serotonergic post-synaptic receptor subtype. These observations on suicide strongly suggest a role of the two serotonin receptor subtypes located in this cortical brain region. Dysfunction of this region may support the diathesis concept (vulnerability) associated to suicidal behavior. In fact, some people display impulsive and self-aggressive behavior as part of their suicidality. This dysfunction is associated with alterations in the polymorphisms of tryptophan hydroxylase gene expression, i.e., the rate-limiting enzyme which in turn modifies the biosynthesis of serotonin, contributing to the reduction of serotonergic activity.
Since the prefrontal cortex and related structures play a major role in mood regulation, their participation in the pathophysiology of affective disorders and suicide is currently being discussed. A circuit integrated by prefrontal cortex, hippocampus, amygdaloid complex, lateral septal nucleus and other functionally related structures could be involved in the regulation of emotional memory, hedonism and decision-taking. The hippocampus is implicated in cognition and is one of the cerebral structures strongly affected by stress.
Structural abnormalities in cortical and hippocampal areas and reduced hippocampal plasticity have been demonstrated in patients suffering from chronic stress and affective disorders. Reduced neurotrophin expression may be associated with structural abnormalities and reduced hippocampal plasticity. A decrease in the content of neurotrophins in the prefrontal cortex and hippocampus could be of relevance in suicidal behavior. Human post-mortem studies supported by living animals studies have demonstrated that antidepressants increase the activity of the brain-derived neurotrophic factor (BDNF) and increase the density of its receptor (BDNF-tyrosine kinase receptor B: trkB), which seems to participate in the therapeutic effects of drugs used in the treatment of depression. On the contrary, the reduction of BNDF trkB-receptor mRNA has been related to suicidal behavior, since a reduction of plasma BNDF levels has been reported in major depression. BNDF levels have also been suggested as a biological marker of suicidal depression.
Abnormalities in the ventromedial prefrontal cortex in suicidal individuals largely correlate with the neurochemical deficits reported in this population. In fact, prefrontal hypofunction and impaired serotonergic responsivity are proportional to the lethality of the suicide attempt. Positron emission tomographic studies indicate lower ventromedial prefrontal cortex activity, behaviorally associated with high impulsivity, higher planning of suicidal intent, and higher-lethality suicide attempts.
Other studies have also related structural abnormalities in amygdala with suicidality. The function of this region is critical regarding fear, anxiety, aggression and the recognition and response to danger, i.e., some behavioral patterns involved in suicidality. Anxiety commonly follows or precedes depression. Therefore, amygdaline dysfunction may increase the risk of suicidal behavior. For depressive-suicide attempters, the suicide act itself occurs at a moment of extreme anxiety, strongly suggesting amygdaloid complex participation in the process.
Lastly, the lateral septal nucleus is related with anhedonia and hopelessness (despair). Since its neuronal firing rate increases after the experimental application of clinically effective antidepressant treatments. The septal nucleus is considered a target of these drugs, a suggestion supported by the observation that anhedonia is one of the main symptoms in depression and lateral septal nucleus activity is involved in hedonic process. Anhedonia, hopelessness and other depressive symptoms are significantly related to suicidal ideation. Taking into account that some patients with major depression are vulnerable to suicide, this vulnerability may result from the interaction of suicidality with environmental precipitants and a lowered threshold for suicidal behavior. Certainly, one of the psychiatric disorders associated with suicide is depression, which suggests a causal relationship and suggests the involvement of these brain structures in suicidality.
Then, an anatomic and functional circuit may be expected. In normal conditions, the environment is perceived through the sensorial systems. Sensorial information reaches circuits located in the temporal lobe, such as amygdala and hippocampus, in which a comparison with previous experiences takes place. It is acceptable to consider that emotional memory comparison and acquisition of new information is a continuous process. By pathways arising from amygdala, the forebrain structures related with hedonic processing, such as lateral septal nuclei, may be involved. In species with a low development of frontal cortex (birds, amphibian, reptiles) many of the functions of prefrontal cortex are likely in charge of thalamic nuclei, namely, its association nuclei. In these species, the circuit reached enough functionality for the species surviving, given that when an animal copes with a dangerous situation it needs a comparison with previous experiences. This first learning of adequate responses takes place much time before, around weanling. But it is enough, since an animal scarcely needs to process a decision, simply attack or escape, approaches or avoid. It is simple, but tremendously efficacious. In human beings, the participation of the prefrontal cortex allow us to select a response, and depending on previous experiences, but namely trait, i.e., the actual contingence and the right functionality of all the circuits, the correct response is going to be selected, and survival strategies may succeed. In other case, if any of the anatomical substrates of emotional memory, hedonic processing or taking decisions circuits is deficiently working, the response to cope must be wrong. This may explain some common mistakes in selecting the right response, but also if the previous experiences and personality trait implicate impulsivity, the consequence may be fatal. We ask ourselves, is it suicidality? It might very well.
Suicidality is also related to the response to stress. The hypothesis of hypothalamic pituitary adrenal axis hyperactivity in suicide is supported by post-mortem findings showing increased cerebrospinal fluid content of corticotrophin-releasing hormone, combined with reduced receptor binding sites for this hormone in the prefrontal cortex.
Although some risk factors have been identified, the complete neurobiological basis of suicide is not well understood yet. Cerebral structures involved in the integration of the affective state, emotional memory, impulsivity and decision-taking may participate in suicide.
Therefore, depending on the previous diagnosis, antidepressants, lithium or second-generation antipsychotics may be the first option in the management of suicidality. Atypical antipsychotics produce beneficial effects on depressed mood in patients with major depressive disorder and in patients with bipolar disorder. In schizophrenic patients, a significant amelioration of suicidality using clozapine, among other atypical antipsychotics, has also been reported. The sudden presence of anxiety, agitation and impulsivity must call the attention in patients suffering from depression, bipolar disorder, schizophrenia or schizoaffective disorder to seek pharmacological treatment combined with psychotherapy.