This review aims to summarize the current scientific knowledge on the correlation between BDNF and GDNF and suicide, to theorize whether neurotrophins could be a reliable marker for an early diagnosis of suicidal risk. Furthermore, this review aims to form the basis for an experimental case study.
4. DiscussionThis systematic review aimed to evaluate and summarize the innovative literature about the association between BDNF and GDNF levels and completed suicide. The eight analyzed papers are case-control studies that regarded the BDNF protein or gene, while only one study investigated the GDNF protein. A lack of interest in GDNF may suggest less involvement in the suicidal dynamic.
Some studies have shown a significant association between reduced BDNF levels and complete suicide. According to Hayley et al. [46], Schneider et al. [47], and Erbay et al. [53], BDNF can be a promising biomarker of suicidal tendencies because peripheral levels can match with central brain levels.Hayley et al. [46] found different BDNF protein expression in the two sexes, which is also in agreement with the epidemiological differences regarding suicidal tendencies between men and women [54]. They found that BNDF levels were lower in the prefrontal cortex (PFC) of depressed women, while in males, there was a reduction in the hippocampus. Furthermore, the basal PFC BDNF protein was lower in males than in females in non-depressed controls, which may be explained by sex differences in the epidemiology of depression and suicidal behaviors. The difference in BDNF transcription could be due to sex hormones; for example, estradiol can regulate the expression of BDNF [55].Schneider et al. [47] compared DNA methylation of the PFC brain in suicidal males and controls through a list of candidate genes, including BDNF. Due to the small sample, the researchers found no individual genes showing significant methylation differences. However, they demonstrated greater methylation of the BDNF promoter in the frontal cortex, in agreement with other studies that found the same evidence in the Wernicke area [56]. In any case, the authors observed that a single gene cannot influence the epigenetics of suicide but that an accumulation of adverse life experiences can increase suicidal risk. Kang et al. [57] noted that BDNF methylation also increased in the blood of suicidal patients. Hence, the authors observed that the methylation patterns in the blood might reflect the methylation patterns in the brain.Misztak et al. [50] showed a reduced level of the BDNF protein in the brains of suicide victims. The authors highlighted the role of the epigenetic component in the expression of BDNF, particularly in histones. According to other authors, the decreased levels of the BDNF protein may be related to the reduction in histone acetylation and the increase in deacetylation and methylation [58,59]. The authors pointed out that BDNF expression is tissue-dependent, particularly in the frontal cortex and hippocampus, which is consistent with other studies [60]. These epigenetic factors are further correlated with depression, suggesting an increasingly close link between depression and suicide [61].Erbay et al. [53] quantitatively assessed the mRNAs and protein levels of BDNF, NGF, and their TrkA and TrkB receptors in the hippocampus. The authors found a significant reduction in neurotrophin proteins and receptors. They also aimed to strengthen the connection between neurotrophins and suicide and identify them as biomarkers of psychiatric pathology. A strength of their study was the sample size and homogeneity, which were greater than those of the other studies analyzed in this systematic review.The other analyzed studies, on the other hand, did not show a significant correlation between BDNF reduction and suicide.
Indeed, Youssef et al. [49] investigated the association between the Val66Met polymorphism of the BDNF gene and low BDNF levels and suicide, major depression, and childhood adversity in brain samples. No differences between suicidal and non-suicidal subjects were shown for the polymorphism and the protein, while an association was evident with depression.Gadad et al. [51] showed that the central (brain and CSF) and peripheral (plasma) levels of BDNF, GDNF, and IL-6 are connected, hypothesizing a dysregulation of the blood–brain barrier. In depression, the increased permeability of the membrane allows the various molecules to pass [61,62]. According to the authors, the plasmatic concentration of IL-6, BDNF, and GDNF could reflect the brain concentration. They found that the brain BDNF levels in suicide were significantly higher than in non-suicide, consistent with other studies [63,64]. Nevertheless, they showed higher BDNF levels in patients treated with medications, confirming the relationship between therapy and BDNF increasing [65].Ropret et al. [52] examined BDNF methylation and BDNF transcriptase levels in the brain and blood. There was no difference in BDNF methylation between the two groups, while there was a reduction in the BDNF protein levels in the blood of suicide victims. They highlighted a higher expression of BDNF transcript I-IX in the Broadmann area 9 of the brain of suicide victims but not in the hippocampus.One crucial factor is the presence of psychiatric comorbidities, such as major depression. In the research of Hayley et al., all samples were affected by major depressive disorder and had not been on antidepressant drugs for at least two months, which was confirmed by toxicological analysis. Gadad et al. [51] divided the sample based on mood disorders and/or alcohol or drug consumption, with or without psychiatric medications. It showed a consistent difference in the BDNF levels between the medication groups.Erbay et al. [53] included only depressed suicidal subjects in the samples, excluding others with psychiatric or neurologic comorbidities and alcohol or drug users. Even in Schneider’s [47] samples, there were only depressed patients. They did not divide the samples into subgroups (based on possible confounding factors such as the use of drugs, comorbidities, etc.) because the literature [66,67,68,69] suggests that suicide-associated DNA methylation patterns are independent of the underlying psychiatric disorders. The two groups of Youssef et al. [49] did not differ in comorbidity, blood alcohol level, or other confounding factors.According to the results of these studies, there may be a connection between BDNF brain levels and complete suicide, although there are discrepancies. The authors use different analysis methods and samples, making it difficult to draw unambiguous conclusions. Another element is the presence of the suicide method in only four studies [46,50,52,53]. Without these elements, it is challenging to hypothesize whether BDNF depletion could be related to a specific suicidal mechanism. Identifying a suicide marker remains a challenge for the scientific and forensic community; they can also be useful in the differential diagnosis in forensic pathology [70,71].
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