To our knowledge, this was the first study to address the relationship between suicide risk and serum VGF levels in patients with MDD. We found that: (1) the level of serum VGF in patients with MDD was significantly lower than in control patients, (2) VGF levels in the high-risk group were significantly lower than in the low-risk group, and (3) the risk of suicide in patients with MDD was closely related to the level of serum VGF.
Our results showed that serum VGF levels were significantly lower in patients with acute MDD who were not taking drugs than in the control group, indicating that peripheral VGF synthesis is decreased in MDD, consistent with previous experiments. For example, Jiang showed that levels of VGF in the peripheral blood were lower in patients with MDD than in healthy controls. After 8 weeks of treatment with the antidepressants escitalopram and duloxetine, the levels of serum VGF were recovered , suggesting that VGF plays an important role in the pathophysiology of MDD. It is not clear whether VGF passes through the blood-brain barrier, but it has been found in certain brain regions, as well as in CSF [21, 22]. Although the role of serum VGF in depression remains to be determined, similar changes have been documented in depression-like rats [23, 24], suggesting that VGF serum fluctuations reflect neurotrophic disorders in the marginal region. These results show that VGF plays an important role in the neurobiology and pathophysiology of MDD.
To our knowledge, only a few studies have focused on VGF in the peripheral blood of patients with MDD, and none have studied the relationship between the risk of suicide and VGF levels. Our study found that patients with high suicide risk had lower serum VGF than those at low risk, and that the risk of suicide was negatively correlated with the level of VGF. Although no previous articles have linked VGF to suicide risk, many have associated other neuropeptides with suicide. For instance, Jahangard et al. found increased binding of cholecystokinin receptors in the frontal lobe and cingulate cortex of suicide victims . In another study, lower levels of neuropeptide Y were found in the prefrontal cortex and caudate nucleus of suicide victims , and Kang et al. found that hypermethylation of brain-derived neurotrophic factor (BDNF) plays a role in the epigenetic susceptibility of patients with acute coronary syndrome who have a history of suicidal ideation. Taken together, these studies suggest that neuropeptides are closely related to suicide risk.
VGF, being a neuropeptide, may therefore play a key role in the human stress response. Stress events such as attempted suicide may alter the responsiveness of the hypothalamic-pituitary-adrenal system, and stress-induced corticosteroids reduce the expression of VGF levels in the blood and brain . Stress events can also enhance the expression of tyrosine hydroxylase, which regulates catecholamine synthesis, while glycopeptide increases with the final increase of norepinephrine transmission [28–30]. This may determine the direct and indirect inhibition of the function of postsynaptic neurons related to depressive behavior.
Another explanation for the low levels of VGF in patients at risk of suicide is that decreased serotonin function in such patients may down-regulate the expression of VGF. Patients with suicidal depression have lower levels of 5-HIAA, which is the main decomposition product of serotonin in the CSF . Low levels of CSF 5-HIAA predict future suicides and attempted suicides. Other indicators of decreased serotonin function in suicidal depression include prolactin insensitivity to fluoroamphetamine and abnormal platelet serotonin function . Both BDNF and serotonin regulate synaptic plasticity, neurogenesis, and neuronal survival. These two signaling molecules are related to each other, while VGF and BDNF regulate each other . Therefore, a damaged serotonin signal may reduce VGF expression in patients with suicidal depression.
The present study had some limitations. Firstly, the sample size was very small. Secondly, it is not clear whether VGF can cross the blood-brain barrier or whether VGF levels in the peripheral blood represent levels in the brain. Thirdly, to highlight the specificity of our findings in patients with suicidal depression, we only tested VGF levels; we did not detect other nutritional factors that have been associated with suicide risk. In future studies, we will evaluate serum VGF levels in a large number of matched control subjects; we will also conduct longitudinal studies to explain these preliminary findings.
In conclusion, the results of the current study showed that VGF levels in patients with MDD were down-regulated, and that the risk of suicide is associated with VGF levels.