Although major depressive disorder (MDD) and suicide are two significant health problems, their pathophysiology is unclear. Although several studies have been conducted to develop biomarkers for their diagnosis, no diagnostic biomarkers are now widely employed in clinical practice for diagnosing either of them.
There are different types of biomarkers which include diagnostic, predictive, prognostic, and therapeutic response. Diagnostic biomarkers can be used to diagnose disease earlier and predict its occurrence in the future using non-invasive approaches. Patients who are likely to benefit from medication can be identified using predictive biomarkers. Prognostic biomarkers give insight into the course and fate of an illness. Biomarkers of treatment response provide insight into the effect of the therapeutic intervention . As a result of the increased potential for biomarkers, numerous bodily fluids have been studied, including urine, plasma, and CSF. Blood, for example, is easy to obtain and requires minimal invasiveness. MacDonald and his colleague, in his study, documented nine diagnostic biomarkers for MDD; some of them are upregulated like glutamate and alanine, while others are downregulated as Myo-inositol, GABA, phenylalanine, creatine, methionine, oleic acid, and tryptophan . A recent study has used metabolomic technique to identify plasma metabolites that could differentiate MDD patients from healthy subjects, investigate the biomarkers in the tryptophan-kynurenine pathway, and find that kynurenic acid (KYNA) may be implicated in the pathophysiology of depression .
These studies, as many other studies, were conducted aiming to find specific biomarkers that could make the early diagnosis of depression available, and at the same time accurate, which not only would be very helpful to the early treatment for depression but also will help in other devastating diseases in which depression could be considered as risk factor like neurodegenerative diseases including dementia . Moreover, depression is regarded as a significant complication of many conditions, for example, post-stroke depression (PSD) which may occur within few days and up to 84% at 3 months following stroke with significant impact on its prognosis as it may increase the risk of adverse complications even death .
Based on that, we conducted our study to shed light on a potential biomarker for diagnosing MDD patients and assessing the therapeutic response of antidepressant medications in those patients with suicidal ideation (SI). We investigated BDNF as an essential neurotrophic protein which is the most prevalent neurotrophin associated with depression through its involvement in the neurogenesis and neuroplasticity processes . Many studies demonstrated a causative association between entorhinal–hippocampal circuitry and neurogenesis and phenotypes of depression and strongly suggest that the hippocampal circuitry could involve the cerebral cortex in neurogenesis, thereby generating a neural circuitry–neurogenesis model may be a viable concept for combating memory, cognitive deficits, and mood disturbance, which are all associated with depression . Recent research utilizing advanced technologies like optogenetics, chemogenetics, and molecular-based methods has emphasized the entorhinal–hippocampal circuitry’s role in controlling neurogenesis and hippocampal-dependent cognitive and affective processes . There is specific activation of entorhinal glutamatergic afferents that improve behaviors associated with depression. According to the preceding studies, impaired neuroplasticity is associated with aberrant neurogenesis, axon branching, dendrites, and synapses. Neuroplasticity abnormalities may be related to variations in the amounts of neurotrophic factors, particularly BDNF, which plays a critical role in neuroplasticity. BDNF production and secretion are activity-dependent, a property associated with neural plasticity .
According to the present study, there was a highly statistically significant difference between the study groups in BDNF. Both MDD groups had lower BDNF than the control group, which was consistent with the results from previous studies [39,40,41,42,43,44,45].
In MDD subgroups, drug-naïve patients had significantly lower BDNF than drug-treated patients. This result was compatible with Aydemir and colleagues, who reported that treatment of depression improves the serum BDNF level . Besides, Ristevska and colleagues investigated the BDNF levels in untreated depressive patients, which were lower than healthy controls, and the lower levels of BDNF had increased after antidepressant treatment . These findings may postulate that low levels of serum BDNF are a state abnormality that is present during the depression and becomes normal during remission.
In contrast to the present study, Bus and colleagues and Chiou and Huang concluded that maintaining or discontinuing the antidepressant medications was not related to BDNF change [45, 47]. These results imply not only that BDNF contributes to depression but also that depression can lead to BDNF deficiency.
In the present study, a statistically significant difference between the drug-treated MDD patients and the control group was consistent with Molendijk and colleagues .
However, Emon and colleagues and Kim and colleagues reported no significant difference in the BDNF levels when comparing drug-treated MDD patients to a control group [48, 49].
In contrast to our study, a recent study by Bilgiç and colleagues found that the mean serum BDNF levels were significantly higher in treatment-free adolescents with MDD than in control subjects .
Moreover, Polyakova and colleagues identified that serum BDNF might be regarded as a biomarker for the successful treatment of MDD .
Treatment options for depression include pharmaceutical and non-pharmacological interventions such as psychotherapy, electroconvulsive therapy (ECT), and transcranial magnetic stimulation (TMS). Psychotherapy has been shown to have beneficial effects on depression, including the reduction of depressive symptoms and an improvement in quality of life .
The involvement of neurotrophins in the mode of action of antidepressant drugs is considerably more obvious than their involvement in depression . Numerous studies reinforce the notion that neurotrophic factors stimulate neural plasticity, enhancing antidepressant responses in MDD patients [53,54,55]. In their recent review article, Yang and colleagues  documented that antidepressants affect neural plasticity on several levels. For example, prolonged antidepressant and acute ketamine therapy improve synaptogenesis and synaptic potency; in addition, ketamine’s actions are dependent on BDNF. Moreover, antidepressants may be used to detect increased neurogenesis in the dentate gyrus, which is dependent on BDNF signaling. Finally, antidepressants promote axon growth and dendritic branching and also the production of plasticity-related proteins. Although many specifics concerning whether this is mediated by BDNF or TrkB signaling remain unknown, it is known that BDNF influences both axonal and dendritic growth. These findings indicate a significant association between neuroplasticity and antidepressant effect mode of action, which implies that the impact of plasticity is conveyed, at least in part, by the BDNF signal . On the other hand, in a recent systematic review assessing the impact of psychotherapy on the levels of BDNF in patients with psychiatric disorders, they found a small amount of research examining the impact of psychotherapies on BDNF and concluded that patients who had only psychotherapy had no rise in BDNF levels; however, those who received concomitant medications had a much greater rise compared to those who had only pharmacological treatment .
BDNF was associated with some demographic characteristics of MDD patients like age, sex, family history, and disease duration in the present study. It is unknown either the lower levels of BDNF in patients with MDD patients are primary or secondary. One theory is that decreased BDNF levels in patients with depression may represent a genetic susceptibility. Another possibility is that stress-induced BDNF deficiency results in neuronal injury, which results in acquired biological susceptibility .
De Azevedo and colleagues concluded that BDNF was positively associated with disease duration, which was found in the present study .
One of the critical findings of this study is the significant relation between serum levels of BDNF and the severity of MDD as a significant negative correlation was found between serum BDNF and HAMD scores. These results are in line with much-related research [39, 41, 48].
On the other hand, studies of Chiou and Huang, Ai and colleagues, and Bilgiç and colleagues showed no significant correlation between BDNF and HAMD scores [19, 45, 50].
Regarding suicide ideation in the present study, high BSS (≥24) was associated with low BDNF in MDD patients. We found a statistically significant negative correlation between BDNF and BSS. Deveci and colleagues reported similar results, as well as Kim and colleagues, Lee and colleagues, Chiou and Huang, and Ai and colleagues [19, 40, 45, 49, 57]. However, Bilgiç and colleagues found no correlations between the levels of serum neurotrophins and suicidality .
Pathological alterations in BDNF expression are thought to be responsible for cognitive impairments associated with suicide. In mice treated to different stress techniques, a decreased BDNF level was seen in both bodily fluids and brain structures . Similarly, clinical investigations have indicated that patients with MDD and exhibiting suicidal behavior had decreased serum or plasma BDNF concentrations . Postmortem examinations of completed suicides reveal lower BDNF levels in the hippocampus and prefrontal cortex but no alterations in the entorhinal cortex or amygdala. It is worth mentioned that patients who had experienced early childhood trauma and/or committed suicide had reduced BDNF levels in the anterior cingulate cortex than no suicidal subjects with no reported childhood trauma .
The current research had certain limitations: First, we examined blood BDNF levels, and the difference between peripheral levels and brain levels of BDNF is controversial . Second, our findings are based on just one measurement of the level of BDNF and at a one-time point besides the relatively small sample size of our sample, so we suggest conducting a more extensive cohort study with a larger sample size and more blood BDNF measurements which would strengthen the findings. Finally, there are various other essential variables like genetic polymorphisms and epigenetics that influence BDNF levels. Unfortunately, we were not able to investigate any of them.