Comments on “An Observational Case-control Study for BDNF Val66Met Polymorphism and Serum BDNF in Patients with Major Depressive Disorder (MDD)”

Dear Editor,

Brain-derived neurotrophic factor (BDNF) has been implicated in depression due to its role in synaptic plasticity. However, despite extensive research on the Val66Met polymorphism and serum BDNF levels, evidence for an association remains inconclusive. ¹

Ramawat et al. ² evaluated the association between serum BDNF levels and Val66Met polymorphism in patients with major depressive disorder (MDD) using a case-control design. The study concluded that the Val66Met polymorphism may not be linked to MDD or influence BDNF levels. However, serum BDNF concentrations were significantly lower in MDD, which is in line with previous reports. The authors presented a well-structured introduction that outlined the background and relevance of the study.

However, the article lacks clearly defined objectives; instead, it provides a broad and generalized aim that limits the clarity of the research. A notable limitation of the methodology is the lack of assessment of the control group and the source from which these controls were recruited. On the other hand, the use of multiple scales to assess cases raises questions, particularly the use of clinically useful depression outcome scale (CUDOS) and clinical global impressions scale (CGI), as Hamilton depression rating scale (HAM-D) already assesses severity, and treatment response was not among the stated objectives. Furthermore, the inclusion of nicotine dependence in both groups, while excluding other substance use disorders, is not justified. The primary concern we wish to highlight is the lack of matching for key confounding variables, such as age, gender, BMI, exercise pattern, and lifestyle, which could influence the outcomes.^3,4 Despite these concerns, the authors should be commended for their detailed description of estimating serum BDNF levels and Val66Met polymorphism, as well as for blinding the researchers performing assay analyses, which strengthens the reproducibility and validity of the study, respectively.

In the results section, which includes the socio-demographic profile (Table 1), key clinical variables such as the number of previous depressive episodes, current suicidality, and presence of psychosis were omitted, despite their relevance to the study’s exposures.^5,6 The inclusion of Hardy-Weinberg equilibrium testing stands out as a key strength, given its importance in genetic association studies. ⁷ Although the study aimed to demonstrate reduced BDNF in MDD, both cases and controls exhibited lower than expected levels, raising concerns about internal validity. This underscores the need to report key methodological details such as storage temperature and duration, freeze-thaw cycles, timing of assays (single or multiple time points), and the sensitivity and specificity of the kits used. ⁸ While comparisons were made between medication-naive patients, those receiving treatment, and controls, further analysis comparing medicated patients with controls could clarify the impact of pharmacotherapy on BDNF levels. Most importantly, the absence of regression analysis is a significant query, as it estimates the relationship between each independent variable and the dependent variable, thereby strengthening the conclusions drawn. ⁹

Other concerns include the grouping of the Val66Met polymorphism into genetic models (Table 3), which lacks clarity and detailed description, and combining multiple analyses in Table 5, hindering interpretation. The mention of the word “observational” in the title is redundant, as “case-control” already implies an observational study. Nevertheless, the authors present a thorough discussion that integrates both supporting and conflicting findings related to their results, offering a balanced perspective on the role of BDNF and Val66Met polymorphism in depression. The integration of Indian studies further enhances the regional relevance.

The aspect that warrants attention is regarding the choice of a case-control study design, as the study does not clarify whether the exposure, namely, low serum BDNF levels and Val66Met polymorphism, preceded the onset of depression. This limitation undermines one of the key strengths of the case-control design, which is its ability to assess the association between past exposures and current disease status. ⁹ Given this, a cross-sectional design with a control group may have been more appropriate for addressing the research objectives. Overall, the study provides valuable insights into the potential influence of BDNF and Val66Met polymorphism on depression, which in turn paves the way for future research to explore their clinical utility.