The aim of this study was (i) to evaluate whether serum protein levels of BDNF and its regulators in the tPA–BDNF pathway, including tPA, BDNF, TrkB, proBDNF and p75NTR, are altered in drug-free MDD patients and to observe their putative changes during antidepressants treatment; (ii) to observe whether these proteins could serve as biomarkers for MDD diagnosis and treatment responsiveness; and (iii) to assess the associations between the clinical variables and serum protein concentrations of the above factors. This evidence concerns the gene NTRK2 and major depressive disorder.