ABSTRACT: Major depressive disorder (MDD) affects millions of people worldwide and is a leading cause of disability. Several theories have been proposed to explain its pathological mechanisms, and the "neurotrophin hypothesis of depression" involves one of the most relevant pathways. Brain-derived neurotrophic factor (BDNF) is an important neurotrophin, and it has been extensively investigated in both experimental models and clinical studies of MDD. Robust empirical findings have indicated an association between increased BDNF gene expression and peripheral concentration with improved neuronal plasticity and neurogenesis. Additionally, several studies have indicated the blunt expression of BDNF in carriers of the Val66Met gene polymorphism and lower blood BDNF (serum or plasma) levels in depressed individuals. Clinical trials have yielded mixed results with different treatment options, peripheral blood BDNF measurement techniques, and time of observation. Previous meta-analyses of MDD treatment have indicated that antidepressants and electroconvulsive therapy showed higher levels of blood BDNF after treatment but not with physical exercise, psychotherapy, or direct current stimulation. Moreover, the rapid-acting antidepressant ketamine has presented an early increase in blood BDNF concentration. Although evidence has pointed to increased levels of BDNF after antidepressant therapy, several factors, such as heterogeneous results, low sample size, publication bias, and different BDNF measurements (serum or plasma), pose a challenge in the interpretation of the relation between peripheral blood BDNF and MDD. These potential gaps in the literature have not been properly addressed in previous narrative reviews. In this review, current evidence regarding BDNF function, genetics and epigenetics, expression, and results from clinical trials is summarized, putting the literature into a translational perspective on MDD. In general, blood BDNF cannot be recommended for use as a biomarker in clinical practice. Moreover, future studies should expand the evidence with larger samples, use the serum or serum: whole blood concentration of BDNF as a more accurate measure of peripheral BDNF, and compare its change upon different treatment modalities of MDD.
