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Background: The predictive therapeutic value of brain derived neurotrophic factor (BDNF) and its changes associated with the use of specific antidepressants are still unclear. In this study, we examined BDNF as a peripheral and NAA as a central biomarker over the time course of antidepressant treatment to specify both of their roles in the response to the medication and clinical outcome., Methods: We examined serum BDNF (ELISA kit) in a sample of 76 (47 female and 29 male) depressed patients in a naturalistic setting. BDNF was assessed before medication and subsequently after two, four and six weeks of antidepressant treatment. Additionally, in fifteen patients, N-acetylaspartate (NAA) was measured in the anterior cingulate cortex (ACC) with magnetic resonance spectroscopy (MRS). Over a time course of six weeks BDNF and NAA were also examined in a group of 41 healthy controls., Results: We found significant lower serum BDNF concentrations in depressed patients compared to the sample of healthy volunteers before and after medication. BDNF and clinical symptoms decreased significantly in the patients over the time course of antidepressant treatment. Serum BDNF levels at baseline predicted the symptom outcome after eight weeks. Specifically, responders and remitters had lower serum BDNF at baseline than the nonresponders and nonremitters. NAA was slightly decreased but not significantly lower in depressed patients when compared with healthy controls. During treatment period, NAA showed a tendency to increase., Limitations: A relative high drop-out rate and possibly, a suboptimal observation period for BDNF., Conclusion: Our data confirm serum BDNF as a biomarker of depression with a possible role in response prediction. However, our findings argue against serum BDNF increase being a prerequisite to depressive symptom reduction., (© 2016 The Author(s) Published by S. Karger AG, Basel.)