Peripheral brain-derived neurotrophic factor (BDNF) as a biomarker in bipolar disorder: a meta-analysis of 52 studies

Background: The neurotrophic hypothesis postulates that mood disorders such as bipolar disorder (BD) are associated with a lower expression of brain-derived neurotrophic factor (BDNF). However, its role in peripheral blood as a biomarker of disease activity and of stage for BD, transcending pathophysiology, is still disputed. In the last few years an increasing number of clinical studies assessing BDNF in serum and plasma have been published. Therefore, it is now possible to analyse the association between BDNF levels and the severity of affective symptoms in BD as well as the effects of acute drug treatment of mood episodes on BDNF levels. Methods: We conducted a systematic review and meta-analysis of all studies on serum and plasma BDNF levels in bipolar disorder. Results: Through a series of meta-analyses including a total of 52 studies with 6,481 participants, we show that, compared to healthy controls, peripheral BDNF levels are reduced to the same extent in manic (Hedges' g = -0.57, P = 0.010) and depressive (Hedges' g = -0.93, P = 0.001) episodes, while BDNF levels are not significantly altered in euthymia. In meta-regression analyses, BDNF levels additionally negatively correlate with the severity of both manic and depressive symptoms. We found no evidence for a significant impact of illness duration on BDNF levels. In addition, in plasma, but not serum, peripheral BDNF levels increase after the successful treatment of an acute mania episode, but not of a depressive one. Conclusions: In summary, our data suggest that peripheral BDNF levels, more clearly in plasma than in serum, is a potential biomarker of disease activity in BD, but not a biomarker of stage. We suggest that peripheral BDNF may, in future, be used as a part of a blood protein composite measure to assess disease activity in BD.BSF is supported by a postdoctoral scholarship and by a research grant MCTI/CNPQ/Universal 14/2014461833/2014-0, both from CNPq, Brazil. CAK is a recipient of a postdoctoral fellowship from CAPES, Brazil. JCS is supported by NIMH grant R01 085667, the Dunn Foundation and the JQ are supported by research fellowship awards from CNPq (Brazil, level IA). AFC is the recipient of a research fellowship from CNPq (Brazil, level II). MB is supported by a NHMRC Senior Principal Research Fellowship 1059660. None of these agencies had any role in the design and conduct of the study, or decision to submit the manuscript for publication. We thank all authors of the included papers, particularly Drs. Natalie L. Rasgon, Deniz Ceylan, Camilla Langan, Pedro Magalhaes, Antonio L. Teixeira, Yuan-Hwa Chou, Iria Grande, Chenyu Ye, Izabela Barbosa, Menan Rabie, Ru-Band Lu, Ana Gonzales-Pinto, Reiji Yoshimura, Flavio Kapczinski, and Christoph Laske, who kindly provided unpublished data for the paper