I read with great interest the recent article by Li et al, describing plasma levels of brain-derived neurotrophic factor (BDNF) in patients with bipolar disorder in their first depressive episode. ^{Reference Li, Zhang, Fan, Yuan, Huang and Chen1} A total of 203 patients with a first major depressive episode, as well as 167 healthy controls, were enrolled. After 3 years of bi-annual follow-up, 164 patients with a major depressive episode completed, and of these, 21 patients were diagnosed as having bipolar disorder and 143 patients were diagnosed as having major depressive disorder. At baseline, patients with bipolar disorder and depression showed significantly lower BDNF mRNA levels (P<0.001 and P = 0.02, respectively) and plasma BDNF levels (P = 0.002 and P = 0.01, respectively) compared with healthy controls. Interestingly, plasma BDNF levels in patients with bipolar disorder were lower than those in patients with depression.

This study suggests that the model for predicting bipolar disorder during a first depressive episode is a combination of BDNF mRNA with plasma BDNF levels. ^{Reference Li, Zhang, Fan, Yuan, Huang and Chen1} BDNF (mature BDNF) is a 13 kDa polypeptide, which is initially synthesised as a precursor protein, preproBDNF, in the endoplasmic reticulum. Following cleavage of the signal peptide, proBDNF (∼32 kDa) is converted to mature BDNF by extracellular proteases. It was initially thought that only secreted, mature BDNF was biologically active, and that proBDNF, localised intracellularly, served as an inactive precursor. However, accumulating evidence shows that both proBDNF and mature BDNF are active, eliciting opposing effects via the p75NTR and TrkB receptors, respectively, and that both forms play important roles in several physiological functions. ^{Reference Hashimoto2}

The enzyme-linked immunosorbent assay (ELISA) kits (R&D Systems) used by Li et al recognise both proBDNF (precursor of BDNF) and mature BDNF, because of the limited specificity of the BDNF antibody. ^{Reference Yoshida, Ishikawa, Iyo and Hashimoto3} Using newly available human proBDNF and mature BDNF ELISA kits, which differentiate between the BDNF forms, we have reported high levels of both proBDNF and mature BDNF in human serum. ^{Reference Yoshida, Ishikawa, Iyo and Hashimoto3} We reported that serum levels of mature BDNF, but not proBDNF, in patients with major depressive disorder were significantly lower than those in healthy controls. ^{Reference Yoshida, Ishikawa, Niitsu, Nakazato, Watanabe and Shiraishi4} And we recently found that serum levels of mature BDNF and the ratio of mature BDNF to proBDNF in mood-stabilised patients with bipolar disorder were significantly higher than in healthy controls. ^{Reference Yoshida, Ishikawa, Niitsu, Nakazato, Watanabe and Shiraishi4} Interestingly, serum levels of proBDNF in mood-stabilised patients with bipolar disorder were significantly lower than those in healthy controls. ^{Reference Södersten, Pílsson, Ishima, Funa, Landén and Hashimoto5} These findings were confirmed in two independent cohorts (Sahlgrenska set and Karolinska set in Sweden). ^{Reference Södersten, Pílsson, Ishima, Funa, Landén and Hashimoto5} Considering the high levels of both proBDNF and mature BDNF in human serum, and their putative opposing functions, it would be clinically and scientifically interesting to measure the individual serum levels of proBDNF and mature BDNF in this cohort study.