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Brain-derived neurotrophic factor levels and bipolar disorder in patients in their first depressive episode: 3-year prospective longitudinal study

  • Zezhi Li (a1), Chen Zhang (a2), Jinbo Fan (a3), Chengmei Yuan (a4), Jia Huang (a4), Jun Chen (a4), Zhenghui Yi (a4), Zuowei Wang (a4), Wu Hong (a4), Yong Wang (a4), Weihong Lu (a4), Yangtai Guan (a5), Zhiguo Wu (a4), Yousong Su (a4), Lan Cao (a4), Yingyan Hu (a4), Yong Hao (a5), Mingyuan Liu (a5), Shunying Yu (a6), Donghong Cui (a6), Lin Xu (a7), Yanyan Song (a8) and Yiru Fang (a4)...

Abstract

Background

Early identification of patients with bipolar disorder during their first depressive episode is beneficial to the outcome of the disorder and treatment, but traditionally this has been a great challenge to clinicians. Recently, brain-derived neurotrophic factor (BDNF) has been suggested to be involved in the pathophysiology of bipolar disorder and major depressive disorder (MDD), but it is not clear whether BDNF levels can be used to predict bipolar disorder among patients in their first major depressive episode.

Aims

To explore whether BDNF levels can differentiate between MDD and bipolar disorder in the first depressive episode.

Method

A total of 203 patients with a first major depressive episode as well as 167 healthy controls were recruited. After 3 years of bi-annual follow-up, 164 patients with a major depressive episode completed the study, and of these, 21 were identified as having bipolar disorder and 143 patients were diagnosed as having MDD. BDNF gene expression and plasma levels at baseline were compared among the bipolar disorder, MDD and healthy control groups. Logistic regression and decision tree methods were applied to determine the best model for predicting bipolar disorder at the first depressive episode.

Results

At baseline, patients in the bipolar disorder and MDD groups showed lower BDNF mRNA levels (P<0.001 and P = 0.02 respectively) and plasma levels (P = 0.002 and P = 0.01 respectively) compared with healthy controls. Similarly, BDNF levels in the bipolar disorder group were lower than those in the MDD group. These results showed that the best model for predicting bipolar disorder during a first depressive episode was a combination of BDNF mRNA levels with plasma BDNF levels (receiver operating characteristics (ROC) = 0.80, logistic regression; ROC = 0.84, decision tree).

Conclusions

Our findings suggest that BDNF levels may serve as a potential differential diagnostic biomarker for bipolar disorder in a patient's first depressive episode.

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Copyright

Corresponding author

Dr Yiru Fang, Division of Mood Disorders, Shanghai Mental Health Center, Department of Psychiatry, Shanghai Jiao Tong University School of Medicine, 600 South Wan Ping Road Shanghai 200030, China. Email: yirufang@gmail.com. Dr Yanyan Song (statistical analysis), Department of Biostaistics, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, Shanghai, China. Email: yanyansong@sjtu.edu.cn

Footnotes

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These authors contributed equally to this work.

Declaration of interest

None.

Footnotes

References

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Brain-derived neurotrophic factor levels and bipolar disorder in patients in their first depressive episode: 3-year prospective longitudinal study

  • Zezhi Li (a1), Chen Zhang (a2), Jinbo Fan (a3), Chengmei Yuan (a4), Jia Huang (a4), Jun Chen (a4), Zhenghui Yi (a4), Zuowei Wang (a4), Wu Hong (a4), Yong Wang (a4), Weihong Lu (a4), Yangtai Guan (a5), Zhiguo Wu (a4), Yousong Su (a4), Lan Cao (a4), Yingyan Hu (a4), Yong Hao (a5), Mingyuan Liu (a5), Shunying Yu (a6), Donghong Cui (a6), Lin Xu (a7), Yanyan Song (a8) and Yiru Fang (a4)...
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eLetters

Can We Predict Switch From Unipolar Depression to Bipolar Disorder?

Genichi Sugihara, Assistant Professor
09 September 2014

Li et al investigated the levels of brain-derived neurotrophic factor(BDNF) in patients with a first major depressive episode to assess the impact of the levels on the development of bipolar disorder during 3-year follow-up.[1] They found that a combination of the levels of BDNF mRNA andplasma BDNF predicted a switch from depression to bipolar disorder in the following 3 years with area under the receiver operating characteristics (ROC) curve of 0.80. Li et al claimed that BDNF levels serve as a differential diagnostic biomarker for bipolar disorder in patients with a first depressive episode. If physicians could predict future development of bipolar disorder during a first depressive episode using biomarkers, itwould benefit decision-making processes to select optimum treatment strategies. However, some caveats should be noted in Li et al's study.

First, in the sample studied by Li et al, the diagnostic conversion rate from depression to bipolar disorder during the 3-year follow-up was as high as 12.8% (i.e., a shift to bipolar disorder occurred in 4.3% of the patients per year). This rate is amazingly high compared with the findings in previous studies, e.g., 1.5% per year[2] and 2.3% per year.[3]If the patients who dropped out were all assumed to remain unipolar depression, the rate would be still high (10.3% during 3 years). This highconversion rate in this sample might be attributable to an inclusion of patients with previous (hypo)manic episode(s) which had been overlooked,[4] and/or a liberal threshold used in the diagnosis of a hypomanic or manic episode in the study. Nonetheless, caution should be exercised in the generalization of the findings.

Second, positive predictive value (PPV) of the combination of the levels of BDNF mRNA and plasma BDNF in detecting the future development ofbipolar disorder was low, even if the high diagnostic conversion rate (12.8% in 3 years) was used; according to the ROC curve in the Figure 3,[1] PPV was 48% with sensitivity of 71% and specificity of 80%. This suggests that 1 of 2 patients who are predicted to develop bipolar disorder within 3 years using this biological index may be mislabelled as latent bipolar disorder despite the fact that the patient remains unipolardepression. Provided the diagnostic switch is assumed to occur in 6% of patients with a first depressive episode over 3 years after the onset of depression, as expected from previous studies,[2,3] PPV in this case wouldfurther fall to 26%. Feasibility and clinical applicability cannot be undervalued.

We agree with the authors that BDNF can be linked with the pathophysiology of mood disorders, and that the impact may be more evidentin bipolar disorder. However, as for use of BDNF as a differential diagnostic biomarker in clinical settings, the low conversion rate from depression to bipolar disorder and the resulting low PPV ought to be takeninto account.

References1.Li Z, Zhang C, Fan J, Yuan C, Huang J, Chen J, et al. Brain-derived neurotrophic factor levels and bipolar disorder in patients in their firstdepressive episode: 3-year prospective longitudinal study. Br J Psychiatry2014; 205: 29-35.2.Angst J, Sellaro R, Stassen HH, Gamma A. Diagnostic conversion from depression to bipolar disorders: results of a long-term prospective study of hospital admissions. J Affec Disord 2005; 84: 149-57.3.Holma KM, Melartin TK, Holma IA, Isometsa ET. Predictors for switch from unipolar major depressive disorder to bipolar disorder type I or II: a 5-year prospective study. J Clin Psychiatry 2008; 69: 1267-75.4.Bschor T, Angst J, Azorin JM, Bowden CL, Perugi G, Vieta E, et al. Are bipolar disorders underdiagnosed in patients with depressive episodes? Results of the multicenter BRIDGE screening study in Germany. J Affec Disord 2012; 142: 45-52.

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Conflict of interest: None declared

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Brain-derived neurotrophic factor (BDNF) and its precursor proBDNF as predictable biomarkers for bipolar disorder

Kenji Hashimoto, Professor
19 August 2014

I read with great interest, the recent article by Li et al.,1 describing plasma levels of brain-derived neurotrophic factor (BDNF) in patients with bipolar disorder (BD) in their first depressive episode. A total of 203 patients with a first major depressive episode as well as 167healthy 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 BD and 143 patients were diagnosed as having major depressive disorder (MDD). At baseline, patients with BD and MDD 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 BD patients were lower than those in MDD patients. This study suggests that the model for predicting BD during a first depressive episode is a combination of BDNF mRNA with plasma BDNF levels.1BDNF (mature BDNF) is a 13 kDa polypeptide, which is initially synthesizedas 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, localized 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.2 The enzyme-linked immunosorbent assay (ELISA) kits (R&D Systems) used by Li et al.1, recognize both proBDNF (precursor of BDNF) and mature BDNF, due to limited specificity of the BDNF antibody.3 Using newly available human proBDNF and mature BDNF ELISA kits which differentiate between the BDNF forms, we reported high levels of both proBDNF and mature BDNF in human serum.3 We also reported that serum levels of mature BDNF, but not proBDNF, in patients with MDD were significantly lower than those of healthy controls.4 In contrast, we recently reported that serum levels of mature BDNF and the ratio of matureBDNF to proBDNF in mood-stabilized BD patients were significantly higher than in healthy controls.4 Interestingly, serum levels of proBDNF in mood-stabilized patients with BD were significantly lower than those in healthycontrols.5 These findings in BD were confirmed in two independent cohorts (Sahlgrenska set and Karolinska set in Sweden). 5Considering the high levels of both proBDNF and mature BDNF in human serumand their putative opposing functions, it would be clinically and scientifically interesting to measure the individual serum levels of precursor (proBDNF) and mature BDNF in this cohort study.

REFERENCES1.Li Z, Zhang C, Fan J, Yuan C, Huang J, Chen J, et al. Brain-derived neurotrophic factor levels and bipolar disorder in patients in their firstdepressive episode: 3-year prospective longitudinal study. Bri J Psychiatry 2014; 205: 29-35.2.Hashimoto K: Brain-derived neurotrophic factor as a biomarker for mood disorders: an historical overview and future directions. Psychiatry Clin Neurosci 2010; 64: 341-357.3.Yoshida T, Ishikawa M, Iyo M, Hashimoto K. Serum levels of mature brain-derived neurotrophic factor and its precursor proBDNF in healthy subjects.Open Clin Chem J 2012; 5: 7-12.4.Yoshida T, Ishikawa M, Niitsu T, Nakazato M, Watanabe H, Shiraishi T, etal. Decreased serum levels of mature brain-derived neurotrophic factor (BDNF), but not its precursor proBDNF, in patients with major depressive disorder. PLoS One 2012; 7: e42676.5.S?dersten K, P?lsson E, Ishima T, Funa K, Land?n M, Hashimoto K, et al. Abnormality in serum levels of mature brain-derived neurotrophic factor (BDNF) and its precursor proBDNF in mood-stabilized patients with bipolar disorder: a study of two independent cohorts. J Affect Dis 2014; 160: 1-9.

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Conflict of interest: Dr. Hashimoto is a holder of the patents "Diagnostic and examination method for eating disorder" (US 7,754,434 B2) and "Diagnostic agent for ischemic heart disease risk group" (US 2013/0310321A1); which pertain to the measurement of BDNF as a biomarker. In addition, Dr. Hashimoto has served as a scientific consultant to Astellas and Taisho, and he has also received research support from Abbvie, Dainippon Sumitomo, Otsuka, and Taisho.

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