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Meta-Analysis
doi: 10.1186/s12916-015-0529-7.

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

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Meta-Analysis

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

Brisa S Fernandes et al. BMC Med..

Abstract

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.

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Figures

Fig. 1
Fig. 1
Forest plots of between-group meta-analyses measuring peripheral brain-derived neurotrophic factor (BDNF) levels in subjects with bipolar disorder compared to healthy controls, separated by mood state and medication status. (a) Mania, studies separated according use of medication. (b) Depression, studies separated according use of medication. The sizes of the circles are proportional to the sample size. Circles depict individual studies and diamonds depict the pooled effect sizes. Serum and plasma BDNF levels were decreased in subjects with bipolar disorder in mania and depression on and off psychiatric medication when compared to healthy controls
Fig. 2
Fig. 2
Forest plots of between-group meta-analysis measuring peripheral brain-derived neurotrophic factor (BDNF) levels in subjects with bipolar disorder in euthymia compared to healthy controls. All studies referred to persons on psychiatric medication. The sizes of the circles are proportional to the sample size. Circles depict individual studies and diamonds depict the pooled effect size. Serum and plasma BDNF levels were not altered in persons with bipolar disorder in euthymia when compared to healthy controls
Fig. 3
Fig. 3
(a) Direct comparison of the effect sizes of the different studies in mania, depression, and euthymia. Peripheral brain-derived neurotrophic factor (BDNF) levels were equally decreased in mania and depression (P = 0.340), and both manic and depressive states presented BDNF levels decreased when compared to euthymic state (P = 0.002). (b) Meta-regression of the effect sizes of peripheral BDNF levels against severity of mania as assessed by the Young Mania Rating Scale (YMRS) scores, showing more accentuated decreases in BDNF levels with increase in YMRS scores (P = 0.004). (c) Meta-regression of the effect sizes of peripheral BDNF levels against severity of depression as assessed by the Hamilton Depression Rating Scale (HDRS) scores, showing more accentuated decreases in BDNF levels with increase in HDRS scores (P = 0.018). (d) Meta-regression of the effect sizes of peripheral BDNF levels against duration of illness in years in euthymic subjects, showing no association between BDNF levels and duration of bipolar illness in years during euthymia (P = 0.577)
Fig. 4
Fig. 4
Forest plots of within-group meta-analyses measuring peripheral brain-derived neurotrophic factor (BDNF) levels in subjects with bipolar disorder before and after treatment for an index acute manic or depressive mood episode. (a) Mania studies grouped according the source of the blood sample. All studies presented response to the manic episode after pharmacological treatment, as defined as a decrease of at least 50 % on the Young Mania Rating Scale scores. Plasma BDNF levels increased after successful treatment of an index manic episode. Serum BDNF levels remained unchanged. (b) Depression studies grouped according the source of the blood sample. Serum and plasma BDNF levels remained unchanged after treatment of an index depressive episode. (c) Depression studies grouped according response or non-response to pharmacological treatment of the acute depressive episode, defined as a decrease of at least 50 % on the Hamilton Depression Rating Scale scores. Serum and plasma BDNF levels remained unchanged after treatment of an index depressive episode regardless of response or non-response to treatment. The sizes of the circles are proportional to the sample size. Circles depict individual studies and diamonds depict the pooled effect sizes
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