Meta-analyses, published in 2008-2010, have confirmed abnormally low serum brain-derived neurotrophic factor (BDNF) concentrations in depressed patients and normalization of this by antidepressant treatment. These findings are believed to reflect peripheral manifestations of the neurotrophin hypothesis, which states that depression is secondary to an altered expression of BDNF in the brain. Since the publication of these meta-analyses, the field has seen a huge increase in studies on these topics. This motivated us to update the evidence on the aforementioned associations and, in addition, to compile the data on serum BDNF concentrations in relation to the symptom severity of depression. Using a manifold of data as compared with earlier meta-analyses, we find low serum BDNF concentrations in 2384 antidepressant-free depressed patients relative to 2982 healthy controls and to 1249 antidepressant-treated depressed patients (Cohen's d=-0.71 and -0.56, P-values <0.0000001). When publication bias is accounted for, these effect-sizes become substantially smaller (d=-0.47 and -0.34, respectively, P-values<0.0001). We detect between-study heterogeneity in outcomes for which only year of publication and sample size are significant moderators, with more recent papers and larger samples sizes in general being associated with smaller between-group differences. Finally, the aggregated data negate consistent associations between serum BDNF concentrations and the symptom severity of depression. Our findings corroborate the claim that altered serum BDNF concentrations are peripheral manifestations of depression. However, here we highlight that the evidence for this claim is slimmer as was initially thought and amidst a lot of noise.

Recent evidence supports ‘the neurotrophin hypothesis of depression' in its prediction that brain-derived neurotrophic factor (BDNF) is involved in depression. However, some key questions remain unanswered, including whether abnormalities in BDNF persist beyond the clinical state of depression, whether BDNF levels are related to the clinical features of depression and whether distinct antidepressants affect BDNF levels equally. We addressed these questions and investigated serum BDNF levels in 962 depressed patients, 700 fully remitted persons (⩾6 months) and 382 healthy controls. We found serum BDNF levels to be low in antidepressant-free depressed patients relative to controls (P=0.007) and to depressed patients who were treated with an antidepressant (P=0.001). BDNF levels of fully remitted persons (whether unmedicated or treated with an antidepressant) were comparable to those of controls. Analyzing the sample of antidepressant-free depressed patients showed that BDNF levels were unrelated to the core clinical features of depression such as its severity or first versus a recurrent episode. The antidepressant associated upregulation of serum BDNF in depressed patients was confined to selective serotonin reuptake inhibitors (SSRIs) (P=0.003) and St John's wort (P=0.03). Our results suggest that low serum levels of BDNF are a state abnormality that is evident during depression and normalizes during remission. Increases in serum levels of BDNF during antidepressant treatment appear to be confined to some antidepressants and do not parallel clinical characteristics, such as the severity of depressive symptoms.

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ObjectivesBrain-derived neurotrophic factor (BDNF) is involved in major depressive disorder and neurodegenerative diseases. Clinical studies, showing decreased serum BDNF levels, are difficult to interpret due to limited knowledge of potential confounders and mixed results for age and sex effects. We explored potential determinants of serum BDNF levels in a community sample of 1230 subjects.MethodsMultiple linear regression analyses with serum BDNF level as the dependent variable were conducted to explore the effect of four categories of potential BDNF determinants (sampling characteristics, sociodemographic variables, lifestyle factors and somatic diseases) and of self-reported depressive symptoms (Beck's Depression Inventory (BDI).ResultsOur results show that BDNF levels decline with age in women, whereas in men levels remain stable. Moreover, after controlling for age and gender, the assays still showed lower serum BDNF levels with higher BDI sum scores. Effects remained significant after correction for two main confounders (time of sampling and smoking), suggesting that they serve as molecular trait factors independent of lifestyle factors.ConclusionsGiven the age-sex interaction on serum BDNF levels and the known association between BDNF and gonadal hormones, research is warranted to delineate the effects of the latter interaction on the risk of psychiatric and neurodegenerative diseases.

RationaleRecent findings show lowered brain-derived neurotrophic factor (BDNF) levels in major depressive disorder (MDD). Exposure to stressful life events may (partly) underlie these BDNF reductions, but little is known about the effects of early or recent life stress on BDNF levels. Moreover, the effects of stressful events on BDNF levels may in part be conditional upon a common variant on the BDNF gene (Val66Met; RS6265), with the Met allele being associated with a decrease in activity-dependent secretion of BDNF compared to the Val allele.MethodsWe investigated cross-sectionally in 1,435 individuals with lifetime MDD the impact of childhood abuse (CA) and recent life events on serum BDNF levels and assessed whether the impact of these events was moderated by the BDNF Val66Met polymorphism.ResultsOverall, BDNF Met carriers had reduced serum BDNF levels when exposed to CA in a dose-dependent way. Moreover, exposure to recent life events was also associated with decreases in BDNF levels, but this was independent of BDNF Val66Met. Moreover, when not exposed to CA, Met carriers had higher BDNF levels than the Val/Val individuals, who did not show decreases in BDNF associated with CA. Finally, these findings were only apparent in the MDD group without comorbid anxiety.ConclusionsThese gene–environment interactions on serum BDNF levels suggest that Met carriers are particularly sensitive to (early) stressful life events, which extends previous findings on the moderating role of the BDNF Val66Met polymorphism in the face of stressful life events.

One of the leading neurobiological hypotheses on depression states that decreased expression of brain-derived neurotrophic factor (BDNF) contributes to depression. This is supported by consistent findings of low serum BDNF levels in depressed patients compared with non-depressed controls. Whereas it has been generally assumed that this is a state characteristic of depression, strong inferences about state or trait effects require a longitudinal study design. To investigate the longitudinal association between serum BDNF and depression, we measured serum BDNF, (current and past) depression status, use of antidepressants, and all potential covariates at baseline and after 2 years in 1751 individuals, consisting of patients with an incident (n=153), remitted (n=420) and persistent depression (n=310) and non-depressed controls (n=868). We analyzed change/differences in serum BDNF across these four groups with analyses of covariance adjusted for covariates and baseline BDNF value, together with the effects of starting and stopping antidepressant treatment. Our analyses revealed a significant difference for the depression course groups (P=0.007). Compared with non-depressed controls, persistently depressed and remitted patients had a steeper decrease of BDNF levels over time (-1.33 (P=0.001) and -0.97 ng ml(-1) (P=0.011), respectively), whereas BDNF reductions in patients with incident depression were similar to those in healthy controls. Initiation or discontinuation of antidepressants was not associated with BDNF change (P=0.72). These findings suggest that BDNF not only contributes to depression, but that depression in turn may also contribute to low BDNF.

Inconsistenties have been reported with regard to an association between val(66)met, a polymorphism on the BDNF gene, and hippocampal volume. We performed a systematic review and a meta-analysis to determine the magnitude and direction of this putative association and estimated the potential influence of demographic, clinical, and methodological characteristics of studies. Tests of publication bias and time-related trends were performed and statistical power of the included studies was calculated. The literature search for MRI studies on differences in total hippocampal volume as a function of BDNF val(66)met returned 25 records that fulfilled our criteria (total N = 3,620). Meta-analysis showed that carriers of a met allele had lower hippocampal volumes relative to val/val homozygotes (d = 0.13, P = 0.02). Between-study heterogeneity in effect size estimates was substantial (Q = 54.47, P < .001) and this could not be explained by demographic, clinical, and methodological differences across studies. Funnel plot inspection and trim-and-fill estimations suggested evidence for publication bias and effect sizes decreased substantially over the years (Pearson's r = -0.54, P < .01). All included studies were underpowered. This meta-analysis shows that carriers of a met allele have lower total hippocampal volumes relative to val/val homozygotes. However, effect sizes converged closer to null with virtually each attempt at replication and were based on underpowered studies. Altogether, this may call into question whether the observed effect is a genuine biological effect of the met allele or whether it is subject to a winners curse, with large effect sizes found in a few early studies and increasingly smaller effect sizes in later studies.

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