Largely in accord with previous findings6, 7
and with the neurotrophin hypothesis of depression,3, 4
our data showed that serum BDNF levels were low in antidepressant-free depressed patients compared with healthy controls. Our data further showed that BDNF levels were low in depressed patients who were not on antidepressant medication compared with antidepressant-free persons who were in full remission and that BDNF levels of this latter group were comparable to those of controls. Herewith, we establish as one of the first14
that low levels of BDNF in serum are a state characteristic for depression. In line with one study that reported low levels of BDNF in euthymic patients,15
we found that patients who were in early remission (1–6 months) had serum BDNF levels that were comparable to those of currently depressed patients. Thus, serum BDNF levels remain low after clinical improvement has set in. This could indicate that low levels of BDNF are a consequence of depressive symptoms that persist into early remission. Alternatively, the low levels of BDNF during early remission might also represent a scar of a depressive episode. These explanations could not be fully elucidated in the current study and longitudinal designs clearly are essential to understand this issue.
We were unable to replicate the earlier findings that a higher depression severity,17, 35
having a recurrent compared with a first episode of MDD16
and the occurrence of suicide ideation36, 37
are accompanied by lower levels of BDNF. In fact, we even found that the early remission phase, which was accompanied by a lower symptom severity of depression (mean inventory of depressive symptoms scores were 22.4±11.4 versus 32.4±12.1 in early remitted and currently depressed patients respectively), was associated with somewhat lower BDNF levels compared with the current depressive state. The other clinical features (that is age at onset of depression, the presence of comorbid anxiety and the chronicity of depression) also were unrelated to serum BDNF in multivariable analyses. These findings, given the size of the current cohort, give us confidence in excluding the clinical features of depression as potential correlates of serum BDNF levels. This might be an important conclusion, as it hints that other (than specifically depression related) factors may be at play in the relative fall of BDNF levels during a depressive episode. Interestingly, being male and having a higher BMI were found to be positively associated with BDNF among antidepressant-free depressed patients. Although these findings were unsought, they parallel the results of some previous studies,17, 38, 39
and they give ground to interesting hypotheses. For example, as weight loss is a prime behavioral abnormality of depression19
and often a residual symptom in early remission40, 41
it could be that, alternations in BDNF levels are mediated by (transient) changes in eating behavior during, or in the aftermath of, a depressive episode. Likewise, weight gain is a documented side effect of antidepressant treatment,42, 43
and thus the absence of weight loss could potentially explain the absence of a relative fall of BDNF in depressed patients during treatment with an antidepressant.
Alternative factors that have been proposed to underlie the low levels of BDNF during depression are exposure to stressful life events. Two studies, for example, found that adverse life events are associated with lower peripheral BDNF levels within a depressed and bipolar patient samples.44, 45
Therefore, it seems worthwhile to integrate a wider range of variables, notably (early) adverse life events, but also genetic variants and their interactions with environmental variables46
in models that study the link between BDNF and depression.
In addition, we found that serum BDNF levels were higher in antidepressant-treated patients compared with patients who were antidepressant free. This finding largely is in accord with previous findings.6, 7
We were able to expand previous findings by showing that the use of an antidepressant is associated with increased serum BDNF during a depressive episode but not during remission. This suggests that antidepressant-induced increases in BDNF occur in a disease state when BDNF functioning might be defective and not in remission when BDNF functioning is normalized. In addition, we found the increase in serum BDNF levels to be a specific associate of the use of SSRIs and St John's wort and not of the use of serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants or NaSSAs. Although not directly confirmed, this finding might be explained by increased availability of extra-synaptic levels of serotonin. It is known that serotonin stimulates the expression of BDNF.47, 48
In line with this, we found the highest BDNF levels in patients who were treated with an agent that generally leads to an increase in the availability of serotonin (that is SSRIs and St John's wort).49, 50
Furthermore, we found the lowest levels of BDNF in patients who were treated with agents that have little or no impact on the availability of serotonin (that is NaSSAs).43, 51
Nevertheless, this antidepressant-specific finding seems at odds with the specific prediction of the neurotrophin hypothesis, stating that increases in BDNF levels are a key mediator for an antidepressant response to occur.3
According to this prediction, one might expect that antidepressants that are known to be about equally efficacious in the treatment of the symptoms of depression50, 51, 52
would have similar effects on serum BDNF levels. Yet another finding that seems hard to reconcile with the neurotrophin hypothesis is that the group of depressed persons who used antidepressants (prolonged and frequently) had the highest BDNF levels, but also the highest symptom severity of depression. This suggests, to our belief that increases in peripheral BDNF levels do not parallel clinical effectiveness, or at least have no direct
effects on the depression characteristics such as its severity. Such a conclusion on the absence of direct effects could also be drawn on the findings that the severity of a depressive episode was unrelated to serum BDNF levels and that persons who were in early remission had similar levels of BDNF yet marked lower levels of depression severity compared with depressed patients.
Caution, however, is warranted when interpreting our findings on the associations between the use of an antidepressant and serum levels of BDNF because our patients were not randomly assigned to the various drugs (or no drug) conditions. Thus, our findings might be confounded by indication. An additional limitation of our study is that we relied on data that were collected in a single wave, precluding any form of causality. Furthermore, we measured serum levels of BDNF and assume that these measurements mirror the amount of BDNF in the brain. This assumption is validated on preclinical work that showed that cortical and peripheral levels of BDNF are correlated53, 54, 55
but remains complicated, because in addition to neurons, several other tissues serve as sources of BDNF in serum.54
However, various strengths of our study seem evident and these include the use of multivariable techniques and the large sample size (that relates positive to all previous studies and to two previous meta-analyses6, 7
In conclusion, we believe that our data indicate that low levels of BDNF in blood serum are a state characteristic of depression and thus an abnormality that is evident during the clinical state and the early remission phase of depression but not when the symptoms of depression are in full remission. Our findings further suggest that some of the core clinical features of depression are unrelated to serum levels of BDNF. Finally, increases in serum levels of BDNF appear to be a specific pharmacological effect of a subset of antidepressants that does not parallel depression characteristics such as the severity of depression.