Brain-derived neurotrophic factor (BDNF), a protein in the neurotrophin family, signals through tropomyosin-related kinase B receptors and is present in both the brain and peripheral tissues. BDNF is essential for neuronal survival, growth, differentiation, and synapse formation, in addition to playing roles in energy metabolism, and it plays a key role in the mechanisms underlying learning and memory formation including learning and extinction of fear memory. Over 2,500 papers have been published on serum, plasma, or whole blood BDNF levels in psychiatric disorders since the year 2000, testifying to the immense interest in this molecule in psychiatric research. This is attributable to the presumed importance of neurogenesis and neurotrophism in psychiatric illnesses and their treatment and to the large number of studies showing abnormal concentrations of BDNF in the peripheral blood of individuals with certain psychiatric illnesses1-7.

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Chronic stress has been shown to decrease BDNF levels in the brain, particularly in regions associated with mood regulation, such as the hippocampus and prefrontal cortex1. This reduction in BDNF can lead to impaired neuroplasticity and cognitive deficits8. Altered BDNF signaling has been implicated in the pathophysiology of several mood disorders, including major depressive disorder (MDD) and bipolar disorder1, 8. Some studies reported lower serum BDNF levels in patients with MDD compared to healthy controls. Additionally, successful antidepressant treatment has been associated with increases in BDNF levels, suggesting its potential as a biomarker for treatment response9.

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Background

While some studies supported the neurotrophic model and showed decreased levels of serum BDNF in individuals with MDD10-14, several other studies did not find any significant differences in BDNF levels comparing sera of MDD subjects and healthy controls15, 16. Variability in results was also shown in posttraumatic stress disorder (PTSD). There have been reports suggesting that PTSD is associated with significantly higher serum BDNF concentrations than their non-PTSD counterparts, leading to the hypothesis of a BDNF-related compensatory mechanism17-20. Conversely, some studies have found lower levels of BDNF among subjects with PTSD, presenting supporting evidence for an apoptotic mechanism21.

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Although the relationship between BDNF and psychiatric disorders remains unclear, there has been substantial data supporting the role of BDNF in antidepressant treatment22. Accumulating evidence has shown that as a transducer, BDNF acts as the link between antidepressant drugs and the neuroplastic changes resulting in the symptom improvement23. Along with its crucial role in neuroplasticity and mood regulation, BDNF has emerged as a promising target for novel therapeutic interventions. Strategies aimed at increasing BDNF levels or enhancing its signaling pathways are being explored as potential treatments for mood disorders1, 8. These include BDNF mimetics, TrkB receptor agonists, and interventions that indirectly boost BDNF levels, such as exercise and certain dietary components1, 8, 24.

Collection and measurement

Enzyme-linked immunosorbent assay (ELISA) is the standard and most widely used technique for quantifying BDNF levels in biological samples (serum or plasma are the most common). Commercial ELISA kits are available and commonly used for this purpose25. BDNF assays using ELISA are generally feasible. Commercial kits can typically detect BDNF in the pg/mL range. Assay reliability will depend on the kit and protocol used. In general, studies have reported coefficients of variation (CV) as low as 5% for BDNF. Inter-assay variability can range from 10% to higher percentages depending on the kit and protocol used1. 

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Peripheral BDNF is sometimes assumed to be a unitary measure, with plasma and serum levels being interchangeable25. Yet, they are strikingly different, with serum levels being about 100-200 times higher than plasma ones, and with BDNF concentrations in serum and plasma showing variable degrees of inter-correlation26. Serum levels reflect intra-platelet as well as extracellular BDNF concentrations26, thus assessing “total” peripheral BDNF. This is due to platelet degranulation (which releases platelet BDNF into the serum), which occurs during blood clotting and serum preparation. Conversely, BDNF concentrations in plasma are affected by sample handling since normal plasma contains some platelets, which could potentially affect the amount of BDNF measured4. Because of the ongoing release from these platelets, BDNF quantification from plasma can be more sensitive to preparation procedures, and plasma BDNF concentrations rise progressively within a few hours of plasma preparation, although this depends on the temperature at which the samples are kept prior to freezing25, 27. Consequently, plasma measures are typically less reproducible and have higher variability than measures in serum4, 7, 28. Also, different anticoagulants used in preparing plasma yield different results27, 29, with some authors recommending the use of K2-EDTA, which may have greater stability with freezing and may yield a narrower range of values29.

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Since clotting and platelet degranulation are time-dependent processes, serum levels of BDNF increase over the first hour of clotting, but are generally stable after that, suggesting a minimum of one hour at room temperature for full blood clotting26  before centrifugation, although one group recommends two hours30. Conversely, the duration of freezer storage of serum may be inversely correlated with measured BDNF levels31, due to the progressive activity of proteolytic enzymes32, although this is less likely at -80 degrees C than at -20 degrees C, and one group reported no effect of freezer time on BDNF levels for either serum or plasma for up to 6 months at -80 degrees C29, 33. Since normal plasma contains some platelets, which could potentially affect the amount of BDNF measured, plasma stored at -20 degrees C for 12 months or longer may show significant increases in BDNF levels29. To minimize this, some manufacturers recommend a second centrifugation of plasma within 30 minutes of collection to remove more platelets26. 

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There is insufficient data on the effect of repeated freeze-thaw cycles on measured levels of BDNF, although two small studies suggested negligible effects of one to two cycles in whole blood samples32 or in serum or plasma samples33. A larger number of freeze-thaw cycles (2-3 or more), however, may be associated with increased BDNF levels, at least in plasma, possibly because the remaining platelets in the plasma release BDNF upon repeated freezing and thawing29. 

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Strengths/Limitations

One strength of studying BDNF in stress and mood disorders is that it can be measured in peripheral blood samples using well-established assays, making it a relatively accessible biomarker compared to direct brain measurements. Although it is still unknown how well peripheral BDNF levels correlate with the CNS levels of BDNF in humans, there have been animal models showing the blood levels of BDNF reflect brain-tissue BDNF levels across species17, 34. In addition, with further consistent validation in larger cohorts, BDNF could potentially become a useful tool for treatment response (and less likely, for diagnosis) and a target for the development of novel antidepressant treatments22.

 

Furthermore, BDNF was shown to be responsive to various interventions, including exercise and antidepressant treatments, allowing researchers to study the biological effects of different therapeutic approaches8, 24. However more data are needed to validate these findings as the literature has been inconsistent. For example one meta-analysis found no change in BDNF concentrations after non-pharmacological interventions, such as electroconvulsive therapy, repetitive transcranial magnetic stimulation, and physical activity9.

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While these strengths make BDNF measurement valuable in psychiatric and psychological research, it's important to note that there are also challenges. Drawing conclusions from the existing body of BDNF data is made difficult by the heterogeneous findings that have been reported 1, 2, 7, 35, 36. This heterogeneity is likely attributable to several factors, including underpowered studies37, publication bias1, differences in populations studied and in medications taken by study participants (e.g., antidepressants, benzodiazepines, lipid-lowering drugs)38, differences in assay kits37 and differences in pre-analytic variables such as specific clinical populations studied (including concomitant medical illnesses), specimen handling and storage procedures25, as discussed in the previous section.

 

Inconsistencies in the literature have even prompted some to reassess the original “BDNF hypothesis of depression” and investigate new theories22. For example, Castren et al. proposed that BDNF is a “tool” in activity-dependent modulation of brain networks, rather than directly controling mood39. Finally, important covariates to consider at the data analysis stage include age, sex, ethnicity, BMI, smoking, alcohol consumption, exercise, platelet number, time of day, fasted status, and concurrent illnesses and medication. To enable cross-study comparisons, relevant information about laboratory techniques and possibly confounding variables should be documented in all research publications
 

​Author(s) and Reviewer(s):

Prepared by Gwyneth W. Y Wu, Victor Reus, Synthia Mellon, and Owen M. Wolkowitz. 

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Version July 2025. Waiting for Review.

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