Moreover, antidepressant treatments can prevent stress-induced reduction of BDNF, 16 and they can restore the corticosterone-mediated decrease in BDNF expression. Several classes of antidepressants, including monoamine oxidase inhibitors MAOIs , selective serotonin reuptake inhibitors SSRIs , tricyclic agents TCAs , serotonin-norepinephrine reuptake inhibitors SNRIs , and noradrenergic and specific serotonergic antidepressants, increase BDNF expression in the brain when given to healthy rodents.
Various factors that influence this antidepressant effect on BDNF include length of administration, route of administration, class of antidepressant, and doses of the drugs. In general, increases in BDNF expression appear only after long-term treatment with antidepressants.
Chronic antidepressant administration may induce plastic changes in the forebrains of rodents. Antidepressant treatment can also modulate chromatin remodeling, which regulates the activity of gene transcription. When histone subunits surround chromosomal DNA, methylation of histone subunits reduces gene transcription, whereas their acetylation enhances transcription.
Wild-type mice that were given antidepressant agents experienced increased phosphorylation of CREB as well as phosphorylation of TrkB in the brain. In addition, the behavioral effects of antidepressants did not occur in BDNF-deficient mice or Trk-defective mice. However, the antidepressant response clearly requires an increase of BDNF activity and recovery of the neuronal network. A neuronal plastic change could positively influence mood or recover depressed mood.
Previous human postmortem studies showed decreased BDNF expression or CREB immunoreactivity in the brains of participants with major depression who had not been treated with antidepressants, but those who were treated with antidepressant drugs had increased BDNF expression and CREB in the brain.
Recent clinical studies have explored serum or plasma BDNF levels in patients with major depression. Some studies suggested a more significant decrease of BDNF in more severe depression. Though our data did not demonstrate any relationship between BDNF and depression severity, we found that relapsed or recurrent-episode MDD patients had much lower plasma BDNF levels than first-onset ones. Many clinical studies have evaluated the changes of plasma or serum BDNF levels before and after antidepressant treatments among MDD patients.
Most studies reported increases of BDNF levels after antidepressant treatment. These data of clinical studies of antidepressant treatment are consistent with those of animal studies on the effects of antidepressants on BDNF changes. Therefore, it is possible that serum or plasma levels of BDNF reflect the state of the neuronal network in patients with major depression.
MDD patients can have decreased BDNF levels before treatment, which can be restored to the normal level through antidepressant treatment or by improving neuronal plasticity. Postmortem studies show that mRNA expression and protein levels of BDNF are reduced in the brains of patients with major depression who commit suicide. T1 is significantly decreased in the brains of suicide patients in postmortem studies.
Their data showed a significantly decreased veno-arterial BDNF concentration gradient in patients at higher suicide risk among MDD participants. These changes of serum or plasma BDNF levels in suicide patients are consistent with BDNF changes of the brain in postmortem studies on patients who died following suicide.
Therefore, the phenomenon of suicidal behavior could be a consequence of a severe dysfunction of the neuronal network or of severely impaired neuronal plasticity in the brain compared to MDD patients.
BDNF is involved in activity-dependent neuronal plasticity, such as learning and memory. Major depression is associated with impaired neuronal plasticity. Suicidal behavior can be a consequence of severely impaired neuronal plasticity in the brain.
Antidepressant treatments promote several forms of neuronal plasticity, including neurogenesis, synaptogenesis and neuronal maturation and also increase BDNF activity, which can develop the antidepressant response. Figure 1 represents these effects of neuronal plasticity or BDNF on major depression, antidepressant treatment, and suicide behavior. BDNF could play an important role in the modulation of neuronal networks. Such neuronal plastic change can positively influence mood or recover depressed mood.
BDNF levels in serum or plasma will be useful markers for clinical response or improvement of depressive symptoms rather than a diagnostic marker of major depression. The neuronal plasticity in major depression, antidepressant treatment, and suicide behavior. Major depression is associated with impaired neuronal plasticity in the brain. Suicide behavior can be a consequence of very severe impaired neuronal plasticity.
Antidepressant treatments promote several forms of neuronal plasticity, including neurogenesis, synaptogenesis and neuronal maturation together with increasing brain-derived neurotrophic factor activity, which can develop the antidepressant response. The neuronal plastic change can influence mood or recover depressed mood.
National Center for Biotechnology Information , U. Psychiatry Investig. Domschke, K. Int J. Egan, M. Cell , — Lu, B.
BDNF and synaptic plasticity, cognitive function, and dysfunction. Handb Exp Pharmacol. Hao, R. Front Cell Neurosci. Miyajima, F. Brain-derived neurotrophic factor polymorphism Val66Met influences cognitive abilities in the elderly. Genes Brain Behav. Harris, S. The brain-derived neurotrophic factor Val66Met polymorphism is associated with age-related change in reasoning skills. Psychiatry 11 , — Mandelman, S. A meta-analysis of the genetic association.
MacArthur, J. Nucleic Acids Res. Furberg, H. Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Lee, J. Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1. Nagel, M. Meta-analysis of genome-wide association studies for neuroticism in , individuals identifies novel genetic loci and pathways. Uchida, S. Epigenetic status of Gdnf in the ventral striatum determines susceptibility and adaptation to daily stressful events.
Neuron 69 , — Fuchikami, M. DNA methylation profiles of the brain-derived neurotrophic factor BDNF gene as a potent diagnostic biomarker in major depression. PLoS One 6 , 4—10 Januar, V. BDNF promoter methylation and genetic variation in late-life depression. Psychiatry 5 , e—7 Kang, H. Longitudinal associations between BDNF promoter methylation and late-life depression. Aging 36 , BDNF promoter methylation and suicidal behavior in depressive patients.
Affect Disord. Roth, T. Lasting epigenetic influence of early-life adversity on the BDNF gene. Psychiatry 65 , — Blaze, J. Differential methylation of genes in the medial prefrontal cortex of developing and adult rats following exposure to maltreatment or nurturing care during infancy.
Caregiver maltreatment causes altered neuronal DNA methylation in female rodents. Zeilinger S. Tobacco smoking leads to extensive genome-wide changes in DNA methylation. PLoS One 8 , Boks, M. The relationship of DNA methylation with age, gender and genotype in twins and healthy controls. PLoS One 4 , 21—23 Carlberg, L. Brain-derived neurotrophic factor BDNF - Epigenetic regulation in unipolar and bipolar affective disorder. Salvat-Pujol, N. Hypothalamic-pituitary-adrenal axis activity and cognition in major depression: the role of remission status.
Psychoneuroendocrinology 76 , 38—48 Ferrer, A. FKBP5 polymorphisms and hypothalamic-pituitary-adrenal axis negative feedback in major depression and obsessive-compulsive disorder. J Psychiatr Res. Sheehan D. Psychiatry 59 , 22—33 Hamilton, M. A rating scale for depression. Psychiatry 23 , 56—62 Thase, M. Psychiatry 13 , 23—29 Spielberger, C. Google Scholar. Bernstein, D. Development and validation of a brief screening version of the Childhood Trauma Questionnaire.
Child Abuse Negl. Barrett, J. Haploview: Analysis and visualization of LD and haplotype maps. Bioinformatics 21 , — Lin, Y. Liu, L. Evidence of association between brain-derived neurotrophic factor gene and bipolar disorder. Real, E. A brain-derived neurotrophic factor haplotype is associated with therapeutic response in obsessive-compulsive disorder.
Psychiatry 66 , — A brain-derived neurotrophic factor BDNF haplotype is associated with antidepressant treatment outcome in mood disorders. Pharmacogenomics J. Honea, R. PLoS One 8 , 1—9 Hennings, J. PLoS One 8 , 1—12 Neves, F. The role of BDNF genetic polymorphisms in bipolar disorder with psychiatric comorbidities.
Striatal adenosine A 2A receptor expression is controlled by S-adenosyl-L-methionine-mediated methylation. Purinergic Signal. Purcell, S.
Maximizing association statistics over genetic models. Pittenger C, Duman RS. Stress, depression, and neuroplasticity: a convergence of mechanisms. Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J Neurosci. Reduced neuronal size and glial cell density in area 9 of the dorsolateral prefrontal cortex in subjects with major depressive disorder. Cereb Cortex. Evolutionary studies of the nerve growth factor family reveal a novel member abundantly expressed in Xenopus ovary.
Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res. Neurotrophic factors, clinical features and gender differences in depression. Neurochem Res. Serum level of nerve growth factor is a potential biomarker of conversion to bipolar disorder in women with major depressive disorder. Psychiatry Clin Neurosci.
Serum brain-derived neurotrophic factor levels and personality traits in patients with major depression. BMC Psychiatry. The impact of antidepressant treatment on brain-derived neurotrophic factor level: an evidence-based approach through systematic review and meta-analysis. Indian J Pharmacol. Brain-derived neurotrophic factor BDNF serum level in women with first-episode depression, correlation with clinical and metabolic parameters. Nord J Psychiatry. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus.
Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: comparison of stressors. Low brain-derived neurotrophic factor BDNF levels in serum of depressed patients probably results from lowered platelet BDNF release unrelated to platelet reactivity. Biol Psychiatry. Platelet and whole blood serotonin content in depressed inpatients: correlations with acute and life-time psychopathology. Serum and plasma BDNF levels in major depression: a replication study and meta-analyses.
World J Biol Psychiatry. Decreased plasma brain-derived neurotrophic factor levels in institutionalized elderly with depressive disorder.
J Am Med Dir Assoc. Brain Res Bull. Serum brain-derived neurotrophic factor levels in subjects with major depressive disorder with previous suicide attempt: a population-based study. J Clin Pharmacol. Longitudinal multi-level biomarker analysis of BDNF in major depression and bipolar disorder. Eur Arch Psychiatry Clin Neurosci. Alterations of serum levels of brain-derived neurotrophic factor BDNF in depressed patients with or without antidepressants.
Ladea M, Bran M. Brain derived neurotrophic factor BDNF levels in depressed women treated with open-label escitalopram. Psychiatr Danub. Changes in BDNF serum levels in patients with major depression disorder MDD after 6 months treatment with sertraline, escitalopram, or venlafaxine. J Psychiatr Res. Glutamate and gamma-aminobutyric acid systems in the pathophysiology of major depression and antidepressant response to ketamine.
BDNF serum levels in subjects developing or not post-traumatic stress disorder after trauma exposure. Brain Cogn. Circulating glial-derived neurotrophic factor is reduced in late-life depression. Age-associated decrease in serum glial cell line-derived neurotrophic factor levels in patients with major depressive disorder.
Prog Neuropsychopharmacol Biol Psychiatry. Decreased levels of whole blood glial cell line-derived neurotrophic factor GDNF in remitted patients with mood disorders. In this study, no change in BDNF levels was observed using venlafaxine. Another important issue is the medium in which BDNF is evaluated, i. Usually, clinical studies have indicated an increase in plasma and serum BDNF levels in MDD antidepressant-treated patients after 45—60 days Yoshimura et al.
However, a small sample size study with a follow-up of 12 months found a variation in serum and plasma BDNF response to antidepressants, with the former persistently low and no changes regarding the latter Piccinni et al. To date, more than 50 studies have been performed aiming to investigate whether BDNF could constitute a depressive episode biomarker and to what magnitude it could signal an antidepressant response. Most of these studies' findings are represented in a large meta-analysis aimed at systematically reviewing the effect size of antidepressants on BDNF serum levels in 9, in 55 studies healthy controls, antidepressant-free MDD patients, and antidepressant-treated MDD patients Molendijk et al.
The BDNF levels were not different between antidepressant-treated patients and healthy controls effect size of 0. However, the meta-analysis performed by Molendijk et al.
Nonetheless, correcting effect size estimates for publication bias resulted in attenuated values for low levels of BDNF and its resultant antidepressant effect, being almost half of the previous values observed in the study. However, the association between BDNF concentration and depressive symptom severity disappeared.
Moreover, most of the studies included were underpowered median sample size of 36 patients. Moreover, four antidepressants presented more than one study and were analyzed individually regarding their role in increasing BDNF levels.
In general, antidepressants had a significant effect on the increase in BDNF concentration after 8 weeks. Although these meta-analyses carry some methodological limitations inherent to this type of study, collectively, yielded evidence raises concern about the utility of serum BDNF as a clinical biomarker for MDD or a predictor for antidepressant efficacy, and further investigations are necessary to recommend the usage of BDNF levels to monitor antidepressant treatment.
As platelets do not cross the blood—brain barrier, plasma levels are more associated with brain levels of BDNF Radka et al. Additionally, during the process of preparing blood samples to measure serum BDNF, coagulation and centrifugation processes result in platelet release of BDNF, increasing its level Fujimura et al.
Several technical issues influence serum or plasma BDNF levels such as clotting time, bioassays, temperature, and a second centrifugation to correct plasma levels, among others Maffioletti et al. Most importantly, platelet alterations are observed in MDD, and several drugs such as antidepressants and antiaggregating medications e. In this sense, we believe that serum BDNF is more reliable for clinical practice and clinical studies, especially when evaluating the serum: whole blood concentration as previously recommended Karege et al.
Rapid-acting antidepressants are mainly represented by low-dose intravenous infusion of ketamine, an N -methyl- D -aspartate receptor NMDA-R antagonist, which produces a fast and significant reduction in suicidal ideation and depressive symptoms in MDD patients Wilkinson et al. Interestingly, the BDNF levels increased after an average time of 4 h after a low-dose infusion of ketamine, completely different from the evidence with other antidepressants, which require a more prolonged time Autry et al.
Additionally, the presence of the BDNF Val66Met polymorphism may blunt the antidepressant and antisuicidal effects of ketamine Laje et al. The rapid and direct effect of BDNF linked to ketamine is reinforced by the lack of the same benefit for other NMDA-R antagonists memantine , a blunt in antidepressant action of ketamine in deletion mutant mice, and a blocked action after infusion of anti-BDNF in the medial prefrontal cortex Autry et al.
Robust clinical evidence is needed to confirm these findings. Notwithstanding, other treatment alternatives to MDD were also investigated regarding a potential increase in peripheral BDNF concentration. This is the case for electroconvulsive therapy ECT , which is a potent catalyst for neurogenesis in the hippocampus of animal models Pereira et al.
ECT is an effective treatment for MDD, but its mechanism is still debatable, involving morphological brain modifications and modulation of monoaminergic neurotransmission, especially 5-HT 1A and 5-HT 2A receptors Baldinger et al.
SMDs of 0. Moreover, evidence from other non-invasive brain stimulation treatments was summarized in a meta-analysis Brunoni et al. A total of patients were included, mostly with treatment-resistant MDD. However, most patients received daily sessions of transcranial direct current stimulation on the left dorsolateral prefrontal cortex.
No alteration in BDNF levels was found in any of the trials included, and a metaregression did not find predictive variables for this outcome. More importantly, no sign of heterogeneity or publication bias was found.
A sensitivity analysis confirmed these findings. Psychological treatment was also investigated regarding BNDF concentration and genetic profile. However, the results are less evident and less consistent. The serum levels of BDNF did not change after 16 weekly sessions of cognitive behavior therapy, and the plasma levels did not predict a response to 12 or 16 sessions of twice-weekly interpersonal therapy for depression in another study Koch et al.
Moreover, a genome-wide meta-analysis did not associate the presence of the Val66Met polymorphism with psychological treatment outcomes for depression Rayner et al. Finally, a recent trial evaluating the presence of the Val66Met polymorphism and pretreatment and posttreatment BDNF serum levels for both cognitive behavior therapy and interpersonal therapy in severe MDD patients did not find any significant association with outcomes after 6 months Bruijniks et al.
These results were not influenced by treatment modality or frequency once or twice per week of therapy. In this study, it was observed that high performance of working memory moderated the relation between higher levels of BDNF and lower posttreatment depression.
This finding can shed some light on the mechanisms by which BDNF may influence psychotherapy results. Cognitive abilities are required in the psychotherapeutic process to reduce depressant stimulants and to cope with negative feelings Bruijniks et al. Previously, cognitive domains such as memory performance Azeredo et al. Physical exercise is an evidence-based treatment strategy to improve depression with a moderate effect size Schuch et al.
Several mechanisms may explain the positive impact of physical exercise, including an increase in neurotrophic support generally combined with an enriched environment. Similar to antidepressants, there are patients with MDD who do not respond to physical activity practice at all Dunn et al. One proposed theory is that the mechanism of action of exercise could involve the neurotrophin pathway, especially the BDNF.
A meta-analysis showed that BDNF was elevated after a single section of physical activity and after a regular program Szuhany et al. Six studies were evaluated in a recent meta-analysis with conflicting results regarding the effect of physical exercise on resting concentrations of BDNF among MDD patients, and the peripheral BDNF concentrations were not increased after an exercise intervention Dinoff et al.
The small sample size in all studies, short-term follow-up, and a high level of heterogeneity were potential limitations in this systematic review. More recently, a secondary analysis of a pilot randomized controlled trial, which examined the combined effects of exercise and psychosocial treatment on depression symptoms, showed a non-significant mediating effect of BDNF Szuhany and Otto, In this small trial, neither a moderate effect of exercise on changes in BDNF levels nor predicted changes in depressive symptomatology were sustained over time.
In mouse depression models, exercises had no behavioral or neuroplastic effects in the presence of the BDNF Val66Met polymorphism Ieraci et al. Whether the BDNF Val66Met polymorphism indeed moderates the effect of physical exercise on depressive symptoms in humans needs further exploration as studies thus far have produced inconsistent results Mata et al.
Interestingly, a recent study showed that the positive impact of physical exercise on cognitive performance was significantly less among depressed patients with the BDNF Val66Met polymorphism than among those without this polymorphism Pitts et al.
Few studies have investigated the relationship between BDNF and late-life depression. Older adults with depression present more cognitive complaints, reduced hippocampal volume, and subcortical vascular abnormalities than younger individuals Beekman, These characteristics could be associated with lower levels of BDNF or at least with the presence of the Val66Met polymorphism in geriatric depression.
However, the presence of the BDNF Val66Met polymorphism was associated with geriatric depression in a previous meta-analysis of studies of late-life depression with low level of heterogeneity and publication bias Pei et al. In late-onset depression, Met allele carriers were associated with higher white matter hyperintensity volumes but without obvious clinical relationships Taylor et al. Interestingly, compared with Val carriers, healthy Met allele carriers showed worse episodic memory function, reduced hippocampal physiologic performance in functional magnetic resonance, and reduced prefrontal and hippocampal gray matter volume in previous studies Egan et al.
Moreover, Met allele carriers also showed increased age-related impairment of hippocampal activation during encoding and retrieval tasks compared with Val carriers independent of structural or performance differences Sambataro et al.
Furthermore, in a large representative sample of older American veterans, the BDNF Val66Met polymorphism moderated the association between depression and lower cognitive performance Pitts et al.
Most studies involving older adults with depression observed lower plasma or serum levels of BDNF Diniz et al. In this study, BDNF concentrations were not different between depressed older adults and controls. Most interestingly, one recent study found that the impact of BDNF serum levels on the course of late-life depression was conditional on the presence of both the use of SSRIs and a history of childhood trauma Dimitriadis et al.
However, the high levels of heterogeneity, publication biases, and lower sample sizes of the studies in this area prevent an extrapolation of this compelling evidence to clinical practice, resulting in a low level of translational evidence.
Moreover, technical issues still negatively influence our trust in peripheral measures of BDNF and its real correlation to brain levels. Several concerns remain to be answered regarding the association between BDNF levels and its 1 relationship with MDD severity, remission, and relapse; 2 direct effects vs. To address this latter issue, we recommend the serum or serum: whole blood level of BDNF as a more consistent measure of its peripheral concentration.
Figure 2. Several antidepressant treatments aimed to increase brain-derived neurotrophic factor with heterogeneous results. Finally, especially considering antidepressant treatment, BDNF may only be a part and a multilevel action of known antidepressants to date. Preclinical and clinical evidence, especially that focused on SSRIs, has shown that the higher levels of serotonin and better interactions of environmental effects, stress-related genes, or stressful environments can blunt this favorable action; healthy environments higher social networks, employment increase antidepressant responses; and psychotherapy that deals with the environment enhances psychopharmacological treatment Branchi et al.
In conclusion, future research must first better address laboratory techniques for peripheral BDNF peripheral detection with a high correlation with brain concentrations; second, it must minimize important heterogeneity factors such as the inclusion of different MDD phenotypes, different quality of patient's environment, the presence of child trauma, and genetic Val66Met polymorphisms; and third, it must explore potential direct BDNF effects depicted from rapid-acting antidepressants such as ketamine.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Ai, M. Personalized Med. Alboni, S. Fluoxetine effects on molecular, cellular and behavioral endophenotypes of depression are driven by the living environment.
Aloe, L. Stress and nerve growth factor: findings in animal models and humans. Amadio, P. Effect of clotting duration and temperature on BDNF measurement in human serum. Autry, A. NMDA receptor blockade at rest triggers rapid behavioural anatidepressant responses. Nature , 91— Azeredo, L. Revista brasileira de Psiquiatria 39, 90— Baldinger, P. Neurotransmitters and electroconvulsive therapy. J ECT 30, — Becker, J.
Stress and disease: is being female a predisposing factor? Beekman, A. Neuropathological correlates of late-life depression. Bernard, R. Altered expression of glutamate signaling, growth factor, and glia genes in the locus coeruleus of patients with major depression. Bersani, G. Data and hypotheses on the role of nerve growth factor and other neurotrophins in psychiatric disorders. Hypotheses 55, — Bleys, D. Bocchio-Chiavetto, L. Serum and plasma BDNF levels in major depression: a replication study and meta-analyses.
World J. Bombin, I. Branchi, I. The double edged sword of neural plasticity: increasing serotonin levels leads to both greater vulnerability to depression and improved capacity to recover. Psychoneuroendocrinology 36, — Antidepressant treatment outcome depends on the quality of the living environment: a pre-clinical investigation in mice. Bruijniks, S. Working memory moderates the relation between the brain-derived neurotropic factor BDNF and psychotherapy outcome for depression.
Brunoni, A. BDNF blood levels after non-invasive brain stimulation interventions in major depressive disorder: a systematic review and meta-analysis. A systematic review and meta-analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression.
Bueller, J. Bus, B. Determinants of serum brain-derived neurotrophic factor. Serum brain-derived neurotrophic factor: determinants and relationship with depressive symptoms in a community population of middle-aged and elderly people. Cahill, L. Why sex matters for neuroscience. Carlberg, L. Brain-derived neurotrophic factor BDNF -epigenetic regulation in unipolar and bipolar affective disorder.
Neurotrophins as mediators of drug effects on mood, addiction, and neuroprotection. Neuronal network plasticity and recovery from depression. JAMA Psychiatr. Brain-derived neurotrophic factor in megakaryocytes.
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