Neurotrophin Hypothesis Of Depression Research Articles

Blood Brain-Derived Neurotrophic Factor (BDNF) and Major Depression: Do We Have a Translational Perspective?

Major depressive disorder (MDD) affects millions of people worldwide and is a leading cause of disability. Several theories have been proposed to explain its pathological mechanisms, and the “neurotrophin hypothesis of depression” involves one of the most relevant pathways. Brain-derived neurotrophic factor (BDNF) is an important neurotrophin, and it has been extensively investigated in both experimental models and clinical studies of MDD. Robust empirical findings have indicated an association between increased BDNF gene expression and peripheral concentration with improved neuronal plasticity and neurogenesis. Additionally, several studies have indicated the blunt expression of BDNF in carriers of the Val66Met gene polymorphism and lower blood BDNF (serum or plasma) levels in depressed individuals. Clinical trials have yielded mixed results with different treatment options, peripheral blood BDNF measurement techniques, and time of observation. Previous meta-analyses of MDD treatment have indicated that antidepressants and electroconvulsive therapy showed higher levels of blood BDNF after treatment but not with physical exercise, psychotherapy, or direct current stimulation. Moreover, the rapid-acting antidepressant ketamine has presented an early increase in blood BDNF concentration. Although evidence has pointed to increased levels of BDNF after antidepressant therapy, several factors, such as heterogeneous results, low sample size, publication bias, and different BDNF measurements (serum or plasma), pose a challenge in the interpretation of the relation between peripheral blood BDNF and MDD. These potential gaps in the literature have not been properly addressed in previous narrative reviews. In this review, current evidence regarding BDNF function, genetics and epigenetics, expression, and results from clinical trials is summarized, putting the literature into a translational perspective on MDD. In general, blood BDNF cannot be recommended for use as a biomarker in clinical practice. Moreover, future studies should expand the evidence with larger samples, use the serum or serum: whole blood concentration of BDNF as a more accurate measure of peripheral BDNF, and compare its change upon different treatment modalities of MDD.

An 8 week prospective study on the relationship between major depressive episode and serum brain derived neurotrophic factor in a Nigerian tertiary hospital

BackgroundCurrent views on the etiology of Major Depressive Diorder(MDD) emphasizes environmental and biological interplay. Recent studies have implicated reduction in Brain Derived Neurotrophic Factor (BDNF) in the pathophysiology and as a biomarker of major depression (Neurotrophin Hypothesis of Depression). This study aimed at showing that the Neurotrophin hypothesis of depression is relevant in the pathophysiology of Major Depressive Episode in Southern Nigeria. MethodsConsecutive consenting patients diagnosed with Major Depressive Episode (MDE) using the Structured Clinical Interview for DSM (SCID) and age and sex matched controls were enrolled into this study. Serum BDNF was measured prior to commencement of treatment as baseline and 8 weeks after treatment. Depression severity was rated with the Hamilton Depression Rating Scale (HAM-D) and Patient Health Questionnaire (PHQ-9). ResultsSeventy-five cases and 75 age and sex matched controls were recruited. The mean ± SD of serum BDNF of depressed patients (26.09 ng/ml ± 1.96) was significantly lower than those of age and sex matched controls (28.13 ng/ml ± 1.47) P < 0.01. The study had a follow up rate of 48% after 8 weeks of treatment. Serum BDNF post treatment was significantly higher than baseline. LimitationsThis was a single center study with a high drop-out rate. ConclusionThe result of this study adds to the mounting evidence in support of the neurotrophin hypothesis of depression.

Serum levels of brain-derived neurotrophic factor in major depressive disorder: state–trait issues, clinical features and pharmacological treatment

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.

Brain-derived neurotrophic factor: role in depression and suicide.

Depression and suicidal behavior have recently been shown to be associated with disturbances in structural and synaptic plasticity. Brain-derived neurotrophic factor (BDNF), one of the major neurotrophic factors, plays an important role in the maintenance and survival of neurons and in synaptic plasticity. Several lines of evidence suggest that BDNF is involved in depression, such that the expression of BDNF is decreased in depressed patients. In addition, antidepressants up-regulate the expression of BDNF. This has led to the proposal of the "neurotrophin hypothesis of depression". Increasing evidence demonstrates that suicidal behavior is also associated with lower expression of BDNF, which may be independent from depression. Recent genetic studies also support a link of BDNF to depression/suicidal behavior. Not only BDNF, but abnormalities in its cognate receptor tropomycin receptor kinase B (TrkB) and its splice variant (TrkB.T1) have also been reported in depressed/suicidal patients. It has been suggested that epigenetic modulation of the Bdnf and Trkb genes may contribute to their altered expression and functioning. More recently, impairment in the functioning of pan75 neurotrophin receptor has been reported in suicide brain specimens. pan75 neurotrophin receptor is a low-affinity neurotrophin receptor that, when expressed in conjunction with low availability of neurotropins/Trks, induces apoptosis. Overall, these studies suggest the possibility that BDNF and its mediated signaling may participate in the pathophysiology of depression and suicidal behavior. This review focuses on the critical evidence demonstrating the involvement of BDNF in depression and suicide.

Brain-Derived Neurotrophic Factor and Antidepressant Action: Another Piece of Evidence from Pharmacogenetics

EVALUATION OF: Gratacòs M, Soria V, Urretavizcaya M et al.: A brain-derived neurotrophic factor (BDNF) haplotype is associated with antidepressant treatment outcome in mood disorders. Pharmacogenomics J. 8, 101-112 (2008). The neurotrophin hypothesis of depression and antidepressant drug action postulates that reduced activity of neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF), plays an important role in the pathogenesis of major depression, and that its restoration may represent a critical mechanism underlying antidepressant therapeutic effect. This hypothesis is supported by numerous animal studies; however, evidence from clinical studies is lacking. This study is the first to use both single-marker as well as haplotype analysis to test the effect of genetic variants of BDNF on the therapeutic effects of antidepressant treatment in mood disorder. Among eight BDNF TagSNPs tested, one allele (rs908867) is associated with antidepressant response, with heterozygote carriers showing a better response than homozygous analog. The authors also identified a haplotype associated with the therapeutic response. This study provides clinical evidence to support the role of BDNF in antidepressant therapeutic mechanisms. However, further work is needed to confirm the findings, for several reasons. First, the study included not only major depression but also bipolar disorder patients; second, various antidepressants were used in this study, which could affect patients' responses; third, the frequency of the haplotype associated with treatment response is rare; and fourth, previous studies of the effects of single BDNF polymorphisms on antidepressant action have reported conflicting findings. Several suggestions for further work are discussed below.

Nature vs. nurture: Can enrichment rescue the behavioural phenotype of BDNF heterozygous mice?

In earlier experiments we have demonstrated that group-housing in a rather impoverished “standard” environment can be a crucial stress factor in male C57Bl/6 mice. The present study aimed at investigating the effect of combining a probable genetic vulnerability – postulated by the “Neurotrophin Hypothesis of Depression” – with the potentially modulating influence of a stressful environment such as “impoverished” standard housing conditions. For that purpose mice with a partial deletion of brain-derived neurotrophic factor (BDNF) were group-housed under standard and enriched housing conditions and analysed in a well-established test battery for emotional behaviours. Standard group-housing affected emotional behaviour in male and female BDNF heterozygous mice, causing an increase in anxiety, changes in exploration as well as nociception. Providing the animals’ cages with supplementary enrichment, however, led to a rescue of emotional alterations, which emphasises the significance of external factors and their relevance for a valid investigation of genetic aspects in these mutants as well as others, which may be examined in terms of stress-responsiveness or emotionality.

New insights into BDNF function in depression and anxiety

The 'neurotrophin hypothesis of depression' is based largely on correlations between stress or antidepressant treatment and down- or upregulation, respectively, of brain-derived neurotrophic factor (BDNF). Genetic disruption of the signaling pathways involving BDNF and its receptor, the tyrosine kinase TrkB, does not seem to cause depressive behaviors, but does hamper the effect of antidepressant drugs. Thus, BDNF may be a target of antidepressants, but not the sole mediator of depression or anxiety. Advances in BDNF cell biology, including its transcription through multiple promoters, trafficking and secretion, may provide new insights into its role in mood disorders. Moreover, as the precursor proBDNF and the mature protein mBDNF can elicit opposite effects on cellular functions, the impact of proBDNF and its cleavage on mood should be considered. Opposing influences of mBDNF and proBDNF on long-term potentiation and long-term depression might contribute to the dichotomy of BDNF actions on behaviors mediated by the brain stress and reward systems.