Back to Archived Journals » Journal of Receptor, Ligand and Channel Research » Volume 7

BDNF–TrkB signaling as a therapeutic target in neuropsychiatric disorders

Authors Du X, Wu YC, Hill RA

Received 26 May 2014

Accepted for publication 24 June 2014

Published 6 October 2014 Volume 2014:7 Pages 61—79

DOI https://doi.org/10.2147/JRLCR.S50404

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3



Xin Du,1 Yeewen C Wu,1,2 Rachel Anne Hill1

1Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia; 2Department of Pharmacology, University of Melbourne, Parkville, VIC, Australia

Abstract: Research evidence points to abnormal brain-derived neurotrophic factor (BDNF) signaling being a common and vital participant in the etiology and pathophysiology of many psychiatric disorders, including depression, schizophrenia, and bipolar disorder. To increase BDNF levels in patients is therefore a necessary goal of any treatment. This review explores the various therapeutic strategies that can increase BDNF brain expression and recover mental health disturbances. From environmental enrichment and exercise to dietary intake, it is apparent that a healthy lifestyle significantly influences BDNF signaling and mental health. We conclude that in order to combat the inefficiency of current treatment methods, more attention should be focused on holistic approaches to achieve this goal, as BDNF is proven to have dynamic responses to environmental influences.

Keywords: BDNF, neurotrophins, mental health

Introduction

Neurotrophins are a family of growth-factor proteins that promote the survival, growth, maturation, and function of neurons. The family of neurotrophins to which brain-derived neurotrophic factor (BDNF) belongs also contains nerve-growth factor (NGF), neurotrophin 3, and neurotrophin 4.1,2 Of these, BDNF is especially assiduous and plethoric; its importance is shown by its highly conserved structure3 and by early postnatal lethality in knockout mouse models.4

Since its identification more than three decades ago,5 BDNF has been found to be vital during embryonic brain development, where it is seminal in early synaptic and neuronal circuit formation.69 Its importance also persists postnatally, where it supports neuronal maturation, homeostasis, and survival,4,10,11 the regulation of synaptic transmission and neuronal plasticity,1214 and the promotion of neurogenesis via enhancing the proliferation,1517 differentiation,18 and survival19 of newborn cells.

The BDNF gene is mapped to chromosome 11p in humans and exhibits highly complex regulation of its expression. It has been found to have eleven exons and nine functional promoters that direct tissue, brain-region, and cellular spatial specificity.20,21 BDNF is synthesized as a 35 kDa prepro isoform, which may then be cleaved to form a 28 kDa proBDNF or a 13.5 kDa mature BDNF. The expression of BDNF is regulated via neuronal activity through calcium-mediated mechanisms,22 and its high-affinity tyrosine kinase-coupled receptor, the tropomyosin-related kinase receptor (TrkB), is also regulated in an activity-dependent manner.23 BDNF also binds with a low affinity to the p75 receptor, which it shares with other members of the neurotrophin family. The mature BDNF isoform has a high affinity for TrkB, and upon binding activates a number of intracellular signaling pathways including phosphoinositide 3-kinase, phospholipase Cγ, and mitogen-activated protein kinase.24 While it is thought that the pro or truncated BDNF isoform has little biological activity, preproBDNF is thought to form a complex with sortilin and p75 to elicit apoptotic signaling.25

Having so many fundamental and diverse influences on the brain naturally led to the linkage of abnormal BDNF expression and function with various psychiatric diseases.2631 One crucial reason is the finding that stress, a great inducer of depression, anxiety, and other psychiatric problems, impairs BDNF and TrkB signaling in limbic areas critically associated with emotionality, such as the hippocampus and frontal cortex.3235 This review focuses on the pathophysiological involvement of BDNF in psychiatric disorders, the therapeutic potential of this prolific growth factor, and the various methods in which restoration of BDNF signaling may be implemented.

BDNF and depression

Depression is a multifarious and debilitating disorder that is among the top three contributors to the global burden of disease.36,37 It is also a disease whose prevalence is on a sharp upward trend.36,38 Depression is a major contributor to suicide39 and is often a symptom of or highly comorbid with other neurological disorders, such as schizophrenia,40 Alzheimer’s disease,41 Parkinson’s disease,4244 and Huntington’s disease,4547 as well as with major diseases such as type 2 diabetes,48 cardiovascular disease,4951 and alcohol withdrawal syndrome,52 to name but a few.

Depression is thought to result from an inability of the brain to make appropriate adjustments and adaptations in response to environmental stressors, due to impaired or inadequate synaptic and neural plasticity.5356 This is evidenced by studies showing altered brain structures in depressed patients, such as reductions in cell number, cell density, and body size as well as reduced glial density in frontal cortical and hippocampal brain regions.5760 These observations led to the hypothesis that a loss of neurotrophic factors, which are essential for the survival, development, and maintenance of neurons61,62 and for regulating synaptic and morphological plasticity,1,63 is directly involved in the pathophysiology of depression and that its restitution may lie at the heart of successful treatment – the neurotrophin theory of depression.27,35,53,64 BDNF, an essential, abundant, and prolific neurotrophin conspicuous for its relationship to various neurological and psychiatric disorders, has been given particular interest.

The link between BDNF and depression has been shown by a wealth of evidence. A common single-nucleotide polymorphism in the BDNF gene at nucleotide 196 (G/A), which causes a valine (Val)-to-methionine (Met) substitution at codon 66 (Val66Met) has been shown to negatively affect memory and induce abnormal hippocampal activity as well as to disrupt normal activity-dependent BDNF secretion65 and dendritic trafficking of BDNF mRNA.66 Those with the Met allele also show reduced hippocampal and prefrontal cortex gray matter volume.65,67 A recent meta-analysis suggests that the Met allele is associated with increased susceptibility to stressful life events and subsequent depression.68 Another study observed a correlation between having the Met allele and increased chronicity of depression with a gene–dosage effect – Val/Met heterozygotes show intermediate chronicity between Val/Val and Met/Met homozygotes, who showed the highest chronicity.69 These findings suggest that disruptions in BDNF signaling increase the propensity to depression.

BDNF can cross the blood–brain barrier,70 and its serum protein levels in the periphery are strongly correlated with protein concentrations in the central nervous system.71 Levels of peripheral BDNF measured in serum and plasma have largely been found to be significantly reduced in patients suffering depression and dysthymia disorder, compared with healthy people.7274 A significant negative correlation between BDNF levels and the severity of symptoms according to the Hamilton Rating Scale for Depression75 as well as the Montgomery-Åsberg Depression Rating Scale76 have also been observed, suggestive of a dose effect. Going hand-in-hand, successful treatment seems to correlate with the restitution of BDNF. Serum BDNF was found to be significantly lower in antidepressant-naïve depressed patients than in healthy controls, whereas patients treated with antidepressants showed a significant elevation in BDNF when compared with nonmedicated patients.77,78 A recent meta-analysis confirmed reduced serum BDNF in antidepressant-free depressed patients versus healthy controls and antidepressant-treated patients, but failed to find the correlation between BDNF concentration and symptom severity.79 Indeed, systematic analysis in more than a thousand patients did not find any association between decreased BDNF and specific symptoms or symptom clusters.80

In postmortem samples, both mRNA and protein expression of BDNF and its receptor TrkB were found to be reduced in the prefrontal cortex and hippocampus of suicide victims.81,82 Hippocampal BDNF levels were found to be higher in both patients with major depression and suicide victims treated with antidepressants at time of death, compared with untreated subjects.82,83 Tying in with this are the neuroimaging studies that have found reductions in frontal-lobe84,85 and hippocampal volume in depressed patients, which correlated negatively with duration of disease.8688 Within a cohort of patients suffering major depression, who exhibited overall reduced hippocampal volumes compared with controls, those with the Met allele had significantly smaller hippocampal volume than patients with the Val allele.89 Hippocampal shrinkage is attenuated in patients undergoing antidepressant treatment.90,91 Likewise, a recovery in dorsal–lateral prefrontal cortical volume was seen in patients after antidepressant treatment and was correlated with a self-reported decrease in depression level.92 Orbitofrontal cortex shrinkage93 was partially attenuated in geriatric patients with depression who had used antidepressants versus those who were drug-naïve.94 A direct positive correlation has also been found via magnetic resonance imaging (MRI) between serum BDNF levels and hippocampal volume of first-episode, medication-free depressed patients,95 suggestive of BDNF’s importance in the etiology and pathogenesis of depression. Despite some inconsistencies between neuroanatomical studies, most likely due to sample differences in illness severity, medication, sex, family history, et cetera,96 the evidence nevertheless suggests that antidepressants arrest brain atrophy and symptom deterioration at least partly by increasing BDNF levels.

This supposition is further fortified by research in rodent models, where a mouse model containing the Met/Met allele exhibited abnormally increased anxiety-like behaviors when confronted by stressful settings, was unresponsive to fluoxetine treatment, and showed decreased hippocampal volume and reduced BDNF secretion, reflective of clinical data.97 In rodents, early life stress (a model of depression) lowered BDNF and altered stress sensitivity later in life,98 whereas increases in BDNF, either via social enrichment or direct infusion into the brain, reduced susceptibility to depression-like behaviors.99101 However, studies also found that increases in BDNF through communal nesting induced a depressive-like phenotype by increasing immobility time in the forced-swim test.102 Other studies examining the role of BDNF in depression have also found that heterozygous knockout of BDNF did not alter anxiety as tested on the elevated-plus maze.103105 BDNF heterozygote mice and mice expressing the dominant negative TrkB receptor TrkB.T1 did not show any differences compared with wild-type mice in their performance on the forced-swim test, therefore suggesting that reduced BDNF signaling alone may not be sufficient to cause depression per se.106

There is accumulating evidence suggesting inflammation as a mediator of the pathophysiology of mood disorders.107,108 Many studies show that depression is often accompanied by an activation of the inflammatory response system, with an increased production of proinflammatory cytokines. Two meta-analyses consisting of 24 studies and 29 studies, respectively, have shown that interleukin (IL)-6, and tumor necrosis factor (TNF)-α are increased in patients with major depression compared with controls;109,110 the 2012 study also reported increased soluble IL-2 receptor levels in depressed patients. Cytokine administration has similar effects as psychogenic stressors through actions in the hypothalamus and limbic areas, making it a candidate in the pathophysiology of depression.111 It has been suggested that the depressive effects of an increased inflammatory response is an adaptive change to encourage individuals to rest and reserve energy as the body combats disease.112 The effect of inflammatory factors on BDNF is rather scant, but studies have shown that IL-1β and TNF-α can decrease BDNF mRNA in the amygdala of rats.113 Interferon-α has been found to reduce BDNF in humans,114,115 as does lipopolysaccharide in rats.116 IL-1β has also been shown to reduce BDNF–TrkB signaling and to interfere with BDNF-induced antiapoptotic effects.117 However, another study found that IL-1β increased BDNF mRNA expression in rat hypothalamic neuron-enriched cultures while it reduced BDNF expression in mixed neuron–astrocyte cultures.118 Inflammatory cytokines also attenuated TrkB phosphorylation, thereby interfering with BDNF signaling.119 Counterbalancing this, imipramine’s ability to offer neuroprotection against lipopolysaccharide-induced apoptosis requires intact BDNF signaling.120 The evidence therefore hints at a complex relationship, but one that could potentially compromise BDNF signaling.

Collectively, these findings suggest that BDNF may be a key molecule involved in various antidepressant treatment strategies. Therefore, restitution of BDNF may be a fundamental goal of treatments targeting depression.

BDNF and schizophrenia

It has been suggested that altered synthesis and/or release of neurotrophins may contribute to the development of schizophrenia.29,30,121 Studies on post-mortem tissue from patients with schizophrenia showed a significant reduction in both BDNF and TrkB transcripts as well as BDNF protein in the dorsolateral prefrontal cortex, compared with controls.122124 Another study, measuring protein concentrations determined by enzyme linked immunosorbent assay (ELISA), showed decreased BDNF levels in the hippocampus but increased BDNF levels in the neocortex and unchanged BDNF levels in the cingulate gyrus and thalamus of schizophrenia patients.125 In contrast, other studies examining the hippocampus of schizophrenia patients showed increased immunostaining of BDNF and TrkB proteins126 and increased BDNF protein but decreased TrkB protein, as measured by ELISA and Western blots, respectively.127 It is unclear why there are these opposite and inconsistent findings between studies, although different methods used to measure BDNF and TrkB could be responsible. For example, ELISA methods, used in the aforementioned studies, typically cannot differentiate between pro and mature BDNF isoforms, while Western blotting can distinguish the two. However, more recently, selective ELISA kits have become available that are advertised to be specific to either mature BDNF (human BDNF ELISA Kit; Adipo Bioscience, Santa Clara, CA, USA) or proBDNF (human proBDNF ELISA Kit; Adipo Bioscience). Indeed, a recent study using the above-mentioned ELISA kits demonstrated a selective reduction in mature but not proBDNF isoforms in patients with major depressive disorder,73 demonstrating the importance of assessing these isoforms individually.

Most studies show significantly reduced serum BDNF protein levels in chronic and medicated patients with schizophrenia compared with healthy controls.128132 This is also true in first-episode and antipsychotic-naive patients with schizophrenia compared with healthy people.133135 However, increased BDNF serum protein levels have also been reported,136 while other studies have failed to find any significant differences.137,138 Komulainen et al139 reported that a reduction in plasma BDNF protein levels was associated with cognitive impairment in a large sample of women aged 57–79 years, but not in men. Further, women who reported using sex hormones (hormone-replacement therapy) performed better in tests of general cognition, memory, and executive function.139 Taken together, clinical data point to a dysregulation of BDNF signaling in schizophrenia.140

The dopamine hypothesis of schizophrenia suggests that schizophrenia is caused by excessive dopaminergic neurotransmission, and consequently, most antipsychotic medications act via dopamine receptor DR2 antagonism. BDNF has been shown to play a critical role in the developmental expression of dopamine receptor DR3 in the nucleus accumbens.141 Conversely, striatal BDNF expression may be altered by activation of dopamine receptors DR1 and DR2.142 Hence, a strong relationship appears to exist between BDNF and dopamine’ signaling, and alterations to either of these systems may underlie the pathophysiology of schizophrenia and may dictate responsiveness to antipsychotic medication.

Indeed, medication-naïve patients have been shown to have lower plasma BDNF levels, suggesting a role for antipsychotics in the regulation of BDNF.143 This positive effect of antipsychotics on BDNF expression is specific to atypical antipsychotics, as typical antipsychotics such as haloperidol tend to reduce BDNF expression levels.143145 However, this tends to be antipsychotic-specific, as a cross sectional survey demonstrated positive effects of clozapine, but not risperidone, on serum BDNF levels.146

Both in vitro and in vivo studies have shown a positive effect of atypical antipsychotics, such as olanzapine and lurasidone, on BDNF mRNA and protein expression in the prefrontal cortex and hippocampus.147,148 Thus alterations in the levels of BDNF may represent one of the mechanisms by which antipsychotics exert their effects.

Several studies have shown an association between the Val66Met BDNF polymorphism and aspects of schizophrenia, including age of onset,149 antipsychotic response,150152 and cognitive function.153,154 Both patients with schizophrenia and healthy participants carrying the Met allele showed poorer verbal memory than their Val homozygous counterparts.155 However, the Met allele was associated with visuospatial impairments that were specific to schizophrenia patients but not healthy participants.155 A 2012 meta-analysis of the association between the Val66Met polymorphism and cognition, including 23 studies up to 2010, reported no significant associations with the polymorphism and measures of general cognitive ability, memory, executive function, visual processing skills, and cognitive fluency.156 These discrepancies in the literature may be due to limited sample sizes, lack of consistency in the cognitive tasks assessed, or other hidden sources of variation such as ethnicity of the subjects (the frequency of the derivative allele ranges from near 0% in Africans to up to 60% in Asians and 17% in Caucasians).156 In addition, it may be that the polymorphism renders the patient more vulnerable to stress-induced disruption (eg, gene × environment). For example, Met carriers exposed to high childhood abuse showed significantly poorer cognitive function when compared with Val carriers,157 suggesting a gene × environment interaction. This gene × environment interaction has been further explored in our laboratory, where we have shown in BDNF heterozygous mice that an additional environmental insult in the form of chronic corticosterone treatment leads to significant impairments in spatial memory.158

Cognitive impairments have also been reported in conditional BDNF knockout mice. For instance, a conditional dorsal hippocampus BDNF deletion in male mice impairs spatial learning in the Morris Water Maze and nonspatial recognition memory in novel-object recognition tests.24,159 Interestingly, Monteggia et al160 found a sex-specific behavioral phenotype in mice with forebrain-specific BDNF deletions. The female conditional knockout mice exhibited normal locomotor activity but a substantial increase in depression-like behaviors, whereas male conditional knockouts showed hyperactivity but normal depression-related behaviors. Other animal models of schizophrenia have also displayed alterations in BDNF expression levels, including rat models induced by postnatal MK-801 or phencyclidine administration,161,162 disrupted in schizophrenia 1 (DISC-1) and Reelin mutant mouse models,163,164 and a prenatal infection (poly-I:C) mouse model.165

Cytokines have been posited to play a role in schizophrenia.166 A comprehensive meta-analysis showed that schizophrenia is associated with altered cytokine profiles. IL-1β, IL-6, and transforming growth factor (TGF)-β all are increased in both acute relapse patients and first-episode patients; this abnormal increase was abolished by antipsychotic treatment. On the other hand, IL-12, interferon-γ, TNF-α, and soluble IL-2 receptor were found to be elevated and remained elevated following antipsychotic treatment,167 suggesting that IL-1β, IL-6, and TGF-β are good state markers. Furthermore, another study found increased IL-6 and TNF-α in first-episode psychotic patients. Linear regression showed that increased psychosocial stress predicted lower BDNF through an inflammation-mediated pathway and that the increased IL-6 correlated with reductions in BDNF and left hippocampal volume.168

Together, the studies above suggest that BDNF may underlie aspects of positive symptoms such as hyperactivity and cognitive dysfunction as well as negative symptoms associated with schizophrenia.

BDNF and bipolar disorder

Bipolar disorder is a devastating psychiatric condition marked with severe mood symptoms, most notoriously by episodes of mania or hypomania typically followed by an episode of depressed mood. Lifetime prevalence stands between 1%–4%.169 Genetic studies show bipolar disorder is highly heritable, explaining about 60%–85% of variance in risk.170 Relatives of a bipolar sufferer have a significantly increased risk of developing bipolar disorder as well as unipolar major depression disorder.170,171

BDNF has been posited as a key candidate gene associated with the etiology of bipolar disorder. A meta-analysis of 14 studies found a significant association between the Val66Met allele and bipolar disorder.172 A recent study showed that serum BDNF levels in drug-free bipolar patients suffering either a manic or depressive episode were reduced compared with healthy controls.173 This is in agreement with a meta-analysis that found reduced serum and plasma BDNF levels in both manic and depressive patients, with an association with the length of illness. It was also found that peripheral BDNF increased after treatment for acute mania, suggesting that BDNF can be a marker for mood episodes.174 A recent study comparing BDNF levels in first major depressive episode patients suffering either from bipolar or major depression found that while both groups showed significantly reduced plasma BDNF, those suffering bipolar disorder had even lower BDNF levels than did the major depression patients.175 However, other studies found either no decrease in plasma BDNF in patients compared with controls176 or even an increase in plasma BDNF compared with controls.177 One study found that improvement in symptoms resulting from quetiapine treatment was accompanied by increases in BDNF in patients with depressive episodes and decreases in BDNF in patients with manic or mixed episodes,178 suggesting differential BDNF alteration according to polarity of disease, adding a layer of complexity in analyzing the role of BDNF.

Postmortem analysis found reduced BDNF mRNA expression in layer VI in the inferior temporal gyrus and layers V and VI of the superior temporal gyrus in patients with bipolar disorder, schizophrenia, or major depression disorder.179 Hippocampal proBDNF levels were also found to be reduced in postmortem bipolar samples to a similar but slightly lesser degree than that of major depression disorder samples.180 MRI revealed decreased gray matter in bipolar sufferers compared with controls, but there were no differences between Val66 versus Met66 allele carriers.181

Examining cytokine profiles in bipolar patients in the depressed, manic, and euthymic phases, Brietzke et al182 found different state-dependent profiles. Manic phase was associated with increases in IL-2, IL-4, and IL-6 compared with controls; patients in depression phase exhibited an increase only in IL-6; euthymic patients show an upregulation in IL-4 only, suggesting that change in cytokine expression profile is a good state marker in bipolar disorder. Looking at early versus late-stage bipolar patients, it was found that BDNF was only reduced in the late stages of disease despite increased IL-6, IL-10, and TNF-α levels at the early phase of disease. A significant negative correlation was seen between BDNF and TNF-α, which continued to increase in the late stages of disease, whereas IL-6 and IL-10 decreased in late-stage patients.183 However, it was found in adolescent bipolar patients that a negative association exists between BDNF and IL-6,184 suggesting negative influences of increased cytokine on BDNF signaling even in early phases of disease.

The evidence suggests that an important role is played by BDNF in mediating both the pathogenesis and symptom severity of bipolar disorder.

Antidepressants and BDNF

In addition to its role in synaptic plasticity, the BDNF signaling pathway is now well known to interact with the serotonergic system at several different levels. A recent review by Homberg et al185 suggests that alterations to the serotonin (5-HT) transporter in 5-HT transporter knockout rats reduced BDNF mRNA and protein expression in both the hippocampus and prefrontal cortex, and this reduction in BDNF may then alter 5-HT1A receptor signaling. In addition, we have shown an upregulation of BDNF protein in the hippocampus of 5-HT2C receptor knockout male mice,186 but a decrease in BDNF protein and TrkB phosphorylation (activation) in the ventral hippocampus of 5-HT1A receptor knockout mice, and this was specific to female mice.187 With this complex interplay between BDNF and the serotonin pathway in mind, it is not surprising then that BDNF is thought to play a role in mediating antidepressant drug effects.

BDNF seems to mediate the positive effect of several classes of antidepressants, including selective serotonin reuptake inhibitors, tricyclics, serotonin noradrenalin reuptake inhibitors, and monoamine oxidase inhibitors, which have been found to increase BDNF in patient serum, cortical astrocytes in vitro, and in the prefrontal cortex and hippocampus of animal models.77,188,189 Gervasoni et al190 found that not only was reduced BDNF in depressed patients was increased following antidepressants, but in both instances BDNF negatively correlated with depression severity as measured by the Montgomery-Asberg Depression Rating Scale. Chen et al83 also found increased BDNF immunoreactivity in the hilus, dentate gyrus, and supragranular zone of postmortem patients on antidepressants at the time of death compared with those who were not on antidepressants.

Rodent models allow closer dissection of the mechanism of antidepressants and further illuminate the importance of BDNF in mediating antidepressant effects. In rats, Nibuya et al191,192 found that chronic but not acute treatment with various antidepressants including sertraline, desipramine, and tranylcypromine increased the gene expression of BDNF and TrkB in different subregions of the hippocampus, including the granule cell layer, CA1, and CA3; this effect was not found using nonantidepressant psychotrophs such as haloperidol and cocaine. Furthermore, chronic antidepressant treatment was also protective against the reduction of BDNF and TrkB induced by restraint stress. In forebrain BDNF-deficient mice, the antidepressant and learning-enhancing effects of desipramine were abolished.106,193 Transgenic mice overexpressing the dominant negative truncated TrkB receptor TrkB.T1, which show reduced TrkB activation in the brain, are resistant to the effects of antidepressants,106 whereas overexpression of TrkB led to resistance to depression-like behavior, with selective serotonin reuptake inhibitors unable to further increase this resistance.194 TrkB agonists have been found to exert antidepressive effects in rodents,195 indicating that TrkB signaling is necessary for the behavioral benefits of antidepressants.

BDNF as a therapeutic target

A key question in the treatment of depression with antidepressants has been why it takes weeks for antidepressants to achieve beneficial effects when they are able to alter synaptic monoamine levels within a matter of hours. It has been theorized that this delay is due to the time required to achieve neuroadaptive changes196,197 and that this action is mediated via BDNF.198200 It is a well-known phenomenon that fewer than half of patients treated with antidepressants derive any benefit.201 Katsuki et al202 found that the difference between responders and nonresponders to treatment with mirtazapine is the ability for the antidepressant to increase serum BDNF. Hence, other means of elevating BDNF is greatly sought. Infusion of BDNF directly into the hippocampus101 or peripherally203 produces antidepressant-like effects in mouse models. However, as a therapeutic or adjunctive treatment, peripherally administered BDNF is unsuitable due to: 1) the tumour promoting properties of BDNF;204 2) the limited ability of BDNF to cross the blood–brain barrier (which remains controversial); 3) poor bioavailability (due to enzyme degradation);205 and 4) short half-life (within hours, therefore requiring multiple doses).206 However, lifestyle alterations and diets including small molecules that can specifically activate the BDNF receptor are attractive candidates for potential therapeutic use.

Environmental enrichment

As BDNF gene expression is triggered by neuronal activity;22 enhancement of cognitive and sensory stimulation has been posited as a way to enhance BDNF expression. Much work has been done in rodent models – the first description of positive effects of environmental enrichment (EE) was made by Donald Hebb, who let his rats roam free in his house and found that these rats performed better in problem-solving tests than rats kept in cages in the laboratory.207 While the ingredients of an enriched environment can differ greatly between laboratories and studies, what it essentially involves is a housing condition that promotes and enhances sensory, cognitive, and motor stimulation relative to standard housing. This is typically achieved through group housing in large boxes with the addition of various objects like tunnels, nesting material, and running wheels to the habitat.208,209

Further investigations in rodents unearthed that environmental enrichment can lead to increased cerebral volume210 as a result of increased cerebral cortical thickness, number of synapses and glial cells.211,212 It has long been known that detraction of environmental stimulation, such as social isolation housing, increases stress and promotes depression-like behaviors.213,214 Being the negative corollary, EE has been found to have the opposite effects – anxiolytic and antidepressant-like actions – in a variety of rodent models of psychiatric and neurologic disorders.215220 Enrichment promotes hippocampal cell proliferation and survival.221 In fact, it has been found that adult neurogenesis is required to facilitate EE benefits to counter depressive-like behaviors induced by psychosocial stress in mice.222 Furthermore, BDNF was seen as the intermediary of increased neurogenesis after EE, as BDNF heterozygous mice that did not show any increase in BDNF after EE did not show any increase in neurogenesis, unlike their wild-type counterparts that showed both an increase in BDNF and a two-fold increase in neurogenesis.223 The positive behavioral effects of EE also correlate with increases in BDNF in the amygdala and hippocampus of rats.224 BDNF heterozygote mice exhibited increased anxiety and altered nociception, which were corrected by enrichment225 as well as increases in BDNF expression in the hippocampus.226 Neuropathic pain is common in psychiatric diseases and this may be due to increased inflammation, which exacerbates nociceptive sensitivity.227 EE has been shown to have immunomodulatory actions228 that counteract inflammation, which, in conjunction with increasing BDNF, may offer a double-pronged beneficial effect in combating depression.

Due to the multifaceted nature of environmental enrichment, it is difficult to untangle the essential key elements of enrichment to allow efficient clinical translation. Systematic clinical studies looking at the equivalent of environmental enrichment are comparatively scant compared with those studying effects of pharmacological treatments. Evidence does suggest that complementary interventions that foster social contact and mental and physical stimulation can have benefits to patients. A recent study found that the act of joining social groups had positive benefits on depression symptoms and decreased the risk of depression relapse in a dose-dependent manner.229 Similarly, social networking benefitted schizophrenia patients, with positive effects persisting long after implementation.230 Gentle yoga intervention was seen to benefit women suffering depression by enhancing connectedness.231 Likewise, patients who joined Argentine tango or meditation lessons showed a significant reduction on their depression measures.232 Massage and yoga also showed anxiolytic and antidepressant effects in prenatally depressed women.233 A review found an overall positive effect of massage treatment for depressed people despite large variations in effect size, most likely due to differences in the protocol used.234 In schizophrenia patients, a recent meta-analysis did not find convincing benefits of yoga.235 Little evidence is available on the effects of these therapies on BDNF expression.

More substantial studies have been performed in looking at music therapy. Psychodynamic music therapy has been found to reduce depression and anxiety symptoms236 as well as altering frontotemporal electroencephalograph activities in patients.237 A review concluded that chronic music listening can reduce depressive symptoms regardless of type of music preferred by the listener.238 Systematic review of music therapy in schizophrenia patients found general positive benefits on various aspects of the disease, including global state, general mental state, depression, anxiety, and negative symptoms, but effects were inconsistent and variable due to variability in protocols.239 Interestingly, rodent studies duplicated the effects of music observed in humans, with one study reporting that chronic exposure to a range of music, including vocal and instrumental (both Oriental and Western), had anxiolytic effects, which were accompanied by increases in BDNF mRNA and protein expression in the prefrontal cortex, hippocampus, and amygdala.240 Interestingly, the elevation of BDNF was seen in BDNF (Met/Met) transgenic and wild-type mice but not in BDNF heterozygous mice. Chronic exposure to slow rhythm music in mice has also been shown to increase BDNF levels in the hypothalamus241 and hippocampus as well as to enhance learning in the passive-avoidance task.242 As music has been demonstrated to stimulate areas of the brain associated with emotionality, such as the hypothalamus, hippocampus, amygdala, and prefrontal cortex,243 the evidence from rodent studies suggests that BDNF may be the mediator of the benefits of music on psychiatric disorders.

Cognitive behavioral therapy (CBT) is a widespread behavioral approach in the treatment of psychiatric disorders. It has been found to show some efficacy in the treatment of depression244 and schizophrenia.245 A meta-analysis however, showed dubious efficacy of CBT on schizophrenia but more robust effects on the treatment of major depression, both in reducing symptoms and preventing relapse.246 This opacity of CBT effect is due to a lack of controls available in studies looking at CBT, unlike the rigorous double-blind, placebo-controlled experiments used to scrutinize the efficacy of drugs.

Physical activity has always been considered an important part of an enriched life, and the majority of EE paradigms include running wheels. Studies have suggested that in fact physical exercise is the key element mediating positive benefits of EE on psychiatric disorders. Rodent studies have indeed found that the element of running is crucial to increasing neurogenesis and mature BDNF levels in the hippocampus, whereas enrichment without running wheels did not achieve these changes in female mice.247 A recent systematic study examining the different constituents of EE, separating out running, environmental complexity, and the social interaction elements, showed that running is the principal neurogenic stimulus.248 Complex environment, despite not increasing neurogenesis, did increase depolarization-associated c-Fos expression in the granule cell layer and reduced stress-induced plasma corticosterone levels, which occurred regardless of running. These results suggest that while environmental complexity and social interaction have certain positive influences, physical exercise might be the prevailing mediator of BDNF upregulation and subsequent benefits.

Exercise

Exercise has been shown to have positive effects on depression,249251 with levels of physical activity negatively correlated with depression symptoms.252 It was found that within a population of patients with major depression, those who are physically active show milder symptoms compared with more sedentary sufferers.253 Blumenthal et al254 found that group-supervised and individual home-based aerobic exercise were equally effective in getting patients into remission as was sertraline across 16 weeks of treatment, with milder side-effects in the exercise groups. Echoing this, a study in rats found chronic running-wheel housing increased BDNF mRNA level to a similar extent as chronic antidepressant treatment. Furthermore, a joint treatment of citalopram with running wheel resulted in a greater rise in BDNF mRNA than either treatment alone,255 suggesting an additive or adjunctive effect.

Exercise has also been shown to impart benefits to schizophrenia patients, reducing both positive and negative symptoms,256258 improving memory and increasing hippocampal volume,259 as well as increasing serum BDNF levels.260 Exercise was found to be associated with lower depressive symptoms but more manic symptoms in bipolar disorder.261 Evidence of a positive influence of exercise on schizophrenia and bipolar disorder are more scant compared with studies in depression.262 A recent study looked at the effect of a 4-week exercise regimen in patients with major depression or schizophrenia matched for age, sex, education, and disease duration. Despite the relatively short duration, the authors found benefits in both groups, with reduced depressive symptoms and anxiety in the depressed patients and reduced negative symptoms in schizophrenia patients. Both groups showed increases in cognitive function and increased subjective ratings on quality of life.263 The efficacy of physical exercise is difficult to gauge due to inconsistencies in regimens, types of exercises, and duration and frequency of exercises undertaken.

While the exact mechanism underlying the benefits of exercise is not understood, BDNF has been posited as a participant. Neeper et al264 first reported that acute exercise can increase hippocampal and caudal neocortical BDNF mRNA in rats. Following from this, evidence is found to show that similarly, a single bout of exercise can induce an acute if transient increase in serum or plasma BDNF in depressed patients.265,266 Subsequent training can augment this response, suggesting a mechanism to long-lasting benefits.267 However, differences in effect are seen in different regimens. For example, 3 months of endurance training at ~70% maximum heart rate and ~65% maximal oxygen uptake for an hour a day in healthy subjects was found to increase basal serum BDNF levels but to have no influence on exercise-induced BDNF levels.268 The same study found that a similar regimen in mice consisting of 5 weeks of 1-hour-long treadmill running, 5 days a week, led to an increase in hippocampal but not cortical BDNF mRNA expression. Another study instituted a 10-week strength-training regimen, after which no increase in either baseline or postexercise serum BDNF or in cognition was seen.269 Similarly, a 12-week training intervention of either moderate endurance training or high-load strength training, despite having positive endurance and strength augmentation, respectively, did not increase baseline plasma BDNF.270 Compared with this, a 5-week regimen of a mixture of moderate to intense endurance exercise induced in healthy young men an increase in both basal and exercise-induced plasma BDNF. This study also examined a cohort of athletes whose plasma BDNF was found to be about three times higher than that in untrained subjects.271

Ferris et al272 found that postexercise increases in serum BDNF were only achieved with a 30-minute bout of intense riding exercise at 10% above ventilator threshold and not after riding at 20% below the ventilator threshold. A recent study examined time as well as intensity of exercise and found that to achieve maximal postexercise increases in serum BDNF, a long duration (40 minutes as opposed to 20 minutes) of intense aerobic exercise (80% of heart rate reserve as opposed to 60%) was the most effective.273 This evidence suggests a certain level of exercise intensity, duration, and chronicity is required to achieve reliable elevation of BDNF that might translate to therapeutic benefits. Consistent with this, it was found in a large cohort of women that those who reported a history of vigorous exercise had the lowest odds of depression symptoms, compared with more sedentary subjects.274 For patients treated for depression, regular exercise after cessation of initial pharmacotherapy or exercise regimen intervention showed benefit at follow-up months later, with the amount of exercise per week correlating negatively with Hamilton Rating Scale for Depression score and positively with the probability of partial remission.275,276 A very recent study examined effects of implementing a 3-month exercise regimen (3 sessions per week; 45 minutes per session) of aerobic exercise (80% maximum heart rate) versus control exercise (consisting of stretching and low-impact exercise such as catching and throwing balls) in outpatients with major depression. The study failed to find any increase in BDNF after the regimen, nor any change in hippocampal volume. However, this study suffered from poor adherence, with an average of only one attendance to exercise sessions per week instead of the planned three, making it hard to draw conclusions as to the effects of exercise on BDNF.277

In support of the clinical evidence, BDNF is found to be upregulated by exercise and environmental enrichment in rodents, contributing to beneficial effects such as induction of cell survival and proliferation and dendritic development, leading to augmented cognitive outcomes.278282 Fang et al283 found that treadmill exercise in rats attenuated reductions in BDNF and phosphorylated TrkB in the hippocampus caused by chronic immobility stress. A recent study found that exercise, via running wheel, in rats compensated for high-fat diet-induced memory deficits measured in the two-way avoidance task and that this correction was associated with increases in BDNF expression in the CA3 subfield of the dorsal hippocampus.284 Intensity of exercise was also a factor, with higher intensity resulting in increased levels of BDNF in the hippocampus as well as increased cell proliferation in rats.285 In mice too, a 6-week voluntary running regimen in male C57Bl/6J mice reduced anxiety-like behaviors and increased gene expression of BDNF.286

The positive effects of exercise may be affected by myriad other factors. A Japanese study found that cycling for 30 minutes at 60% maximal oxygen uptake induced an increase in serum BDNF in 18/33 subjects, which, when aggregated, was not significant. The authors attributed the inconsistency to lifestyle and environmental idiosyncrasies.287 Another recent study conducted in Japan found that during 9 weeks of intense military training, despite increased physical activities as shown by serum levels of muscle enzymes creatine phosphokinase and lactate dehydrogenase, decreased plasma BDNF, which recovered 4–5 days after cessation of military training.288 This study attributed this decrease to reduced sleep quality as well as to stress and fatigue. This suggests that any benefits of exercise may be compromised by stress and fatigue. Interestingly, a study reported that the increase in BDNF resulting from cycling was negated in those cycling near a major road where air pollution was high.289 Agreeing with this, a recent Chinese study examining the effects of closure of a highly polluting coal-burning power plant found that babies born to mothers after the closure of the plant had reduced polycyclic aromatic hydrocarbons–adducts and increased BDNF compared with those born before the closure, highlighting the impact of pollution on developmental BDNF expression.290 Babaei et al291 indeed found that a 6-week endurance training regimen increased serum BDNF only in healthy subjects and not in subjects with metabolic syndrome. Metabolic syndrome, linked with unhealthy diet and lifestyle, is very prevalent in psychiatric illness292 and may be a factor preventing obvious benefits of exercise intervention. These studies suggest a multitude of environmental and lifestyle factors can influence the effect of exercise on BDNF expression.

Healthy diet

In 1988 Christensen and Christensen293 reported that the ratio of dietary saturated to polyunsaturated fat was a major predictor of outcome for schizophrenia. Animal model studies have shown that levels of BDNF, which are reduced in schizophrenia, have been shown to be reduced in the hippocampus of rats fed a high-fat, refined-sugar diet.294 This effect of a high-fat diet on hippocampal BDNF expression has recently been replicated and was also shown to disrupt performance in active-avoidance memory tasks. Furthermore, exercise recovered hippocampal BDNF and memory performance in rats fed a high-fat diet, suggesting that a combination of healthy diet and exercise are highly effective in regards to memory performance.284,295 A high-fat diet has also been shown to induce anxiety-like behaviors (burrowing and spontaneous wheel running), depressive behavior (forced-swim test), and impairments in fear-conditioning responses alongside reduced hippocampal and cortical BDNF.296298

Offspring derived from mothers fed a high-fat diet show increased anxiety with an increase in BDNF expression in the dorsal hippocampus, suggesting significant developmental effects of a high-fat diet.299 In line with the report from Christensen and Christensen on the ratio of saturated to polyunsaturated fats, perinatal and postweaning diets rich in omega-3 polyunsaturated fatty acids have been shown to increase cortical BDNF, TrkB, and nerve growth-factor expression in C57Bl/6 mice.300 This would suggest that while high-fat diets rich in saturated fats may reduce BDNF, altering memory performance, anxiety, and depressive behaviors, foods rich in polyunsaturated fats increase BDNF and may therefore be beneficial to mental health. However, once again there are inconsistencies in the literature, with other reports showing no effect of omega-3 on brain BDNF expression, but increases in serum BDNF in a ketamine-induced rat model of schizophrenia.301

Overall, it is evident that a high-fat diet reduces BDNF expression and can affect learning and memory as well as anxiety-like and depressive-like behaviors. What is promising is that the effects of a high-fat diet can be reversed by exercise and other dietary supplements. Below we will discuss a variety of dietary supplements that have been shown to increase BDNF expression and improve mental health.

Dietary flavonoids

There is a wealth of literature that describes the cognitive-enhancing effects of a group of phytochemicals known as flavonoids. A variety of different flavonoids have been shown to increase hippocampal BDNF and neurogenesis, reduce neurotoxic and neuroinflammatory cell damage/loss, and increase brain blood flow, making flavonoids prime therapeutic targets for neurodegenerative disorders.302 Probably the most consistent finding is the positive effect of flavonoids on BDNF expression. Given the role of BDNF in mental health disorders (described above), more recent studies have explored the use of flavonoids in animal models of psychiatric disorders.

7,8-dihydroxyflavone (7,8-DHF)

One of the most commonly studied flavonoids is 7,8-dihydroxyflavone (7,8-DHF). 7,8-DHF is a naturally occurring flavonoid from the plant Godmania aesculifolia, which binds with a high affinity to the TrkB receptor to initiate dimerization and autophosphorylation.303 Following characterization of 7,8-DHF, one of the first behavioral studies reported antidepressant-like effects; with oral administration of 7,8-DHF shown to activate TrkB in the mouse hippocampus and to reduce immobility in the forced-swim test and tail-suspension test.304 In addition, deficits in learned fear in neocortical BDNF knockout mice were rescued by a peripheral intraperitoneal injection of 7,8-DHF.305 This same group showed beneficial effects of 7,8-DHF on appetitive and aversive memory domains in neocortical BDNF knockout mice.306 Another group was able to show that systemic 7,8-DHF administration (5 mg/kg administered intraperitoneally) was able to activate TrkB receptors in the amygdala and enhanced fear acquisition and extinction.307 7,8-DHF has therefore been suggested as a potential therapeutic for posttraumatic stress disorder.308

Acute 7,8-DHF in striatal slices potentiated dopamine release.309 In addition, treatment with 7,8-DHF improved deficits in prepulse inhibition (a measure of sensorimotor gating) in mice after administration of methamphetamine.310 Furthermore, 14 days of 7,8-DHF treatment increased TrkB phosphorylation at multiple sites, promoted hippocampal synaptic plasticity, and rescued spatial working memory in a MK-801–induced animal model of schizophrenia.311 Thus there is great potential for the use of 7,8-DHF as an adjunctive treatment for the cognitive and attention impairments associated with schizophrenia.

Other flavonoids

In a recent study exploring the effects of a range of flavonoids on synthesis and secretion of neurotrophic factors, 33 flavonoids were assessed in cultured rat astrocytes. The isoflavones calycosin and genistein and the flavanol isorhammnetin were particularly strong activators of BDNF expression,312 while baicalein had no effect and icariin (a flavonoid from the Chinese medicinal herb Epimedii) produced only mild increases in BDNF. In animal models, baicalein elevated BDNF–phosphorylated cAMP (adenosine 3′5′ cyclic monophosphate)-response element binding protein signaling in the hippocampus and prevented spatial learning and memory deficits following whole brain irradiation in C57Bl/6 mice.313 However, others have shown no effect of baicalein on spatial memory in the Morris Water Maze.314 Nobiletin (a dietary flavonoid isolated from citrus fruit), as well as blueberry powder (Vaccinium corymbosum) and icariin have all been shown to increase hippocampal BDNF and improve spatial memory in rodents.315318 Soy isoflavone supplementation, including daidzein, genistein and glycitin, have also shown beneficial effects on spatial memory in human319 and rodent studies,320 and this coincided with an increase in hippocampal BDNF expression in the rodent study.

Flavonoids also show antidepressant effects in several animal models. In a rat model of depression induced by chronic unpredictable mild stress, baicalein recovered hippocampal BDNF expression and extracellular-signal-regulated kinase phosphorylation and significantly reduced immobility time in the forced-swim test and tail-suspension test.321 Nobiletin, as well as astilbin (a tea extract) and icariin, have also shown antidepressant properties,322324 which were proposed to be regulated by activation of the BDNF signaling pathway.323325 Phytoestrogens such as flaxseed (secoisolariciresinol diglycoside) and Tualang Honey show antidepressant effects, also thought to be regulated via BDNF.326,327

Polyphenols

Interestingly, a recent study analyzing the effects of phenolic acids on spatial memory found that in comparison to alcohol-matched controls, aged rats receiving Champagne wine for 6 weeks showed improved spatial working memory and hippocampal and cortical BDNF protein.328 Other polyphenols such as curcumin from turmeric, Epigallocatechin gallate from green tea, and olive polyphenols have also been shown to increase BDNF expression and alleviate depressive symptoms.329,330 Theanine (a component of green tea and black tea) has also been shown to increase levels of BDNF and has been suggested as a therapeutic for a wide range of mental health disorders, including schizophrenia and depression.331

Conclusion

Research evidence points to abnormal BDNF signaling being a common and vital participant in the aetiology and pathophysiology of many psychiatric disorders including depression, schizophrenia, and bipolar disorder. To increase BDNF levels in patients is therefore a necessary goal of any treatment. To combat the inefficiency of current treatment methods, more attention should be focused on holistic approaches to achieve this goal, as BDNF is proven to have dynamic responses to environmental influences.

Hippocrates, the father of medicine, has never been more prescient than when he remarked “walking is man’s best medicine” and “let food be thy medicine and medicine be thy food.” We have reviewed evidence in the literature that suggests that lifestyle alterations such as increased social interaction, mental stimulation, exercise, and a healthy diet including low fat and increased flavonoids and polyphenols can have positive effects in psychiatric diseases via increasing BDNF. This “lifestyle medicine” is already advocated in developed countries for the prevention and treatment of major health issues such as obesity332 and should be promoted not as a replacement but as an adjunct and iatrogenic to conventional treatments for psychiatric disorders. Advocating these lifestyle changes can potentially curtail and prevent pathogenesis in those vulnerable to developing psychiatric disorders due to environmental or genetic reasons by maintaining healthy levels of BDNF in the face of adverse circumstances. In patients with reduced BDNF, these regimens can likely complement and enhance pharmacological treatments, resulting in faster, fuller, and longer-lasting recovery of BDNF.

Disclosure

The authors report no conflicts of interest in this work.


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