Brain-Derived Neurotrophic Factor (BDNF) in Depression: A Mini Review of Clinical and Preclinical Evidence
Owen R Thornton*1
1 University of North Carolina Chapel Hill
- September 2023
- International Neuropsychiatric Disease Journal 20(3):47–56
- Thornton; Int. Neuropsy. Dis. J., vol. vol. 20, no. 3, pp. 47–56, 2023; Article no.INDJ.97952
Thornton , O. R. (2023). Brain-Derived Neurotrophic Factor (BDNF) in Depression: A Mini Review of Clinical and Preclinical Evidence. International Neuropsychiatric Disease Journal, 20(3), 47–56. https://doi.org/10.9734/indj/2023/v20i3399
Abstract:
Depression is a complex psychiatric disorder that significantly impacts millions of individuals worldwide. Despite advances in our understanding of its neurobiological underpinnings, treatment options remain limited, and not all patients respond adequately to available therapies. Emerging evidence has implicated brain-derived neurotrophic factor (BDNF), a critical regulator of neuronal plasticity, in the pathophysiology and treatment of depression. This review examines the role of BDNF in the brain, its relationship to depression in preclinical and clinical studies, and its potential as a diagnostic and prognostic biomarker and therapeutic target. We discuss the impact of various antidepressant treatments on BDNF, including pharmacological and non-pharmacological interventions. Finally, we address the challenges and future directions in targeting BDNF for depression treatment. By deepening our understanding of BDNF and its relationship with depression, we can move towards more effective and personalized interventions for this debilitating disorder.
Keywords: Brain-derived neurotrophic factor; depression; neuroplasticity; biomarker; treatment.1.
INTRODUCTION
Background on Depression
“Depression, also known as major depressivedisorder, is a prevalent mental health conditioncharacterized by persistent feelings of sadness,hopelessness, and a lack of interest or pleasurein daily activities” [1]. According to the WorldHealth Organization [2], “depression is a leadingcause of disability worldwide, affecting over 260million people”. “The etiology of depression ismultifactorial, involving a complex interplaybetween genetic, environmental, andpsychological factors” [4,5]. “Major depressivedisorder is a debilitating disorder affectingmillions of people each year. Brain-derivedneurotrophic factor (BDNF) and inflammation aretwo prominent biologic risk factors in thepathogenesis of depression that have receivedconsiderable attention” [5,6].
1.2 Neurobiological Basis of Depression
Numerous studies have sought to elucidate theneurobiological underpinnings of depression,with several key findings emerging. At themolecular level, alterations in neurotransmittersystems, including serotonin, norepinephrine,and dopamine, have been linked to depression[7,8]. Additionally, neuroinflammation, oxidativestress, and neuroendocrine dysregulation havealso been implicated in the pathophysiology ofthe disorder [9,10,11].Increasingly, researchers have focused on therole of neuroplasticity and synaptic dysfunction inthe development and maintenance of depression[12,13]. Studies have demonstrated reducedhippocampal volume and decreasedneurogenesis in both animal models and humanpatients with depression, suggesting a crucialrole for neural plasticity in the disorder[14,15,16].
1.3 BDNF:
A Protein of InterestBrain-derived neurotrophic factor (BDNF) hasemerged as a protein of particular interest in thecontext of depression due to its critical role insupporting neuroplasticity and synaptic function[17,18]. BDNF is a member of the neurotrophinfamily of proteins, which are essential for thegrowth, differentiation, and survival of neurons[19]. BDNF has been implicated in numerousneurobiological processes, such as neuronaldifferentiation, synaptic plasticity, and long-termpotentiation (LTP) [20,21].A growing body of evidence, encompassing bothpreclinical and clinical research, has highlightedthe relationship between BDNF and depression,pointing to BDNF as a potential biomarker andtherapeutic target in the treatment of the disorder[22,23]. This review aims to synthesize thecurrent understanding of the link between BDNFand depression and to explore the potentialimplications for diagnosis, prognosis, andtreatment.
2. BDNF AND ITS ROLE IN THE BRAIN
2.1 BDNF Synthesis and ReleaseBDNF is synthesized as a precursor protein,proBDNF, which is cleaved to generate themature BDNF protein [24]. Both proBDNF andmature BDNF are stored in dense core vesiclesand secreted in an activity-dependent manner,with their release modulated by neuronal activityand environmental factors [25, 26]. BDNFsynthesis and release are regulated by varioussignaling pathways, including the cyclic AMPresponse element-binding protein (CREB)pathway, which plays a crucial role in BDNFgene transcription [27]
.2.2 BDNF Receptors and SignalingPathwaysBDNF exerts its effects by binding to two distinctreceptors: the tropomyosin receptor kinase B(TrkB) receptor and the p75 neurotrophinreceptor (p75NTR) [28]. The binding of BDNF toTrkB receptors initiates several intracellularsignaling cascades, such as the mitogen-activated protein kinase (MAPK),phosphoinositide 3-kinase (PI3K), andphospholipase C-γ (PLCγ) pathways, whichcontribute to neuronal survival, differentiation,and synaptic plasticity [29, 30]. In contrast,binding to p75NTR may lead to cell death orsurvival, depending on the cellular context andthe presence of coreceptors [31
2.3 BDNF and NeuroplasticityBDNF plays a pivotal role in neuroplasticity,which refers to the ability of the brain to adaptand reorganize its structure and function inresponse to environmental changes [32]. BDNFis involved in various forms of synaptic plasticity,including long-term potentiation (LTP) and long-term depression (LTD), which are essential forlearning and memory processes [20,21]. BDNFhas also been shown to promote neurogenesis,particularly in the hippocampus, a brain regionimplicated in depression and cognitive function[33,34].
3. PRECLINICAL EVIDENCE LINKINGBDNF AND DEPRESSION
3.1 Animal Models of Depression andBDNF ExpressionNumerous animal models of depression havedemonstrated a relationship between BDNFlevels and depressive-like behaviors. Chronicstress, a well-established risk factor fordepression, has been shown to reduce BDNFmRNA and protein levels in the hippocampusand prefrontal cortex of rodents [35,36].Conversely, antidepressant treatments, such asselective serotonin reuptake inhibitors (SSRIs),have been reported to increase BDNFexpression in these brain regions [37].
3.2 BDNF Knockout and OverexpressionStudiesGenetic manipulation of BDNF in animal modelshas provided further evidence for its involvementin depression. Mice with reduced BDNF levelsdue to heterozygous knockout or conditionalknockout exhibit increased depressive-likebehaviors, such as anhedonia and behavioraldespair [38,39]. Conversely, overexpression ofBDNF in the hippocampus or prefrontal cortexresults in antidepressant-like effects in variousbehavioral paradigms [40,41]. These findingshighlight the importance of BDNF in modulatingmood-related behaviors and support itspotential role in the pathophysiology ofdepression.
3.3 BDNF Infusion and Antidepressant-like EffectsDirect infusion of BDNF into specific brainregions has further corroborated the link betweenBDNF and depression. Intracerebroventricular(ICV) or localized infusion of BDNF into thehippocampus, prefrontal cortex, or nucleusaccumbens results in significant antidepressant-like effects in rodent models of depression[42,43,44]. These findings suggest thatincreasing BDNF levels in specific brain regionsmay be a potential therapeutic strategy fortreating depression.Collectively, these preclinical studies providesubstantial evidence for the involvement of BDNF in the development and treatment ofdepression. The observed alterations in BDNFexpression in response to stress andantidepressant treatments, as well as thebehavioral consequences of BDNF manipulation,underscore the importance of BDNF in theneurobiology of depression. Future researchshould continue to explore the molecular andcellular mechanisms through which BDNF exertsits effects on mood and behavior, with theultimate goal of developing novel, BDNF-targetedtherapies for depression.
4. CLINICAL EVIDENCE LINKING BDNFAND DEPRESSION: IMPLICATIONSFOR DIAGNOSIS, EVALUATION,TREATMENT, AND PROGNOSIS
4.1 Peripheral BDNF Levels in DepressedPatients: Diagnostic and Evaluative Potential
Several studies have reported decreasedperipheral BDNF levels in patients with majordepressive disorder (MDD) compared to healthycontrols [45,46]. Moreover, BDNF levels havebeen found to be negatively correlated with theseverity of depressive symptoms [47]. This suggests that BDNF levels could potentially beused as a diagnostic biomarker for depressionand to evaluate the severity of the disorder.However, further research is needed to establishreliable reference values for BDNF levels, takinginto account factors such as age and gender (Suliman et al., 2018).
BDNF as a Treatment Monitor andPrognostic IndicatorPeripheral
BDNF levels have been shown toincrease following successful antidepressanttreatment, suggesting a potential role for BDNFin monitoring treatment response and predictingprognosis [45] (Yoshimura et al., 2017).However, more studies are needed to confirmthese findings and establish standardizedmethods for measuring BDNF levels in a clinicalsetting.
Given the associations between BDNF anddepression, it is possible that modulating BDNFlevels or activity could be a novel treatmentstrategy for depression. Recent research hasinvestigated the potential of ketamine, a rapid-acting antidepressant, to increase BDNF levelsand exert its antidepressant effects [13,48].However, more research is needed to investigatethe safety, efficacy, and potential side effects ofBDNF-targeted therapies.
4.4 Post-mortem Brain Studies andBDNF Measurement
Post-mortem studies of depressed patients haveprovided valuable insights into the associationbetween BDNF and depression. A reduction inBDNF protein and mRNA levels has beenobserved in the hippocampus and prefrontalcortex of depressed suicide victims compared tocontrols [49] (Tripp et al., 2012). These findingsfurther support the involvement of BDNF in thepathophysiology of depression. Standardizedmethods for measuring BDNF levels in braintissue samples are necessary to validate thesefindings and better understand the role of BDNFin depression.
4.5 BDNF Gene Polymorphisms andDepression Susceptibility
Genetic studies have investigated theassociation between BDNF gene polymorphismsand susceptibility to depression. The most widelystudied polymorphism is the Val66Met (rs6265)variant, which has been associated with areduced activity-dependent release of BDNF[50]. Several meta-analyses have reported asignificant association between the Met alleleand an increased risk of depression, particularlyin Caucasian populations [51] (Wang et al.,2018). Further research on the clinicalimplications of BDNF gene polymorphisms,including their potential role in personalizedmedicine, is warranted.
5. THE IMPACT OF ANTIDEPRESSANTTREATMENTS ON BDNF
5.1 Antidepressant-induced BDNFUpregulationVarious classes of antidepressants, includingselective serotonin reuptake inhibitors (SSRIs),tricyclic antidepressants (TCAs), and monoamineoxidase inhibitors (MAOIs), have been shown toupregulate BDNF expression in animal modelsand human studies [52,35]. This upregulation ofBDNF may contribute to the therapeuticeffects of antidepressants by promotingneuroplasticity and resilience to stress (Duman etal., 1997).
5.2 Ketamine and Rapid-ActingAntidepressant Effects on BDNFKetamine, an N-methyl-D-aspartate (NMDA)receptor antagonist, has demonstrated rapid andsustained antidepressant effects in treatment-resistant depression [53,54]. Preclinical studieshave revealed that ketamine increases BDNFexpression and signaling in the hippocampusand prefrontal cortex, which may underlie itsrapid antidepressant effects [55,56].
5.3 Non-pharmacological Interventionsand BDNF LevelsNon-pharmacological interventions, such aselectroconvulsive therapy (ECT), repetitivetranscranial magnetic stimulation (rTMS), andexercise, have also been shown to influenceBDNF levels. ECT and rTMS treatments havebeen associated with increased BDNF levels inboth animal models and patients with depression[57,58]. Additionally, physical exercise has beenfound to enhance BDNF expression and improvedepressive symptoms, further supportingthe role of BDNF in the treatment of depression[59,60].
6. BDNF AS A BIOMARKER ANDTHERAPEUTIC TARGET INDEPRESSION
6.1 BDNF as a Diagnostic and PrognosticBiomarkerThe accumulating evidence linking BDNF to thepathophysiology of depression has raised thepossibility of using BDNF as a diagnostic andprognostic biomarker. Decreased peripheralBDNF levels have been shown to correlate withthe severity of depressive symptoms [61], whilesuccessful antidepressant treatments tend toincrease BDNF levels [62,63]. Therefore,monitoring BDNF levels may help to guidepersonalized treatment strategies and evaluatetreatment response in patients with depression[45].
Strategies for Modulating BDNFLevels in Depression Treatment
Given the importance of BDNF in depression,several therapeutic strategies have beenproposed to modulate BDNF levels. In addition toconventional antidepressant treatments,ketamine has shown promise as a rapid-actingantidepressant by increasing BDNF expressionand signaling [55,56]. Non-pharmacologicalinterventions, such as ECT, rTMS, and exercise,have also been found to enhance BDNFexpression and may be particularly useful forpatients who do not respond to orcannot tolerate pharmacological treatments[57,58, 59].6.3 Challenges and Future DirectionsWhile the potential of BDNF as a therapeutictarget in depression is promising, severalchallenges remain [64–67]. The complexity of theBDNF signaling pathway and its interactions withother neurotrophic factors and neurotransmittersystems need to be better understood to developtargeted interventions (Rantamaki & Castren,2008). Additionally, the relationship betweenperipheral and central BDNF levels and theirrelevance to depression pathophysiologyrequires further investigation [45]. Furtherresearch on these topics will be essential for thedevelopment of novel treatments targeting BDNFand improving patient outcomes indepression[68–70].7. CONCLUSIONThe role of BDNF in depression has becomeincreasingly evident through preclinical andclinical studies. BDNF signaling plays a criticalrole in neuroplasticity, and alterations in BDNFexpression and function have been implicated inthe pathophysiology of depression. The potentialof BDNF as a diagnostic and prognosticbiomarker, as well as a therapeutic target, offersexciting opportunities for future research and thedevelopment of innovative treatments fordepression. By deepening our understanding ofBDNF and its relationship with depression, wecan move towards more effective andpersonalized interventions for this debilitatingdisorder.CONSENT AND ETHICAL APPROVALIt is not applicable.DISCLAIMERThis paper is an extended version of a preprintdocument of the same author.The preprint document is available in this link:https://www.researchgate.net/publication/369251226_Brain-Derived_Neurotrophic_Factor_BDNF_in_Depression_A_Mini_Review_of_Clinical_and_Preclinical_Evidence_Brain-Derived_Neurotrophic_Factor_BDNF_in_DepressionCOMPETING INTERESTSAuthor has declared that no competing interestsexist
(PDF) Brain-Derived Neurotrophic Factor (BDNF) in Depression: A Mini Review of Clinical and Preclinical Evidence. Available from: https://www.researchgate.net/publication/373637339_Brain-Derived_Neurotrophic_Factor_BDNF_in_Depression_A_Mini_Review_of_Clinical_and_Preclinical_Evidence [accessed Sep 04 2023].
References:
(PDF) Brain-Derived Neurotrophic Factor (BDNF) in Depression: A Mini Review of Clinical and Preclinical Evidence. Available from: https://www.researchgate.net/publication/373637339_Brain-Derived_Neurotrophic_Factor_BDNF_in_Depression_A_Mini_Review_of_Clinical_and_Preclinical_Evidence [accessed Sep 04 2023].
(PDF) Brain-Derived Neurotrophic Factor (BDNF) in Depression: A Mini Review of Clinical and Preclinical Evidence. Available from: https://www.researchgate.net/publication/373637339_Brain-Derived_Neurotrophic_Factor_BDNF_in_Depression_A_Mini_Review_of_Clinical_and_Preclinical_Evidence [accessed Sep 04 2023].
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