Brain-Derived Neurotrophic Factor and Psychiatric Disorders

#### **Chapter 1**

## The Role of Brain-Derived Neurotrophic Factor in Psychiatric Disorders

*Sudhiranjan Gupta and Rakeshwar S. Guleria*

#### **Abstract**

Brain derived neurotrophic factor (BDNF) is one of the most extensively studied and widespread growth factors in the brain. BDNF and its receptors are the critical factors having multipotent impact on the central nervous system (CNS). The biological function of BDNF primarily mediated by two receptors, tropomyosin receptor kinase B (TrkB) receptor and p75 neurotrophin receptor. BDNF contributes a pivotal role in neuronal and glial development, modulation and maintaining overall synaptic plasticity of the brain; therefore, widely involved in psychiatric diseases. Current hypotheses indicates that abnormal BDNF level, a vital condition for psychiatric and neurodegeneration diseases are mainly due to the disruption of the BDNF-associated signaling cascades. It is, therefore, crucial to understand how BDNF coordinate the psychiatric diseases in the brain. This review begins with the history of BDNF and its biology in brain homeostasis and focuses on several aspects of BDNF signaling. In addition, the review addresses the impact of BDNF level in diverse neuropsychiatric disorders including major depressive disorder, schizophrenia, bipolar disorder, posttraumatic stress disorder and, possible biological mechanisms of BDNF that may shed new insight for future therapeutic use and drug development.

**Keywords:** BDNF, inflammation, brain homeostasis, brain plasticity, psychiatric disorders

#### **1. Introduction**

Brain-derived neurotrophic factor (BDNF) is a neurotrophin classified as dimeric polypeptide regulating a wide array of neuronal activities including but not limited to neurogenesis, neuronal growth, differentiation, excitability, and plasticity. BDNF was originally identified by Barde et al. [1] as a factor from cultured embryonic chick which showed survival of sensory neurons. Soon after its discovery, BDNF was recognized and laid a foundation for neuronal plasticity in the adult brain and further observed its' pivotal role in neuronal activity [2–4]. Subsequently, BDNF was considered for antidepressant treatments therapy as it was shown that neurotrophins promoted the growth and helped in maturation of neurons [5–7]. Interestingly, injection of BDNF in the hippocampus elicited antidepressant-like effects in rodents led to advocate a critical role for BDNF in the setting formulating antidepressant

drugs [8–10]. The line of research identified BDNF and its cognate receptor tropomyosin receptor kinase (TrkB, neurotrophic tyrosine kinase receptor, NTRK2) in the hippocampus and cortex suggested antidepressant drug action into neuronal plasticity [11].

BDNF contributed a key role in the development of the nervous system by regulating neuronal development, growth, differentiation, neurogenesis, synaptogenesis, and synaptic plasticity [12–14]. Moreover, neurodegenerative, and neuropsychiatric diseases appear to be linked with insufficient BDNF level leading to the defects in synaptic plasticity [15, 16]. As a result, strategies to increase the BDNF level in circulation was advocated for therapy in neurological diseases.

This article reviews the current understanding and future directions in BDNFrelated research in the central nervous system, with an emphasis on the possible therapeutic application of BDNF in modifying fundamental processes underlying neural disease.

#### **2. BDNF, a neurotrophin family member: synthesis, secretion and function**

Nearly three decades earlier discovery of nerve growth factor (NGF) by Rita Levy-Montalcini [17], prompted Yves-Alain Barde searched for a growth factor with similar properties and function like NGF in neurons. The study culminated into a purified protein from pig brain named BDNF [1]. Later, amino acid sequence revealed that BDNF shared a significant homology with NGF along with other members like neurotrophin 3 and neurotrophin 4, together constitute a conserved neurotrophin family [18].

Synthesis and maturation of BDNF is a multistage process, involving formation of several precursor isoforms. BDNF is initially synthesized in the Golgi after cleaving the signal sequence from pre region as a precursor form (pro-BDNF) containing 129 amino acids N-terminal prodomain and a 118 amino acids C-terminal mature domain [19]. The mature domain forms a cysteine knot structure, leading to non-covalent dimerization of the mature domains [20]. When the prodomain is cleaved from intact pro-BDNF, through the actions of proconvertase at a conserved RVRR sequence, the dimeric mature domains are released, and are called mature BDNF, or simply BDNF [21]. Secretion of m-BDNF and pro-BDNF into the extracellular space enables their physiological action (see the diagram, **Figure 1**).

In neuronal cells, both pro-BDNF and m-BDNF are released following cellular membrane depolarization and maintained a dynamic balance [22–24]. Both isoforms are important in neuronal function in the brain, but mature-BDNF (m-BDNF) appeared to offer neurogenesis, neuroprotection, synaptic plasticity, and synaptic function in neurons [25, 26]. The m-BDNF is axonally delivered into axon vesical terminals followed by the secretion into axonal cleft [22]. Mechanistically, BDNF requires to bind its' partner/receptor, Tr, located both pre- and post-synaptic membrane, to complete its function. BDNF is highly conservative and is expressed as a single gene, *Bdnf* transcript and is dynamically regulated and showed cell-specific neural activity. The human *Bdnf* gene, a ~ 70 kb, is in the chromosome 11 consisting of 11 exons (I-IX along with Vh and VIIIh) in the 5′ end and 9 promoters in tissues and brain regions [27, 28]. Apart from the above-mentioned BDNF isoforms, the function of BDNF is potentially affected by single nucleotide polymorphism of methionine (Met) to valine (Val) substitution at 66th position of *Bdnf* gene.

#### **Figure 1.**

*Schematic presentation of synthesis and maturation of BDNF. In the intracellular pathway, the pre-pro-BDNF precursor molecule is produced in the endoplasmic reticulum and transported to the Golgi apparatus. During intracellular cleavage, the pre-region is removed, resulting in formation of immature isoform of BDNF called pro-BDNF. Finally, the pro-domain is removed and the mature isoform of BDNF, m-BDNF is produced. The cleavage process is mediated by intracellular proteases, convertases, and furin resulting the release of both pro-BDNF and m-BDNF isoforms into the extracellular space. Here, it is further processed by metalloproteinases 2 and 9 (MMP2 and MMP9), and plasmin.*

Considering BDNF neuronal function, it is more appreciated as differentiation factor than survival neurotrophin [29, 30]. In addition to synaptic transmission, BDNF elicits long-term potentiation in hippocampus and modulate neuronal circuit function [31]. Moreover, changes in BDNF level in rodent models demonstrated aberrant function in hippocampal regions, including impaired memory, aggression, and hyperphagia [32].

#### **3. BDNF receptors and intracellular signaling**

BDNF signals are mediated by TrkB receptor and p75 neurotrophin receptor. BDNF binds with high affinity with TrkB, a tyrosine kinase receptor family, and the p75 neurotrophin receptor (p75 NTR), a member of the tumor necrosis factor (TNF) receptor family and low with p75 receptor. The TrkB is widely expressed in brain including cortex, hippocampus and in spinal cord nuclei [33]. It is noted that the

mature BDNF binds to TrkB whereas pro-BDNF binds to p75NTR. The pro-BDNF/ p75NTR signaling primarily promoting synaptic elimination by activating c-Jun N-terminal Kinase (JNK) pathway and triggers apoptosis. Other family members of Trk are TrkA which is specific to NGF [34] and TrkC which binds other neurotrophins [35]. This review will focus TrkB and its' signaling.

Activation of BDNF begins by binding to TrkB, and dimerizing and activating intrinsic kinase cascade before going to autophosphorylation. The BDNF/TrkB complex gets internalized into the neuron and serves as a docking site for diverse signaling platforms, protein phosphorylation and secondary signaling events [36, 37]. Next, the binding of BDNF to TrkB receptor, BDNF/TrkB in complex, leads to phosphorylation and translocation of TrkB into cellular membrane lipid rafts, and activating diverse important intracellular signaling cascades for performing cellular functions that include mitogen-activated protein kinase/extracellular signal-related kinase (MAPK/ERK), guanosine triphosphate hydrolases (GTP-ases) of the Ras homolog (Rho) gene and phospholipase C-γ (PLC-γ), phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathways [38–41]. It is evidenced that PI3K/ AKT pathway contributed to synaptic plasticity and cell survival or antiapoptotic activity response by modulating N-methyl-D-aspartate receptor (NMDAR) [40, 42]. Furthermore, BDNF-dependent neuroprotection is mediated via NMDAR/Ca2+ synaptic signaling resulting eliminating glutamatergic toxicity and preventing mitochondrial dysfunction and cellular apoptosis [43, 44]. The PLC g-dependent signaling triggers Ca2+-calmodulin-dependent protein kinase (CAMK) and protein kinase C (PKC) to stimulate actin/microtubule synthesis and enhance synaptic plasticity and neuronal fiber growth [40, 45, 46]. The MAPK/Ras signaling regulates neural differentiation [45]. The ERK ½ and cAMP response element-binding protein (CREB) activation are necessary for cytoskeleton protein synthesis for dendritic growth and branching [40, 47]. In summary, the participation of BDNF in several physiological roles in the brain involves different signaling and is pivotal in maintaining a dynamic balance between the stimulus and its' function. A diagrammatic presentation of BDNF receptor and signaling is shown in **Figure 2**.

#### **4. BDNF and brain homeostasis**

Homeostasis is a fundamental process and equates to a dynamic balance between interdependent element and the physiological function in the organ of a living system. BDNF plays a significant role in neuronal plasticity in the central and peripheral nervous system [48]. BDNF is expressed throughout the development and adulthood in neurons of the brain and contributing a critical role in many physiological functions. One of the functions is energy homeostasis in the hypothalamus. Energy homeostasis is a complex gets interaction between the brain and peripheral tissues. Neuronal circuitry in the hypothalamus and hindbrain contributes a critical role in orchestrating the peripheral signals associated with energy storage by regulating nutrient intake and energy expenditure. BDNF is synthesized in several regions of hypothalamus including ventromedial hypothalamic nucleus (VMH), the dorsomedial hypothalamic nucleus (DMH), the paraventricular nucleus (PVH) and the lateral hypothalamic area (LH) [49, 50]. In particular, the energy balance is reported to be in the PVH region as evidenced by loss of body weight by injecting BDNF in this region [51]. The report showed that decrease in food intake resulted in increased resting metabolic rate, partly due to upregulation of uncoupling protein 1 (UPC1)

*The Role of Brain-Derived Neurotrophic Factor in Psychiatric Disorders DOI: http://dx.doi.org/10.5772/intechopen.112567*

#### **Figure 2.**

*BDNF signaling cascade. The BDNF is primarily transcribed as a precursor (pro-BDNF) which is later cleaved intra or extracellularly into mBDNF. The pro-BDNF exhibits affinity to sortilin and p75NTR receptors leading to the activation of nuclear factor κB (NF-κB), RhoA and JNK signaling pathways. The functional outcome of theses pathways includes neuronal survival, development, and apoptosis. The mBDNF showed highest affinity towards TrkB receptors. The mBDNF/TrkB complex triggers signaling pathways linked to phosphatidylinositol 3-kinase (PI3K), phospholipase C-γ (PLC-γ) and mitogen activated protein kinase (MAPK) via CREB. The pathways are involved in dendritic growth and branching, synaptic plasticity, and cytoskeleton protein activation.*

in the brown adipose tissue [51]. Hypothalamic injection of BDNF promotes switching white adipose tissue to brown adipose tissue via sympathetic neuron activation and accelerates UCP-1 expression [52, 53]. This is an example of the role of BDNF in increasing energy expenditure by modulating metabolic rate and temperature. The data indicated that BDNF enhanced energy expenditure suggesting an anorexigenic function [52]. Another finding attested the role of BDNF in thermogenic regulation in lateral hypothalamus [54]. On the contrary, deletion of *Bdnf* gene caused hyperphagia, decreased locomotor activity and impaired thermoregulation [54]. Moreover, it is evident that mutation in the *Bdnf* gene or its receptor (TrkB) leads to obesity in mice [55, 56]. The *Bdnf* gene mutation data is corroborated with hyperphagia and impaired cognitive functions in humans [57–62]. Together, it is suggested that PVH region is critical in energy balance in the brain.

In addition, BDNF plays a key role in energy management in non-neuronal cells. Selective ablation of BDNF in liver cells in mice showed reduction in hyperglycemia and hyperinsulinemia caused by a high fat diet [63]. Compromised BDNF signaling is also linked with obesity and the metabolic syndrome in humans [64]. Furthermore, BDNF administration reduced serum glucose and insulin in obese *db/db* mice or improvement of glucose tolerance compared to their vehicle treated counterparts [65, 66]. The underlying molecular mechanism may be the interaction of BDNF with glucagon like peptide 1 (GLP1). Gotoh et al. showed that administration of BDNF

decreased the portal glucagon level and did not show any effect on insulin [67]. It is also observed that the intraportal administration of GLP-1 increases BDNF levels in the pancreas and reduces glucagon secretion [67]. Recent study also suggested a role on pancreatic-islet-expressed TrkB to promote peripheral insulin secretion [68]. In addition to BDNF and TrkB, the pro-BDNF receptor, p75NTR is suggested to play a role in glucose homeostasis and insulin sensitivity. Conditional knockout of p75NTR showed improvements of glucose and insulin tolerance in adipose and skeletal muscle [68, 69]. Regarding signaling context of BDNF and metabolic homeostasis, it is yet to be defined which receptor mediated action is more appropriate. The rational lies that pro-BDNF exclusively binds to p75NTR and appeared to show an opposite effect to BDNF-TrkB activity [70]. It established that a single nucleotide polymorphism (SNP) in pro domain of BDNF (Val66Met) is linked with neuropsychiatric disorders in humans and seemed to function through p75NTR [71]. The SNP (Val66Met) variant indicated increased appetite in mice via p76NTR [72], along with alteration of anxiety and anorexic-related behavior [73, 74]. The data may suggest a unique control of energy balance in food intake and anxiety. Finally, the downstream signaling between pro-BDNF and mature BDNF are quite distinct and may appeared to reflect different outcome in neuronal cells. TrkB promotes MAPK/ERK, PI3K, and PLCg1, pathways, while p75NTR promotes JNK and Rho pathways [36, 41, 75–77].

#### **5. BDNF and psychiatric diseases and disorders**

We often use the term disorder and diseases in psychiatric illness. There is a subtle difference exists between them however, they are considered as mental illness. The term disease defines an involuntary response of biological, physiological, or pathological consequences of illness and, the underlying cause can be measured. The disorder defines disturbance of normal physical or mental health status and is a collection of signs and symptoms closely associated with specific disease. In general speaking, we can say that all diseases are disorders but not all disorders are diseases.

BDNF is one of the most widely studied neurotrophin signaling molecules in the brain responsible for neurite growth, maturation of synapses during development, and synaptic plasticity. We have discussed BDNF's biology, receptor alignment for signaling events in the brain. Essentially, BDNF-TrkB signaling, and its intermediate proteins contributed a critical role in different phases of synaptic development and neuroplasticity in the brain [78]. Moreover, BDNF regulates learning and memory process in young and adult humans [79]. Therefore, aberrant expression or imbalance in BDNF level and its cognate TrkB receptor are associated with many psychiatric disorders (diseases) and neurodegenerative diseases. In addition, anomaly of BDNF level and signaling are linked to diverse cardiovascular, metabolic, and inflammatory diseases [80–85]. This section will discuss the contribution of BDNF in brain illness or psychological diseases (disorders) including major depressive disorder (MDD), schizophrenia (SZ), bipolar disorder (BD) and post-traumatic stress disorder (PTSD).

#### **6. BDNF and MDD**

BDNF is well studied molecule in MDD. Eisch et al reported that an increase level of BDNF in the ventral tegmental area (VTA)-nucleus accumbens (NAc) region

#### *The Role of Brain-Derived Neurotrophic Factor in Psychiatric Disorders DOI: http://dx.doi.org/10.5772/intechopen.112567*

contributed the onset of depression in rats [86]. A following mechanistic study by the same group using viral-mediated mesolimbic dopamine-specific BDNF knockdown determined the pivotal role of BDNF in depression like behavior [87]. Interestingly, reduced BDNF in cornu ammonis (CA3) and dentate gyrus (DG) of the hippocampus and prefrontal cortex (PFC), resulting in depression-like behavior in mice [88]. Furthermore, targeted deletion of BDNF using NSE-tTA x TetOp-Cre line in the VTA area determined that BDNF in the DG was essential for therapeutic intervention as an antidepressant [89]. Similarly, reduced BDNF protein levels were observed in patients with MDD compared with the healthy control [90, 91]. Taken together, these findings suggest that BDNF acts within the VTA-NAc pathway to induce a depression-like phenotype, whereas in the hippocampus and PFC it produces antidepressant-like effects [92]. It is further observed that TrkB, the receptor for BDNF played a role in MDD. Patient with MDD showed elevated level of TrkB compared to the healthy control [93, 94]. However, it is unclear regarding the role of the partners in MDD and may be the focus of future investigation.

Epigenetic modification like DNA methylation is frequently studied in *Bdnf* gene and BDNF exon I and IV promoters. A methylation profile in CpG island of exon I of BDNF promoter showed differential pattern of methylation that can distinguish between major depression vs. and healthy controls and suggested to be a good biomarker for MDD [95]. But exon IV did not show any changes. A similar study reported higher methylation of BDNF exon I promoter in patients with MDD [96]. This study further showed reduced methylation pattern with antidepressants treatment [96]. Interestingly, patient with MDD showed poor treatment response when methylation of CpG site −87 of BDNF exon IV promoter was lacking [97].

An association between BDNF Val66Met polymorphism and MDD is extensively studied. Meta analyses revealed that there is no association between Val66Met polymorphism and MDD (depression) [98–100]. However, few studies have indicated that BDNF Val66Met polymorphism moderated the relationship between stress and depression [100–103].

#### **7. BDNF and Schizophrenia (SZ)**

Schizophrenia is a complex heterogenous disease characterized by multiple symptoms such as hallucinations, social avoidance, withdrawal, paranoia, cognitive deficit, and disorganized thought [104]. The role of BDNF in SZ is well studied because BDNF is involved in neurotransmission. In general, BDNF level is reduced in SZ patients [105, 106] and study has shown further that serum BDNF is positively correlated with antipsychotic drug (clozapine) [107]. This is an interesting finding for a therapeutic purpose. However, recent evidence implicated that BDNF mRNA expression remained unchanged in SZ patients compared to healthy control in postmortem brain samples [108].

Reports are emerging regarding epigenetic mechanism in *Bdnf* gene and development of SZ [109]. Epigenetic mechanism encompasses DNA methylation, histone modification, chromatin remodeling and DNA methylation is widely studied in SZ [109, 110]. A significant positive correlation was observed in BDNF gene methylation in patients with SZ compared to healthy controls [111]. Another study showed higher methylation level at BDNF promoter compared to controls [112]. Moreover, a differentially methylated CpGs has been identified in SZ patients of postmortem human brains [113]. Moreover the Val66Met SNP on the *Bdnf* gene has implicated

schizophrenia incidence and a recent meta-analysis provided evidence that there was an association between brain volume alterations and variations on the Val66Met SNP in patients of SZ [114–116]. While studies have shown a positive correlation between reduced level of BDNF and SZ episode, but have not evaluated the role of demographic characteristics such as age, gender, race, and education. Therefore, adequate meta-analysis including demographic factors should be added and warranted further investigation.

#### **8. BDNF and bipolar disorder (BD)**

Bipolar disorder is a multifactorial psychiatric disorder characterized by mood fluctuation or instability, depressive, manic episode, and euthymic states [117, 118]. BD makes a distinct category in Diagnostic and Statistical Manual of Mental Disorders, 5th edition into BD I, BD II based on severity of manic episodes [119]. The thirst for potential biomarker in BP is emerging and BDNF is extensively studied in this area. In 2005, Laske et al. first reported reduced BDNF level in the serum of manic and major depressed patients compared to healthy control [120]. Since, then several studies have been conducted in BD and majority of the studies suggested a decline level of peripheral BDNF and considered it as a marker [121–125], however, BDNF levels were not different in euthymia when compared to controls [126]. Furthermore, at transcription level, BDNF mRNA showed downregulation in postmortem brains of both manic and depressive subjects [127, 128]. Antipsychotic drugs like mood stabilizers are frequently prescribed for manic or depressive disorder but the study did not show any improvement of BDNF level in four weeks treatment [122]. However, another study of sixteen-week follow-up, using extended-release quetiapine showed increase in BDNF levels, but decreases with time in a manic/mixed episode [129].

A common genetic variation in *Bdnf* gene, the Val66Met, is established as a common platform linked with reduced secretion of BDNF and is associated with many neuropsychiatric disorders and BD is not an exception. Earlier finding suggested an association between BDNF Val66Met polymorphism and BP [130, 131] but recent meta-analyses showed opposite results [132, 133]. Therefore, more data are warranted to determine the role of Val66Met polymorphism in BD.

Epigenetic modulation is well documented in psychiatric disorders and a positive correlation is shown in CpG methylation in BDNF promoter and BD subjects [134–136]. Alterations in DNA methylation patterns in patients with BD have been extensively investigated for the past years, and possibly recognize a potential biomarker [137–139]. It may be the case that DNA methylation alters the differences in BDNF level and contributed in part in BD, so, targeting BDNF methylation could be strategy to treat BD.

#### **9. BDNF and post-traumatic stress disorder**

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric disorder characterized by hyperarousal, re-experiencing, negative emotions, increased anxiety, and fearful memories following exposure to severe trauma [119]. The role of BDNF in PTSD is emerging. In 2009, a small human study was conducted in University of Pisa, Italy where they recruited 18 drug naïve PTSD patients (12 women and 6 men)

#### *The Role of Brain-Derived Neurotrophic Factor in Psychiatric Disorders DOI: http://dx.doi.org/10.5772/intechopen.112567*

with no psychiatric comorbidity and 18 healthy controls in outpatients' facility. The finding showed reduced level of BDNF in the plasm compared with healthy control [140]. War Veterans have continuously suffered from PTSD and cognitive deficit caused by traumatic brain injury. The possible first combat Veteran study aiming BDNF as a marker in PTSD was investigated in Croatia, 2022. The results revealed a marked reduction in plasma BDNF in Veterans with PTSD and mild cognitive impairment compared with healthy controls [141]. The epigenetic influence in BDNF played a critical role in psychiatric disorders including PTSD, as few studies were conducted to investigate DNA methylation in CpG island and Val66Met polymorphisms. A study was conducted using US military service members deployed in the Middle east for Operation Iraqi Freedom (OIF)/Operation Enduring Freedom (OEF) with PTSD showing a significant association between BDNF Val66 Met genotype and traumatic stress in post deployment [142]. Another study of Vietnam war active service members from South Korea showed an association between higher DNA methylation in BDNF promoter in PTSD subjects suggesting a biomarker of PTSD [143]. Interestingly, another study of Vietnam war Veterans by the Australian or New Zealand Defense Force showed that PTSD was associated with decreased methylation at three BDNF CpG sites [144]. Furthermore, it was observed that BDNF Val66Met was linked with differential *Bdnf* expression in the peripheral tissues [144]. Another study supported the finding that methylation of CpG island (CpG1, CpG 7 and CpG 18) in BDNF promoter was closely related to PTSD and suggested as a biomarker to PTSD [145].

Although studies have shown a positive correlation between BDNF level and Val66Met polymorphism in PTSD, there were reports that showed the opposite effect. There was a report showing no relationship between BDNF Val66Met and PTSD in victims of urban violence [146]. In addition, two case studies (small sample size) failed to establish the association between Val66Met and PTSD [147, 148]. Moreover, an elevated level of BDNF was observed in patients with PTSD suffering from trauma [149]. A meta-analysis showed that BDNF level is increased in PTSD patients compared to healthy subjects [150]. A discrepancy was noted in OEF/OIF Veteran study. Recently, Wu et al. reported for the first time that a higher serum level of BDNF in chronic combat PTSD Veterans independent of symptom severity [151]. These reports contradict previous findings.

Together it appeared that genetic variants of *Bdnf* gene and PTSD did not provide any conclusive relationship. The higher and lower value of BDNF were possibly observed due to heterogenous population or low percentage of homozygous Met alleles. More longitudinal and follow-up studies are necessary to make a definitive conclusion.

#### **10. BDNF-miRNAs-psychiatric disorders**

The miRNAs are non-coding RNAs, a new class of epigenetic modulators emerging as an attractive molecule for therapeutic intervention. The miRNAs are small 21–23 nucleotides that have the capability to inhibit mRNA and protein resulting in gene regulation [152]. Literature search showed 2844 articles have been published where miRNAs were associated with psychiatric diseases. Interestingly, BDNF-miRNA axis in psychiatric diseases showed 131 reports indicating therapeutic potential of BDNF. Recent studies indicated that several miRNAs target 3′ UTR of *Bdnf* gene modulated the function associated with psychiatric disorders [153–158].

In rodent model of anxiety disorder and schizophrenia, miR-124a regulated anxiety like behavior by targeting *Bdnf* gene [159] and miR-148b is implicated in regulating *Bdnf* gene in methylazoxymethanol acetate model [160]. In mouse model of PTSD, a set of miRNAs, miR-15a-5p, miR-497a-5p, miR-511-5p and let-7d-5p were shown to be associated with *Bdnf* and *FKBP5*, the two key PTSD-linked genes [157]. Moreover, a prolong stress induced rat PTSD model, miR-142-5p is shown to be upregulated in amygdala with a target gene, Npas4 which was reduced [161]. The inhibition of miR-142-5p appeared to reduce the PTSD symptoms by restoring Npas4 and BDNF level suggesting a crucial link between them. In BD condition, a human cohort study was conducted and revealed an association between miR-206 and BDNF polymorphism [162]. Another study showed a panel of miRNAs, miR-7-5p, miR-221-5p and miR-370-5p that are involved in BD II patients by modulating BDNF level [163].

In summary, the data showed promising direction in miRNA-BDNF-axis modulation in psychiatric disorders. However, a strong clinical correlation regarding miRNA-BDNF needs to be established for the development of new diagnostic and therapeutic application to mitigate the cognitive deficit.

#### **11. Conclusion**

BDNF is well studied in major psychiatric disorders or diseases. Modern techniques provided us new insights regarding BDNF's role in psychiatric disease progression and treatment responses. The dysregulation of BDNF/pro-BDNF and its receptors TrkBs resulting in a cascade of neuropathophysiological events leading to the impairment of synaptic plasticity and cognitive deficit. Several lines of evidence support the notion that BDNF is nodal mediator across an array of neuropsychiatric disorders. It is further to make a note that many second-generation antipsychotic drugs showed some promise in providing neuroprotection by enhancing BDNF level, however, a definitive conclusion cannot be made based on few medications. Future investigation including using small molecule compound (mimetics or agonists) for enhancing BDNF synthesis and gene therapy using nanoparticle mediated encapsulation of BDNF, is necessary to extend this efficacy at therapeutic standpoint. Peripheral BDNF level is used as a biomarker in many psychiatric disorders, however, in some cases like MDD, it showed disagreement. This may be due to heterogenous nature and epigenetic modifications that contributed significantly for making a universal conclusion. Nonetheless, it helped to pave the way for better understanding the role of BDNF deep inside human brains. Future studies are warranted to uncover the mechanism of methylation and SNPs of *Bdnf* gene for better therapeutic treatment.

#### **Acknowledgements**

This material is the result of work with resources and the use of facilities at the VISN17 Center of Excellence for Research on Returning War Veterans and the Central Texas Veterans Health Care System (CTVHCS). The authors would like to acknowledge Richard W. Seim, Ph.D., Director of the VISN 17 Center of Excellence for Research on Returning War Veterans, (Texas Waco, USA) for his support. The views expressed herein are those of the authors and do not necessarily reflect the official policy or position of the Department of Veterans Affairs or the United States Government.

*The Role of Brain-Derived Neurotrophic Factor in Psychiatric Disorders DOI: http://dx.doi.org/10.5772/intechopen.112567*

#### **Funding**

The present study was supported by VISN17 Center of Excellence's internal funds to Biomarkers & Genetics Core.

#### **Conflict of interest**

The authors state that they do not have any conflict of interest.

#### **Notes/thanks/declaration**

None.

### **Author details**

Sudhiranjan Gupta\* and Rakeshwar S. Guleria Biomarkers and Genetics Core, VISN 17 Center of Excellence for Research on Returning War Veterans, Central Texas Veterans Health Care System, Waco, Texas, United States

\*Address all correspondence to: sudhiranjan.gupta@va.gov

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 2**

## The Role of Brain-Derived Neurotrophic Factor in Autism Spectrum Disorder: Current Findings and Future Directions

*Mumin Alper Erdogan and Oytun Erbaş*

#### **Abstract**

Brain-derived neurotrophic factor (BDNF) is a crucial neurotrophic factor that plays an essential role in neuroplasticity and neurodevelopment. Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects social interaction, communication, and behavior. The relationship between BDNF and ASD has been studied extensively, with conflicting results. While some studies suggest that decreased BDNF levels may contribute to the development of ASD, others do not confirm this finding. The effects of BDNF on synaptic plasticity and cognitive functions have also been investigated, with some studies indicating that BDNF may be associated with impairments in learning, memory, and attention in individuals with ASD. Additionally, physical exercise and cognitive and behavioral therapies may help alleviate ASD symptoms by increasing BDNF levels and enhancing neuroplasticity. Further research is needed to better understand the mechanisms underlying the relationship between BDNF and ASD and to develop more effective treatment strategies for individuals with ASD.

**Keywords:** BDNF, autism spectrum disorder, neuroplasticity, cognitive functions, therapeutic interventions

#### **1. Introduction**

The growth and plasticity of the brain are significantly influenced by the protein BDNF. A neurodevelopmental disorder called Autism spectrum disorder (ASD) causes social and behavioral difficulties. Numerous experts have conducted considerable study on the link between BDNF and ASD.

A neurotrophic factor known as BDNF helps neurons across the central nervous system to survive, develop, differentiate, and function. The nervous system's capacity to adapt to structural and functional changes is known as neuroplasticity. Understanding how BDNF affects neuroplasticity is important for learning, memory, and cognitive functions as well as for understanding the origins and therapies of neurological and neuropsychiatric illnesses.

### **2. The effect of BDNF on neuroplasticity**

BDNF plays a critical role in regulating synaptic plasticity processes. Synaptic plasticity can be defined as the strengthening or weakening of synapses, leading to changes in the connections between neurons. BDNF particularly influences the following neuroplasticity processes: [1–3].


#### **2.1 BDNF and Learning, Memory, and Cognitive Functions**

Neuroplasticity is considered a fundamental mechanism in learning and memory processes, and BDNF's effects on these processes are of great importance. BDNF is particularly associated with the following cognitive functions: [2–4].


*The Role of Brain-Derived Neurotrophic Factor in Autism Spectrum Disorder: Current Findings… DOI: http://dx.doi.org/10.5772/intechopen.112471*

#### **2.2 BDNF and neurological and neuropsychiatric disorders**

The regulation of neuroplasticity and BDNF plays a significant role in the pathogenesis and treatment of neurological and neuropsychiatric disorders. Decreased BDNF levels and impaired neuroplasticity processes have been associated with the following diseases: [2–4].


#### **2.3 BDNF and neuroplasticity: applications and future research directions**

Current research on BDNF and neuroplasticity has provided important insights into the understanding and treatment of neurological and neuropsychiatric disorders [1]. Some important areas of future research that could be focused on in this field include:


in early life and cognitive and neurological changes associated with aging. Such studies could lead to the development of specific strategies to support neuroplasticity at different stages of life [4].

4.Personalized medicine: Research on BDNF and neuroplasticity could help determine the impact of individual genetic and environmental factors on disease risk and treatment effectiveness. Such information could contribute to the development of personalized treatment approaches and more effective management of neurological and neuropsychiatric disorders [5, 6].

Future research on BDNF and neuroplasticity has a great potential to provide a better understanding of how neuronal and synaptic functions change in different disease states and stages of life. Specifically, gaining more knowledge on how BDNF and neuroplasticity mechanisms interact and influence each other could lead to the development of more effective treatment strategies and better management of neurological and neuropsychiatric disorders. Progress in this field could play an important role in improving patients' quality of life and contributing to public health.

#### **3. BDNF's biological and functional properties and effects**

#### **3.1 Biological properties of BDNF**

BDNF is a protein produced in nerve cells in the brain and plays an important role in many biological processes such as neurodevelopment and synaptic plasticity [7]. BDNF is converted from proBDNF, a protein synthesized in brain cells and sent to neurons, to mature BDNF (mBDNF) by proteolytic cleavage [8]. BDNF is particularly expressed in brain regions such as the hippocampus, prefrontal cortex, striatum, and amygdala [9, 10].

#### **3.2 Functional properties and effects of BDNF**

BDNF is a protein that affects communication between neurons in the brain and plays an important role in many biological processes such as neurodevelopment and synaptic plasticity [6]. BDNF promotes the growth and healthy development of neurons. Moreover, BDNF strengthens synaptic connections between neurons and supports the formation of new synaptic connections [7, 8]. BDNF is also important for learning and memory and plays a role in memory formation [9]. BDNF also plays an important role in regulating stress response and mood [10].

The effects of BDNF are mediated through receptors. BDNF binds to a receptor called TrkB to promote the growth and healthy development of neurons [6]. Additionally, TrkB receptor strengthens synaptic connections between neurons and supports the formation of new synaptic connections [11]. TrkB receptors are also responsible for the effects of BDNF on learning and memory formation [12].

As BDNF plays a significant role in regulating nervous system functions, BDNF levels can vary in many diseases associated with processes such as neurodevelopment and synaptic plasticity [13]. Therefore, BDNF levels are also used as a potential biomarker for the pathophysiology, diagnosis, and treatment of neuropsychiatric disorders [14].

*The Role of Brain-Derived Neurotrophic Factor in Autism Spectrum Disorder: Current Findings… DOI: http://dx.doi.org/10.5772/intechopen.112471*

#### **3.3 BDNF and neurodevelopment**

BDNF promotes the growth, migration, and differentiation of nerve cells during neurodevelopment. BDNF also assists nerve cells in forming the proper connections. A deficiency in BDNF can result in errors in neurodevelopment and the failure of neurons to make the proper connections [11]. The effects of BDNF on neurodevelopment have been studied extensively in relation to neurodevelopmental disorders [12].

#### **3.4 BDNF gene expression**

BDNF gene expression is necessary for the production of BDNF protein. The BDNF gene can be expressed by neurons and other cell types [13]. BDNF gene expression is influenced by many factors, such as activity, stress, and neurodevelopmental processes [14]. BDNF gene expression has been studied extensively in relation to neurodevelopmental disorders and other brain diseases [9].

#### **3.5 BDNF's roles in different brain regions**

The roles of BDNF vary in different regions of the brain. In the hippocampus, BDNF is involved in learning and the formation of memories [15]. BDNF also plays a crucial role in regulating stress response and emotion in the prefrontal cortex [16]. Additionally, other brain regions such as the striatum and amygdala also rely on BDNF for proper functioning [17].

#### **4. Autism spectrum disorder**

Autism spectrum disorder (ASD) is a condition that stems from the interplay of both genetic and environmental elements and affects neurodevelopment. ASD is defined by symptoms such as challenges with social interactions, communication deficits, and repetitive and restricted behavior patterns [18].

1.Pathophysiology of ASD:

The exact cause of autism spectrum disorder (ASD) remains unclear, but it is thought to be the result of a complex interplay between genetic, epigenetic, and environmental factors affecting the development and function of the brain [19]. Many researchers suggest that ASD arises from dysfunctions in brain development and function [20]. Brain development is related to the proper migration, differentiation, and connection of neurons. In addition, the proper formation and function of synaptic connections between nerve cells is also important [21].

#### 2.Relationship between ASD Neurodevelopment and BDNF

The relationship between the neurodevelopmental abnormalities in ASD and BDNF has been studied by many researchers. It has been found that BDNF levels are decreased in individuals with ASD, especially in those with low functional levels on the autism spectrum [22, 23]. In contrast, BDNF receptor levels in individuals with ASD are normal or increased [24].

#### 3.BDNF and ASD Symptoms:

BDNF is a key factor in synaptic plasticity and neurodevelopment, and a decrease in its levels may be linked to the symptoms of ASD. Specifically, a decrease in BDNF levels can result in an increase in social interaction difficulties and repetitive behaviors among individuals with ASD [25]. Additionally, the decreased BDNF levels observed in individuals with ASD have been linked to emotional disorders and increased obsessive-compulsive behaviors [26].

#### 4.BDNF, ASD Treatment, and Medications:

BDNF may be a potential target in the treatment of ASD. The neurodevelopmental effects of BDNF can be used to improve brain function in individuals with ASD [27]. Increasing BDNF levels may increase synaptic plasticity and reduce ASD symptoms. Therefore, drugs that increase BDNF levels are being investigated as a potential strategy in the treatment of ASD [28].

ASD and BDNF Gene Expression: Decreased expression levels of the BDNF gene in individuals with ASD may be associated with developmental dysfunctions. Some studies have shown that BDNF gene expression levels may be decreased in individuals with ASD [29, 30].

BDNF and ASD Medications: Drugs that increase BDNF levels are being evaluated as a potential strategy for ASD treatment [31]. For example, antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs) are thought to reduce ASD symptoms by increasing BDNF levels [32]. Additionally, BDNF agonists are being investigated as a potential treatment strategy for reducing ASD B symptoms [33].

#### **4.1 Clinical features, diagnosis, and treatment of autism spectrum disorder**

Early childhood is when autism spectrum disorder (ASD) first appears. ASD is characterized by challenges with social interaction and communication as well as limited and repetitive behavioral patterns. The three core characteristics of ASD, as defined by the DSM-5, include difficulties with social interaction and communication, as well as restricted interests and repetitive behaviors. These signs can be mild to severe and last a person their entire life [18]. A thorough assessment of a child's behavioral traits, such as social interaction, language and communication abilities, repetitive habits, and interests, can lead to the diagnosis of ASD. Specialists frequently utilize standardized tests and autism screening instruments to make their diagnoses. However, identifying ASD cannot be done with a single test or clear indication. Input from a child's family, teachers, and other healthcare experts may also be included in a thorough review [34]. Multidisciplinary therapy is necessary for ASD. A child's treatment frequently starts as early as feasible and lasts their entire lives. Education, speech and language therapy, behavior therapy, family counseling, and medication are all possible treatment modalities. Children can have better results with early diagnosis and treatment [35].

#### **5. BDNF and autism spectrum disorder**

BDNF is a member of the neurotrophic factor family and is critical for neurological functions such as neuroplasticity and neurogenesis. BDNF functions as a protein that regulates the growth, maturation, survival, and synaptic plasticity of neurons [36].

#### *The Role of Brain-Derived Neurotrophic Factor in Autism Spectrum Disorder: Current Findings… DOI: http://dx.doi.org/10.5772/intechopen.112471*

Changes in BDNF levels in individuals with autism spectrum disorder (ASD) may contribute to the pathophysiology of ASD. Many researchers have found evidence that changes in BDNF levels may be associated with ASD. Some studies have shown that BDNF levels are lower in individuals with ASD and that these lower levels are associated with ASD symptoms [37]. However, other studies suggest that normal BDNF levels may be associated with ASD. For example, one study found that individuals with ASD had normal BDNF levels compared to a control group, but differences in the regional distribution of BDNF in the brain may contribute to ASD symptoms [38]. Additionally, genetic variations in the BDNF gene have been investigated in individuals with ASD. One study found that certain variations in the BDNF gene were associated with an increased risk of ASD [39]. However, another study found that these variations in the BDNF gene were not associated with ASD [40]. The relationship between BDNF and ASD is not yet fully understood and further research is needed in this area. Taken together, the evidence discussed suggests that BDNF may have an important role in the pathophysiology of ASD, although the precise nature of this role warrants further research.

The relationship between ASD and BDNF may be important for the pathophysiology of ASD, and further research in this area is needed. Many researchers have shown that BDNF levels are decreased in individuals with ASD and that these low levels are associated with ASD symptoms. However, other studies suggest that normal BDNF levels may also be associated with ASD.

BDNF levels may be used as a potential therapeutic target to alleviate ASD symptoms. A study has shown that BDNF deficiency in mice leads to ASD-like symptoms and that BDNF infusion can reverse these symptoms. This study suggests that BDNF may be a potential agent for ASD treatment.

In conclusion, while the relationship between ASD and BDNF is not yet fully understood, it is known that BDNF is critical for neurological functions such as neuroplasticity and neurogenesis and may play a role in ASD pathophysiology. The diagnosis and treatment of ASDB require a multidisciplinary approach, and early diagnosis and treatment may help achieve better outcomes. BDNF levels may be used as a potential therapeutic target in ASD treatment.

#### **6. BDNF's role in the pathophysiology of autism spectrum disorder and clinical outcomes**

Although the exact role of BDNF in the pathophysiology of ASD is still not fully understood, studies in this area have made significant progress. Changes in BDNF levels have been shown to be associated with ASD, and BDNF receptors and signaling pathways are also thought to play an important role in ASD pathophysiology.

#### **6.1 Changes in BDNF levels**

Changes in BDNF levels may be related to ASD pathophysiology. Some studies have shown low levels of BDNF in individuals with ASD [41–45]. These low levels have also been suggested to be associated with ASD symptoms [42]. Some research suggests that changes in BDNF levels are associated with factors that affect BDNF production in the brain. For example, one study showed that maternal antibodies inhibited BDNF production in fetal mice, resulting in ASD-like symptoms [46]. Another study showed that early-life stress in mice resulted in decreased BDNF levels, which were associated with ASD-like symptoms [47].

#### **6.2 BDNF receptors and signaling pathways**

BDNF's effects are mediated by tropomyosin receptor kinase B (TrkB) receptors, which are high-affinity receptors on the cell surface [48]. Activation of TrkB receptors by BDNF affects a series of signaling pathways critical for neurological functions such as neuroplasticity and neurogenesis [49]. BDNF activates signaling pathways that affect many neurological functions, including neurotransmitter release, synaptic plasticity, cell proliferation, and cell differentiation, through TrkB receptors [50, 51]. Therefore, the role of TrkB receptors and these signaling pathways in the pathophysiology of ASD is also being investigated.

Some studies have shown that TrkB receptor levels are low in individuals with ASD [51]. These low levels may contribute to ASD pathophysiology by reducing the effects of BDNF. In addition, other components of BDNF signaling pathways may also play a role in the pathophysiology of ASD. For example, a study showed that the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is involved in BDNF's neuroprotective effects and may also play an important role in the pathophysiology of ASD [52].

#### **6.3 Clinical implications of BDNF and ASD**

While the exact role of BDNF in ASD pathophysiology is not fully understood, research in this area has made significant progress. Changes in BDNF levels have been shown to be associated with ASD, and BDNF receptors and signaling pathways may also play an important role in ASD pathophysiology.

Several studies have shown that low BDNF levels are associated with ASD symptoms [48, 49]. It has also been suggested that an increase in BDNF levels may alleviate ASD symptoms [50]. Additionally, BDNF levels could be a potential therapeutic target for ASD treatment. Some studies have shown that BDNF agonists, in particular, may have a potential role in alleviating ASD symptoms [51, 52].

However, further research is needed to fully understand the potential use of BDNF in ASD treatment. The side effects of BDNF, especially with long-term use, are not yet fully understood and require careful investigation.

#### **6.4 Relationship between BDNF levels and severity of ASD**

Studies on individuals with ASD indicate that BDNF levels are associated with the severity of the disorder. Specifically, low levels of BDNF have been linked to more severe ASD symptoms [53]. Various studies have reported that plasma and serum BDNF levels in individuals with ASD are lower compared to those without ASD [54]. However, it is believed that changes in BDNF levels may vary across different subtypes of ASD [55]. Furthermore, a positive correlation has been reported between BDNF levels and social functioning [56]. This relationship suggests that an increase in BDNF levels is paralleled by improvement in social skills. These findings suggest that BDNF plays an important role in regulating the neurobiological mechanisms and modulating symptom severity in ASD.

#### **6.5 The effect of BDNF on cognitive and social functions in individuals with ASD**

BDNF plays an important role in the development and regulation of cognitive and social functions. Studies conducted in individuals with ASD have shown that BDNF levels affect learning, memory, language skills, and social skills [57]. For example, a

*The Role of Brain-Derived Neurotrophic Factor in Autism Spectrum Disorder: Current Findings… DOI: http://dx.doi.org/10.5772/intechopen.112471*

study conducted in children with ASD found a positive correlation between BDNF levels and language development and social skills [58]. These results indicate that BDNF is an important modulator of language and social skill development in individuals with ASD. Increasing BDNF has been associated with improvements in cognitive function and social skills [59]. Therefore, increasing BDNF levels is considered a potential treatment approach for improving cognitive and social functions in individuals with ASD [54]. Pharmacological treatments and lifestyle changes targeting BDNF, particularly BDNF agonists, are evaluated as promising methods to enhance cognitive and social functions in individuals with ASD. These treatments may target neurotraumatic factors, synaptic plasticity, and neurogenesis processes to increase BDNF levels. However, further research is needed to fully understand the effects of BDNF on cognitive and social functions in individuals with ASD. Future studies should focus on evaluating the efficacy and safety of treatment strategies targeting BDNF and improving our understanding of the complex interactions between BDNF and ASD [2, 60].

#### **7. BDNF genetic and epigenetic regulations: Their association with autism spectrum disorder (ASD)**

#### **7.1 BDNF genetic regulations and ASD**


#### **7.2 BDNF epigenetic regulations and ASD**


Genetic and epigenetic regulations in the BDNF gene play an important role in the neurobiological basis of autism spectrum disorder (ASD). BDNF gene polymorphisms and epigenetic regulations can affect synaptic plasticity and neuroplasticity, and therefore have been associated with ASD risk and severity. Understanding the role of BDNF's genetic and epigenetic regulations in the etiology of ASD may contribute to the development of new intervention and treatment strategies.

#### **8. The role of BDNF in the neurodevelopment, neuroplasticity, and cognitive functions of autism spectrum disorder**

BDNF is a crucial neurotrophic factor for the survival, development, and function of neurons [65]. Additionally, it has a significant impact on neuroplasticity and neurodevelopment, and has been linked to neurological disorders such as autism spectrum disorder. While some studies suggest a decrease in BDNF levels in individuals with ASD, others have not confirmed this finding [32, 66, 67]. Synaptic plasticity is an important mechanism for neurons to modify their ability to communicate with each other, and is essential for neurodevelopment and learning processes. BDNF's effects on synaptic plasticity have been associated with neurological disorders like autism spectrum disorder, with some studies indicating that synaptic plasticity may be impaired in individuals with ASD [68, 69]. The effects of BDNF on cognitive functions have also been investigated. A decrease in BDNF levels in individuals with autism spectrum disorder may lead to cognitive impairments, with some studies suggesting that memory, learning, and attention may be affected in individuals with ASD [61, 70].

Based on the literature findings regarding the role of BDNF in the neurodevelopment, neuroplasticity, and cognitive functions of individuals with autism spectrum disorder (ASD), changes in BDNF levels may play a role in the pathophysiology of ASD, but the exact mechanism is still not fully understood. BDNF deficiency, as suggested by some studies, can affect ASD in several ways. For example, BDNF deficiency can affect the maturation and function of synapses in neurons during neurodevelopment. However, BDNF deficiency is thought to be particularly effective on synaptic plasticity and cognitive functions in brain regions such as the hippocampus and amygdala. BDNF deficiency may also be associated with fundamental symptoms of ASD, such as social behavior and communication. Some studies suggest that BDNF deficiency could help develop various treatments to alleviate ASD symptoms. For instance, treatments that increase BDNF levels have been shown to support the development of social interaction, language skills, and cognitive functions in children with ASD.

#### **9. BDNF and neuroinflammation in ASD**

Neuroinflammation is a factor associated with the pathogenesis of ASD. BDNF's anti-inflammatory properties and neuroprotective effects may play a role in managing neuroinflammation in ASD.

#### **9.1 Neuroinflammation and ASD**

Neuroinflammation is a process involving inflammatory responses and release of inflammatory mediators by nervous system cells. In the context of ASD pathogenesis, *The Role of Brain-Derived Neurotrophic Factor in Autism Spectrum Disorder: Current Findings… DOI: http://dx.doi.org/10.5772/intechopen.112471*

possible mechanisms of neuroinflammation include immune cell activation, cytokine and chemokine production, oxidative stress, and neurotransmitter imbalances.

Neuroinflammation in ASD is associated with activation of immune cells such as microglia and astrocytes in the brain. These activated cells produce proinflammatory cytokines and chemokines, which contribute to the maintenance of neuroinflammation and disruption of synaptic function.

#### **9.2 The anti-inflammatory and neuroprotective effects of BDNF**

BDNF is one of the neurotrophic factors that are important for the survival, growth, and differentiation of nerve cells. The anti-inflammatory and neuroprotective properties of BDNF may contribute to the management of neuroinflammation in ASD by reducing inflammation and protecting nerve cells. BDNF can regulate inflammatory processes and decrease the activation of immune cells. As an instance, BDNF could decrease neuroinflammation by promoting the generation of antiinflammatory cytokines, including interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β). Furthermore, BDNF may alleviate the effects of neuroinflammation by reducing oxidative stress and regulating neurotransmitter balance. BDNF may contribute to the preservation of synaptic function and maintenance of neuroplasticity, thereby affecting the development and severity of ASD [71].

#### **9.3 Modulation of BDNF and neuroinflammation in ASD**

Studies investigating the potential role of BDNF in managing neuroinflammation in ASD indicate that this neurotrophic factor may contribute to reducing inflammation and protecting nerve cells [72–74]. For example, the effect of BDNF on astrocytes, which play an important role in regulating neuroinflammation, may affect inflammatory processes in ASD [75]. In addition, interventions targeting BDNF may have positive effects on reducing neuroinflammation and protecting nerve cells in individuals with ASD. Pharmacological agents or gene therapy methods used to increase BDNF levels may contribute to managing neuroinflammation in ASD and alleviating its symptoms [76]. In conclusion, the role of neuroinflammation in the relationship between BDNF and ASD is an important area of research for better understanding the potential impact of this neurotrophic factor on the pathogenesis and treatment of ASD. Future studies examining the modulation of neuroinflammation and the preservation of synaptic function in ASD by BDNF may contribute to the development of new and effective treatment strategies. These investigations are of great importance for the development of methods that may be used for the treatment of ASD and other neurodevelopmental disorders by improving the understanding of the anti-inflammatory and neuroprotective properties of BDNF.

#### **10. BDNF's potential effects on treatment of autism spectrum disorder**

#### **10.1 BDNF and ASD treatment**

The effect of BDNF on neuroplasticity and synaptic function may play an important role in alleviating ASD symptoms. Pharmacological and behavioral approaches that increase BDNF levels and enhance neuroplasticity can be used in ASD treatment.

#### **10.2 Pharmacological approaches**


#### **10.3 Behavioral approaches**


In conclusion, BDNF and ASD treatment is a promising research area for alleviating ASD symptoms using a combination of pharmacological and behavioral approaches. By increasing BDNF levels and promoting neuroplasticity, these approaches can enhance the quality of life and social adaptation of individuals with ASD. Furthermore, treatment strategies that increase BDNF levels can provide further insights into the pathophysiology and treatment of ASD by elucidating their effects on neuroplasticity and synaptic function. BDNF plays a significant role in regulating neurodevelopment, synaptic plasticity, and cognitive function. Therefore, BDNF-targeted therapies may have potential benefits for the treatment of autism spectrum disorder.

#### **10.4 BDNF targeted treatment options**

BDNF targeted treatment options include both pharmacological and nonpharmacological approaches. Pharmacological treatments include medications such as antidepressants, antipsychotics, and sodium valproate. Some studies have shown that sodium valproate can reduce symptoms of autism spectrum disorder by increasing BDNF levels [79]. Antidepressants may be effective in treating comorbid symptoms commonly seen in autism spectrum disorder, such as obsessive-compulsive disorder and depression. Antipsychotics are used to treat disruptive behaviors in autism spectrum disorder. Non-pharmacological treatments include exercise, diet, cognitive therapy, and cognitive-behavioral therapy. Exercise, in particular, is thought to increase neurodevelopment and synaptic plasticity by leading to an increase in BDNF levels [80]. Diet can also be helpful in treating symptoms of autism spectrum disorder. For example, one study showed that omega-3 fatty acids can reduce hyperactivity symptoms in autism spectrum disorder [81]. Cognitive therapy and

*The Role of Brain-Derived Neurotrophic Factor in Autism Spectrum Disorder: Current Findings… DOI: http://dx.doi.org/10.5772/intechopen.112471*

cognitive-behavioral therapy are effective treatment options for symptoms such as anxiety and depression in autism spectrum disorder.

#### **10.5 Possible side effects of using BDNF**

Potential side effects of BDNF-targeted treatments include headaches, sleep disturbances, and sexual dysfunction with antidepressants; movement disorders and weight gain with antipsychotics; and impaired liver function with sodium valproate [82, 83].

These studies suggest that increasing BDNF levels may help improve symptoms of autism spectrum disorder. However, the effectiveness of BDNF-targeted treatments is still being investigated, and further research is needed. In this section, BDNFtargeted treatment options, both pharmacological and non-pharmacological, as well as possible side effects of BDNF use will be discussed.

BDNF-targeted treatments include BDNF agonists and BDNF enhancers. BDNF agonists increase the effects of BDNF by binding to BDNF receptors, while BDNF enhancers increase BDNF production and enhance the response of neurons to BDNF. Animal studies have shown that BDNF agonists may be effective in improving symptoms of autism spectrum disorder. However, the effectiveness of these treatments in humans is still being investigated.

Pharmacological treatments that can increase BDNF levels include antipsychotics, antidepressants, and psychostimulants. However, the side effects of these medications should also be considered. In particular, metabolic side effects of antipsychotics are a significant concern for their use in children and adolescents.

Non-pharmacological treatments that can increase BDNF levels include physical activity, exercise, meditation, and therapy. For example, physical activity and exercise have been shown to increase BDNF levels and enhance neuroplasticity. Similarly, stress management techniques such as meditation and therapy have been shown to increase BDNF levels.

Possible side effects of BDNF-targeted treatments may include neurotoxicity due to excessive BDNF increases and BDNF's pro-inflammatory effects. Therefore, these treatments should be carefully managed.

In conclusion, BDNF-targeted treatments may have potential benefits for autism spectrum disorder. However, the side effects and effectiveness of treatment options need to be considered. Further research is needed to ensure the appropriate use of BDNF-targeted treatments.

#### **11. Recent research findings and future research directions on BDNF**

An essential neurotrophin known as BDNF is involved in the cognitive, neurodevelopmental, and neuroplastic aspects of autism spectrum disorder. More details on the function of BDNF in the pathophysiology of autism spectrum disorder have come to light recently. Future study is required since it is yet unknown how BDNF affects the therapy of autism spectrum disorder.

#### **11.1 Control of BDNF gene expression**

The usage of BDNF in the treatment of autism spectrum disorder can be improved by managing the expression of the BDNF gene. More investigation is required, in particular, on how the BDNF gene-associated SNPs affect the likelihood of developing

autism spectrum disorder. A correlation between BDNF polymorphisms and autism spectrum disorder was discovered in one study [84], however further investigation is required to fully understand this correlation.

The usage of BDNF in the treatment of autism spectrum disorder can be improved by managing the expression of the BDNF gene. It is necessary to do additional study on the nature of the association between BDNF polymorphisms and autism spectrum disorder in order to better understand the processes that enhance or decrease BDNF gene expression. According to one study in this field, people with autism spectrum disorder have changed gene regulatory regions that boost the expression of the BDNF gene [85]. This finding raises the possibility that the pathophysiology of autism spectrum disorder may include the control mechanisms of BDNF gene expression.

#### **11.2 Examination of BDNF receptors and signaling pathways**

The effects of BDNF are dependent on the activation of BDNF receptors on the cell surface. Therefore, examining the BDNF receptors and signaling pathways may help to better understand the effects of BDNF in the treatment of autism spectrum disorder. One study showed that the effects of BDNF are mediated through the activation of TrkB receptors [86]. However, the subtypes of these receptors and the exact workings of the signaling pathways are still unclear. BDNF affects synaptic plasticity and neurodevelopment through the TrkB receptor. Therefore, a better understanding of the effects of the TrkB receptor and BDNF signaling pathway on the pathophysiology of autism spectrum disorder is needed. One study showed that BDNF increased social behavior through activation of the TrkB receptor and restored normal social behavior in mice with social behavior deficits, which are also present in autism spectrum disorder patients [87]. These results suggest that the TrkB receptor and BDNF signaling pathway may have a significant impact on symptoms of autism spectrum disorder, such as social behavior.

#### **11.3 Understanding the effects of BDNF on behavioral and social functions**

A better understanding of the effects of BDNF on behavioral and social functions may assist in the development of BDNF-targeted therapies for autism spectrum disorder (ASD) treatment. Specifically, the effects of BDNF on social functions are still not clear and further research is needed in this area. One study has shown that BDNF treatment improved social learning and increased social memory [88].

These results suggest that BDNF may play a significant role in regulating social functions and the effects of BDNF on behavioral and social functions are seen as a potentially useful area for ASD treatment. BDNF is considered a potential target for treating symptoms of ASD, such as social function impairment, especially social function disorder.

Many studies have demonstrated the positive effects of BDNF on social learning and social memory. For example, one study showed that BDNF application improved social learning and increased social memory [65]. The effects of BDNF are thought to be useful for treating symptoms of ASD, such as social function disorder observed in ASD.

A better understanding of the effects of BDNF on social functioning is important for the development of BDNF-targeted treatments. To do this, more research is needed to understand the role of BDNF in regulating social functioning, particularly its effects on processes such as social learning, processing, and memory. Such studies *The Role of Brain-Derived Neurotrophic Factor in Autism Spectrum Disorder: Current Findings… DOI: http://dx.doi.org/10.5772/intechopen.112471*

can help us better understand how effective BDNF-targeted treatments may be in treating symptoms such as social dysfunction in autism spectrum disorder.

#### **11.4 Future perspectives in BDNF and ASD research**

In autism spectrum disorder (ASD) and brain-derived neurotrophic factor (BDNF) research, future studies are expected to focus on developing more comprehensive and effective strategies for understanding and treating the disease. Here are some important areas related to these perspectives:


8.Early diagnosis and prognosis of ASD with BDNF: The number of studies investigating the use of BDNF levels as a potential biomarker for early diagnosis and prognosis of ASD should be increased [100]. Early diagnosis and prognosis are important for initiating effective interventions in a timely manner and improving outcomes [101].

In summary, future perspectives in BDNF and ASD research should focus on comprehensive and innovative studies that will fill the gaps in knowledge and contribute to the development of more effective diagnosis and treatment methods for individuals with ASD. These studies will help us better understand the neurobiological basis of ASD and develop effective treatment strategies.

#### **11.5 Personalized ASD treatment and BDNF**

Personalized treatment approaches aim to improve the quality of life and functionality of individuals with autism spectrum disorder (ASD) by offering customized treatment plans based on each individual's genetic, biochemical, and environmental factors. Brain-derived neurotrophic factor (BDNF) can be considered an important target in personalized ASD treatment.

Firstly, identifying BDNF levels and genetic variations can help in selecting appropriate treatment methods based on individual differences. Studies examining BDNF levels and interactive factors can contribute to optimizing treatment options specific to the needs and sensitivities of individuals with ASD.

In addition, pharmacological and lifestyle interventions targeting BDNF can be used in personalized ASD treatment. For example, drugs that increase BDNF levels and support synaptic plasticity can be evaluated as a potential treatment to improve the cognitive and social skills of individuals with ASD, taking into account individual differences. Lifestyle interventions, especially regular physical activity and appropriate nutrition, can help increase BDNF levels and improve the quality of life and functionality of individuals with ASD.

In conclusion, knowing the precise functions of BDNF in ASD and using this information to individualized treatment plans will help to create more successful and focused therapies for people with ASD. Future studies should investigate the relationship between BDNF and the underlying causes of ASD, the variables that control BDNF levels, and the efficacy of BDNF-targeting therapies. Examining BDNF levels and effects in various ASD subtypes and individual variations can also help with the creation of more sensitive and efficient treatment approaches because of the varied character of ASD.

#### **12. Prevention of neurodevelopmental disorders and policies related to ASD**

Understanding the relationship between BDNF and ASD can contribute to the prevention of neurodevelopmental disorders and the development of policies and strategies for individuals with ASD. In this context, the following steps are recommended:

1.Increasing Awareness: Raising awareness about the relationship between ASD and BDNF can help the community understand and support the lives of individuals with ASD. This can be achieved through educational programs, public awareness campaigns, and media efforts.

*The Role of Brain-Derived Neurotrophic Factor in Autism Spectrum Disorder: Current Findings… DOI: http://dx.doi.org/10.5772/intechopen.112471*


In conclusion, the better understanding of the relationship between BDNF and ASD provides important insights into the prevention and management of neurodevelopmental disorders. Specifically, studies on the genetic and epigenetic regulations of BDNF offer new perspectives on the etiology and treatment of ASD. In the future, it is important to conduct more detailed research on the relationship between BDNF and ASD and apply this knowledge to develop effective policies and strategies. This approach can contribute to improving the quality of life of individuals with ASD and enhancing the general ability of society to cope with neurodevelopmental disorders.

#### **13. Conclusions**

In conclusion, this section discussed the current scientific literature on the relationship between BDNF and ASD. BDNF was highlighted as an important protein in neuronal functions such as synaptic plasticity, neurogenesis, and gliogenesis, and therefore, it has significant importance in the pathophysiology and treatment of ASD. The role of BDNF in the specificity of ASD and the relationship between individualized ASD treatment and BDNF were also addressed.

BDNF has emerged as a possible target for the therapy of autism spectrum disorder (ASD), as it is a protein that is crucial for neurodevelopment, synaptic plasticity, and cognitive skills. According to recent studies, BDNF levels are linked to ASD symptoms. To ascertain the efficacy and safety of BDNF-targeted therapies, more study is necessary.

BDNF levels have been found to be low in patients with ASD, making BDNFtargeted treatments a potential target for the treatment of ASD. Pharmacological treatment options include antidepressants, antipsychotics, and sodium valproate. Some studies have shown that sodium valproate can increase BDNF levels and reduce symptoms of ASD. However, further research is needed to determine the effectiveness and safety of these treatments.

Non-pharmacological treatment options include exercise, nutrition, and therapy options. Particularly, exercise can increase BDNF production and help reduce symptoms in children with autism spectrum disorder. Cognitive therapy and cognitivebehavioral therapy are also effective treatment options for symptoms such as anxiety and depression in autism spectrum disorder. However, further research is needed on the effects of these non-pharmacological treatments on BDNF levels.

Controlling BDNF gene expression may help in developing the use of BDNF in autism spectrum disorder treatment. Examining BDNF receptor and signaling pathways can also play an important role in developing BDNF-targeted treatments. For example, it has been shown that activation of BDNF's TrkB receptors enhances social behavior and restores normal social behavior in mice with social behavior deficits similar to those seen in autism spectrum disorder patients.

Pharmacological and non-pharmacological options for BDNF-targeted treatments include antidepressants, antipsychotics, sodium valproate, exercise, diet, cognitive therapy, and cognitive-behavioral therapy. The side effects of these treatment options should also be taken into consideration.

The potential effects of BDNF-targeted treatments include increased neurodevelopment and synaptic plasticity, reduced symptoms, and improved behavioral and social functioning in individuals with autism spectrum disorder (ASD). However, the relationship between BDNF and ASD is not yet fully understood, and further research is needed. Understanding the relationship between BDNF and ASD could have significant benefits for clinical and research applications. Specifically, using BDNF levels and genetic variations in the diagnosis and prognosis of ASD could provide opportunities for early intervention and support. Additionally, BDNF-targeted treatment approaches could contribute to the development of potential therapies aimed at improving cognitive and social skills in individuals with ASD. Lastly, evaluating BDNF levels and interactive factors in individualized ASD treatment could provide optimized treatment options tailored to each individual's unique needs and sensitivities. Future research focusing on BDNF gene expression control, BDNF receptors and signaling pathways, and better understanding the effects of BDNF on behavioral and social functioning could help develop BDNF-targeted treatments for use in ASD.

There are some limitations to consider in BDNF and ASD research, as well as suggestions for future studies. Firstly, many current studies may not fully reflect the heterogeneous nature of ASD and may overlook the relationships between different ASD subtypes and individual differences in BDNF levels and effects. Therefore, future research should focus on examining the relationships between the underlying mechanisms of ASD and the levels and effects of BDNF. Additionally, the number of studies evaluating the factors regulating BDNF levels and the effectiveness of BDNFtargeting therapies should be increased. These studies can help us better understand the fundamental mechanisms underlying the relationship between BDNF and ASD and develop more effective treatment strategies for individuals with ASD. The diversity of sample sizes and methodologies used in related research may pose some difficulties in evaluating the relationship between BDNF and ASD. Therefore, studies conducted with larger sample sizes and standardized methods can increase the reliability and generalizability of findings.

Future research should look at the precise functions of BDNF in ASD, paying close attention to age and gender differences. The quality of life and functional abilities of people with ASD may be improved by greater early-life chances for intervention and support.

*The Role of Brain-Derived Neurotrophic Factor in Autism Spectrum Disorder: Current Findings… DOI: http://dx.doi.org/10.5772/intechopen.112471*

In conclusion, BDNF and ASD research can significantly contribute to the development of effective and targeted treatments that provide individuals with ASD with a better quality of life and functionality. Therefore, ongoing research aimed at understanding the relationship between BDNF and ASD should be supported and encouraged.

#### **Conflict of interest**

The authors declare no conflict of interest.

#### **Author details**

Mumin Alper Erdogan1 \* and Oytun Erbaş2,3

1 Faculty of Medicine, Department of Physiology, Izmir Katip Celebi University, Izmir, Turkey

2 ERBAS Institute of Experimental Medicine, Gebze-Kocaeli, Türkiye

3 ERBAS Institute of Experimental Medicine, Illinois, USA

\*Address all correspondence to: alpero86@gmail.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 3**

## New Approach for Treatment-Resistant Depression

*Berzah Güneş, Lora Koenhemsi and Oytun Erbaş*

#### **Abstract**

Depression is one of the major mental illnesses seen worldwide, which in some cases can result in suicide. Although different drugs and methods can be used for treatment, one-third of the patients show resistance to conventional treatments. Treatment-resistant depression (TRD) is defined as a condition where a patient shows a response rate of less than 25% to at least two adequate trials of antidepressants with distinct mechanisms of action. Research on the use of ketamine in such patients has been ongoing for more than 20 years. Ketamine is a dissociative anesthetic mainly used for the induction and maintenance of anesthesia for animals and humans. Ketamine's routine clinical usage for depression treatment is limited due to its dissociative effects, alterations in sensory perception, intravenous route of administration, and abuse potential. These limitations have prompted researchers to investigate the precise mechanisms of action behind ketamine's antidepressant clinical responses in order to better understand its key targets. One of the primary elements behind ketamine's quick and strong antidepressant response is thought to be a brain-derived neurotrophic factor (BDNF)-mediated mechanism. Ketamine may help repair the neurobiological alterations associated with depression by restoring BDNF levels while stimulating neuroplasticity. This chapter aims to provide an overview of the existing literature regarding the relationship between antidepressant treatment and BDNF levels in depression. Understanding these mechanisms may contribute to the development of more targeted and effective treatments for depression and related disorders.

**Keywords:** treatment-resistant depression, ketamine, brain-derived neurotrophic factor, N-methyl-D-aspartate, rat

#### **1. Introduction**

Depression is one of the most common mental illnesses in the world, and it can lead to suicide in some situations. Depression became more frequent in recent years, with prevalence rates climbing from 10.3% in 2015 to 15.5% in 2019 and 17.2% in 2020 [1]. Abnormal functional activity and changes in neuronal/glial integrity have been observed in various brain regions, such as the prefrontal cortex and hippocampus, in association with depression [2].

Depressive symptoms were caused by deficits in serotonin, norepinephrine, and dopamine. Since then, all antidepressant medicines have targeted this system to

provide relief, including selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, and tricyclic antidepressants [3]. After their introduction, antidepressant drugs have proven to be beneficial for a wide range of depressed patients. These drugs are now considered first-line treatments for moderate to severe depression. Unfortunately, this treatment was insufficient for around one-third of the patients to obtain an effective result (treatment-resistant depression [TRD]) [4, 5]. Even more than seven decades after the first antidepressants were introduced in clinical practice, TRD remains a difficulty for psychiatrists. According to a recent expert consensus, TRD is now defined as a condition where there is less than a 25% response to at least two adequate trials of antidepressants with different mechanisms of action [6, 7]. In addition, TRD has been linked to a much higher illness burden than severe depression [8].

The prevalence of undesirable side effects caused by currently available antidepressants, the apparent delay in reaching meaningful therapeutic benefits, and the high proportion of patients who are resistant to therapy are the main causes of the treatment difficulties [9, 10]. Furthermore, some medications may require a 4- to 12-week waiting period before they begin taking effect [11]. In this case, new therapeutics and interventional approaches are required [9]. Recent research supports the significance of glutamate in depression, such as N-methyl-D-aspartate (NMDA) receptors and serotonin receptors [9, 11–13]. NMDA is one of the ionotropic glutamate receptors [5, 11]. The NMDA is becoming more and more clear as a key participant in the pathophysiology of psychopathologies. Medications that inhibit NMDA receptor activation have been found to have faster-acting antidepressant characteristics in both clinical and preclinical studies [5, 9, 13]. However, during the past 10 years, clinical evidence has started to support this idea [10].

Ketamine is a non-competitive high-affinity NMDA receptor antagonist [9, 13]. Ketamine is an anesthetic agent that is licensed for use in diagnostic and surgical operations in both animals and humans [10]. Ketamine is being researched for its immediate antidepressant benefits in people who have not responded to traditional therapy [14]. Numerous meta-analyses have been conducted to evaluate the effectiveness of ketamine, primarily centering on its application in TRD [12]. The remission rates of ketamine in depressed patients range from 29 to 44% [14]. Hypotheses about how these effects of ketamine occur are still incomplete. Most researchers agree that brain-derived neurotrophic factor (BDNF) plays an important role in the mechanism of ketamine in depression [6]. Several depression hypotheses have been postulated, including the monoamine theory, neuroendocrine mechanisms, neuroimmune mechanisms, and cytokine hypothesis. These hypotheses, however, have not been sufficient for fully describing the pathophysiology and management of depression. Neural plasticity theories of depression have recently gained popularity. According to this theory, brain plasticity failure is a key mechanism of depression. Furthermore, inadequate signaling by neurotrophic factors is critical in brain plasticity. BDNF is the most significant neurotrophin associated with depression [2].

BDNF promotes neuron survival and synaptogenesis in the central nervous system (CNS) in humans and animals. Hippocampal, cortical, cholinergic, nigral dopaminergic, and serotonergic neurons have all shown these effects. According to studies, individuals with major depression have been found to have decreased levels of BDNF, and these reductions have been shown to be associated with the severity of depression. In addition, pharmacological studies have also determined that antidepressant treatment has an impact on BDNF levels. Ketamine has also been shown to boost serum BDNF levels in animals and patients with TRD [6]. However, the exact role of BDNF in this mechanism

is still being investigated [3]. In this chapter, we aimed to summarize the connection between ketamine and BDNF in depression according to the current literature.

#### **2. The pharmacology of ketamine**

Ketamine is a phencyclidine derivative and glutamatergic agent that predominantly works as an antagonist of the N-methyl-D-aspartate (NMDA) receptor. Ketamine-free base is a lipid-soluble substance that penetrates the blood–brain barrier quickly [9, 15].

Ketamine is a racemic combination of two enantiomers, (S)-ketamine (esketamine) and (R)-ketamine (arketamine). Although the majority of commercially available pharmacological formulations are a balanced combination of the two, the distinct enantiomers have been studied separately to varying degrees [4, 16]. Interestingly, when compared to (S)-ketamine, (R)-ketamine had stronger impacts on reduced dendritic spine density, BDNF–TrkB signaling, and synaptogenesis [10]. According to studies in rodents the (R) isomer is more powerful and has less negative effects than the (S) isomer [17].

#### **3. History of ketamine usage**

Ketamine was first synthesized at the Parke Davis Laboratory by Calvin Stevens in 1962, and approved by the US Food and Drug Administration (FDA) in 1970. During the years it was introduced, ketamine was mostly used in veterinary medicine [4]. It was discovered to be a potent anesthetic and analgesic in the initial clinical studies [15, 18]. Due to its quick onset and recovery, ability to maintain or elevate blood pressure in trauma conditions, and little effects on the respiratory system, ketamine was used as a battlefield anesthetic in the Vietnam War after receiving FDA approval. Due to these characteristics, it is still commonly utilized as an anesthetic in human and veterinary medicine [16].

Ketamine usage expands in direct proportion to the number of studies conducted. Ketamine is effective as an adjuvant in the multimodal management of acute perioperative pain, and it lowers postoperative opioid demand and adverse effects. There are also articles on its effectiveness in chronic pain syndrome [15]. While ketamine was being researched as an anesthetic, its potential use in the treatment of psychiatric and psychological disorders was also being taken into consideration [15]. Ketamine is, therefore, used in major depressive disorder (MDD) and bipolar disorder (BD), obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), treatment-resistant depression (TRD), and addiction [3, 19]. Dr. Edward Domino conducted the initial clinical study in 1960 on ketamine usage for depression. Domino noticed that patients stated these medications worked far better than the antidepressants they were administered [19]. In Iran, in addition to psychotherapy, ketamine has been reported to be an effective abreaction agent in many conditions such as depression, anxiety, obsessive-compulsive neurosis, conversion reaction, and hypochondriasis [20]. It has also been used in Argentina as an antidepressant adjunct for similar purposes [19]. Following these findings, the FDA approved the isomer (s)-ketamine as the first glutamatergic antidepressant in the form of an intranasal spray named Spravato in 2019 [3]. In addition, Kolp et al. [21] studied the use of ketamine as part of psychedelic psychotherapy sessions in patients with neurosis and personality

disorders in Mexico. In addition to these studies, there are others that demonstrate its efficacy in the treatment of alcoholism [16]. First placebo-controlled, double-blinded trial to assess the treatment effects of a single dose of Ketamine by Berman et al. in 2000 [22]. In a comparable randomized, placebo-controlled double-blind crossover study of 18 patients with treatment-resistant depression, Zarate et al. [23] validated ketamine's rapid-acting antidepressant effects.

#### **4. Ketamine usage in depression**

Ketamine has been administered through a variety of methods for the treatment of depression, including intravenous (IV), intramuscular (IM), intranasal, sublingual, and oral [15]. When compared to the intramuscular formulation, oral ketamine has a lower bioavailability [13]. The approximate numbers for bioavailability are as follows: IV (100%), IM (93%), intranasal (45%), sublingual (30%), and oral (20%) [15].

Ketamine has rapid action in depression treatment [16]. The quickest substantial antidepressant response was observed within 2 hours, and the slowest after 4 hours [11]. (S)-ketamine and (R)-ketamine both appear to have immediate antidepressant effects [16]. In studies, the antidepressant effect of ketamine lasted 1–2 weeks after a single dose. Recent studies showed that this period is prolonged [3, 4, 11].

#### **5. Ketamine and BDNF**

Ketamine's neuropharmacology is complicated. The particular mechanisms underlying ketamine's antidepressant effects are still unknown. But, synaptic plasticity and BDNF signaling are thought to play important roles in ketamine's mechanism of action in depression recovery. BDNF is a central nervous system growth factor that is essential for neuronal survival, growth [14, 24, 25]. It is largely responsible for neuroplasticity in the brain [3, 26]. Regulation of neurogenesis, dendritic length, and spine density in the hippocampus and prefrontal cortex (PFC) are only a few structural modifications caused by changes in neurotrophic factor production and activity [27]. BDNF helps and supports particular neuronal populations throughout development as well as mediates synaptic plasticity involved with learning and memory. This neurotrophin has been linked to a variety of mental disorders in numerous studies [5, 6, 24, 28]. In a study of people who committed suicide as a result of depression, BDNF levels were found to be low in the hippocampus [29]. Most clinically effective antidepressants had effect on BDNF induction [26]. Chronic administration of traditional antidepressants raises mRNA encoding BDNF and BDNF-immunoreactive fibers in the hippocampus of rats [9].

Acute ketamine treatment raised BDNF protein levels in the hippocampus of rats was found in a study [30]. In addition, ketamine efficiently restores stress-induced reductions in BDNF levels in the mouse hippocampus and ventromedial prefrontal cortex [3]. According to Siuciak et al. [25], antidepressant effects were demonstrated in animals as a result of BDNF administration in two separate animal models of depression.

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist [5, 9, 13]. NMDARs are heterotetrameric glutamatergic ligand-gated ion channel receptors that have seven different subunits [5]. Ketamine blocks the NMDA receptors, especially the GluN2B subunit, which is involved in the regulation of synaptic plasticity and

neurotransmission [5, 9, 13]. It was found in studies that ketamine treatment had no effect on behavioral distress in mice lacking NMDARs specific to GluN2B found in pyramidal neurons. The intriguing aspect of the event is that, in contrast to ketamine, the mechanisms of action of medicines that target this area are developed extremely slowly. It is unknown how ketamine, which has no preference for inhibiting GluN2B subunits, specifically acts at this location to provide antidepressant effects [5].

The mechanism underneath is thought to be because interneurons fire more frequently than pyramidal neurons, which increases the amount of depolarizationdependent Mg2+ block relief, allowing ketamine to bind to the NMDAR channel pore on interneurons with more specificity [5]. By inhibiting these receptors, ketamine leads to increased extracellular glutamate release, specifically in the prefrontal cortex in rats [9, 13, 31]. The increased glutamate release triggers a cascade of events. Ketamine increases glutamate release at postsynaptic locations, which in turn activates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors [19]. Ionotropic transmembrane glutamatergic receptors known as AMPARs are the primary receptors for rapid synaptic neurotransmission in the brain. Multiple signaling pathways that control synaptic plasticity use AMPARs as their targets. Synaptic plasticity and potentiation both require the activation of AMPARs and NMDARs [5, 32]. AMPARs increase tropomyosin receptor kinase B (TrkB) receptor stimulation, which in turn promotes the mammalian target of rapamycin (mTOR) signaling [19]. TrkB, a high-affinity BDNF receptor, has been demonstrated to be required for the behavioral effects of antidepressants [5, 33]. Blocking extrasynaptic GluN2Bcontaining NMDARs would inhibit protein synthesis and cause antidepressant effects via a mTOR-dependent mechanism [5]. After the BDNF is produced by mTORC activation, it is released to the synapse by the neuron. It then stimulates its receptor on the same postsynaptic neuron, TrkB. As a result, mTOR activation is further stimulated, creating a positive feedback loop [3, 10].

mTOR is a serine/threonine protein kinase that regulates protein synthesis, cell motility, growth, and proliferation. According to the findings, mTOR may have an essential role in the pathophysiology of depression [34]. For this reason, mTOR signaling is used in many classic depression medications [5]. mTOR is activated by both AMPA receptor activation and the antagonism of NMDA receptors caused by ketamine binding [3]. Duman and Li [27] found in their study that, ketamine caused a rapid induction of synaptogenesis and spine formation in the PFC through stimulation of the mammalian target of the rapamycin signaling pathway and increased synthesis of synaptic proteins. In mice, pre-treatment with the selective mTOR inhibitor rapamycin through intracerebroventricular administration effectively prevents ketamine-induced synaptic molecular changes. Due to these studies, ketamine's fast antidepressant impact is attributed to the mTOR-induced rapid creation of synapses [35].

All of the mTOR results up to this point have a number of limitations. First, there are changes in mTOR signaling that appear to be sex-dependent. BDNF mRNA levels were elevated by ketamine treatment only in female mice. Additionally, compared to male rats, female rats exhibit increased sensitivity to ketamine at lower doses. The heightened sensitivity to ketamine was actually absent in female rats who had undergone ovariectomies. It was restored after the administration of synthetic progesterone and estrogen. According to this information, gonadal hormones may play important roles in the action of ketamine [29, 36].

Different rodent models of depression are another limitation of these studies. When a resistant model of depression is chosen, despite the behavioral recovery,

mTOR levels in the prefrontal cortex are dramatically lowered, implying that an increase in these levels does not always reflect a behavioral antidepressant response [3].

In a rat model of depression, administration of a TrkB inhibitor to the hippocampus prevents the behavioral and biochemical effects of ketamine [37]. Future research has demonstrated that a TRkB antagonist can prevent both of ketamine's antidepressant effects in mice [16]. In a study, Rafao-Uliska and Pałucha-Poniewiera [38] found that the R- and S-isomers had different effects with the mechanism of ketamine needing activation of the TrkB receptor. While S-ketamine had no behavioral effects, R-ketamine needed TrkB receptors to work [38]. These data firmly argue that BDNF– TrkB signaling is involved in the mechanism of ketamine, even though more research is necessary [3].

There are several cis-regulatory elements found in BDNF promoters, but the ones that mediate promoter IV's neuronal activation are the best understood. Inhibition of promoter IV-driven Bdnf expression results in depression-like behavior in mice, while a rat depression model exhibits epigenetic change at the promoter [39]. Histone deacetylase 5 (HDAC5) binds to Bdnf promoters I, II, and IV. HDAC5 is abundantly expressed in the brain, particularly in forebrain areas such as the hippocampus, cortex, and amygdala [40]. Adaptations of behavior to persistent emotional stimuli are epigenetically regulated by HDAC5 in the nucleus accumbens. HDAC5 overexpression in the hippocampus inhibits the antidepressant effect in stressed mice [41]. Choi et al. [39] determined that ketamine regulates BDNF expression in neurons by phosphorylating HDAC5, and ketamine's elevation of BDNF expression may be due to the reduction of HDAC5's repressive activity.

Ketamine's impact on gene expression is primarily attributed to alterations in neural signaling pathways [39]. The influence of the Val66Met (rs6265) single nucleotide polymorphism (SNP) in the BDNF gene on brain plasticity in humans is a topic of ongoing debate [5, 29]. Research conducted by Laje et al. suggests that individuals with the Met rs6265 allele, who suffer from major depressive disorder, do not typically exhibit a positive response to ketamine treatment [42]. In contrast, individuals with the Val/Val BDNF allele at rs65 are more likely to respond favorably to intravenous ketamine, leading to improvements in depression symptoms and a reduction in suicidal tendencies [3]. It is important to note that scientific consensus on this matter is still developing, and further investigations are necessary to fully understand the relationship between ketamine, gene expression, and treatment outcomes, particularly in individuals with specific genetic variations.

Patients with MDD (major depressive disorder) have lower blood BDNF levels, which are increased in individuals who respond to antidepressant medication [28]. Blood BDNF levels increased after 2 h and 24 h following the ketamine infusion in healthy participants in a study by Woelfer et al. [14]. Additionally, BDNF levels in the hippocampus, amygdala, dentate gyrus, and rodent serum are acutely raised by ketamine [3].

Eukaryotic elongation factor 2 kinase (eEF2K), also referred to as calmodulindependent protein kinase III, is a member of the atypical alpha-kinase family. The activity of eEF2K relies on the levels of calcium and calmodulin within the cell. Its primary target, eEF2, plays a crucial role in governing protein synthesis and synaptic plasticity, thus impacting cellular functions related to these processes [43]. Through the inactivation of eEF2K, decreased eEF2 phosphorylation, and subsequent desuppression of BDNF translation, ketamine-mediated antagonistic activity of postsynaptic NMDA receptors also increases BDNF production [13, 16]. The lower eEF2 phosphorylation caused by ketamine-mediated NMDA receptor inhibition at rest may *New Approach for Treatment-Resistant Depression DOI: http://dx.doi.org/10.5772/intechopen.112658*

inhibit CaMKIII kinase and depress BDNF translation [13]. Ketamine administration resulted in fast decreases in p-eEF2 in the hippocampus, while artificially inhibiting eEF2K resulted in enhanced BDNF protein expression. Additionally, BDNF's role in ketamine's effects is supported by the fact that decreasing eEF2K in BDNF knockout mice exhibited no antidepressant-like effect [3, 5].

BDNF levels in a living human brain cannot be assessed directly so the only option is to measure BDNF protein in the blood [28]. In rat experiments, there was a positive association between BDNF levels in the blood and the cortex [28, 44]. Similar to these studies Klein et al. [45] showed the same correlation in pigs. According to this research, BDNF levels in the blood alter in a similar way to those in the brain.

It was discovered in a study by Yang et al. [34] that acute ketamine treatment at a dose of 10 mg/kg boosted the expression of BDNF, whereas 5 mg/kg did not. This is due to dose-dependent signaling proteins in the mTOR pathway [3]. Although acute administration of ketamine had lower levels of BDNF [30], Garcia et al. [9] found that continuous ketamine treatment had an antidepressant effect in animals without changing BDNF levels in the hippocampus. The differences in BDNF expression between acute and chronic treatment suggested that alternative signaling pathways may also underlie the antidepressant effect of ketamine [9, 33]. Another explanation is the adaptive mechanisms or the development of tolerance to ketamine effects on hippocampus BDNF levels [9].

Recent neuroimaging studies support the potential anti-depressant effects of Ketamine. Ketamine-induced alterations in the brain's dorsomedial prefrontal cortex (dmPFC) have been discovered in various PET and fMRI investigations. The dmPFC is the area of the brain associated with emotional expectation and reward that is most affected in major depression [14].

However, not all research found that BDNF was involved in the fast antidepressant effects of ketamine [13]. According to Lindholm et al. [45], BDNF signaling does not significantly contribute to the antidepressant benefits of glutamate-based medicines. Despite providing a typical antidepressant-like response, neither ketamine nor the AMPA-potentiator LY 451656 increase BDNF signaling, according to researchers [32, 46].

#### **6. Side effects**

There is a lot of evidence to support ketamine's safety profile when used as an anesthetic drug, but there is far less information available regarding its safety when used repeatedly at subanaesthetic doses [10]. To the best of the author's knowledge, no such safety trials have been conducted with depressed patients. According to Zarate et al. [23], adverse effects occurred more frequently in ketamine-used participants than in placebo. Ketamine has been linked to a number of temporary psychoactive and hemodynamic side effects, including moderate dissociation emotions, blurred vision, dizziness, anxiety, impatience, and headaches [13]. Also, ketamine raises blood pressure and heart rate through sympathetic activation while maintaining respiratory activity, making a deadly overdose unlikely [13, 15]. Although the long-term safety profile of ketamine is unknown, it can cause bladder and urethral inflammation and irritation, and analogous changes in the biliary tract have recently been identified, resulting in acute or chronic cholestatic liver damage [4, 10, 15, 17]. Stopping the drug's use may help to reverse these adverse effects [17]. Madal et al.

[11] and Naughton et al. [10] found that the side effects were improved one hour after using ketamine in depressed patients.

#### **7. Conclusion**

Ketamine is a new and effective alternative drug for depression with a rapid beginning of action for the future. Slow intravenous ketamine treatment results in significant improvement in people with severe depression. However, there are still a number of gaps that remain, both in terms of clinical and research plans. In addition, the exact mechanism by which these antidepressant effects occur is still not fully resolved. We believe that future studies will shed light on new information on this subject.

### **Author details**

Berzah Güneş1 \*, Lora Koenhemsi<sup>2</sup> and Oytun Erbaş3,4

1 Department of Physiology, Demiroğlu Bilim University, Istanbul, Turkey

2 Faculty of Veterinary Medicine, Department of Internal Medicine, Istanbul University-Cerrahpaşa, Istanbul, Turkey

3 ERBAS Institute of Experimental Medicine, Gebze-Kocaeli, Türkiye

4 ERBAS Institute of Experimental Medicine, Illinois, USA

\*Address all correspondence to: berzahgunes2020@gmail.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*New Approach for Treatment-Resistant Depression DOI: http://dx.doi.org/10.5772/intechopen.112658*

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### Section 2
