New Approach for Treatment-Resistant Depression

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.

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, 12, 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 depolarization-dependent 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 GluN2B-containing 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 calmodulin-dependent 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 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.