Emergence of Ketamine as a Rapid Acting Antidepressant: Mechanistic Insights and Future Directions

*Atamjit Singh and Preet Mohinder Singh Bedi*

## **Abstract**

Ketamine is a phencyclidine derivative and N-methyl-D-aspartate receptor antagonist, widely popular as a dissociative anesthetic. Its use as an anesthetic in humans was progressively fallen out due to its associated adverse effects and the emergence of newer and safer anesthetics. In recent few decades, various reports related to its efficacy in the treatment of resistant depression with anti-suicidal potential draw significant attention from researchers around the globe. The rapid clinical effect of ketamine within hours as compared to traditional antidepressants that take several weeks makes it a hot topic in antidepressant research. Studies conducted in the recent past suggest its mechanism of action through glutamate modulation via receptors like NMDA, AMPA as well as downregulation of BDNF etc. This chapter will shed light on the various mechanisms of ketamine related to antidepressant activity. Along with that its pharmacokinetics, toxicology and ongoing clinical trials will also be discussed.

**Keywords:** ketamine, depression, antidepressant, NMDA, BDNF

## **1. Introduction**

From last few decades with rapid development and modernization, significant improvements in the lifestyle of humans has been observed but with pros there are associated cons and so is major depressive disorder (MDD) which is affecting teenagers to adults and majorly observed in young working professionals. It is emerging as major contributor in global disease burden and reported as the second leading causes for disability [1]. According to the study conducted by mental health in Canada, MDD has lifetime prevalence of 11.3% [2]. Besides being a major challenge for healthcare system its pathophysiology is still not uncovered completely. One hypothesis based on monoamines suggest that it may resulted from functional deficiency of neurotransmitters named serotonin and/or noradrenaline which is widely utilized for categorization of antidepressant drugs [3]. But conflict is also standstill with the time frame of the effect and dose administration as clinical symptoms are observed after several weeks from the onset of therapy and only half are noted to have actual clinical response [4–7]. Apart from that one-third patients suffers from treatment resistant depression (TRD) that are nonresponsive to currently approved medications [8]. Non-responsiveness of currently available therapy especially for TRD arise the emergency need of more effective and safer antidepressant therapy.

Ketamine is a phencyclidine derivative and N-methyl-D-aspartate (NMDA) receptor antagonist, widely popular as a dissociative anesthetic. Ketamine was first reported for its efficacy in depression in year 2000, when sub-anesthetic intravenous dose of ketamine rapidly reduced the symptoms of MDD and effect continued up to 72 hours [9]. Taking lead from this, further clinical trials were conducted which showcase its efficacy in TRD patients with 60–70% response rate [10–14]. Onset of action was reported within 2–4 hours and last for 1 week with singe infusion while repeated infusions have effect up to 18–19 days. Clinical data also suggest the responsiveness of ketamine up to 44% on patients with comorbidities and ultraresistant depression [15, 16]. In addition to this ketamine has been reported for its anti-suicidal and anti-anhedonic properties [14, 17, 18]. All this reports points toward the different mechanism of ketamine form traditional antidepressants.

### **2. Basic chemistry, pharmacology and pharmacokinetics of ketamine**

Recently discovered antidepressant and anti-suicidal action of ketamine significantly attracted the researchers working in the field of psychiatry [9, 11, 19]. Ketamine is a phencyclidine derivative and a mixture of R(−) and S(+) enantiomers. Both R(−) and S(+) enantiomers has been explored widely and it was observed that S(+) enantiomer has higher potency than R(−) enantiomer (R-ketamine) for phencyclidine site on glutamate NMDA receptor along with stronger analgesic activity [20–24]. Inspired form these outputs, S(+) enantiomer also known as esketamine is now under investigations for antidepressant potential [25]. However

**Figure 1.**

*General layout of metabolic pathway of ketamine showcasing stereoseletive metabolism through various cytochrome P450 enzymes.*

*Emergence of Ketamine as a Rapid Acting Antidepressant: Mechanistic Insights and Future… DOI: http://dx.doi.org/10.5772/intechopen.99765*

conflict between these two is also exist with the side effects profile of both enantiomers related to dissociation, psychoses and cognition [26]. Reports suggest the rapid onset of antidepressant effects with R-ketamine but higher side effects than esketamine [27–34]. Ketamine undergo metabolism through CYP2B6- and CYP3A4 mediated N-demethylation resulting norketamine which further catabolized into hydroxynorketamines (HNKs) and dehyronorketamine (**Figure 1**). Investigations was also carried out on metabolites of ketamine. 2R,6R-HNK has been observed to have antidepressant like efficacy with nil side effects on rat models while several contradictory reports are also available [35–43]. Specifically, metabolite of esketamine i.e. S-norketamine showed antidepressant like properties with lesser side effects as with esketamine [44]. When talk about bioavailability, ketamine has varying bioavailability profile with different routes i.e. 100% with intravenous, 45% with intranasal, 30% with sublingual, 20% with oral, 93% with intramuscular while 30% with rectal route [24, 30, 44].

### **3. Overview of the status of clinical trials with ketamine and its enantiomers**

Report on antidepressant efficacy of ketamine by Berman group in 2000 [9] initiated series of studies related to antidepressant activity of ketamine all around the globe. Multiple meta-analysis now established the candidature of ketamine against major depressive episodes in both bipolar as well as unipolar depression while efficacy was higher in unipolar as compared to bipolar depression [45–50]. In addition to this, numerous studies reported its effect last up to a week only for unipolar while it is up to 3–4 days in case of bipolar depression [46, 47, 49]. Randomized Controlled trials (RCT) exist in which effect of repeated infusions of ketamine for depression is studied but there is still lack of long term trial [51–53]. Studies on different routes of administration were also conducted that majorly include intranasal, sublingual and intramuscular [54–57]. In fact intranasal esketaminerecently got FDA clearance for TRD which was based on three acute-phase and two maintenance phase studies. These acute studies were conducted on severely depressed patients [58]. Maintenance trials were conducted up to 88 weeks where patient was administered esketamine weekly or every second week showcase reduced after relapse risk and also assured safety up to a year [59, 60]. A phase three trial consisted of 200 patients suggest the significant improvements in depression with ketamine adjuvant to an antidepressant [61]. There is another 5 year ongoing trial by Janssen for safety [62]. Keeping in view the antidepressant efficacy if R-ketamine, a phase I trial was started by Perception Pharmaceuticals but results are not processed yet [28].

## **4. Mechanistic insight into the antidepressant activity of ketamine**

#### **4.1 AMPA, BDNF and mTOR**

Glutamate is one of the major excitatory neurotransmitters in central nervous system of human body that mainly acts on NMDA, ionotropic α-amino-3 hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (co-localized with NMDA) and metabotropic glutamate receptors. Glutamate activates AMPA receptors at synaptic cleft, which permit the entry of sodium ions into postsynaptic membrane. Entry of sodium ions results in depolarization of postsynaptic membrane that cause removal of NMDA receptor channel voltage-dependent magnesium ion block that activate NMDA receptor which allow the entry of

sodium as well as calcium ions. Ketamine is a well-established non-competitive type NMDA receptor antagonist. Brain-derived neurotrophic factor (BDNF) and mTOR are two major proteins that are suspected to be involved in mechanistic window of ketamine. BDNF is a growth factor protein in central nervous system that promote neurogenesis and synaptogenesis along with support in survival of existing neurons. On the other hand, mTOR is suggested to have major role in neuronal development and circuit formation. mTOR further made two sub complexes known as mTOR complex 1 (mTORC1) and mTOR, from which mTORC1 is a target of ketamine [63, 64].

It has been observe that glutamatergic neurotransmission is deregulated in MDD and enhanced levels of glutamate levels in serum and plasma were observed in patient's dealing with MDD that why plasma glutamate levels are directly correlated with severity of depression [65–68]. Enhanced glutamate cause by loss of glial cells in MDD increases extra synaptic glutamate levels that suppressglutamatergic neurotransmission via activation of metabotropic glutamate receptor 2 (mGluR2) autoreceptors. A study suggest that change in depression symptoms by non-ketamine NMDA receptor antagonists like traxoprodil, lanicemine and rapastinel was much lower ass compared to ketamine [34, 69–71]. Ketamine good antagonistic activity for NMDA receptors present on γ-aminobutyric acid (GABA) that prevent activation of GABA interneurons resulting in downstream disinhibition of glutamatergic neurons that cause glutamate surge. Elevated levels of glutamate initiates activation of postsynaptic AMPA receptors that potentiate BDNF andmTORC1 signaling pathways. Ketamine demonstrated activate glutamate release and transmission in rat prefrontal cortex (RPC) [72]. Ketamine was also observed to enhance AMPA-evoked electrophysiological responses in the rat hippocampus and medial PFC pointing toward the involvement of ketamine in AMPA receptor transmission [73–77]. In a mouse model, ketamine was observed to increase the expression levels of two subunits of AMPA receptor known as GluA1 and GluA2 [34, 78].

Increased levels of BDNF and mTOR in rat hippocampus were observed within 30 minutes of treatment with ketamine [73, 79, 80]. Important to mention here that analgesic tramadol enhanced the effect of ketamine on force swim test along with upregulation of mTOR in the PFC and hippocampus of rat [81]. It is interesting to observe that increased BDNF and mTOR levels in hippocampal and RFC are controlled by AMPA because in a study treatment with AMPA receptor antagonist increased forced-swim test immobility time with reduced levels of BDNF and mTOR while with agonist immobility time reduced along with increased levels of both BDNF and mTOR [82]. Reports were also observed that suggest the nullification of antidepressant activity of ketamine with pre-treatment of rapamycin an mTORC1 inhibitor [83].

Numerous reports are present in the literature suggesting the possibility of ketamine's antidepressant activity via BDNF. No antidepressant activity was observed on treatment of ketamine in genetically modified mice lacking BDNF [73]. It is proposed that antagonism of NMDA through ketamine deactivates the eukaryotic elongation of factor 2 (eEF2) kinase that de-supress the translation of BDNF. Mice having Val66Met single-nucleotide polymorphism in BDNF gene showed impairment in BDNF release and mRNA trafficking. Administration of ketamine in these mice showed reduced antidepressant activity [84]. Reversal of anhedonicbehaviour with ketamine was observed in rats with chronic mild stress along with complete restoration of dendritic atrophy and dendritiv BDNF mRNA trafficking [85]. In social defeat stress model of mice, ketamine lessen reduction in BDNF, spine density of dendrites, synaptogenesis markers (GluA1 and PSD-95) in PFC, CA3 and dentate gyrus region of hippocampus at 8th day of treatment [86]. Elevated levels of BDNF were supposed to be associated with the lower severity

*Emergence of Ketamine as a Rapid Acting Antidepressant: Mechanistic Insights and Future… DOI: http://dx.doi.org/10.5772/intechopen.99765*

#### **Figure 2.**

*Flow diagram of antidepressant activity of ketamine. (1) ketamine binds with N-methyl-d-aspartate receptors (NMDARs) and reduce excitability of* γ*-aminobutyric acid (GABA) ergic interneurons that results, (2) noninhibition of glutamatergic neurons, (3) that further increase glutamate release which binds with* α*-amino-3 hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors resulting inflow of sodium and calcium into cell, (4) cause activation of voltage gated calcium channels, (5) that further triggers the release of brain-derived neurotrophic factor (BDNF) into glutamate synapse. (6) BDNF from synapse binds with tropomyosin receptor kinase B (TrkB) resulting activation of MEK–ERK and PI3K-Akt signaling cascades that converge on to mTOR lead to (7) increased synaptic protein translation. (8) increased proteins in synapse lead to increased AMPAR-mediated synaptic transmission causing elevated synaptogenesis. All these events are hypothesized to restore disrupted connectivity between key brain regions and can be the possible reason of rapid and sustained antidepressant action of ketamine.*

of depression like symptoms on rating scale [87, 88]. A study carried out on three depressed patients, suggest their response to ketamine and have increased levels of plasma mTOR expression and eEF2 phosphorylaton [89]. It is worth to note that in a trial conducted on 20 patients, pre-treatment with rapamycin tripled the response rate after 2 weeks from treatment thus may be due to targeting of rapamycin on neuroinflammation through its immunisupressant activity or may be due to promotion of haemostatsis of synaptic density (**Figure 2**) [90].

#### **4.2 D-serine**

D-serine is a potential co-agonist at NMDA receptor which is a possible biomarker in depression. Numerous studies highlighted the abnormality of D-serine levels in depression highlighting the antidepressant properties of D-serine [91–95]. Ketamine was found to inhibitor the transport of D-serine while ketamine metabolites were observed to decrease intracellular (PC-12 cells) concentrations of D-serine thus increasing plasma D-serine levels which is possible prediction related to its to antidepressant action [96–99].

#### **4.3 Opioid system**

Ketamine also have capability to bind with opioid receptors (mu, delta and kappa), monoaminergic receptors and transporters, and muscarinic and nicotinic cholinergic receptors [100]. Proposition is made that anti-suicidal as well as antidepressant actions of ketamine is related to the opioid system which is confirmed from the pre-treatment of naltrexone after that antidepressant effect was attenuated in patients [100, 101]. However many discrepancies are also exist along with [102, 103] because buprenorphine and methadone both are agonists to the opioid receptors and does not have any effect on antidepressant properties of ketamine [103]. These results rebels the role of opioid system in ketamine's antidepressant effects. Thus role of opioid in ketamine's antidepressant effects is yet unclear and controversial.

#### **5. Future trends**

With unique mechanism of action as compared to traditional antidepressants along with anti-suicidal properties, ketamine successfully attracted the researchers and physiologists toward itself in last two decades. However large mechanism of actions are still need to uncover thus it will be continue to be a hot topic and active area of research in psychiatry. There if a dire need to investigate the appropriate safety to efficacy ration of ketamine in depression therapy along with establishment of appropriate regimens for maintenance of therapy and discontinuation too. Reliable biomarkers are also needed to properly predict the response and adverse effects of ketamine. Numerous reports are also present in literature that caution the utilization of ketamine as an antidepressant in clinical practice [76, 104–108]. Keeping these thing apart, currently ketamine is emerging as a promising approach for treatment of patients suffering from TRD. Ketamine and its related neurochemical biomarkers can act as leads for development of future antidepressants.

#### **6. Conclusion**

Rapid antidepressant effect of ketamine depression therapy and important discovery in depression research. Its efficacy against TRD and anti-suicidal potential is a boon in depression research but at the same time its negative side effects and potential for being abuse is not to be neglected. However pathways like BDNF, mTOR, AMPA along D-serine and opioid receptors provided sufficient understanding but large portion of its mechanisms are still need to uncover. Even some studies create conflict to each other which is needed to be resolved. Overall analysis suggest that there is an important need to discover all aspects of ketamine in depression therapy to efficient use of this drug as an antidepressant in clinical practice. Moreover, ketamine can act as a lead for the development of new class of rapidly acting future antidepressant agents.

#### **Acknowledgements**

The authors are also thankful to Guru Nanak Dev University, Amritsar for providing various facilities to carry out the work.

#### **Conflict of interest**

The authors declare no conflict of interest.

*Emergence of Ketamine as a Rapid Acting Antidepressant: Mechanistic Insights and Future… DOI: http://dx.doi.org/10.5772/intechopen.99765*

## **Author details**

Atamjit Singh1 and Preet Mohinder Singh Bedi1,2\*

1 Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, India

2 Drug and Pollution Testing Laboratory, Guru Nanak Dev University, Amritsar, Punjab, India

\*Address all correspondence to: preet.pharma@gndu.ac.in

© 2021 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 11**

## Perspective Chapter: Ketamine, Depression, and Gender Bias

*Tahani K. Alshammari, Sarah Alseraye, Nouf M. Alrasheed, Anfal F. Bin Dayel, Asma S. Alonazi, Jawza F. Al Sabhan and Musaad A. Alshammari*

## **Abstract**

Our knowledge regarding pathological and treatment resistance mechanisms involved in depression is far from understood. Sexual dimorphism in this topic is well acknowledged. However, the need to highlight sex-based discrepancies is unmet. Ketamine, the dissociative anesthetic, has emerged as a rapid antidepressant. This chapter reviewed sexual dimorphism in pharmacological and genetic models of depression, emphasizing ketamine-related antidepressant effects. Aiming by this report, we would extend our knowledge, highlight gender as one of the vital factors in examining depression in preclinical studies, and elucidate complex antidepressant effects associated with ketamine administration. Our central goal is to encourage neuroscientists to consider gender in their studies of mood disorders.

**Keywords:** ketamine, depression, sexual dimorphism, ketamine isomers

#### **1. Introduction**

The physiological and pharmacological applications of Ketamine's evolved historically. In the mid-1950s, it was initially introduced as an anesthetic agent, and it was short-acting with better post-operational effects compared to phencyclidine. Phencyclidine by itself is linked to multiple undesirable effects, including severe and prolonged post-surgery hallucinations, agitation, and delirium that made it undesirable for human use [1, 2]. Functionally, ketamine is a safer derivative of phencyclidine [3]. Both are psychoactive arylcyclohexamines agents, a unified feature of these compounds is their molecular antagonism of the N-methyl-daspartate (NMDA) receptor [4]. Ketamine lacks the complete unconsciousness state and is characterized by catatonia, catalepsy, and amnesia [3]. However, ketamine still retains some adverse events, such as abuse potentials and dissociative effects, and neurotoxicity when administered through the spinal cord.

In the seventies, the Food and Drug Administration (FDA) approved ketamine, and it became commercially available as a rapid and short-acting anesthetic agent [3]. Among other anesthetics, ketamine is characterized by a more significant safety, which makes it advantageous compared to other anesthetics. On the level of circuitry, as an agent, it does not elevate the blood pressure. Additionally, physiologically, it is not linked to respiratory depression in both intravenous doses of 1–2 mg/ kg or intramuscular doses of 4–11 mg/kg [3, 5]. At subanesthetic doses, ketamine

exhibited an analgesic effect and can be clinically used in numerous conditions associated with pain in a mechanism similar to opioids but with less respiratory depressive effects [3]. Overall, high-priced patient-monitoring tools and equipment are not necessary for clinical applications of ketamine. Thus, it is a good anesthetic of choice, especially in the middle- and low-income countries. Due to the fact ketamine, clinical applications were indispensable. It has been listed on the World Health Organization (WHO) Essential Medicines List since 1985 [6]. Also, ketamine was reported sedation in individuals with severe behavioral disturbances in clinical settings. In some cases, agitated patients may require police interference to handle them, and in comparison, to the standard sedative induction protocol, ketamine was found to be effective in parenteral relatively low doses (about 5 mg/kg) [7].

The chronic use of ketamine is linked to abuse liabilities and issues with the urinary tract system [8]. The illicit use of ketamine is well-acknowledged. However, ketamine overdose is not a common event. According to the recommendations of the WHO Expert Committee on Drug Dependence in 2016, ketamine should not be listed in the international drug control conventions [6].

In general, multiple uncovered potential novel uses of ketamine were identified including the neuroprotective effect of ketamine and its use in the management of epilepsy, chronic pain, migraine, inflammation, and tumors. Interestingly, in the past few years (the 2000s), ketamine has progressively received increased attention, and there has been significant research into the potential use of ketamine as an expeditiously acting treatment for MDD, treatment-resistant depression (TRD), and suicidality [6, 9]. Intranasal (S)-ketamine has recently been approved for depression by the FDA [10]. However, it is currently too expensive for the widespread use and is unlikely to be cost-effective for the management of TRD in the United States unless its price falls by more than 40% [11].

The chemical basis of ketamine is a similar composition of a racemic mixture, in a ratio of 1:1. This mixture is composed of arketamine (R-ketamine) and esketamine (S-ketamine) [12]. Functionally, these enantiomers are different. In the mid-eighties, white and his colleagues [13] conducted the first comparative study to examine the clinical differences between ketamine isomers using the electroencephalographic monitoring of brain activity in healthy volunteers. They observed that the arketamine exhibited less hypnotic and analgesic effects compared to the esketamine. The arketamine was associated with a faster recovery rate, regarded as the reduced central nervous system depressant effects [13]. Subsequent studies reported more functional and pharmacological differences. For example, the esketamine has greater potency toward the NMDA receptors (as an antagonist), and thus it is pharmacologically more active than the R-ketamine. Additionally, the arketamine exhibits higher potency toward the μ-opioid receptor (an agonist) [14].

In clinical settings, the esketamine was found to be as twice as potent in anesthetic effect compared to the racemic mixture and as threefold potent compared to arketamine [3, 14]. Furthermore, esketamine is described as the less psychotomimetic and the greater analgesic enantiomer. In comparison to arketamine the esketamine is linked to reduced clinically significant side effects such as drowsiness, fatigue, and altered cognitive function [14]. In another clinical study, they examined the recovery effects of both isomers. One hour following the intravenous administration of ketamine isomers, individuals who received the esketamine exhibited better concentration and memory retention [15]. Accordingly, in analgesic and anesthetic applications, esketamine is more favored [14].

Besides, they exhibit neuroprotective differences. In primary cultured rat hippocampal neurons, the esketamine exerts neuroprotective effects. It prevents the release of arachidonic acid and modulates axonal outgrowth measured by the expression of microtubule-associated protein at different time points [16].


#### **Table 1.**

*The main differences between ketamine isomers.*

Interestingly, even if the potency is comparable among the isomers, the molecular mechanism may differ. In guinea pig histamine-mediated preconstricted strips, both isomers were found to mediate spasmolytic effects. Even though their potency was similar, the mechanism was quite different. The esketamine exerts more effects through adrenaline signaling, whereas arketamine spasmolytic modulation was through calcium signaling [17].

Preclinical evidence using various depression animal models suggests the potential antidepressant advantages of arketamine over esketamine. Despite the lower affinity of arketamine, NMDA receptors exhibited superior potency and more prolonged antidepressant effects than esketamine. For that reason, other molecular targets may play an essential role in mediating ketamine antidepressant effects [10, 18]. Importantly, arketamine also has fewer side effects than either (R, S)-ketamine or esketamine as it may not induce psychotomimetic side effects or exhibit abuse potential in rodents and monkeys [11, 14, 19].

A previous report examined the enantiomers' molecular targets selectivity and potency. Their impact on multiple neurotransmitter systems revealed that both isomers have similar effects. They increased the release of serotonin, dopamine, and noradrenaline neurotransmitters. The magnitude of their effects was quite different [18]. Arketamine showed a significant impact on the release of serotonin than esketamine. At the same time, esketamine increases dopamine release more than arketamine [19]. **Table 1** summarizes the main differences between ketamine isomers.

#### **2. Ketamine, the antidepressant**

Major depressive disorder (MDD) places a considerable burden on the community [22]. Among mood disorders, MDD is a common one, and it is considered one of the debilitating psychiatric disorders. Commonly prescribed antidepressants are of limited efficacy and take weeks to months to yield full therapeutic effects [21]. Most existing treatments have been found by serendipity. However, there are several limitations. First, the response to antidepressants is relatively heterogeneous; in fact, a considerable number of patients do not respond well to the treatment, the TRD [23]. An additional challenge is to distinguish TRD from inadequately treated depression [24]. Furthermore, differences are exhibited in patients' pharmacokinetic and pharmacodynamics characteristics, which could be a key reason for the discrepancy

in sex-related efficacy [25]. Moreover, most drugs are intolerable [26, 27], frequent, and enduring [28]. For these reasons, there is a need to identify and develop effective and ideal antidepressant agents.

Recently, Ketamine gained a lot of attention in its fast-onset and effectiveness when applied to depressed patients. Overall, the ketamine efficacy was successfully recorded in severely depressed patients using different validated rating scales [14]. In early 2000, Berman and his colleagues recorded the fast, moderately persistent, and robust pharmacological effects in depressed patients [29]. The double-blinded trial showed that depressed patients were significantly improved 3 days following the ketamine administration, which opened a new avenue in the management of MDD. Over the last 20 years, studies have indicated the antidepressant properties of ketamine. As an antidepressant agent, it functions in quite different mechanisms and onset than conventional antidepressant agents. Of particular interest, it brings an antidepressant effect in patients with refractory depression [30].

The central nervous system pharmacological targets of ketamine are diverse and ubiquitous. One of the main pharmacological targets for ketamine is the excitatory NMDA receptors. It is believed that ketamine mediates the anesthetic and analgesic effects through the direct noncompetitive NMDA receptors antagonist. It stimulates glutamate release in preclinical [31], and clinical studies [32]. The in vivo magnetic resonance spectroscopy clinical studies indicated that the metabolism of the 13-C-glutamate is elevated in cortical brain regions [33, 34].

Additionally, ketamine act—in lower affinity—molecularly at the inhibitory receptor the γ-aminobutyric acid (GABA) [35]. In fact, a previous report suggested the deficit of both GABAergic and glutamatergic is a unified pathological feature of MDD [36].

The AMPA receptor is another target for ketamine. Functional activation of AMPA receptors is essential for recruiting multiple pathways in modulating ketamine-induced antidepressant effects [37]. Preclinical evidence has found that the activation of AMPA receptor is critical for mediating rapid and sustained ketamine-induced antidepressant effects [38]. Ketamine was reported to elevate the hippocampal expression of AMPA receptor subunits, the glutamate receptor (GluA)1 and 2 subunits [39]. A previous study indicated that the AMPA-mediated Ketamine-induced antidepressant effects involve the glycogen synthase kinase-3 [40]. Electrophysiological studies indicate that AMPA signaling is essential for mediating the ketamine-induced antidepressant effects [38, 41]. A meta-analysis study based on in vivo and ex vivo studies indicated that ketamine elevates the level of dopamine in different brain regions relevant to the pathology of depression, including the frontal cortex, striatum, and nucleus accumbens [42].

Another molecular target for ketamine is opioid signaling. Ketamine was reported to be a weak agonist to opioid receptors isoforms, including the mu, delta, and kappa. Studies indicated that the involvement of the opioid receptor is essential for ketamine-induced antidepressant effects [14, 43].

Additionally, in a double-blind clinical study using suicidality-specific rating scales, naltrexone—an opioid receptor antagonist—was found to weaken the antisuicidality effects of ketamine. Indicating that opioid receptor activation plays a major role in the anti-suicidality effects of ketamine [43].

The dopaminergic, cholinergic, serotonergic, and opioid, receptors are implicated in ketamine-induced antidepressant effects [44]. Furthermore, ketamine acts on the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Moreover, ketamine provides anti-inflammatory activities. It decreases the production of proinflammatory cytokines including the nuclear factor κB, the tumor necrosis factor-α, the interleukin 6 (IL-6), and the inducible nitric oxide synthase [3].

Another molecular target for ketamine is the glucocorticoids pathway. The administration of ketamine was found to stimulate the release of glucocorticoid downstream component, the Serum glucocorticoid kinase 1 (SGK1). Indicating that the pharmacological function of ketamine may recruit the glucocorticoid receptor pathway [45]. **Table 2** describes the primary molecular targets for ketamine-mediated antidepressants effects.


*NMDAR, N-methyl-D'aspartate receptor; AMPAR,* α*-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors; mTORC1, mechanistic target of rapamycin complex 1; eEF2, eukaryotic elongation factor 2; BDNF, brain-derived neurotrophic factor.*

#### **Table 2.**

*The main molecular targets for ketamine-mediated antidepressants effects.*

## **3. Ketamine sexually dimorphic antidepressant effects**

The prevalence of depression is almost twice as high among women as men [46–48]. The clinical symptoms are also more prolonged and severe in women, with a high rate of recurrence compared to men [49]. Additionally, exposure to psychosocial stress is a significant risk factor for stress-related disorders, including depression. Most importantly, the physiological responses to stress are sexually dimorphic [50–52].

One possible explanation for sexually dimorphic stress responses is the locus coeruleus, a brain stem nucleus responsible for most of the noradrenergic system [53]. Triggering the locus coeruleus is a critical component of stress responses. A previous report demonstrated that neuronal populations within the locus coeruleus are substantially sensitive to the corticotropin-releasing factor in female rats compared to males [54]. We previously reported considerable evidence indicating that sexual dimorphism is a confounding factor facing a complete understanding of pathological mechanisms involved in depression and in finding an effective treatment [55].

Multiple studies have reported that ketamine-induced antidepressant effects are exerted in a sexually dimorphic manner. For instance, in a transgenic animal model, the intraperitoneal injection of ketamine exhibited sexually dimorphic molecular changes. It was found to elevate the mRNA level of Bdnf in females [56]. In another example, ketamine exhibited neurobehavioral and neurochemical alterations in a sex-dependent manner. A single sub-anesthetic ketamine dose was found to alter the 5-hydroxyindoleacetic acid to the 5-hydroxytryptamine ratio in the prefrontal cortex of female rats in 24 h post ketamine injection. While performing the forcedswim test in a behavioral setting, female rats exhibited more sensitivity to lower doses of ketamine than male rats [57]. Indicating the profound effects of hormones over the ketamine-mediated antidepressant effects. In line with this, another report found that ketamine-induced antidepressant effects were not observed in ovariectomized rats. Additionally, these effects were functionally observable following the administration of both estrogen and progesterone [58].

Interestingly, the sub-anesthetic ketamine dose was found to exhibit pharmacological dissociative effects in a sexually dimorphic manner. Whereas female rats were more sensitive and developed more significant ataxia in comparison to male rats. Besides, the magnitude of head weaving in female rats during their diestrus phase was more significant compared to females in their other stages of the estrous cycle [59]. Also, pharmacokinetics profiling of ketamine in rats indicated that both ketamine and ketamine-metabolites were presented in higher plasma concentrations in female rats than in males, suggesting the rate of hepatic clearance and metabolism might be affected by female hormones [60].

The effect of ketamine on neuroplasticity markers was examined at the proteomic level in the different brain regions following multiple ketamine bolus doses. Different bolus doses were found to induce the protein expression of c-Fos in the amygdala of female rats, not the male rats. Also, in the prefrontal cortex, this expression was modulated by the estrous cycle [61]. The administration of ketamine in female mice exposed to chronic unpredictable mild stress was reported to be mediated via the extracellular-signal-regulated kinase and glucose transporter 3 (ERK/GLUT3) signaling pathway [62].

The glucose transporter 3 (GLUT3) was found to be essential for modulating neuronal circuitry and metabolic functions [63]. This isoform of glucose transporters is predominantly expressed in neuronal populations [64]. Additionally, glut3 heterozygous mice exhibited seizures, cognitive impairments, and altered sociability behaviors in a sex-dependent manner [65].

On the other hand, ERK signaling is a crucial modulator of physiological roles affected by gender. For instance, a previous report indicated that the ERK pathway *Perspective Chapter: Ketamine, Depression, and Gender Bias DOI: http://dx.doi.org/10.5772/intechopen.103656*

regulates the hypothalamic-pituitary-gonadal axis, and the functional maturation of the female reproduction system in pituitary-targeted ERK knockout mice is altered [66]. In line with this, in a model of psychiatric disorders, the neonatal ventral hippocampal lesion, a validated animal model of schizophrenia, the ERK signaling was reported to function in a sex-dependent manner. In the report, the content, and the phosphorylation level of different components of the ERK signaling was found to be sexually dimorphic [67].

The whole gender-related variable psychological, neurobehavioral, and molecular effects in clinical and preclinical studies are not a characteristic of ketamine alone. Other antidepressants function in a sexual-dimorphism manner. For example, males reported better outcomes than depressed females in response to tricyclic antidepressants, classical antidepressant agents. On the other hand, females exhibited better responses to selective serotonin reuptake inhibitors [68]. Indicating the significant role of gender and the hormonal system in the pathology of depression.

### **4. Organizational and activational hormonal effects**

Whether a depression model is environmental [55], pharmacological, or genetic, organizational, and activational hormonal effects cannot be overlooked. The organizational and activational hypothesis was introduced in the late 1950s [69]. This hypothesis suggests that sex hormones regulate the central nervous system's organization, development, and function. Organizational effects refer to the effect of steroid hormones on the brain during early developmental stages. At the same time, activational effects are lifelong hormonal effects [70].

A review conducted by Arnold [71] proposed a framework for the organizational and activational hypothesis. In his report, this hypothesis's fundamentals include prenatal masculinization, where the prenatal exposure of female guinea pigs to testosterone alters their behavior later on. These females behaved like a male guinea pig. These changes were permanent, which could be mediated by the hormonal effect on neuronal development (the organizational effect), and that indicates the central nervous system's vulnerability during this critical period of development. Overall, this framework supports the notion that steroid hormones' cellular, molecular, and behavioral effects vary [71]. Extensive reports reviewed this hypothesis [71–73]. However, steroidal hormones' activational versus organizational effects have not yet been clearly characterized [74].

#### **5. Conclusions**

Further investigation into sexual dimorphism in the neurobiology of depression is quite essential. This knowledge could potentially improve the diagnosis and treatment of depression and provide a basis for sex-based interventions. These interventions could take into account the pharmacodynamic and pharmacokinetic differences between men and women. It can further consider molecular targets for each gender.

This can be achieved if sex-oriented research on the mechanism of depression in both sexes is conducted at clinical and pre-clinical levels. Despite their limitations, animal models provide a wealth of knowledge on depression neurobiology. This chapter aimed to review existing pre-clinical research on sex differences in the neurobiology of depression and, therefore, to highlight the unmet need to investigate depression with respect to gender as a variable and, most importantly, encourage researchers to establish disease-based studies.

## **Conflict of interest**

The authors declare that there is no conflict of interest.

## **Author details**

Tahani K. Alshammari1 \*, Sarah Alseraye1 , Nouf M. Alrasheed1 , Anfal F. Bin Dayel1 , Asma S. Alonazi1 , Jawza F. Al Sabhan2 and Musaad A. Alshammari1

1 Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia

2 Department of Clinical Pharmacy, King Saud University, Riyadh, Saudi Arabia

\*Address all correspondence to: talshammary@ksu.edu.sa

© 2022 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.

*Perspective Chapter: Ketamine, Depression, and Gender Bias DOI: http://dx.doi.org/10.5772/intechopen.103656*

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## **Chapter 12**

## Ketamine Anesthesia in Electroconvulsive Therapy

*Maiko Satomoto*

#### **Abstract**

Electroconvulsive therapy (ECT) is highly effective both Major Depressive Disorder (MDD) and Bipolar Disorder (BD). Ketamine, an antagonist of the N-Methyl-D-aspartate receptor, has been described to have antidepressant properties. There is a hypothesis that ECT performed with anesthesia using ketamine is more effective than conventional ECT. Also, although ECT is the gold standard for BD and MDD, there are questions about which is more effective, ketamine treatment or ECT, and whether ketamine is more effective when used in combination with ECT. In this chapter, we review the current literature on the effectiveness of ECT and ketamine. Furthermore, we discuss whether ketamine can be an alternative treatment to ECT for patients with TRD.

**Keywords:** ketamine, electroconvulsive therapy, depression, side effect, cognitive impairment

### **1. Introduction**

Major Depressive Disorder (MDD) and Bipolar Disorder (BD) are very popular psychiatric disorders that affect 10–15% of people in their lifetime. If symptoms do not improve during episodes of depression with at least two types of antidepressants, this condition is referred to as Treatment-Resistant Depression (TRD), which is observed in 12–20% of patients with depression [1]. The gold standard treatment for TRD is Electroconvulsive Therapy (ECT) [2]. ECT is a safe and effective treatment for TRD. Data shows that the efficacy rate is 79%, and the remission rate is 75% when ECT is used for patients with MDD [3]. Various oral treatments have been introduced since the 1990s. Tricyclic and tetracyclic antidepressants had emerged by the 1990s, and second-generation antidepressants such as selective serotonin reuptake inhibitors (SSRI) and serotonin-noradrenaline reuptake inhibitors (SNRI) were introduced at the end of the 1990s. Although the cause of depression is not clear, the monoamine hypothesis attributes depression to a decrease in neurotransmitters such as serotonin and noradrenaline, which are monoamines, and the action mechanism of the antidepressants is often explained based on the monoamine hypothesis. SSRI and SNRI have fewer side effects, such as dry mouth and dysuria, compared with tricyclic antidepressants, and internationally, they are recognized as the standard treatment. However, the availability of many antidepressants does not necessarily mean that the drug therapy for depression is adequate. STAR\*D [4], a large-scale clinical trial investigating the efficacy of switching to the next stage of treatment in patients with depression showing inadequate response to antidepressant medication, found that about half of the total population responded

to the initial SSRI treatment, with one-third achieving remission; the response and remission rates decreased with each switch to a different treatment.

Remission has been pointed out to be related to social functioning and prognosis, which is emphasized [5] as a therapeutic goal of depression treatment. According to the results of STAR\*D [4], the cumulative remission rate is approximately 67% when medication is switched thrice. This finding suggests that a certain number of patients do not show an adequate response even after treatment with multiple antidepressants, and the limited efficacy of standard treatments is a clinical problem.

### **2. What is ECT?**

Electroconvulsive therapy (ECT) is a treatment method in which generalized seizure activity is induced in the brain through electrical stimulation, producing neurobiological effects to improve clinical symptoms. The history of ECT can be traced back to 1938 when Cerletti U and Bini L of Italy developed a method to induce seizures by passing an electric current through the brain from the scalp on the head, which was the beginning of ECT. Since then, ECT has spread rapidly. Earlier in ECT, an electric current was passed without pretreatment, such as intravenous anesthesia, causing generalized tonic-clonic seizures, feeling of extreme fear experienced by patients, and side effects such as bone fractures or dislocations due to seizures were the problems posed by the treatment. For this reason, ECT was developed, in the 1950s, to pass an electric current without causing seizures of skeletal muscles by keeping patients on mechanical ventilation and administering a combination of anesthetics and muscle relaxants under the supervision of an anesthesiologist.

### **3. Indications for ECT**

ECT is said to have no absolute contraindications. Relative contraindications include (1) intracranial lesions, (2) increased intracranial pressure, (3) recent myocardial infarction, (4) recent cerebral infarction, (5) unstable aneurysm or vascular malformation, (6) pheochromocytoma, and (7) patients with poor physical condition (physical status of 4 or 5 as per the American Society of Anesthesiologists, i.e., with severe threatening systemic disease or moribund). Although medical history interview (allergies, asthma, and history of surgery), blood biochemical tests, electrocardiogram, chest and abdominal X-rays, head CT, and electroencephalogram are performed and recorded before ECT, an echocardiogram, head MRI, and MRA should also be conducted. The cognitive function should also be evaluated in advance, as postictal delirium and transient cognitive impairment may occur, which are described later. ECT is indicated for psychiatric disorders such as depression, schizophrenia, and mania, and has also been shown to be effective in treating Parkinson's disease, malignant syndromes, and chronic pain. The effectiveness of ECT differs depending on the subtype of schizophrenia. At the same time, the treatment is effective for catatonic and acute onset paranoia cases, and there is little effect in hebephrenic and chronic cases. The primary use of ECT should be considered in the following situations: (1) severe symptoms, such as the high risk of suicide attempt or extreme agitation; (2) general deterioration of the patient's condition due to psychiatric symptoms, such as refusing food or catatonic condition; (3) high risk of other forms of treatment, such as in the case of elderly patients or pregnant women; (4) history of ECT treatment with a favorable response; and

(5) preference of the patient. The secondary use of ECT may be considered when the patient is resistant to drug therapy or the patient's tolerability to drug therapy is poor. The indication for ECT is determined based on a combination of diagnosis, symptom type, severity, treatment history, consideration of the expected risks and benefits of ECT with other treatments, and patient's preference.

## **4. Side effects of ECT**

The most common side effects of ECT are postictal delirium and transient cognitive impairment. However, the stimulation dose can be adjusted according to the seizure threshold of each patient by using pulse wave therapy devices, which has significantly reduced seizures compared with conventional treatments. Although the parasympathetic nervous system is dominant immediately after an electric current is passed during ECT, the sympathetic nervous system subsequently becomes dominant. Therefore, bradycardia and sinus arrest may temporarily occur early on. Thereafter, tachycardia and elevated blood pressure are observed, and ventricular arrhythmias may also occur. Although tachycardia and elevated blood pressure are transient, patients with a history of hypertension or ischemic heart disease should be intravenously administered antihypertensive drugs. Even with using muscle relaxants in ECT, the masseter muscle contracts when an electric current passes and can damage the teeth and oral cavity. Although dentures are removed to prevent this, and a bite block is used, dental treatment may be required before ECT if the teeth shake significantly. Other side effects include headache, myalgia, nausea, and prolonged convulsions. Manic episodes may also occur in bipolar depression.

## **5. Procedure of ECT**

ECT is performed in the operating theater under respiratory and circulatory management by an anesthesiologist. In addition to stimulation electrodes and Electroencephalogram (EEG) electrodes (two channels on the left and right) attached to the forehead, Electrocardiogram (ECG) electrodes and Electromyography (EMG) electrodes (on the dorsum of one foot) are attached, the vital signs of the patient are checked, and intravenous anesthesia is administered. When the patient falls asleep, the blood flow to the lower leg with the EMG electrodes is restricted by applying a pressure equal to or more than the systolic blood pressure using the manchette of a sphygmomanometer and a muscle relaxant is administered intravenously. After muscle relaxation is confirmed, a bite block is inserted in the patient's mouth. After passing an electric current, tonic-clonic seizures are observed only in the lower leg with restricted blood flow. The bag-valve-mask ventilation is used when the patient falls asleep until it is confirmed that the patient has resumed spontaneous breathing. The vital signs are rechecked after the patient is fully awake and taken out from the operating theater. Even after returning to the ward, a monitor is attached to the patient for around 1 hour to check the vital signs. This procedure is performed 2–3 times a week, for a total of 8–12 times.

## **6. Drugs commonly used in ECT**

Short-acting intravenous anesthetics are used. Propofol and thiopental are commonly used. The higher the dose of the anesthetic drug, the less likely that seizures will occur; hence, the minimum dose of the intravenous anesthetic drug that puts

the patient to sleep is administered. The muscle relaxant used is succinylcholine, which is a depolarizing muscle relaxant. Although non-depolarizing muscle relaxants may also be used to reduce myalgia and increased intragastric pressure, their long duration of action may lead to problems such as the need for a muscle relaxant antagonist [6] after ECT and residual muscle relaxation. Anesthesiologists are also aware that hyperventilation can lead to seizures.

#### **7. Information on ketamine**

Although ketamine is an old N-methyl-D-aspartate (NMDA) receptor antagonist, in recent years, the use of subanesthetic doses of ketamine as a therapeutic agent has been reported to have antidepressant effects. Some reports indicate remission rates exceeding 80% with the use of low doses of ketamine [7–10]. There have also been reports that the response to seizures was good when used as an adjunct to ECT, so we did a comprehensive study of the reports. Ketamine may be used independently or as an adjunct, in addition to propofol or thiopental.

We have cited reference Jankauskas et al., [11], which includes a summary up to 2017. Most studies show that when ketamine is used independently or in combination with non-barbiturates such as propofol at doses of 0.8 mg/kg or more during ECT, there is a faster improvement in symptoms and a significant improvement in depressive symptoms compared with the control group where ketamine is not used [12–16]. Seizures during ECT are longer in the intravenous anesthesia group with ketamine or ketamine alone than the intravenous anesthesia group without ketamine [14, 17, 18]. Ketamine was observed to significantly improve cognitive function in the original cases of cognitive decline [14]. Some results show a faster recovery in the ketamine group even if there is no change in the outcome [14, 19].

On the other hand, even if ketamine prolongs the duration of seizures, according to some reports, ketamine is not better than other anesthetics in reducing depressive symptoms or improving cognition [16, 20–23]. The effect of ketamine on the duration of seizures during ECT has been evaluated differently in each study, and the ECT protocols vary from institution to institution making efficacy assessment difficult [11]. The additional problem is that the assessment items (seizure duration, early stage of rapport, or cognitive improvement) do not match.

Since propofol suppresses the disadvantages of ketamine such as agitation, cardiotoxicity, nausea, and psychotomimetic effects, the combination of propofol and ketamine is good as propofol suppresses the disadvantages of ketamine without compromising its efficacy [13, 17]. Ketamine also reduces hypotension, a side effect of propofol, another reason for considering the combination as good [17]. Many reports indicate that the benefits of ketamine are not effective when used in combination with barbiturates due to the anti-seizure action of barbiturates and did not show a reduction effect for depression [12, 16, 20, 24].

Safety concerns with ECT include high rates of hypertension, prolonged QTc interval, transient arrhythmias, confusion or fear, and hallucinations that may occur upon awakening from the anesthetic [12, 13, 17, 20, 25–27]. The incidence of hallucinations has a positive correlation with the increase in ketamine dose, especially in the dose range of 0.8–2.0 mg/kg [13, 17, 20, 25–27]. Caution should be exercised when using ketamine in patients with cardiovascular diseases, as the drug increases blood pressure. Caution should also be exercised when using ketamine in patients with a history of psychomimetic episodes, as there is a possibility of psychotogenesis.

Concomitant use of propofol may be considered to mitigate some of these adverse effects [13]. However, the complexity and cost of the medication will increase. Most of the adverse effects such as agitation, cardiotoxicity, nausea, and psychotomimetic effects are temporary [12, 16]. Therefore, an analysis of individual risks and benefits needs to be considered.

## **8. Role of ketamine in ECT in recent years**

Although studies of varying scales and assessment have continued, some studies have found the addition of ketamine to ECT to be effective [28, 29], and some have found the addition as not effective [30]. We will introduce one such study. A multi-site randomized, placebo-controlled, double-blind trial, "Ketamine-ECT study" was planned at the University of Newcastle in the United Kingdom to investigate whether the adjunctive use of ketamine can attenuate the cognitive impairment caused by ECT [31]. ECT continues to be the gold standard for severe and treatment-resistant depression. However, a significant limitation contributing to the declining use of ECT is its association with cognitive impairment, especially in anterograde and retrograde memory and functional impairment.

On the other hand, preliminary data suggest that ketamine, used either as the sole anesthetic drug or in addition to other anesthetics, may reduce or prevent cognitive impairment after ECT. A hypothesis has been postulated that ketamine protects from excess excitatory neurotransmitter stimulation during ECT through glutamate receptor antagonism. The primary aim of the "ketamine-ECT study" was to investigate whether the adjunctive use of ketamine can attenuate the cognitive impairment caused by ECT. The secondary aim was to examine if ketamine increases the speed of clinical improvement with ECT. The summary of the study is that moderately to severely depressed patients who had been prescribed ECT were randomly grouped on a 1:1 basis to receive either adjunctive ketamine or saline in addition to standard anesthesia for ECT. A 0.5 mg/kg dose of ketamine was administered as a bolus instead of continuous administration. The primary neuropsychological outcome is anterograde verbal memory (Hopkins Verbal Learning Test-Revised delayed recall task) after four ECT treatments. Secondary cognitive outcomes include verbal fluency, autobiographical memory, visuospatial memory, and digitization span. Efficacy was assessed using evaluation by observer and report of subjects on the depressive symptoms by patients.

This randomized trial validated the hypothesis that low doses of ketamine administered with a course of ECT treatment would improve outcomes in depression. We did not find significant evidence for cognitive and efficacy outcomes by administering a dose of 0.5 mg/kg ketamine as an adjunct in patients treated with ECT for depression.

However, the number of subjects was less than the number of patients recruited, which implies that the small to medium benefits and medium to extensive harms of ketamine cannot be ruled out. Therefore, it is not always possible to conclude based on only these results. It is also debated that evaluation in this field is complicated, especially the evaluation of cognitive function after ECT. For example, although patients recover most of the cognitive decline after ECT within a few days to a few weeks after the completion of treatment, it is challenging to accurately measure the recovery of retrograde autobiographical memory, which is the primary concern for patients. Although this paper has been discussed extensively, the study did not indicate that ketamine improved the outcome of depression. However, since treatment-resistant depression still exists and some papers have shown that ketamine is effective, we believe it is worth continuing research by evaluating various subgroups or using an optimal psychological index to determine the efficacy.

### **9. Future of ketamine in ECT**

As introduced in Section 8, there are more than 130 papers on the adjunctive use of ketamine with ECT; however, only a few are definitive. Although well-conceived studies with sufficient resources are needed, they are not conducted, and the availability of funding is also not likely. Many papers have recognized the efficacy of ketamine with small-scale studies. ECT is an effective treatment method in clinical practice since patients showing resistance to treatment with only oral medication are high at 33%. Memory impairment caused by ECT is a significant problem faced by patients. The condition of patients with depression before ECT treatment varies widely; hence, it is necessary to divide them into subgroups. If there is a possibility that ECT can improve cognitive impairment, we consider that further studies are needed to evaluate the effects of ketamine by dividing patients into more specific subgroups.

### **10. Ketamine as an alternative to ECT**

As described in Section 8, the decline in cognitive function after the ECT procedure causes significant distress to patients [32]. Unfortunately, additional ECT is sometimes required due to the frequent recurrence of TRD. The recurrence rate of TRD within 6 months of ECT is reported to be between 39% (with continued medication) and 84% (without continued medication) [33]. If patients become aware of their cognitive impairment even once, ECT treatment becomes unbearably painful for them [33]. There is a pressing need to develop a treatment with the same effectiveness as ECT but with fewer side effects and recurrences. Ketamine, an NMDA receptor antagonist, has repeatedly shown an immediate and strong antidepressant effect in patients with MDD [34, 35]. Ketamine demonstrates a positive effect even in patients with severe TRD [36]. Whether ketamine can be an alternative treatment to ECT for patients with TRD is discussed in this section. There are six papers at present [37]. While randomized control trials [38–40] are discussed in three papers, the other three cover open-label trials [41–43]. The results suggest that ketamine therapy develops antidepressant effects more quickly than ECT, but perhaps the effect is not sustained compared with ECT. Unlike ECT, cognitive impairment was found to be less with ketamine therapy. The sample size of the studies was limited, followed different treatment protocols, and long-term follow-up was lacking in most trials. The occurrence of assignment bias is high as the trials were not randomized, and performing ECT and ketamine therapy in double-blind trials is difficult. The results of the current studies do not provide convincing evidence to indicate that ketamine therapy is an equally effective alternative to ECT for patients with TRD. If ketamine is used in high doses for chronic cases because of its advantages over ECT during treatment at the initial stage, it may cause memory impairment [44]. Long-term maintenance therapy with ketamine may make patients prone to ketamine-related addiction. This risk should be considered when comparing ketamine therapy to ECT. The reported acute side effects of ketamine therapy are dizziness, headache, blurred vision, body numbness, depersonalization, vertigo, double vision, and nausea. The reasons for discontinuing ketamine were dissociative symptoms, hypertension, and unpleasant experience. The impact of acute and chronic adverse events attributable to ketamine therapy needs to be compared with the common side effects of ECT treatment, such as cognitive impairment, myalgia, arthralgia, headache, and risks associated with general anesthesia. Studies with larger sample sizes and longer follow-up duration are needed.

## **11. Conclusions**

ECT is still the gold standard for severe and treatment-resistant depression patients, but cognitive dysfunction after ECT is the problem. Although the antidepressant effect of ketamine has been attracting attention in recent years, it cannot be said that ketamine is an effective treatment alternative to ECT at this stage. Many studies have shown that adding small amounts of ketamine during ECT is effective with small-scale studies. Although well-conceived studies with sufficient resources are needed, they are not conducted.

## **Acknowledgements**

This work was supported by Grants-in-Aid for Scientific Research (KAKENHI) Grants No. 19 K18308.

## **Conflict of interest**

The author declares no conflict of interest.

## **Author details**

Maiko Satomoto Department of Anesthesiology, Toho University Omori Medical Center, Tokyo, Japan

\*Address all correspondence to: maiko.satomoto@med.toho-u.ac.jp

© 2021 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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