Perspective Chapter: Ketamine, Depression, and Gender Bias

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.

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-d-aspartate (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].

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.

	Esketamine	Arketamine	References
Potency	This isomer is considered as functionally more potent than the racemic mixture (2× more than the racemic mixture, and 3× more than R-ketamine)	This isomer is a less active one.	[3, 14]
NMDAR antagonizing affinity	Greater affinity	Lower affinity	[20]
μ-Opioid receptor agonism Affinity	Greater affinity	Lower affinity	[20, 21]
Side effects (psychotomimetic, drowsiness, lethargy, and cognitive impairment, and abuse liabilities)	More side effects	less side effects	[12]

Table 1.

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 anti-suicidality 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.

The pathway	Description of the action	The mechanism of actions	References
NMDAR	The disinhibition hypothesis	At subanesthetic doses, ketamine inhibits NMDARs on GABAergic interneurons	[29, 46]
		Leading to alteration in the disinhibition and the overall feedback and feed-forward mechanisms.	[47]
		Another consequence, changing the postsynaptic AMPARs activations.	[32, 37]
	Direct inhibition of extra-synaptic NMDARs	Ketamine directly prevents the extra-synaptic GluN2B. Leading to precluding the glutamate-induced activation of glutamatergic receptors. Overall, this would alter protein synthesis	[37]
	Blocking spontaneous NMDAR activation)	On principal cells—at rest—ketamine directly inhibits NMDARs	[32]
		Preventing the tonic activation leading to activation of other pathways such as eEF2 and BDNF signaling	[46]
AMPA receptor	The activation of AMPA receptor	ketamine-induced antidepressant effects are linked to the functional activation of AMPA receptors	[37]
		Preclinical evidence has found that AMPA receptor activation is critical for mediating rapid and sustained ketamine-induced antidepressant effects	[38]
BDNF	The activation of BDNF	Ketamine-induced behavioral antidepressant effects are mediated through BDNF release in hippocampal primary neuronal cultures	[48]
		Ketamine-induced cellular effects through BDNF release in rats.	[49]
		In a clinical setting, the level of plasma BDNF in treatment-resistant depressed patients correlates with the infused level of ketamine.	[50]
eEF2	The inhibition of eEF2	The ketamine glutamatergic-mediated mechanisms reduce eEF2 kinase activation, leading to alterations in synaptic plasticity	[32]
Monoamines	Increases monoamines levels	Ketamine prevents serotonin reuptake	[29]
		Ketamine prevents dopamine reuptake	[51]
		Ketamine prevents norepinephrine reuptake
Opioid system	Opioid agonism	Weak agonistic effects are mediated toward multiple isoforms of opioid receptors, including the mu, delta, and kappa	[14]
		Multiple studies indicated that activation of the opioid receptor is essential for ketamine-induced antidepressant effects	[51]

Table 2.

The main 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.

3. Ketamine sexually dimorphic antidepressant effects

The prevalence of depression is almost twice as high among women as men [46, 47, 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, 51, 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 forced-swim 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 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, 72, 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.