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Ketamine’s Cinquecento

by Laura Mittelman

art by Mina Kamara

Ketamine is currently piloting a shift in clinical advancements for the treatment of depression. In 2019, the FDA approved Spravato, a nasal spray drug containing esketamine, a derivative of ketamine, for treatment-resistant depression and acute suicidality [1]. Spravato hit the market as the first new medication for treatment-resistant depression (TRD), marking a major advancement in clinical psychiatry and for ketamine’s recognition as a useful alternative to current treatments for depression [2]. Spravato’s inauguration points to a recent wave of hope for ketamine and other novel treatments for a variety of mental health issues. The renaissance of esketamine has shown the world of clinical psychiatry that it might be possible to allocate attention to different brain systems, targeting them in depression research and therapy. Esketamine has even shown that, in the future, there is potential for medicine that might help patients who experience extreme depression and are at imminent risk for suicide [1]. There is a glimpse of hope that the ongoing mental health crisis in the United States can change for the better, and that more treatment options can become available to help the lives of many individuals struggling with mental illness.


A Trip Down Ketamine Lane

Initially known for its anesthetic properties, ketamine originally occupied a corner in the pharmaceutical reservoir of anesthesiologists and clinicians treating pain [3]. After its arrival on the hospital scene in 1970, it gained notability for its unique coalescence of hypnotic (sleep-inducing), analgesic (pain-relieving), and amnesic (short-term memory loss) effects, a combination of which no other anesthetic drug could produce [3]. The remarkable properties of ketamine allow it to boast a long shelf life, the ability to keep in various environmental extremes, be cost-effective, and a fast-action sedative [4]. It was notably used as the primary anesthetic for soldiers during the Vietnam War because of its rapid onset and safe administration in medical settings. These marked characteristics, which proved highly advantageous on the front lines of war, lead to Ketamine’s appearance on the U.S. Special Operations Command Tactical Trauma Protocols in 2008 [4]. Hence, Ketamine first gained its reputation as a reliable anesthetic, marking the first period in its journey through a modern-day renaissance.

Meanwhile, however, ketamine’s mind-altering effects were being rediscovered at home. Beginning in the 1980s, ketamine hit the party scene as ‘Special K’ and became popular within rave and club cultures due to its hallucinogenic properties [5]. Nonetheless, a negative stigma around the recreational use of the drug began to develop after people discovered its adverse effects, which include slurred speech, confusion, and risk of losing consciousness [5, 6]. Similarly, the popularization of ketamine as a party drug also contributed to its stigmatization. Media outlets perpetuated this reputation by amplifying ketamine’s negative side effects, and placing its potential for addiction under scrutiny [6]. The Drug Enforcement Administration (DEA) registered ketamine as a Schedule III controlled non-narcotic substance due to its “moderate-to-low potential for physical and psychological dependence” [7]. However, since its official scheduling, ketamine has emerged on the fringes of medical science. Ketamine’s identity as a restricted substance could present itself as a burden to research and perpetuate its past stigmas within the field.


Ketamine’s Modern Renaissance

Fast-forwarding to present day, ketamine has coursed through periods of worldwide anesthetic use and club-drug abuse before making its way into the third period of its renaissance. Ketamine is currently making its debut in the field of clinical psychiatry due to its remarkable potential to help treat persistent cases of major depressive disorder (MDD) [8]. Research findings on ketamine’s ability to lift a clinically depressed patient’s mood within hours first began to surface in the early 2000s, and ketamine since then has both grown in promise and popularity, animating researchers who had been seeking new ways to treat severe cases of depression that were not responding to traditional treatments [9]. Now, with the explosion of research and recent findings on the potential of ketamine and approval of Spravato, a medicine containing esketamine, ketamine clinics are beginning to pop up around the country, as the buzz around the drug continues to grow louder [10].

However, ketamine’s growing clinical prevalence is amplifying potential safety concerns, which are further reinforced by stigmatizations prevailing from its previous era as a club drug [6]. Thus, fear of judgment surrounding the clinical usage of ketamine could pose a significant barrier to its assimilation into clinical practice. In the meantime, experts urge cautious regulation of the clinical use of ketamine while more research is done to assess its safety as a depression therapy and establish appropriate administration guidelines for the medication [11].


The Details of Depression

For years, scientists have been grappling ​​with understanding the underlying biological mechanisms of depression [12]. Depression is a complex condition that presents very differently among individuals and lacks a streamlined model of its underlying biology [13].

Thus, researchers have focused on depression at its most basic level in the brain and are striving to understand the neurochemical brain processes fundamentally involved in the disorder [12]. Recently, ketamine's role in the brain's glutamate system has pioneered a redirection to establish a more holistic understanding of depression.

Major depressive disorder is characterized as a mood disorder by the American Psychiatric Association [14]. MDD can be a debilitating condition, causing a depressed mood, feelings of inadequacy, and feelings of hopelessness, which can manifest into harmful internal dialogues marked by self-blaming emotions and self-disgust [15]. Research shows that more than 90 percent of patients diagnosed with MDD experience these symptoms [15]. It’s important to remember that the effects of depression are individualized, and a formal diagnosis for the disorder can only occur after an assessment by a qualified mental healthcare provider [16].

MDD affects nearly 12 percent of adults worldwide, and in the United States, its prevalence is highest among women, adolescents, and the elderly [17]. In 2020, an estimated 14.8 million U.S. adults experienced at least one major depressive episode that severely impacted their everyday functioning [18]. Moreover, recent research also suggests that over the past three years, disturbances caused by the COVID-19 pandemic have continued to exacerbate mental health issues [17, 19]. Thus, the increasing prevalence of the disorder is begging, now more than ever, for advances in research and potential new therapies.

Clinically-diagnosed depression is most commonly treated with therapy and antidepressant drugs [20]. Traditional antidepressants target neurotransmitter systems, the brain’s chemical messaging networks [21]. Common targets include serotonin and dopamine, which are both members of the "monoamine" family of neurotransmitters [17]. Selective serotonin reuptake inhibitors (SSRIs), for example, increase the amount of serotonin in the brain [22]. However, among all individuals receiving pharmacological treatment, 70% of patients either experience alleviation of only some depression symptoms or do not respond to treatment at all [23]. In some cases, patients can develop treatment resistant depression (TRD), meaning they have tried at least two antidepressants without adequate relief of their symptoms [24].


Contemporary Models of Depression

Understanding the pharmacology of monoamine antidepressants, such as MAOIs, originally provided a means for formulating a chemical model of depression known as the monoamine hypothesis [12]. The monoamine hypothesis of depression, which characterizes depression as a chemical imbalance of monoamine neurotransmitters, such as serotonin, in the brain, was met with a broadened approach to the development of new drugs such as SSRIs [21]. While there were many research studies supporting the monoamine theory, the administration of SSRIs as a treatment for MDD has been met with quite a few limitations.

The primary concern is that despite a near-immediate change in serotonin levels in the brain, serotonin-based antidepressants take weeks to improve symptoms, and only work in about one-third of depressed individuals, but it remains unclear as to why [17]. These observed inadequacies in the monoamine hypothesis have led researchers to begin searching for other relevant brain systems involved in depression [17]. The glutamate system has caught the attention of many researchers and has led to the current advancement of ketamine as a potential therapeutic drug for MDD and TRD.

Recently, the physiological understanding of major depressive disorder has undergone a conceptual shift away from the monoamine hypothesis and towards a more dynamic model. Glutamate is the primary excitatory neurotransmitter in the central nervous system, meaning it is a signaling molecule that typically increases brain activity, and is critical to ensuring that the brain works properly [25]. Under normal conditions, glutamate helps with brain development, mediates the growth of new connections between neurons, and aids learning and memory [25].

Interestingly, clinical neuroimaging studies on humans have also suggested an important association between glutamate and depression. Some of the most compelling research has focused on the glutamate receptors, rather than the neurotransmitter itself. Receptors are a diverse group of proteins that sit on the surface of neurons and bind neurotransmitters like a lock and key; this allows these signaling molecules to elicit their effects throughout the brain. For example, the binding of glutamate to its receptors can activate neurons, allowing for communication between cells and information processing across brain regions [26]. Specifically, the glutamate receptor subtype mGluR5 appears to be less present in the thalamus and hippocampus–two areas linked to information and memory processing–of depressed individuals [27]. Collectively, findings regarding this glutamate receptor subtype five have hinted that this glutamate receptor could be a culprit.


How the Brain Responds to Ketamine

Importantly, ketamine is administered at subanesthetic doses for its antidepressant effects [28]. This dosage is critical to understanding the physiological effects of the drug: at low concentrations, ketamine only inhibits a fraction of glutamate receptors.

Ketamine acts specifically on NMDA receptors, a type of glutamate receptor that transmits excitatory, or activating, signals when bound by glutamate. As an antagonist of the NMDA receptor, ketamine prevents glutamate from binding. Effectively, this inhibits the activation of the receptors [28]. Thus, the observed effects of ketamine therapy in relieving depression symptoms are likely a result of reductions in glutamate signaling.

However, a key fact is that ketamine does not act on all the glutamate receptors in the brain: the previously discussed mGluR5 receptors are not blocked by ketamine. The mGluR5 receptors differ from the NMDA receptors in that when glutamate binds to them, a complex biological pathway is activated [26]. The NMDA receptors are much simpler in their mode of action, essentially just allowing neurons to communicate with each other [26]. Researchers have suggested that it may be the intricate mGluR5 pathways that explain the involvement of this receptor in depression [29]. Thus, a possible hypothesis could be that by blocking NMDA receptors, ketamine somehow works to remedy the effects of abnormal or imbalanced mGluR5 signaling.

On the other hand, a clinical study investigating glutamate directly found abnormal levels of glutamate in individuals with MDD [29]. In comparison with healthy subjects, neuroimaging techniques revealed that glutamate levels were reduced in localized areas throughout the prefrontal cortex, which is the area of the brain behind your forehead, responsible for executive functioning and regulating your thoughts, actions, and emotions [30]. The same study also found depression patients had increased levels of glutamate in the occipital cortex, the anterior-most region of the brain whose primary functions are visuospatial processing, object and face recognition, and memory formation [29, 31]. These findings suggest that, in addition to dysregulation occurring at the level of the glutamate receptor, there also seem to be imbalanced levels of the glutamate neurotransmitter itself between distinguished brain regions.

However, despite these various strides in research, there remains a clear need to develop a stronger understanding of an abnormal glutamate system implicated in depression, which will inevitably lead the way for further investigation into the connections between ketamine’s mode of action and its fast-acting relief of MDD or TRD symptoms [29]. Still, growing evidence suggests that the glutamate system is pivotal in understanding the pathophysiology of MDD and TRD, and is serving as an important target for developing novel and improved therapeutics and medications [17]. Ketamine is prevailing at the forefront of this advancement.


Clinical Findings

For the last two decades, researchers have experimented with sub-anesthetic doses of ketamine delivered intravenously to patients with TRD [32]. Several of the studies found that more than 50 percent of the patients experienced a decrease in depression symptoms 24 hours following ketamine therapy in a controlled clinical setting [33]. More impressively, some patients with TRD saw improvements in their symptoms as soon as four hours after a single ketamine infusion. These positive outcomes of a single ketamine dose, while promising, appear to be rather short-term, with effects fading within one week on average [32]. Noteworthy results were also found concerning the administration of ketamine in patients with MDD experiencing suicidal thoughts. Clinical studies found that a single infusion of

ketamine, in conjunction with standardized pharmacotherapy, such as SSRIs, reduced suicidal ideation in severely depressed patients within just 24 hours [34]. These observed results were found to last, on average, up to six weeks. While traditional antidepressants can reduce suicidal thoughts by reducing overall depression, onset of the medication can take weeks. Ketamine is providing a new avenue for specifically targeting suicidal thoughts in crisis situations; having access to a rapid intervention for acute suicidality would be groundbreaking [34].

However, despite proving it’s useful for something other than anesthesia and clubbing, ketamine remains a short-term treatment for depression and must be followed by a long-term treatment plan [32]. At this junction, more experimental data is needed regarding the endurance and security of ketamine as a long-term therapy.

Nevertheless, it has been encouraging in the scientific community to find that ketamine is seven times as effective as a placebo at inducing observable clinical improvements: a very impressive statistic that speaks volumes about ketamine’s potential [32].


Esketamine: Ketamine's More Potent Descendant

In present-day clinical practice, esketamine is the only FDA-approved ketamine-derived drug (marketed as Spravato) for adults with TRD. Esketamine is a specific form of ketamine that can be three to four times more potent [35]. It is more powerful than normal ketamine due to its chemical structure, allowing it to bind more tightly to NMDA glutamate receptors and block them more effectively [36]. This may allow for a lower dosage of the drug to produce the wanted antidepressant effects [36]. Moreover, Spravato is administered as a

nasal spray, rather than an intravenous injection, which allows the drug to be taken more easily in a treatment center, under the direct supervision of a doctor [37]. But as with any new drug, esketamine has its fair share of safety concerns and should be approached with cautious optimism concerning its therapeutic potential.

In the past, most clinical trials have monitored the short-term side effects of ketamine use, with much less data on the potential long-term side effects of the drug. However, the FDA approval of esketamine was accompanied by a surge in clinical trials. As a result, safety concerns around the repeated dosing and long-term usage of Spravato nasal spray as an antidepressant began to surface [38]. Short-term studies on the side effects of Spravato reveal that dizziness, dissociation, nausea, and headaches are common. However, few studies have monitored patients receiving ketamine for repeat doses, and no studies have studied the effects of ketamine administration over a time period longer than one year [38]. Ultimately, the unknown nature of ketamine’s long-term efficacy and safety raises important questions about its future integration into the clinical landscape.

Currently, esketamine is taken in combination with conventional antidepressants, and it is believed by psychiatrists that esketamine may be more effective when combined with cognitive behavioral therapy [37, 39]. For these reasons, esketamine is not yet considered a first-line treatment option for MDD, and as previously mentioned, is only prescribed to patients with severe MDD that has not responded to other treatment methods.


Limitations on Ketamine’s Use in Practice

Despite ketamine’s off-label use both by clinical psychiatrists and infusion clinics across the United States and Europe, there is limited supporting information outlining the details of how, where, and when to use esketamine during moments of crisis, such as acute suicidality [37]. This lack of information, research, and clinical precedent for esketamine’s role in crisis situations has hindered its potential in practice [37].

Although the prospect of ketamine may sound promising in some respects, it doesn’t mean that other traditional antidepressant medications will be replaced. While there is currently a shortage of clear guidelines on when psychiatrists should prescribe ketamine, it is highly unlikely that it will evolve into a first-line treatment [21]. SSRIs and similar drugs are currently the best option for primary treatment, and they are incredibly helpful for many patients, working to improve symptoms of depression and saving many lives [22]. SSRIs are relatively safe and have clinical documentation of typically causing fewer side effects than other lesser-known antidepressants [22].

Furthermore, the future outlook for more integrative TRD treatment plans includes using esketamine in conjunction with other antidepressants [40]. Esketamine as a nasal spray is currently seen as a more short-term treatment, as it has demonstrated efficacy for TRD in several short-term clinical studies. In contrast to the available data on the short-term effectiveness of esketamine, little is known about how well the antidepressant effects of esketamine are maintained over time [40]. Overall, the recent trend towards offering ketamine therapy begs questions of how medical care providers and governments alike plan to assimilate the drug into clinical practice on a national scale, address the associated safety concerns of drug administration, and ensure equitable access to the treatment [41].


Researchers Don’t Keta-Say What They Don’t Keta-mean:

On top of the safety and ethical concerns of ketamine’s therapeutic administration, there are also several practical concerns when it comes to ketamine clinics. It is not uncommon for ketamine clinics across the nation to promote the drug as a universal treatment for several conditions beyond just depression [10]. Through online ads to targeted audiences suffering from the above-listed mental conditions, some ketamine clinics are taking advantage of individuals who are desperate for an effective therapy. While ketamine clinics are not formally FDA-approved, the off-label administration of ketamine is permissible under specific guidelines issued by the FDA [11]. Ketamine’s use in this situation is further contingent on the benefit it provides to the patients, but many of the ketamine clinics in the United States today stray away from these guidelines [10]. Thus, systemic issues arise as ketamine clinics become more prevalent. To avoid malpractice, psychiatrists should understand the pharmacology of ketamine, the ethics behind using it for therapy, and the frameworks outlining its treatment for patients who have demonstrated a need for novel therapeutic procedures [11].

Moreover, another big issue with ketamine clinics has roots in its affordability, both on the behalf of the patients and the business itself [11]. Ketamine isn’t typically reimbursed by insurance, so patients must pay out of pocket for a dose costing up to around $1,000 [42]. Similarly, the high price of IV ketamine and its independence from insurance coverage presents economic barriers for many individuals who identify with socioeconomically marginalized groups. This reimbursement barrier is significant, as just a single infusion can cost up to $1000, and common practice indicates that IV ketamine should be administered two-to-three times per week, over the course of a couple of weeks [11, 42]. On a similar note, esketamine is not yet affordable for the vast majority either. It was estimated that esketamine prescription and administration costs between $590 and $895 per visit, which may present significant economic barriers depending on one’s insurance benefits and economic resources [42]. If ketamine and esketamine see a future as a more common second-line treatment for severe and treatment-resistant depression, there needs to be a reformed clinical landscape of the drugs that is equally accessible and affordable to all populations [11].

Ultimately, while there is a lot of progress that needs to be made in the field of ketamine psychiatry, the recent findings of ketamine have proven to be influential in furthering research on depression and therapeutic medications. Many scientists have shown interest in the possibility of finding new fast-acting therapeutic agents that perhaps act on the glutamate system or other related systems. However, this is a difficult feat, and the prospect of such developments in the future would likely take many years of tireless research. Currently, there are no extremely promising candidates for a possible new drug similar to ketamine [43]. Nevertheless, that does not mean ketamine’s neurochemical mechanisms of action on the glutamate receptor will not prove to be powerful tools in advancing the future of how we treat major depressive disorder and treatment-resistant depression.


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