Learning Objectives

After the webinar, clinicians should:

1. Understand ketamine and esketamine’s unique history, antidepressant properties, hypothesized mechanism of action, and potential side effects when used as an antidepressant
2. Demonstrate proficiency in evidence-based protocols, monitoring techniques, risk mitigation strategies, and appreciate select clinical and logistical elements crucial for effective care delivery
3. Recognize one example of an agent from the evolving pipeline under investigation in anticipation of related new interventions

Transcript edited for clarity.

Hello everyone and welcome to this discussion of ketamine and the evolving psychopharmacologic pipeline for depression. My name is Robert Meisner and I serve as the Medical Director for McLean Hospital's Ketamine Service and as an attending psychiatrist in the Acute Psychiatry Service at Massachusetts General Hospital.

CONTEXT: Disease Burden

Before we dive in, I think it's helpful to take a step back as a way of setting the stage, and to think about why we're here. These are particularly challenging times in psychiatry and in many specialties. There are a few observations that I find both sobering and also very motivating during those weeks that are especially difficult.

Disease Burden

Key Points

• MDD is the leading cause of disability worldwide, with suicide growing at an alarming pace.
• From 1999 through 2018, the age-adjusted suicide rate in the United States increased by 35%.

Both nationally and internationally, we've all experienced both morbidity and mortality in many psychiatric domains are on the rise. The statistics speak for themselves and serve as poignant reminders of the urgency behind our work. Major depressive disorder (MDD) stands as the primary cause of disability worldwide according to the WHO. Additionally, the alarming escalation of suicide rates, which increased by almost 35% from 1999 to 2018, is a critical concern. Noteworthy is the fact that suicide ranks as the second leading cause of death among individuals aged 34 to 54. These observations serve as a stark reminder of why we persist through difficult days and underscore the imperative nature of our work. For today's discussion, these insights set the stage as we delve into strategies that directly address these concerning statistics, aiming for improvements in the future.

CONTEXT: Treatment Stasis 

• Key point: the need for innovative approaches

Let's explore how we arrived at this juncture. Where do we stand in the treatment landscape of MDD, especially treatment-resistant major depressive disorder (TRMDD), leading to the statistics we've just discussed? Undoubtedly, various psychosocial factors are crucial within a comprehensive biopsychosocial model. However, I'd like to focus momentarily on two opposing forces that, in my view, contribute significantly to the current public health crisis.

Firstly, there's a noticeable treatment stagnation regarding what tools we have at our disposal for treating TRMDD. For approximately three decades, the monoamine hypothesis guided most drug development efforts in depression. While SSRIs, SNRIs, and similar medications have been invaluable and lifesaving in some instances, they largely resemble one another in their mechanisms. This lack of innovation has resulted in a relative stasis in the pharmacological approaches to TRMDD and MD. Simultaneously, we grapple with escalating morbidity and mortality, within a world characterized by substantial psychosocial and political uncertainties, varying by geographical location.

This is where ketamine stands out due to its unique mechanism of action, rapid efficacy, and its ability to address specific problematic symptoms in a way that diverges from existing treatment paradigms for MDD and TRMDD. This novelty is why many of us harbor a cautious optimism about its potential moving forward. However, I want to stress emphatically that my message today isn't to tout ketamine and related agents as miracle drugs for universal application. Rather, it's crucial to underscore the significance of evidence-based, data-driven, and safety-focused practices in their utilization.

Navigating the Ketamine Landscape

Over recent years, we've observed the emergence of various ketamine applications lacking substantial evidence. Practices have surfaced that deviate from what could evolve as the standard of practice, leading to adverse and sometimes catastrophic outcomes. These instances jeopardize the progress potential within the ketamine and emerging psychedelic pipeline. It's paramount that when considering this modality, practitioners adhere strictly to evidence-based, data-driven, and safety-centric approaches. Cautious optimism is warranted, but it must align with these criteria to ensure responsible progress.

Let's remain vigilant in pursuing evidence-based practices, staying true to data-driven methodologies, and prioritizing safety measures. These are the cornerstones that should guide us as we navigate the landscape of ketamine and its promising potential in mental health therapeutics.

About The Learning Objectives

In the spirit of cautious optimism, our learning objectives today are threefold. We're going to review ketamine and esketamine's unique history. We're going to talk about its antidepressant properties. We're going to briefly review its hypothesized mechanism of action, because remember, that's one of the things that's exciting about this area. potential side effects, adverse events, et cetera. Second, we want to try to appreciate, uh, examples of evidence-based protocols, recommended monitoring techniques, understand risk mitigation strategy, especially REMS program, through which esketamine is delivered. And then finally, we’ll look at one evolving pipeline molecule that's under investigation in anticipation of the related and newer interventions that will follow ketamine that the FDA has signaled are high priority because of the potential that they offer.

What Are Ketamine and Esketamine?

Key Points

• Ketamine is a synthetic, racemic mixture created in an effort to produce a General Anesthetic 
• Esketamine is a synthetic compound that is exclusively of the “s” enantiomer. It is the sole ketamine that carries FDA approval for psychiatric indications
• Esketamine was approved with a specific dosing and administration schedule and requires participation in a risk mitigation system (REMS)

Ketamine and esketamine are related compounds, both used in psychiatric treatments, yet they possess distinct characteristics and regulatory approvals.

Ketamine, in its typical form, refers to a racemic mixture. In organic chemistry, some molecules exhibit "handedness," where they exist as mirror images of each other. These mirror images are called enantiomers. Ketamine, as a racemic mixture, consists of both the R and S enantiomers. When we refer to "ketamine," we're often speaking of racemic ketamine, which includes both R ketamine and esketamine in a one-to-one ratio.

Racemic ketamine is commonly utilized in IV infusion protocols, usually starting at around 0.5 mg per kg, supported by the evidence base, although there's ongoing exploration regarding dosage ranges.

The evidence for IV ketamine as an antidepressant primarily exists at sub-anesthetic doses. At 0.5 mg per kg dosing, the peak plasma concentration ranges from approximately 70 to 200 ng per milliliter, significantly lower than the concentrations required for general anesthesia, which typically range from 2000 to 3000 ng.

Esketamine, on the other hand, is one isolated enantiomer of ketamine. It was patented initially as a general anesthetic and is now available in generic form for off-label use. However, esketamine has gained FDA approval specifically for psychiatric purposes and is associated with a Risk Evaluation and Mitigation Strategy (REMS). It stands as the only ketamine formulation with an FDA-approved indication for psychiatric treatment.

The distinction between esketamine and racemic ketamine is crucial. While racemic ketamine is a mixture of two enantiomers and is utilized off-label, esketamine is FDA-approved for psychiatric indications, administered intranasally, and is subject to a risk mitigation system known as REMS.

This distinction between racemic ketamine and esketamine reflects their origins and evolution within the broader context of psychiatric history and their respective regulatory paths.

Ketamine Historical Context

The historical context of ketamine is a complex interweaving of sociocultural and clinical dimensions, shedding light on its unique biological and clinical significance within the broader history of medicine.

Synthesized in the 1960s by chemist Calvin Stevens, racemic ketamine was initially aimed at replacing PCP as a general anesthetic. However, a dark chapter in its history emerged when, during the 1960s, it was experimentally used on prison populations. By 1970, the FDA granted approval for its use as a general anesthetic.

Following its FDA approval, ketamine gradually became widely utilized in various settings. As it went off-label, becoming more affordable, its usage expanded notably in conflict zones, resource-poor environments, and veterinary medicine. Remarkably, according to the WHO, ketamine remains the most commonly prescribed general anesthetic globally.

In veterinary practices, especially in remote settings lacking access to specialized veterinary anesthesiologists, ketamine's manageable side effect profile made it a preferred choice. Simultaneously, in conflict zones and resource-limited areas lacking extensive technological or pharmacological support, ketamine gained popularity.

Notably, in a darker historical moment, ketamine was administered to American soldiers during the Vietnam War for emergency use on the battlefield.

In recognition of its widespread utility, ketamine was added to the WHO's essential medication list in 1985. The turning point came in 2017 with a consensus statement in JAMA from a distinguished pharmacologist. This statement emphasized the potential moral and ethical responsibility to consider making ketamine available, under appropriate circumstances, to patients grappling with Major Depressive Disorder (MDD), acknowledging its potential as an antidepressant based on compelling evidence.

Despite lacking FDA approval, this consensus statement spotlighted ketamine's promising evidence base, implicitly acknowledging the improbability of racemic ketamine securing FDA approval by itself.

In contrast, esketamine, being a single enantiomer of racemic ketamine, was patentable and underwent a distinct FDA approval process. In 2018, esketamine received FDA approval as an augmentation therapy for Treatment-Resistant Major Depressive Disorder (TRMDD), subsequently acquiring additional FDA approvals.

The Evidence Base: Early Interest

Key Points

• Ketamine can decrease depressive symptoms within hours of administration instead of weeks
• A single infusion may only yield a few days of response

Let's delve into pivotal moments within the evidence base that underpins our cautious optimism for the use of both racemic ketamine and esketamine. We'll explore the evolution of basic and clinical research from the early 2000s to the present, highlighting some key findings that have continued to intrigue researchers and clinicians.

In 2000, Berman's work demonstrated that ketamine had the potential to rapidly reduce depressive symptoms within a remarkably short timeframe, sometimes even minutes after an infusion. Notably, the majority of evidence in this realm, even today, centers around a dosage of approximately 0.5 mg per kg infused over about 40 minutes. This specific dosage regime, around 0.5 mg per kg over 40 minutes, has become a standard parameter within the field, despite some variations observed in the literature.

To contextualize this dosage, achieving a serum level of around 70 to 200 ng per milliliter is common with a 0.5 mg per kg dose, while a general anesthetic concentration typically ranges between 2000 to 3000 ng per milliliter. This highlights a significant difference in serum concentrations between those required for general anesthesia and those demonstrating antidepressant effects.

Interestingly, research suggests that administering excessively high doses of ketamine to depressed patients might not yield an antidepressant response; instead, it could potentially overshoot the desired effect. Furthermore, in individuals without a diagnosis of major depressive disorder, ketamine has been observed to potentially exacerbate mood symptoms.

The Early Evidence Base, 2000 and Forward

Berman, Zarate and Diazgranados and Others

As the evidence base continued to evolve since 2000, there's been a notable shift from primarily examining single ketamine infusions to exploring the effects of repeated infusions. Pioneering work by various researchers including Zarate, Young, Diazgranados, among others, demonstrated that repeated infusions led to a sustained duration of effect beyond the immediate hours or days typically seen with single infusions. By administering two infusions per week over a course of multiple treatments at varying frequencies, researchers observed a sustained effect that persisted even after treatment cessation.

Key Points:

• Rapid and robust responses could be achieved after a single infusion.
• Notably, suicidal tendencies showed a particularly swift response.

It's crucial to understand that ketamine's efficacy isn't solely due to its presence in the serum or its potential to induce a "high" in patients. Ketamine's beta half-life of approximately two to three hours indicates its swift metabolism through the P450 metabolic systems. Consequently, when utilized appropriately, ketamine doesn't induce a prolonged psychedelic or dissociative experience separating patients from their depression. Improvement is sought after ketamine has left the system, rather than during the actual infusion itself.

Subsequent studies broadened the understanding of ketamine's efficacy, demonstrating its potential not only in MDD and TRMDD but also in bipolar depressions. Moreover, current investigations have started exploring potential indications beyond mood disorders, although these areas are still in the evolutionary stage and won't be discussed extensively today. Let's now shift our focus to understanding the mechanism of action.

Mechanism of Action

The mechanism of action of ketamine presents a fascinating yet complex picture within psychiatry, often described as a 'dirty medicine' due to its multifaceted receptor interactions. While the exact mechanisms remain uncertain, several hypotheses help elucidate its effects.

Ketamine primarily acts as an antagonist of the NMDA receptor. Meanwhile, esketamine functions by antagonizing the NMDA receptor on GABAergic interneurons. This antagonism leads to AMPA receptor activation, triggering a cascade involving BDNF (Brain-Derived Neurotrophic Factor), mTOR (Mammalian Target of Rapamycin), and other pathways.

One significant impact of ketamine is the release of glutamate in the synapse, resulting in an elevated glutamatergic activity. This surge in glutamate prompts various downstream effects involving multiple second messenger systems and signaling pathways. These include but are not limited to eEF2, IGF1, CREB, and EF2X, among others. These signaling systems seem to be active simultaneously or through cascading downstream effects, potentially contributing to ketamine's antidepressant effects.

It's important to note that ketamine also exhibits activity as an opiate, binding to three subclasses of opiate receptors. Considering the ongoing opiate epidemic, this aspect warrants careful consideration. Recent consensus among researchers suggests that while ketamine's opiate receptor activity is notable, it's viewed as “necessary but not sufficient” for producing the antidepressant effects. This implies that while opiate receptor activity is a contributing factor, it's not solely responsible for the observed antidepressant outcomes.

The Mechanism of Action (cont’d)

Indeed, the effects of ketamine on synaptogenesis offer an intriguing insight into its mechanism of action. Synaptogenesis refers to the creation of new synaptic connections between neurons, crucial for neuronal communication.

To illustrate this concept, imagine a tree during winter and then envision the same tree during springtime. This analogy reflects the changes observed in neurons before and after synaptogenesis. A depressed or stressed neuron, akin to a tree in winter, exhibits lower dendritic or spinal density. However, with ketamine treatment, akin to the arrival of spring, neuronal structures show an increase in new branches and an uptick in dendritic spine density. Consequently, neurons display an enhanced ability to communicate with other neurons.

This functional enhancement through synaptogenesis differs somewhat from the concept of neuroplasticity, which is a broader term encompassing the brain's ability to reorganize and form new neural connections. Notably, while ketamine demonstrates significant synaptogenic effects, existing SSRIs (selective serotonin reuptake inhibitors) and SNRIs (serotonin-norepinephrine reuptake inhibitors) also exhibit some degree of neuroplasticity in their mechanisms of action.

Side Effects During Treatment

Let's discuss the side effects commonly observed during the traditional 40-minute infusion of ketamine at approximately 0.5 mg per kg to around 1.0 mg per kg, a range that's been established in our service based on research, notably the work of Chris Cusin and others.

Within this dosing range, several side effects are often observed. Patients might experience headaches and distinct dissociative sensations, feeling disconnected from themselves. While they might appear fatigued, they typically do not fall asleep. Anxiety, tearfulness, and mood swings can also manifest during or after the infusion. Additionally, patients may encounter challenges with their sense of time, have difficulty recalling words, and experience slightly slurred speech.

It's important to note that blood pressure elevation is a common occurrence, sometimes significantly so. In some cases, diastolic blood pressure readings might exceed 100 mmHg, affecting approximately 20-30% of patients according to one study. The average increase in systolic blood pressure hovers around 20 mmHg, while the mean diastolic increase measures at least 13.4 mmHg. These changes in blood pressure, particularly if they reach high levels, may necessitate intervention. Medications like metoprolol are often administered intravenously or orally to manage elevated blood pressure. Stopping the ketamine infusion can also naturally lead to a decline in blood pressure.

It's crucial to monitor patients closely during the infusion to manage these potential side effects effectively and ensure their safety.

Potential Adverse Events and Toxicities 

Among the adverse events and toxicities, I want to note that this comes mostly from the addictions literature associated with ketamine, are the following:

• Liver / hepatobiliary injuries
• Transaminitis
• Ulcerative or interstitial cystitis
• Urinary tract / kidney
• Cognitive impairment
• Substance use

Certainly, within the realm of addiction literature, occurrences of transaminitis (elevated liver enzymes) in liver function tests (LFTs) among patients using ketamine are not uncommon. Notably, when ketamine administration ceases, LFTs tend to normalize. However, there have been reports indicating cases where transaminitis progressed to severe liver conditions, including cirrhosis.

Furthermore, a condition referred to as interstitial cystitis, or alterative cystitis, has been observed in association with ketamine use. This condition can be challenging to diagnose due to its nonspecific symptoms, often resembling urinary tract infections or complex urinary tract issues.

Patients experiencing urinary symptoms while undergoing ketamine treatment might present symptoms that could be misconstrued as a regular urinary tract infection. However, due to the nonspecific nature of these symptoms and the potential influence of ketamine, ruling out ketamine-induced problems often necessitates visualizing the bladder under sedation in a controlled setting, which could lead to non-trivial subsequent diagnostic workups.

Additionally, it's crucial to acknowledge that ketamine, categorized as an opiate, has a history of recreational use under various street names, such as "Special K." While the United States may not experience the same widespread epidemics of ketamine use as seen in the past, significant areas and communities worldwide continue to grapple with ketamine use, abuse, and related disorders. Concerns persist regarding the substantial impact of ketamine use disorders on the body, underscoring the severity of its effects and the importance of vigilance in monitoring its use.

Esketamine and Ketamine: Key Distinctions

Certainly, there are several key distinctions between ketamine and esketamine that warrant consideration. Initially, racemic ketamine was FDA-approved as a general anesthetic and has since lost its patent. In contrast, esketamine received recent FDA approvals and remains under patent, implying potential differences in raw material costs and regulatory oversight. These distinctions have implications for clinicians in terms of cost, logistics, and oversight when utilizing these agents.

Racemic ketamine treatment protocols exhibit significant variability nationally and internationally, prompting concerns about profit-driven protocols lacking evidence-based foundations. For instance, some practices administer racemic ketamine excessively frequently, possibly motivated by financial considerations. On the contrary, esketamine, falling under the REMS system, mandates reporting with each administration, thereby restricting inappropriate dosing frequencies. The treatment algorithm for esketamine is well-defined, involving specific dosing frequencies over defined periods, promoting a standardized approach.

In contrast, determining appropriate repeat dosing or maintenance versus booster strategies for racemic ketamine is complex due to diverse and incomparable international studies. Clinicians often establish best practices through collaboration, analyzing existing evidence while considering known limitations and uncertainties regarding long-term consequences.

Both ketamine and esketamine are recognized for their novel mechanisms acting through the NMDA receptor and several signaling pathways, leading to glutamatergic surges and notably, synaptogenesis—enhancing neuron communication. Ketamine has shown rapid effects, particularly in reducing suicidality in some cases of TRMDD, challenging previous notions of the relationship between suicidality and MDD diagnosis.

Esketamine, with its FDA-approved status and clear dosing paradigms, offers distinct advantages. Both agents cater to different patient populations within TRMDD, influenced by various factors such as insurance coverage and geographical differences. The comparative efficacy of these agents across all patient groups remains somewhat uncertain, with ongoing research aiming to identify superior efficacy for certain subgroups or broader use.

In conclusion, both ketamine and esketamine serve crucial roles in MDD treatment. Their distinct characteristics cater to different patient populations, potentially affected by factors such as insurance coverage and geographical location. Ongoing research aims to determine broader efficacy, shedding light on which agent might offer superior outcomes for specific subgroups or across the broader population.

Ketamine 2.0: Emerging Pipeline Therapies

• Psilocybin is one example of a “pipeline” agent actively being studied for its anti-depressant potential (GAD, OCD, EtOH Dep, MDD among potential indications)
• Psilocybin carries “Breakthrough Therapy” designation from the FDA

Looking toward the future, the evolving psychedelic pipeline introduces substances like psilocybin, which exhibits promising antidepressant potential and has secured FDA breakthrough therapy designation. This designation affords it special attention and potentially faster evaluation processes.

Psilocybin, in contrast to ketamine, appears to offer the possibility of less frequent administration, potentially resulting in prolonged efficacy when combined with psychotherapeutic methods focusing on what's termed "consolidation."

This is not solely true for psilocybin; other agents within the psychedelic pipeline, such as NMDA, also show promise and may introduce similar advantages in terms of less frequent dosing and sustained effectiveness when utilized alongside specific psychotherapeutic approaches emphasizing consolidation techniques. These emerging possibilities are being actively explored and hold significant promise in the treatment landscape for various mental health conditions, including depression.

Psilocybin: Example of Related Pipeline Agent

• Small sale feasibility study (response rate = 67% one week after administration)
• 7 of 8 patients met criteria for “remission”
• 58% of patients maintained response status for 3 months

In various smaller studies and meta-analyses, intriguing findings emerge, such as a significant response rate of 67% in one study and a notable 60% maintenance of response status for three months in another. These statistics suggest a durability of response not typically observed after a single ketamine treatment. The evolving landscape shows promise in offering clinicians and patients the added value of less frequent dosing and prolonged effectiveness, particularly when coupled with certain psychotherapeutic modalities.

Psilocybin is classified as a non-selective serotonin 2A receptor agonist, similar to other emerging agents in this category. However, it's essential to note that not all agents within the psychedelic category fit this precise profile. When considering substances like LSD, MDMA, and others, the complexity increases. Categorizing all these substances under the umbrella term "psychedelics" may oversimplify their diverse pharmacological profiles. Interestingly, the term "psychedelic" originates from literary rather than clinical history, coined by a British psychiatrist writing to author Aldous Huxley in the 20th century while in Canada. This linguistic distinction raises questions about the term's clinical applicability and the need for a more nuanced approach.

As we focus on psilocybin's potential as a selective serotonin 2A receptor agent in depression treatment, it's crucial to highlight ongoing investigations exploring its efficacy in generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), alcohol dependence, and various other conditions. The evolving landscape of psychedelic therapy demands careful consideration of the specific pharmacological characteristics and clinical implications of each agent, moving beyond the generalized label of "psychedelics."

Psilocybin: Example of Pipeline Agent

It's imperative to acknowledge the complexity and distinctions among these agents, often muddled by misinformation in social and mainstream media. Moving away from generalized labels and striving for precision in our discussions is vital for clarity in public discourse and private conversations alike.

As our time today draws to a close, I want to emphasize the value of resources like FDA.gov, particularly concerning the evolving pipeline of therapeutic agents. Both the FDA and the DEA have demonstrated a keen interest in safely exploring this space due to its potential.

Returning to our initial point, there isn't a single magic solution for TRMDD and MDD. The biopsychosocial model remains profoundly significant, and while the concept of a "magic bullet" is popular in cultural narratives, it's beyond the scope of any singular agent.

Maintaining a cautiously optimistic outlook toward ketamine, esketamine, and other evolving agents is important. However, it's equally vital to exercise caution, particularly in non-FDA approved realms, where motivations behind clinical parameters and safety protocols may be concerning. The absence of adequate oversight and regulation is a significant worry.

Nevertheless, the emergence of robust, high-quality clinical data and the evolving landscape of clinical translational work provide reasons for hope and optimism as we navigate the future of psychiatric therapeutics. Thank you very much for joining me today. Please feel free to reach out by email with any questions.

Click to download the slides

Earn CME for watching our webinars with a Webinar CME Subscription.

REFERENCES:

Hedegaard H, Curtin SC, Warner M. Increase in Suicide Mortality in the United States, 1999-2018. NCHS Data Brief. 2020;(362):1-8
Wei Y et al, Pharmacol Biochem Behav 2020;190:172870 
Sancora G et al, JAMA Psychiatry 2017;74:399-405
Berman RM et al, Biol Psychiatry 2000;47(4):351-354
Diazgranados N et al, J Clin Psychiatry 2010(12):16051611
Ionesco et al, J Clinical Psychiatry 2016;77;6.
Vande Voort et al, J. Affective Disorders 208 (2016) 300
Li et al, Science 2010;329(5994):959-964
Dwyer JM and Duman RS, Biol Psychiatry 2013;73(12):1189-1198
Drewniany E et al, J Clin Pharm Ther 2014;40(2):125-130
Dwyer JM and Duman RS. 2013 Jun 15;73(12):1189-1198
Zhu W et al, Neurosci Bull 2016;32(6):557-564
https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/breakthrough-therapy
Carhart-Harris RL et al, Lancet Psychiatry 2016;3(7):619-627

__________

The Carlat CME Institute is accredited by the ACCME to provide continuing medical education for physicians. Carlat CME Institute maintains responsibility for this program and its content. Carlat CME Institute designates this enduring material educational activity for a maximum of one-half (.5) AMA PRA Category 1 Credits^TM. Physicians or psychologists should claim credit commensurate only with the extent of their participation in the activity.