A Curious Juxtaposition

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FROM THE EDITOR

Over the past 3 years, I have become increasingly befuddled by 2 opposing clinical practices in psychiatry: the required and appropriate risk evaluation and mitigation strategies (REMS) protocol in place for the use of intranasal esketamine (Spravato) vs the casual clinical use of non–evidence-based treatments that have known harms but are often regarded as though they were the best treatment since penicillin for infections.

Two blatant examples are the non–evidence-based clinical uses of ketamine (which is approved by the US Food and Drug Administration for general anesthesia induction and maintenance) and the schedule I drug psilocybin (which has no FDA approval).

Unfortunately, when the COVID-19 pandemic resulted in the need for the Drug Enforcement Administration (DEA) to relax certain scheduled-drug requirements to enable ongoing treatment during the pandemic, it created a window of opportunity for ketamine and psychostimulants to establish a foothold in virtual clinics, which devolved into non–evidence-based practices.

An offshoot has been a huge upsurge in routine clinical practice of medication-assisted psychotherapy utilizing ketamine and psilocybin as the assisting medications in both virtual and in-person settings. It is not uncommon for ketamine to be prescribed without the clinician ever seeing the patient in person, without a thorough initial medical evaluation, and with no elements of the mandated REMS protocol used with intranasal esketamine for psychiatric indications. (Interested readers may review prior editorials related to this topic.^1,2)

Medication-Assisted Psychotherapy

Medicine in the United States is built on the foundation of evidence, whereby different regulatory agencies review data for safety and efficacy and either approve or deny the evaluated treatment. This process provides guide rails to maximize safety and minimize harm. To date, ketamine, esketamine, and psilocybin are not approved by the FDA to assist with psychotherapy, nor have any of these drugs submitted an application for consideration of approval to the FDA.

Yet, despite the lack of evidence-based vetting and FDA approval, prescribing ketamine and encouraging the use of psilocybin to assist psychotherapy are seemingly ubiquitous throughout the United States and have resulted in the impression by potential patients—and even more remarkably by licensed clinicians in a wide range of specialties—that it is acceptable to engage in these practices.

Physicians—and I would like to think all licensed clinicians—have taken an oath to do no harm to our patients, and these practices go against that oath.

In sharp contrast, as I previously described in great detail,³ 3,4-methylenedioxymethamphetamine (MDMA), along with manualized therapy with trained therapists, has been extensively studied in completed phase 2 and 3 clinical trials and has consistently demonstrated a significant improvement in posttraumatic stress disorder (PTSD) symptoms.⁴

Lykos Therapeutics (formerly the Multidisciplinary Association for Psychedelic Studies Public Benefit Corp) submitted an application to the FDA on December 12, 2023, requesting approval of the combination of MDMA with psychotherapy for treating PTSD; it is under review.

The rigorous, scientific, and comprehensive clinical development leading to this application stands as an exemplary model for how research in medication-assisted psychotherapy should proceed. Although ClinicalTrials.gov lists numerous trials registered with the FDA to evaluate the potential risks and benefits of ketamine and/or psilocybin in assisting psychotherapy, their potential harm has not been adequately characterized and mitigated.

The Ketamine Story

Our first signal that racemic ketamine had antidepressant effects came from observations by anesthesiologists. By the late 1990s, ketamine had been studied by psychiatrists at various institutions, and the first published study demonstrating a rapid antidepressant effect—within 72 hours following the intravenous administration of ketamine—was published in 2000.⁵ The proposed antidepressant effect was antagonism of the N-methyl-d-aspartate glutamate receptor (NMDA receptor).

Hence began an aggressive 2 decades of research—ethically designed and monitored by research review boards—that ultimately led to the FDA approval of the first glutamate-based treatment for treatment-resistant major depressive disorder in 2019, namely esketamine (Spravato).

Esketamine’s approval was the result of many years of tedious clinical research and the development of an intranasal device that predictably delivered the determined amount of esketamine shown to be associated with its antidepressant effect.

A Required REMS Protocol

Due to the well-established abuse, misuse, diversion, and serious adverse events associated with ketamine—especially when it is used at high dosages for prolonged periods of time—the FDA and Janssen (the company that developed Spravato) agreed that more than the DEA Schedule III designation of ketamine and esketamine would be needed to ensure safety.

Hence, when esketamine (intranasal Spravato) was approved for the treatment of resistant major depressive disorder, its administration required REMS protocol. (For reference, of the thousands of FDA-approved medications, approximately 60 require REMS protocols, including clozapine and isotretinoin.)

The REMS protocol to use esketamine requires certification by the clinic/administering prescriber, the dispensing pharmacy, and detailed informed consent by the patient. A REMS treatment form must be filled out and submitted after each dose of esketamine for the duration of treatment. Hence, for every administered dose of intranasal esketamine since its approval in 2019, there is a growing database of information to ensure the safety and quality of treatment.

Additionally, intranasal esketamine administration is carefully monitored. The preparation needs to be handed to the patient by the prescriber. Following administration, the patient must remain in the office or clinic for 2 hours. During that time, a trained medical assistant regularly monitors the patient’s blood pressure and addresses any patient concerns.

There is a safety evaluation after 2 hours to ensure the patient is safe to leave the treatment center, and there is a strict requirement that the patient not engage in any activities that require attention and cognitive competence until they wake up the following morning. In fact, patients are not allowed to drive themselves home. This REMS protocol is designed to maximize benefits and minimize potential harm.

Returning to the seemingly casual use of ketamine, it is important to remember the exact same risks from esketamine exist for ketamine (Table).

Table. Risks From Esketamine and Ketamine Use

Yet, ketamine is commonly used with minimal safety guidelines and without REMS protocols. This is a deviation from good clinical practice that I do not understand.

Clozapine was discovered in 1959, but its approval in the United States was delayed until 1989 due to serious concerns about the risk of neutropenia, despite its exceptional efficacy in treatment-resistant schizophrenia in countries outside the United States where it was in use.

The FDA finally approved it as the brand name Clozaril only if prescribed with the required REMS monitoring program, which still exists today. Imagine if there existed an isomer of clozapine, a hypothetical “esclozapine,” that was approved by the FDA for a type of rare cancer, and it started being prescribed for treatment-resistant schizophrenia without any absolute neutrophil count monitoring or other Clozaril REMSdefined guidelines. In my opinion, that is how ketamine is being used for psychiatric treatments.

Dissociation and Neuroplasticity

As we advance our understanding of the neuronal circuitry and molecular pathways involved in neuroplasticity and synaptogenesis, growing evidence supports the hypothesis that the experience of dissociation is not required to achieve the activation of mTOR, which is believed to be the final step in the orchestration of neuroplasticity.⁶

NMDA receptor antagonism is believed to result in a presynaptic glutamate surge that agonizes postsynaptic glutamate α-amino- 3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Antagonism of the NMDA receptor is responsible for the dissociation, sedation, and increase in blood pressure, 3 of the troubling adverse effects of ketamine and esketamine.

Nonclinical research consistently supports the hypothesis that it is agonism of the glutamate AMPA receptor that then directs the synthesis of brain-derived neurotrophic factor, which ultimately facilitates the chemical cascade that activates mTOR, which is essential. When AMPA receptors are antagonized, downstream synaptogenesis is blocked when an NMDA antagonist is administered.^7,8

Additionally, hydroxynorketamine, a metabolite of racemic ketamine that has also demonstrated rapid antidepressant activity in a ketaminelike manner, is dependent upon increased agonism of the AMPA glutamate receptor while not requiring activity at the NMDA receptor.^9,10

Concluding Thoughts

Over the past 25 years, glutamate modulation has earned an important place in the treatment of major depressive episodes. Registered clinical trials are underway to establish other potential psychiatric benefits from targeting the extensive glutamate circuitry in the human brain, as well as developing additional agents to treat major depression.

Since 2019, the FDA has approved 2 glutamatergic drugs to treat unipolar major depressive episodes: intranasal esketamine (Spravato) and a dextromethorphan/bupropion combination (Auvelity). The FDA has classified both agents as rapid-acting antidepressants.

Esketamine and dextromethorphan bind to different sites on the NMDA receptor and, not surprisingly, have different adverse events (described in detail in their respective FDA-approved product inserts). Due to well-established significant risks, esketamine must be prescribed with a rigorous REMS protocol to maximize patient safety.

Although ketamine is the drug that paved the way in targeting the glutamate system for the treatment of unipolar major depression, it has not been studied comprehensively, nor is it approved by the FDA for use in depression, psychiatric disorders, or medication-assisted psychotherapy.

The significant increase in the ubiquitous and casual prescribing of ketamine in the treatment of psychiatric disorders concerns me greatly. The lack of a REMS protocol for ketamine exponentially increases the likelihood of risks and serious adverse events. Without a REMS postdose report to monitor for adverse ketamine events, we have no database to assess these risks.

The dramatic clinical juxtaposition of how a licensed medical provider prescribes, administers, and manages FDA-approved intranasal esketamine vs all other formulations of ketamine is not consistent with the medical training that I am proud of.

Clinical trials with agents that interface with the glutamate system by targeting the putative pathway downstream from the NMDA receptor are well underway. Over the next 10 years, we may very well add FDA-approved glutamate modulators that do not bind to the NMDA receptor to our medication armamentarium, and this would likely negate the need for any REMS protocol for these agents.

Until then, let us practice medicine with good clinical acumen.

Dr Miller is Medical Director, Brain Health, Exeter, New Hampshire; Editor in Chief, Psychiatric Times; Staff Psychiatrist, Seacoast Mental Health Center, Exeter; Consulting Psychiatrist, Insight Meditation Society, Barre, Massachusetts.

Dr Miller discloses that he is part of the Janssen and Axsome Therapeutics speaker bureaus.

References

1. Miller JJ. Virtually malpractice. Psychiatric Times. 2022;39(10):7-8.

2. Miller JJ. Keep the cart behind the horse: privilege and responsibility as a provider. Psychiatric Times. 2023;40(1):9-11.

3. Miller JJ. Medication pipeline: schizophrenia and PTSD. Psychiatric Times. 2024;41(1):1,9-12.

4. Jerome L, Feduccia AA, Wang JB, et al. Long-term follow-up outcomes of MDMA-assisted psychotherapy for treatment of PTSD: a longitudinal pooled analysis of six phase 2 trials. Psychopharmacology (Berl). 2020;237(8):2485-2497.

5. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351-354.

6. Miller JJ. Ketamine/esketamine: Putative mechanisms of action. Current Psychiatry. 2020;19;(1):32-36.

7. Li N, Lee B, Liu RJ, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329(5994): 959-964.

8. Hoeffer CA, Klann E. mTOR signaling: at the crossroads of plasticity, memory, and disease. Trends Neurosci. 2010;33(2):67-75.

9. Zanos P, Moaddel R, Morris PJ, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533(7604):481-486.

10. Collo G, Cavalleri L, Chiamulera C, Pich EM. (2R,6R)-Hydroxynorketamine promotes dendrite outgrowth in human inducible pluripotent stem cell-derived neurons through AMPA receptor with timing and exposure compatible with ketamine infusion pharmacokinetics in humans. Neuroreport. 2018;29(16):1425-1430.