A Ketamine Journal, Interrupted

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A KETAMINE JOURNAL

When I started researching, learning, and then doing ketamine-assisted psychotherapy (KAP), I was well aware that this was outside the usual realm of practice for most psychiatrists. KAP is often done by social workers and therapists of every ilk, by doctors in other specialties who have never had psychiatric training, and by companies who mail patients ketamine and then do the psychotherapy with videoconferencing. In my entry, “Melding Science with Woo-Woo,” I reference the fact that many feel ketamine should only be used in the intranasal esketamine form, Spravato, that has US Food and Drug Administration (FDA) approval and is part of the risk evaluation and mitigation strategy (REMS) program, which collects ongoing data on every single administration of Spravato.

Ketamine was first synthesized in 1962 and has had FDA approval as a dissociative anesthetic since 1970. Serendipitous antidepressant effects have been noted since 2000; ketamine’s use in psychiatric disorders has become more common in the last (approximately) 12 years. KAP is even newer on the scene, with little oversight or defined protocols—I note that some consider the practice sketchy and for my own practice, I have tried to focus first on safety. Ketamine is not part of the REMS program, but I have followed their monitoring protocols.

I was well aware that the Editor-in-Chief of Psychiatric Times, John J. Miller, MD, is opposed to the use of ketamine for assisted psychotherapies, and that he feels strongly that ketamine should be subjected to the same scrutiny as Spravato, and should be included in REMS.¹ Still, I was disappointed when I heard he wanted this series halted.

This led to a friendly, but very long Zoom conversation with Dr Miller. He began by telling me that he feels Psychiatric Times should only be promoting evidence-based medicine, and he was concerned my KAP journal would lead readers to believe that Psychiatric Times endorses the use of KAP. He worried that by mentioning that KAP is being done in nonmedical settings, I was condoning these practices (I am not).

KAP is not standard or conventional psychiatric treatment, it is used as an off-label treatment and its use is legal. My malpractice provider assured me that KAP is covered and the risk manager I spoke with was surprised to hear that I would remain in the room with patients. Off-label intravenous (IV) ketamine has been used without psychotherapy to treat depression for years now, there is less skepticism surrounding it, and psychiatrists refer patients with less hesitation. A multi-center, cross-over study showed that IV ketamine is comparable in efficacy to ECT in outpatients.² We certainly have reason to believe that ketamine works as an antidepressant, though the results are sometimes short-lived, and this has been a concern.

KAP is newer and there are no defined protocols—we do not have a standard for how much to give, by what route, and for how many treatments. All psychotherapy protocols around ketamine involve preparation and integration sessions, and attention to the content of the dissociative experience, but different practitioners use different types of psychotherapy. There are studies on the efficacy of KAP, but as we have seen with the recent attempt to get FDA approval for MDMA, it is not easy to conduct a double-blind and unbiased study with psychedelic agents. For the moment, we are left with the question of whether our positive outcomes are glorified placebo effects, or innovative psychiatry, and we have certainly been duped before. I recall a time when many patients with bipolar disorder were treated off-label with gabapentin, a neurologic agent with no FDA indications for psychiatric conditions.

Many people presume that ketamine is not safe, and the tragic death of actor Matthew Perry has done nothing to ease this concern. His story is one of an addiction fueled by illegal medical practices and irresponsible supervision, not anything that resembles the work responsible clinicians are doing. There are studies that demonstrate safety for ketamine, including one conducted by Mindbloom, a mail-order service with video-conference treatment that recorded adverse effects for 11,441 patients.³ There are certainly risks with ketamine, including the risk of addiction, and of permanent bladder damage after prolonged use, but with proper screening and monitoring, the risks are low. As with any medication, there may be adverse effects, but since treatment is usually limited to a determined number of treatments, there are not the on-going adverse effects and risks we often see with medications that may be indicated for life.

Should ketamine be used at all when FDA-approved Spravato is available and insurance will pay for it? For many of my patients, the logistics of getting Spravato includes hurdles—the insurance approval takes time, the treatment occurs during work hours, and they go on for weeks to months. The KAP protocol I am using is only 3 sublingual ketamine treatments, done in the evenings or sometimes on Saturdays, and even that is a challenge. It has been suggested that when a patient is this ill, it is like deciding whether to have an appendectomy, but when patients are employed, they often do not see it that way. Furthermore, we do not know if intranasal esketamine is more or less effective than other forms of ketamine.

Just as I thought we would not find any common ground, we happened upon it: Dr Miller agreed that the articles about my experiences with KAP had worth and asked for a disclaimer that my writing did not reflect the views of Psychiatric Times.

I am writing about a personal conversation because we are left with so many questions when we choose to treat patients with any medication. FDA approval is good, it gives a seal of approval, a sense of protection for both ourselves as professionals, and a level of rigor to the studies that showed it to be safe and effective. But it is not perfect, many medications that have been approved by the FDA have later been withdrawn, including some that were on the market for decades. Psychiatrists should be aware of treatments that are being offered in the community, whether they wish to add them to their arsenal or not, and it is important to have these conversations. We still do not know if KAP is misguided or innovative, and it does not serve us to squelch the conversation. Thankfully, Psychiatric Times continues torecognize the need to keep the dialogue open on all issues relevant to psychiatry, even the contentious ones.

Evidence-based medicine is about finding safe and effective treatments for populations, using double-blind placebo-controlled studies. These studies are expensive, often financed by pharmaceutical companies for new medications. They take years and can be very difficult to do with psychedelic agents. Evidence-based medicine does not tell us if any given treatment might help any specific individual.

This is not the first time a psychiatrist has criticized my use of KAP. Early on, another colleague told me that psychiatrists should only practice evidence-based medicine. The people who come for this treatment have had treatment-refractory depression, most have had years of treatment, sometimes more than 20 medication trials, some have had transcranial magnetic stimulation and/or electroconvulsive therapy, and a handful have tried psilocybin.

It leaves me to wonder exactly how many years of evidence-based medication trials a patient should be expected to endure before it is okay to try the unconventional with a safe off-label agent.

My thanks to John Miller for his time, energy, and thoughtfulness in considering KAP and its place in Psychiatric Times.

The views and practices expressed in these commentaries are solely those of the author and do not necessarily represent the position of Psychiatric Times or its editors.

What do you think about the use of ketamine? Join the conversation by emailing PTEditor@mmhgroup.com.

References

1. Miller JJ. A curious juxtaposition. Psychiatric Times. June 10, 2024. https://www.psychiatrictimes.com/view/a-curious-juxtaposition

2. Anand A, Mathew SJ, Sanacora G, et al. Ketamine versus ECT for nonpsychotic treatment-resistant major depression. N Engl J Med. 2023;388(25):2315-2325.

3. Mathai DS, Hull TD, Vando L, Malgaroli M. At-home, telehealth-supported ketamine treatment for depression: findings from longitudinal, machine learning and symptom network analysis of real-world data. J Affect Disord. 2024;361:198-208.