Ketamine: A Cautionary Tale

By Dr Steve Levine

I have always had an interest in people and the human experience. When considering my choice of medical specialty, I soon realized psychiatry would allow me to put that appreciation of people’s stories at the center of my clinical practice.

As I proceeded with my career, I quickly understood the limited number of options available to people living with depression. Selective serotonin reuptake inhibitors, or SSRIs, are widely used antidepressants but are effective only in approximately 50 percent of patients.

I saw that mental health care and the treatment of depression were in desperate need of innovation, and I began to actively search for other options. Soon I became aware of, and interested in, the early research into ketamine as a mental health treatment.

Known to many as a party drug, ketamine has long been licensed for medical use as an anesthetic. Taken intravenously in low, subanesthetic doses it is thought to regulate mood by altering the chemistry of neuroreceptors in the brain. At that point, in the early 2010s, the treatment existed primarily in research and academic settings. I therefore began to open my own clinics, establishing a framework of care delivery. Ultimately, I treated around 6,000 patients with 60,000 infusions.

Rapid growth and a race to the bottom

Over the course of a decade, I saw an industry emerge and grow, based around ketamine treatment for depression. In that time, the therapy helped many people. But this wasn’t a new treatment, it was off-label prescribing of an old treatment existing outside medical regulatory standards and relying heavily on self-policing by healthcare providers.

From 2012 on, hundreds of ketamine clinics started to open. However, no regulation means no standardization of treatment. Even when defining what ketamine-assisted therapy is, different providers are likely to give different answers, reflecting variable quality of screening, diagnosis, and monitoring.

Giving clinics the freedom to set their own rules has had negative consequences, as is common with self-regulation. Patient recruitment methods began to rely on advertising and marketing rather than medical recommendation. In this direct-to-consumer business model, patients often select clinics offering the cheapest treatment with the best branding, often offering inducements prohibited in conventional, regulated healthcare, and taking the focus away from the therapy itself.

Because ketamine already exists as an off-label treatment, the trials that exist are small, academically driven, and motivated by interest alone. There is no incentive to fund large-scale clinical trials to generate data that could show for whom the treatment is safe and effective and from which regulatory approval could be sought. This is the path typically required to gain reimbursement by insurers, the gatekeepers of broad patient access.

Academic trials have shown ketamine therapy to produce response (50% reduction in symptoms) in roughly 50% of patients. In stark contrast, many clinics are quoting a 90% success rate. Of course, because they exist outside any medical regulatory framework or standards, they are not obligated to prove their claims.

Stepping away from ketamine therapy

I have mixed feelings about my personal legacy when it comes to ketamine. On the one hand, ketamine use has opened a door to the expectation of new and more rapid-acting treatments. It has pushed innovation forward in mental health care by demonstrating the real-world effectiveness of the first truly novel antidepressant drug target in decades, and it has helped many people. But in the end, I chose to step away.

The inherent limitation is that intravenous ketamine is an off-label treatment. Care is being delivered in an environment unsupported by medical regulation. Corners can be cut in the name of profit, and things could go off the rails quickly, as we have seen with the current opioid crisis, and may occur with the shipment of ketamine directly to patients’ homes.

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Even when things do go well and care is given responsibly, access to treatment still remains an issue. The off-label therapy is most often not covered by insurance plans, as there is insufficient clinical trial data for seeking FDA[1] approval. The therapy must be paid for directly by the individual seeking treatment. The resulting treatment costs, which can be thousands of dollars, prevent many from accessing the therapy. Ketamine therapy, given in this way, can never be broadly accessible.

Impact of esketamine approval

The recent FDA approval of esketamine, or Spravato, as a therapy for treatment-resistant depression is a step in the right direction for the equitable treatment of mental disorders. The drug, a derivative of ketamine, is administered as a nasal spray in conjunction with oral antidepressants. By going down the conventional regulatory route, esketamine has secured coverage from payers and enabled greater levels of access through prescription.

Esketamine is not without its shortcomings. As a therapist, I believe that the practical elements of this new mental health treatment have not been fully considered. The development of esketamine did not include therapist support, and the reimbursement codes developed after its commercial launch do not pay for this potentially vital aspect of the therapy. The addition of a psychotherapy dimension has the potential to enhance treatment, but we cannot be sure as it hasn’t been studied.

Further innovation

Mental health care is in desperate need of innovation, and ketamine and its derivatives are a promising move forward after decades of stagnation in drug development that produced mainly me-too options. But the drug is not the be-all-and-end-all. It does not offer an absolute cure, but an additional tool in the toolbox. We need more tools, and for that, we need more data.

Large-scale clinical trials are required for FDA approval. The example set by esketamine is now being followed by other drugs. Psychedelic compounds such as psilocybin, DMT, and LSD are all undergoing clinical testing, with the aim of receiving FDA approval to treat a range of mental health disorders. This path requires significant investment but will ensure that all those seeking mental health care can have the options they need, given the high rates of patients that don’t benefit from existing options.

Ketamine is often included in the discussions around psychedelic therapies. However, ketamine is not a psychedelic and the two should not be conflated. The unregulated behavior of ketamine clinics and the inequitable access could otherwise pose a risk to any roll-out of psychedelic medicines and how they will be perceived.

The use of ketamine to treat depression and its mechanism of action has increased knowledge of the etiology of mental health conditions. However, to move on constructively, we must take forward the lessons learnt from off-label use of ketamine and continue to seek out regulatory approval, ensuring equitable and safe access to new therapies in mental health care.

[1] FDA = Food and Drug Administration

Dr Steve Levine

Source: Steve Levine, with permission

Dr Steve Levine is a board-certified psychiatrist and VP of Patient Access at COMPASS Pathways, as well as co-founder and chairman of the board of Heading Health. Dr. Levine was formerly the founder and Chief Medical Officer of Actify Neurotherapies, pioneering the clinical use of intravenous ketamine for treatment-resistant depression. Dr. Levine completed his psychiatry training at New York-Presbyterian Hospital Weill Cornell Medical Center, followed by subspecialty training in psychosomatic medicine/psycho-oncology at Memorial Sloan-Kettering Cancer Center and New York Presbyterian.