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Recently, I had the good fortune to attend the Ketamine and Related Compounds International Hybrid Conference held in Oxford and hosted by Dr. Rupert McShane. The conference was attended by many academics who made landmark discoveries in the rapid-acting antidepressant (RAAD) space, including Robert Berman, who was the first author of the first study of intravenous ketamine in patients with depression in 2000. Dr. Carlos Zarate of the National Institute of Mental Health (NIMH), the lead author of the second 2006 study, was also present at the event. Here are my main takeaways from the conference:

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The tone of the conference was one of optimism regarding the safety and efficacy of ketamine and related compounds.

• Of particular interest to clinicians: Three oral compounds were mentioned in various stages of the clinical trials process that you may eventually use in your practice. These include an extended-release oral ketamine formulation developed by Paul Glue and his colleagues; a combination of dextromethorphan and bupropion in development by Axsome therapeutics; and esmethadone (an opioid inactive isomer of racemic methadone that acts primarily as a low-affinity, low-potency N-methyl-D-aspartate (NMDA) receptor antagonist) by Relmada Pharmaceuticals. Additionally, Perception Neuroscience discussed early data on an IV formulation of arketamine that may not elevate blood pressure or have abuse potential (the data is still preliminary).

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Dr. Gerry Sancora, from Yale, shared the important lessons learned in the 22 years since the first clinical trial of IV ketamine.

• Berman and colleagues were amazed that ketamine had such rapid antidepressant (AD) effects, and that they lasted well after the drug had been metabolized. It was a revolution in thinking at the time.
• We knew depression was more than dysfunction of the monoaminergic neurotransmitter system 20 years prior to the first clinical trial of ketamine. For example, Trullas & Skolnick (1980) showed that inescapable stress led to a depression phenotype in animal models reversed by NMDA-R antagonists. However, only some, NMDA-Rs act as ADs which complicates our understanding of ketamine’s mechanism of action (MOA).
• Another major advance in the advent of ketamine occurred when researchers started ethical clinical trial research in severely ill patients with active suicidal ideation. This was a huge step forward for the field.
• Dr. Sanacora said characterization of the safety and efficacy of ketamine infusion therapy (KIT) has lagged since its initially promising start in 2000. The second trial of KIT for depression was published by Zarate and colleagues in 2006 and it wasn’t until 2015 that Newport and colleagues had enough data to do a meta-analysis (although with fewer than 200 patients). In addition to the small number of patients studied, it took too long to figure out dosing strength and cadence. In fact, there have only been two formal dose-ranging studies measuring the effects of a single KIT infusion. One study looking at peak AD effect as a function of dose (Fava et al. 2020) found that 0.5 mg/kg and 1 mg/kg outperformed lower doses. The other study looked at the time to relapse, based on dose, and found 1 mg/kg outperformed lower doses (Salloum et al. 2020). Singh et al. 2016 eventually gave us the concept of induction, which is that 4-6  infusions over 2-3 weeks enhance response over single infusions.

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Dr. Sanacora outlined three reasons why progress to bring ketamine to mainstream psychiatry is slow. He also talked about fears that it is a drug of abuse with many negative associations when taken illegally.

• It has been difficult to work out the MOA of ketamine. This is in part because animal studies have been contradictory between at least two major labs working in this area, including Gould Lab and the Monteggia Lab. For example, it turns out that the results of the forced swim test, an animal distress paradigm of depression, depend in part upon the gender of the experimenter. Without a clear MOA, it is hard to have confidence that a treatment is safe, even if it appears to be efficacious.

• Lack of funding. As ketamine is a generic medication there has been less enthusiasm to fund studies for its use. Also, resources are generally scant for mental health research.

• Lost opportunities for gathering real-world evidence. Dr. Sanacora pointed out a survey of ketamine providers by Wilkinson and colleagues, published in 2017. The survey made it clear that thousands of patients received KIT in community clinics. However, we did not have a central registry to record the patient responses and adverse effects. Dr. Sanacora called out Osmind for its first JAD paper, ORKA-1, which describes KIT outcomes in real-world patients. He also hopes we will make progress toward establishing a registry for ketamine patients. 

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Dr. Sanacora highlighted the many unexpected results that can materialize when trying to understand behavior.

• Dr. Sanacora highlighted another story from animal models of depression. The AD effects of ketamine are thought to be mediated, in part, by stimulation of the mechanistic target of rapamycin complex 1 (mTORC1) which in turn results in enhanced neuroplasticity. Rapamycin, an immunosuppressive drug blocks mTORC1 mediated AD effects of ketamine in mice but in humans, it actually enhanced response, which confounded investigators. (Abdallah et al. 2020). Have we identified higher orders of behavior that we cannot model in humans? He closed the discussion by urging the audience not to forget the importance of set and setting for ketamine therapy.‍

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Experts from academia and the NIMH declared clinician-administered ketamine/esketamine is a safe and effective treatment for TRD, out to one year.

• At the conference, Dr. Zarate declared that esketamine and ketamine are safe and effective medications for depression. However, he said we still need to know more about appropriate doses for ketamine and the best strategies for maintenance with both drugs. He cited a meta-analysis that he recently co-authored in support of this assertion (Bahji et al. 2022). Shortly after the Oxford conference, a review article authored by Dr. Samuel Wilkinson (Sina et al. 2022) entitled ‘Long-term safety of ketamine and esketamine in depression’ reflected more support regarding the safety of these therapies. They concluded as others have, that acute adverse events of ketamine or esketamine are transient and generally easily managed (dissociation, elevated heart rate and blood pressure, headaches, and nausea). They noted that U.S. Food and Drug Administration (FDA) trials of esketamine found cognition remains stable or increases over time, although the data only extends to one year, with the caveat that among older patients (ages 65 or greater), reaction time slowed starting around week 20 of the maintenance phase. They also found long-term treatment with esketamine may lead to an increased risk of lower urinary tract symptoms including dysuria or urgency, but they did not see any incidences of severe interstitial or ulcerative cystitis. Finally, a posthoc analysis of data from several large trials of esketamine in treatment-resistant depression did not show any significant correlation between dissociative and antidepressant effects (Chen et al. 2022).

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Reference: Chen G, Chen L, Zhang Y, Li X, Lane R, Lim P, Daly EJ, Furey ML, Fedgchin M, Popova V, Singh JB, Drevets WC: The relationship between dissociation and antidepressant effects of esketamine nasal spray in patients with treatment-resistant depression. The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP) 2022

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About Dr. Alison McInnes

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Dr. Alison McInnes is Vice President, Medical Affairs at Osmind. She is a nationally recognized expert in psychiatry and mood and anxiety disorders, having specialized in treating refractory disease for over a decade. She is an expert in ketamine treatment and psychedelic medicine. McInnes founded and served as Medical Director for Kaiser Permanente's ketamine infusion therapy program for a number of years, and was previously an Associate Professor of Psychiatry at Mount Sinai School of Medicine for 8 years where she ran a lab in psychiatric genetics. She was also an adjunct clinical professor at UCSF.

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Dr. McInnes is regularly invited to speak at national and international conferences and consults for biopharmaceutical companies working at the cutting edge of neuropsychiatry. She is a member of the American Society of Ketamine Physicians, Psychotherapists and Practitioners (ASKP3) Certification Governance Commission, which is an autonomous governing body that oversees the development, implementation, and management of a certification program for clinicians offering ketamine therapy. In her current clinical practice, she focuses on treatment-resistant mood disorders and complex cases.

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Dr. McInnes received Bachelor’s and Master’s degrees from Stanford University and her MD from Columbia University. She completed her residency at UCSF and research at the VA Research Fellowship and Howard Hughes Physician Research Fellowship in Psychiatric Genetics at UCSF.