ORKA-1

ORKA-1 is the largest real-world analysis of ketamine intravenous therapy (KIT) outcomes in a community sample to date. Our work was published in the Journal of Affective Disorders as a peer-reviewed research article titled “A retrospective analysis of ketamine intravenous therapy for depression in real-world care settings.” Our paper follows a large body of significant ketamine studies that have been published in this journal over the past few years. We completed ORKA-1 in conjunction with leading physician-scientists at Stanford University School of Medicine.

McInnes, L.A., Qian, J.J., Gargeya, R.S., DeBattista, C., Heifets, B.D. (2022). A retrospective analysis of ketamine intravenous therapy for depression in real-world care settings. Journal of Affective Disorders.

Osmind Announces Publication of the Largest Real-world Analysis of Ketamine Infusion Therapy for Depression

Summary of main findings

Overview

We analyzed ketamine infusion therapy (KIT) outcomes in a subset of 537 depressed patients (out of 9016 patients) between 2016 to 2020 at one of 178 community practices across the United States. This is the largest published real-world analysis of KIT outcomes in a community sample to date. Data was collected through a measurement-based care tool.

Induction

• The most common induction protocol by far was 6 infusions in 2-3 weeks.
• We observed a ~54% response rate and ~30% remission rate at 2-4 weeks post-induction.
• The effect size of KIT induction was d=1.5.
• Response rates were equal across all levels of baseline depression severity.  The largest reduction in depressive symptoms were observed in the most severe patients, but those patients also had the lowest likelihood of remission.
• Just over 40% of patients who had suicidal ideation (SI) at baseline no longer experienced this symptom after induction and over 70% of patients experienced an overall improvement in SI.
• After induction, ~8% of patients worsened in depressive symptoms and ~6% of patients reported increased SI.

Maintenance and relapse

• A patient who responds to KIT induction has an approximately 80% probability of sustaining response at 4 weeks and approximately 60% probability at 8 weeks, even without maintenance infusions.
• Just over 50% of patients elected to go into maintenance treatment. The average number of maintenance infusions was between 2-3.

Key takeaways

1. KIT is a rapid and robust treatment for depression.

• A >50% response rate after 2-3 weeks of ketamine treatment is better than that of any other type of intervention for mood disorders that psychiatry offers, and is comparable to that of TMS which is covered by insurers.
• KIT’s effect size of 1.5 is much higher than that of SSRIs and other antidepressants (e.g. see Munkholm et al., 2019).
• We acknowledge that the lack of demographic and clinical data in our study could temper conclusions, but our data is approximately in line with that of academic trials conducted by Phillips et al. (2019), Singh et al. (2016), Aust et al. (2019) and Wilkinson et al. (2018) who observed response rates between 45-59% after an induction protocol.
• Furthermore, prospective clinical trials typically have narrow inclusion criteria and protocols that do not reflect what happens in clinics in everyday typical usage. Patients in retrospective real-world studies such as this one typically have more complex psychiatric histories than those in a clinical trial and do not always perfectly adhere to protocols. Therefore, to see a positive response in a more heterogeneous group of patients and clinics is encouraging for the field.

2. The response to KIT is also relatively durable, even in the absence of maintenance treatments.

• The probability of sustaining response over time after completing induction was quite high even without maintenance treatments. This finding is important because it alleviates the concern that KIT’s effects are not durable (and therefore requires many infusions over the long-term, which could have unknown health effects and major economic considerations).
• The sustained response to repeated infusions that we observed contrasts with the transient response to single infusions seen in the literature (single infusion protocols do not mirror actual clinical practice, though they are commonly studied in clinical trials). Our data supports the utility of the KIT induction model which has become widely adopted.
• Most patients only return for 2-3 boosters over the course of 2-3 months after induction, presumably because the treatment is so effective, although cost and inconvenience could also explain the relatively short duration of care.

Significance of the study for ketamine clinicians

Clinical

• This study builds on top of existing evidence that KIT is a rapid and effective treatment for depression.
• This study affirms the utility of the KIT induction model providing ~6 infusions in 2-3 weeks followed by a variable maintenance schedule. Treatment response to repeated infusions is more durable than response to single infusions, so it is recommended to provide repeated infusions as part of an induction protocol even if response is seen after the first infusion.
• As some patients experienced increased depressive symptoms or SI, clinicians should exercise caution when treating only mildly ill individuals. KIT is not without potential adverse consequences.
• Clinicians should utilize measurement-based care with rigorous outcomes tracking to track patient improvement over time and provide care personalized to that individual.

Administrative / business

• As persons deeply invested in bringing off-label treatments to patients in need, we hope you can use this paper to obtain broader access to care for your patients and to attract new clients to your practice.
• “This type of real-world evidence is important for establishing the safety and efficacy of new treatments for our patients and for obtaining the support we need from payors to ensure broader access to care for our patients. Throughout my experience advocating for robust insurance coverage of treatments such as ketamine and TMS with major payors, I have found that large sample real-world studies such as this one are paramount for success.” - Carlene MacMillan, MD
• You can use this manuscript and/or its key findings as supporting documentation for conversations with payers or upstream providers (e.g. PCPs who don’t know much about ketamine). When you or your patients seek coverage for KIT for depression, you can include the abstract or entire paper in your requests for consideration to payers. This could be part of an initial request or it could be submitted when appealing an initial denial. This approach is relevant for requesting out-of-network reimbursement, in-network reimbursement, or single case agreements.
• You can use this manuscript and/or its key findings in marketing materials with your prospective or existing patients by highlighting the real-world effectiveness of KIT. You can also showcase how you are at the forefront of providing rigorous measurement-based care, helping fight for improved access to care, and helping contribute to a deeper understanding in the field in order to advance patient outcomes.

"This study alone presents data on more patients than have ever been studied in clinical trials of IV ketamine and underscores the importance of real-world evidence (RWE), especially for the use of off-label medications like ketamine. Clinical trials enroll relatively small numbers of carefully screened patients that may not represent the patients you will see in your practice. RWE furthers the preliminary understanding that we gain from clinical trials to establish the safety and efficacy of treatment interventions in the general population. For example, it will certainly be less expensive for insurers to reimburse for ketamine than for TMS and the two treatments appear to have at least comparable efficacy. Osmind is already working on follow up studies with fuller demographic and clinical data on patients to assess longer term ketamine outcomes and safety."
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- Alison McInnes, MD, MS
Lead author of the paper and VP Medical Affairs at Osmind

"Ketamine therapy for depression is rapidly changing the face of mental health care in the US. The truth is, the need for relief has far outstripped the academic community's ability to generate high quality prospective data on the ever-expanding variety of real world therapeutic practices involving ketamine. The innovation is now happening in the field — our study is the largest of its kind to capture a snapshot of what real-world ketamine clinics are doing, and how their patients fare. I’m thrilled to have teamed up with Osmind to take a first look at such a large set of real-world outcomes, and I'm looking forward to digging deeper into what works, and for whom."
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- Boris Heifets, MD, PhD
Senior author of the paper; professor, physician, and neuroscientist at Stanford

"RWE data collection is taking off in the ketamine space, and it's clear Osmind are field leaders here. I look forward to seeing RWE initiatives being utilised when MDMA and psilocybin therapy become available for patients. It will be essential for assessing their relative merits versus already existing treatment options, including KIT."
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- Robin Carhart-Harris, PhD
Ralph Metzner Distinguished Professor of Neurology and Psychiatry and Founding Director of the Neuroscape Psychedelics Division at UCSF

"The data from this new, retrospective analysis of ketamine infusion therapy by Osmind provides real world evidence that ketamine reduces suicidal ideation and depression. This study is also one of the first analyses to show the durability of the effects of ketamine over time. This coincides with what we have been observing in the real world from applied usage. This study provides real world evidence that ketamine infusion therapy is life changing and should be accessible for all patients through insurance coverage."
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- Kimberly Juroviesky, WHNP, CNM
President of The Ketamine Taskforce for Access to Safe Care and Insurance Coverage

"The pandemic has accelerated the need for real-world research and new, effective treatments that address the global burden of mental health disease. Osmind's first real-world ketamine study underscores the commitment this team has made as a Public Benefit Corporation to operating on principles of social justice and inclusivity, and ensuring robust access to care for patients of all backgrounds."
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- Steve Jurvetson
Prominent philanthropist supporting psychedelic science (e.g. the Psychedelic Science Funders Collaborative); Co-founder of Future Ventures and DFJ