Yale-Led Study Will Compare Effectiveness of IV Ketamine and Esketamine Nasal Spray

Patients are now being recruited for a study to compare the effectiveness of IV ketamine and esketamine nasal spray (otherwise known as Spravato) for people who suffer from treatment-resistant depression.

Physicians from Yale School of Medicine are leading the study and are collaborating with scientists from Emory University in Atlanta, the University of Michigan, and three community sites to recruit about 400 people with depression who seek treatment with either racemic ketamine (IV ketamine), delivered intravenously, or esketamine (Spravato), delivered as a nasal spray. These patients will be randomly assigned treatment with either IV ketamine or Spravato if they are appropriate candidates to receive esketamine.

The study is being funded by a $12.6 million grant from the Patient-Centered Outcomes Research Institute (PCORI). PCORI supports research that produces results that are broadly applicable to a diverse range of patients and care situations and can be more quickly adopted in routine clinical practice.

Gerard Sanacora, MD, PhD, George D. and Esther S. Gross Professor of Psychiatry, and Samuel Wilkinson, MD, associate professor of psychiatry, are the principal investigators on the grant.

Treatment-resistant depression is a type of depression where people do not experience benefits with standard oral antidepressants. The Yale study will be the first to directly compare the two treatment approaches.

Rachel Katz, MD, assistant professor of clinical psychiatry at Yale School of Medicine and a physician at Yale Interventional Psychiatry Service, said researchers want to learn whether IV ketamine and Spravato have similar antidepressant effects.

“We will be treating patients that we often see in our clinic, trying to rigorously answer the question in a real-world setting rather than retrospective data analysis,” Katz said. “We’re hoping to set the record straight about clinical efficacy and comparability.”

IV ketamine has not been approved by the U.S. Food and Drug Administration to treat depression, but Spravato has. Insurance companies often decline to pay for IV ketamine treatments because of the lack of FDA approval, but until now no prospective, randomized study has compared the two treatment options for effectiveness from the patient’s perspective.

There is less long-term data available about the administration of IV ketamine treatments than esketamine. Some scientists, including those at Yale, have advocated for the creation of a ketamine registry to make information about ketamine treatments, including dosage, frequency, and outcomes, more accessible and standardized.

“Not only would (a registry) provide better oversight and safety for patients and patient care, but it would allow an incredible amount of data and information to be collected and categorized,” Katz said.

The patients will give reports on their depression, anxiety, and satisfaction with treatment. The researchers will observe the patient’s response to the drugs and the tolerability of treatments.

The data will be used by the researchers to learn whether IV ketamine and Spravato have similar antidepressant effects or whether they induce different effects.