Sophie Holmes, Contributing Photographer

Yale researchers are currently conducting the first clinical trial that tests the use of ketamine as an antidepressant for patients with Parkinson’s disease. 

Sophie Holmes, an assistant professor of psychiatry and neurology at the Yale School of Medicine, is spearheading this research. According to Gerard Sanacora, the director of the Yale Depression Research Program and a professor of psychiatry at the medical school, research on the use of ketamine as an effective antidepressant in rodents has been widely available for over 20 years. However, no researchers have been able to translate the findings in mice into clinical research for human use. 

“I’ve been using neuroimaging to research depression for the past 10 years, but since coming to Yale [I] have been particularly interested in ketamine — given its ability to rapidly reduce symptoms of depression,” Holmes wrote in an email to the News. “Specifically, I wanted to understand how it works in the brain — what are the mechanisms that underlie its therapeutic effects? Can we capture these changes using brain imaging?” 

Sanacora explained that, at the clinical level, depression often occurs alongside Parkinson’s disease. At the same time, standard antidepressants such as Prozac or Zoloft are often less effective in patients suffering from Parkinson’s. In addition, neurodegenerative processes, such as those induced by Parkinson’s disease, may be halted or reversed by a drug like ketamine that induces neuroplasticity, the brain’s ability to form new synapses.  

Previous studies have shown that rodents in chronic stress models, meaning models designed to emulate the conditions of depression, undergo visible neurodegeneration. In these cases, the administration of ketamine led to increased synaptic density in these rodents.

“Animal work consistently shows that chronically stressing out rats results in a loss of synaptic connections and depressive-like behavior,” Holmes wrote. “In other words, synaptic loss, especially in brain regions associated with emotional regulation, is thought to underlie depression. We think ketamine works by restoring these lost synapses and forming new pathways that can bypass rigid pathways associated with negative thought patterns and depression.” 

However, Sanacora added, there is no way to ask the rodents how they are feeling, so researchers have struggled to quantify the efficacy of ketamine treatments. 

Holmes added that work in animal models has proven that ketamine enhances synapses and has “neuroprotective” effects. Since ketamine works by increasing synaptic density and Parkinson’s disease is characterized by a loss of synapses, the decision to study ketamine as a potential solution for the neurodegenerative actions of the disease was logical.

The current trial is split into two experimental methods. According to Sanacora, the first section is a randomized placebo control clinical trial. Since the Federal Drug Administration has already approved the use of S-ketamine in treating depression, researchers can actually administer ketamine to patients at Yale New Haven Hospital. 

“Patients with Parkinson’s and symptoms of depression will have a course of ketamine or placebo treatment,” Sanacora said. “It will be completely randomized, whether a patient gets active ketamine or a placebo. The primary measure there is how well their depressive symptoms respond.”

Holmes added that 50 patients will either receive six “infusions” of ketamine or a placebo over the course of the next three weeks. 

Then, the second experimental method is to select a subset of participants for brain imaging. The researchers will use MRIs or PET scans to measure the effects of the ketamine infusions on the patients’ brains.

“A lot of research suggests that ketamine works by increasing the number of synaptic connections in the brain, making the brain more ‘malleable’ and allowing new pathways to form, which can encourage new, more helpful ways of thinking,” Holmes wrote. “Using PET imaging, we will explore whether changes in synaptic density after ketamine treatment underlie any therapeutic effects.”

According to the U.S. National Library of Medicine, the ketamine infusion will be replaced by a saline infusion for the patients receiving a placebo. In addition, the clinical trial is currently in phase 2, meaning that researchers are “gathering preliminary data on whether a drug works in people who have a certain condition/disease” — in this case, Parkinson’s disease. 

This current trial is addressing a major unmet need in medical care for patients with Parkinson’s disease, according to Sanacora. He emphasized that there is a strong need for effective antidepressant treatments for patients suffering from this disease, yet there currently is no alternative to the standard treatments.

“Depression takes a major toll on patients with Parkinson’s disease.” Sanacora said. “The ability to develop something that can mitigate that feeling is so important, especially as the population ages.”

For Holmes, this trial also has personal significance. Her father was diagnosed with Parkinson’s disease around five years ago. By watching his experience and reading to learn more about the disease, she realized how “pervasive” and “debilitating” depression can become for patients suffering from Parkinson’s disease.

The study began on Nov. 23, 2021 and is planned to end in August 2024.