At-home ketamine tablet may alleviate symptoms of severe depression, trial finds

Over the last 20 years, scientists have shown that ketamine can effectively reduce the symptoms of depression, even in individuals who have not responded to previous antidepressants, which is called treatment-resistant depression.

Research shows that injected ketamine works better than the nasal version, known as esketamine. Also, larger doses are most effective.

A major difference between ketamine and standard antidepressants is the time they take to work. Standard antidepressants can take weeks, whereas ketamine can start working within hours.

Medical News Today spoke with Dr. Pamela Walters, an accredited medical director and consultant psychiatrist who works at Eulas, a ketamine-assisted psychedelic clinic in Scotland.

“Traditional medications often take weeks to start working, and there’s usually a period where it ‘gets worse’ before it gets better,” Walters, who was not involved in the study, explained. “With ketamine, it can relieve depressive symptoms within hours to days.”

MNT also spoke with Chris Pagnani, MD, medical director and founder of Rittenhouse Psychiatric Associates, who was not involved in the study.

“Ketamine can be very effective for patients who have failed multiple medication trials with traditional anti-depressants. It has even been shown to be relatively effective in individuals with severe suicidal ideation,” he told us.

“You can imagine that if someone is struggling with severe depression, a rapid change in their mental state cannot only be appealing, but lifesaving.”
— Chris Pagnani, MD

However, he also explains ketamine’s downsides. Firstly, it “has abuse potential,” and several potential side effects:

• elevated blood pressure
• elevated pulse (tachycardia)
• bladder dysfunction
• liver damage
• nerve damage
• nausea and vomiting
• dizziness
• anxiety
• dissociation

The authors of the recent study hoped that a slow-release oral version of ketamine might also help reduce some of these health risks.

The recent study, called the BEDROC study, tested an experimental slow-release ketamine capsule designed by Douglas Pharmaceuticals in New Zealand called R-107. The drug is designed to slowly release ketamine over 24 hours.

The scientists split the 168 participants with treatment-resistant depression into five groups. One group received a placebo, while the other four groups received varying doses of R-107. In this way, they hoped to identify which dosage might be most effective.

Those in the four ketamine groups took the drug orally twice each week for 12 weeks. They took most of these doses at home.

Compared with the placebo group, all other groups had improvements in their depression symptoms. However, this difference was only statistically significant between those taking the highest dose and those taking the placebo.

The treatment was well-tolerated, but there were some side effects. The most common were:

• dizziness
• headache
• dissociation
• feeling abnormal
• fatigue
• nausea

Participants rated most side effects as mild or moderate. However, eight participants reported severe side effects, including severe depression, severe headache, and chest pain.

The scientists also assessed participants using urine, vital signs, body weight, and heart electrocardiograms but noted no significant changes. This is important because other forms of ketamine are linked to cardiovascular side effects, like hypertension.

As the authors of the study explain, “Other notable differences from adverse events commonly reported after administration of ketamine or esketamine were the absence of cardiovascular side effects, especially relating to increased blood pressure, low rates of dissociation, and also very low rates of sedation.”

Although experts are still investigating the precise mechanisms involved in ketamine’s antidepressant effects, the picture is growing clearer.

MNT spoke with David Merrill, MD, PhD, geriatric psychiatrist and director of the Pacific Neuroscience Institute’s Pacific Brain Health Center at Providence Saint John’s Health Center in Santa Monica, CA.

“Ketamine acts as an NMDA receptor antagonist, which leads to a cascade of neurochemical events in the brain,” explained Merrill, who was not involved in the study.

By binding to NMDA receptors, “it increases glutamate transmission and promotes synaptic plasticity, which are believed to rapidly alleviate depressive symptoms.”

The drug may also work via other mechanisms. For instance, Merrill told MNT that it affects the brain’s default mode network — an area that is activated when the brain is resting but awake — and reduces inflammation, both of which may help reduce symptoms.

“It may also increase brain-derived neurotrophic factor (BDNF) in the brain,” Merrill continued, “something which has also been shown with electroconvulsive therapy” — another treatment option for people with treatment-resistant depression.

While the results of the recent study are hopeful, there is a long road ahead before this drug is widely available.

Next, Douglas Pharmaceuticals needs to conduct longer, larger trials in multiple sites globally to replicate their findings. They will likely need to spend millions more before R-107 reaches the clinic.

However, they are upbeat about the challenge. The company’s chief scientific officer, Dr. Peter Surman writes:

“Should R-107 perform in Phase 3 studies as in the BEDROC study, this would be a life-changing medication for many individuals who suffer from treatment-resistant depression, and one that could be taken safely at home.”