Portrait of a peaceful female.Share on Pinterest
New research finds that ketamine may be a more effective treatment for severe depression than electroconvulsive therapy. damircudic/Getty Images
  • A new study compares ketamine with electroconvulsive therapy in people with treatment-resistant depression.
  • The researchers identify subsets of people who respond better to ketamine and vice versa.
  • This study will help guide a more personalized treatment of the condition.

Antidepressants are not effective for all people. Treatment-resistant depression refers to someone who has tried two or more drugs without adequate improvement.

Currently, there is a focus on personalizing treatment plans to increase the chances that the next type of treatment will work for these people.

In a recent study, scientists compared intravenous (injected) ketamine with electroconvulsive therapy (ECT) in people with treatment-resistant depression. While both are common treatments for the condition, they only work in approximately half of patients.

However, the latest study published in JAMA Network Open identifies certain factors that will help doctors determine the course of treatment most likely to work for the individual.

Healthline spoke with one of the study’s authors, Manish Jha, MD, an associate professor of psychiatry at UT Southwestern Medical Center in Dallas, TX.

He explained that if two or more antidepressants have failed to produce results, it “usually indicates that subsequent trials of commonly used antidepressant medications may not be effective.”

According to Jha, two of the remaining options for these individuals are ketamine therapy and ECT.

In previous research, Jha and colleagues showed that both options are effective for some people with treatment-resistant depression. They found that 55.4% of people who underwent ketamine therapy and 41.2% of those who had ECT had significantly improved symptoms.

While these results are positive, they mean that only around half of the participants benefited. In the latest study, Jha and his fellow scientists re-analyzed data from the initial study.

This time, they wanted to drill into the data to identify patient features that might help doctors predict which treatment will work best for them. The results will help shape personalized treatment plans for people with this difficult-to-treat condition.

The new study used data from 365 people with treatment-resistant depression and a mean age of 46. The researchers split them into two groups: 195 in the ketamine group and 170 in the ECT group.

They found that people who started treatment as outpatients and those with less severe symptoms benefited most from ketamine. Conversely, those who started treatment as in-patients and had more severe symptoms responded more quickly to ECT.

Some measures of cognitive function were also related to treatment success. For instance, people who scored worse on a test of verbal intellectual ability responded more favorably to ketamine than ECT.

Similarly, the use of other drugs influenced how well ketamine and ECT worked. The re-analysis showed that 42.9% of people taking atypical antipsychotics alongside ketamine improved significantly. These drugs are often used after other depression treatments have failed. In contrast, however, of those taking atypical antipsychotics alongside ECT, only 10.6% improved.

Jha told Healthline that they were surprised by this “big difference in remission rates.”

“We found the remission rates to be about four-fold higher in the ketamine treatment group as compared with ECT,” he explained. However, when they adjusted the data to account for a range of variables, this effect disappeared.

So, according to Jha, “these findings will need to be replicated.”

Interestingly, the analysis also showed that people with a higher body mass index (BMI) were more likely to respond well to ketamine than those with lower BMIs. Although scientists do not know why this might be, there are some theories.

Jha suggested that it might be due to the size of the dose — the researchers gave people 0.5 milligrams per kilogram, so someone who is heavier will receive a larger total amount of ketamine.

“Other potential reasons include ketamine’s impact on circuits that are affected by inflammation,” he explained, “obesity is a common factor resulting in a state of inflammation, which in turn has been associated with symptoms of depression. However, these are speculations, and more work is needed to understand this association better.”

Healthline spoke with David Merrill, MD, PhD, a 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.

In agreement with Jha, Merrill, who was not involved in the study, explained that “there could be biological factors related to adipose [fat] tissue and the inflammatory state often associated with higher BMI that ketamine effectively targets.”

Understanding which treatments will work best or most quickly is important. People with treatment-resistant depression have a higher likelihood of harming themselves and experiencing other distressing symptoms.

By the time an individual has received a diagnosis of treatment-resistant depression, they have likely spent months or years trying treatments. Making sure they finally receive a treatment that works is vital.

How soon could these results be used to guide clinical practice?

“The findings can be useful in clinical practice right away by informing shared decision-making approaches,” he told Healthline. “However, definitive prospective studies are needed to validate these findings to implement large-scale system-wide changes.”

Merrill was also excited by the results, “The finding that ketamine can be more effective for outpatients and those with moderately severe depression is particularly noteworthy and somewhat surprising given the traditional dominance of ECT in severe cases.”

Jha told Healthline that intravenous ketamine is not always covered by insurance, which will be a barrier for many people.

Merrill echoed this sentiment, saying, “It would be great to see insurance coverage of the various forms of ketamine treatment now widely available as cash-pay services.”

“Unfortunately,” he continued, “this has created at least a two-tier system of haves and have-nots. Others literally take on debt to see if non-covered treatments will work, which is understandable but ultimately further destabilizes those with treatment-resistant depression.”

To answer this question, Healthline spoke with Dr. Pamela Walters, an accredited medical director and consultant psychiatrist who works at Eulas, a ketamine-assisted psychedelic clinic in Scotland.

“​​Ketamine relieves depression by working on the brain in a unique way,” explained Walters, who was not involved in the study. “It essentially blocks NMDA receptors, which are involved with the neurotransmitter glutamate.”

“This blockade,” she continued, “increases glutamate levels, promoting the growth of new connections between neurons, particularly in areas of the brain that regulate mood. This process helps restore normal brain function and alleviate depressive symptoms quickly.”

She also explained that ketamine influences a wide range of pathways and receptors in the brain.

Most standard antidepressants take weeks or months to work. Ketamine is different in this respect, making a measurable difference, sometimes within hours.

“Compared to other treatments, ketamine’s fast action and novel mechanism provide a valuable option, especially for those who haven’t found relief with other medications,” explained Walters.

The results of a new study will help guide clinicians as they choose treatment options for people with treatment-resistant depression.

By re-analyzing data, they showed that certain populations are more likely to respond to ketamine than ECT, and vice versa.

Although more research is needed, the results will help get people started on the most effective treatment for them.

As Merrill told Healthline, “This nuanced understanding helps clinicians tailor treatments more effectively to individual patient needs, potentially improving outcomes and patient satisfaction.”