Depression: 4-week ketamine injections prove effective

In 2019, the Food and Drug Administration (FDA) approved Spravato (esketamine), a commercially developed nasal spray, for treatment-resistant depression in adults and depressive symptoms in adults with major depressive disorder with acute suicidal ideation.

Racemic ketamine it is approved for use as an anesthesia in the United States. Doctors also use it as an off-label depression treatment, meaning they prescribe it for a different condition than the FDA-approved specifications.

Racemic ketamine is too less expensive by Spravato.

For the present study, conducted by researchers at the University of New South Wales Sydney (UNSW) and its affiliate Black Dog Institute, participants received biweekly injections of either racemic ketamine or a placebo.

Dr Colleen Loo, trial lead researcher and clinical psychiatrist and professor of psychiatry at UNSW, said Medical News Today who began looking into the effects of ketamine on depression in 2011. Previously, he had researched the use of ketamine within anesthesia for electroconvulsive therapy (ECT)

This clinical trial, he said, is the largest to compare racemic ketamine with a placebo for treatment-resistant depression.

Dr. Loo pointed out another key aspect of the study: About a quarter of the participants had already received and failed to respond to ECT treatment.

ECT is a highly effective treatment for severe, treatment-resistant depression, so it means these people had high-end treatment-resistant depression, he explained.

This group [is] usually excluded from studies, because it is very difficult to get any treatment to work once people have had ECT and are still not well. This study provides evidence for the efficacy of ketamine at least in the racemic form in depression with a high level of treatment resistance.
Dr. Colleen Loo

The fact that the study participants received injections of racemic ketamine rather than more expensive and time-consuming infusions is also noteworthy, according to Dr. Loo, as it means that this cheaper alternative is also effective.

The researchers enrolled 184 people with treatment-resistant depression in the study, which they called Ketamine for Adult Depression (KADS). The research was conducted at six clinical centers for mood disorders in Australia and one in New Zealand.

Participant recruitment began in August 2016 and concluded in April 2020.

The researchers hoped to recruit more participants for the trial, but when the pandemic hit, they decided to stop recruiting, Dr Loo explained to MNT extension.

Participants were 18 years of age or older and had been suffering from major depressive disorder for at least 3 months. Furthermore, they must have had an inadequate response to at least two antidepressants.

Participants had to have been taking the same dosage of their current antidepressant for more than 4 weeks before starting the study. They also needed to score at least 20 on the Montgomerysberg Rating Scale for Depression (MADRS).

Participants were randomly assigned to receive injections of racemic or ketamine midazolamwhich is often used to help patients relax before surgery.

Healthcare professionals injected the participants’ abdominal walls twice a week for 4 weeks, with at least 3 days off between each treatment.

Participants didn’t seem to mind getting injections in the abdomen, according to Dr. Loo.

The injection used a very small needle to inject ketamine under the skin, she said. It can be done anywhere arm, leg, abdomen but we did it in the abdomen because there is usually more fat there under the skin [so] it’s more comfortable.

Neither the participants nor the researchers administering the drug knew which participants were receiving racemic ketamine. Midazolam was chosen as a placebo because, like ketamine, it causes sedation, which helped prevent participants from knowing which drug they would receive.

Initially, 73 participants were randomized to receive a fixed dose of 0.5 milligram per kilogram of racemic ketamine or 0.025 milligram per kilogram of midazlolam.

A drug dosing review was recommended at a routine Data Safety Monitoring Committee meeting because no participants in the entire masked sample had remitted and the safety profile was good, study authors write.,

As a result, the dosing was revised and in a second group, 108 participants were randomized to receive flexible dosing of ketamine or midazolam. Response-guided dosing has been implemented. If patients had not improved 50 percent from baseline scores in sessions two, four, or six, doses of racemic ketamine were increased to 0.6 milligram per kilogram, 0.75 milligram per kilogram, and 0.9 milligram per kilogram. Participants who received midazolam also received increased doses.

Participants were included in the study if they received at least one injection. The study authors note that the majority received all eight doses.

Most participants in the flexible dosing group switched to the higher dose of racemic ketamine. This proved to be an important aspect of the study, according to Dr. Loo. He has shown that individual dose adjustments, down to the dose each person requires for response, are very important for best results, he said.

The researchers used the Ketamine side effects tool (KSET) to understand the acute and long-term side effects associated with multiple treatments of racemic ketamine.

They followed up with the participants after the final injection and again four weeks later. Participants who had relapsed could enter an open-label treatment phase, meaning they would be aware of the treatment they were receiving.

The study used a very detailed and comprehensive approach to safety monitoring, tracking the cumulative effects between treatments, not just in the two hours following each treatment, or just investigating at the end of the four weeks, said Dr. Loo.

In the study paper, the researchers write that if ketamine treatment is stopped after 4 weeks, the benefits are not maintained for all remittances and that ongoing treatment should be considered.

The researchers added that most participants chose to start open-label treatment at the end of the 4 weeks.

About 1 in 5 participants receiving a flexible dose of racemic ketamine achieved total remission of symptoms one month after the injections compared with only 2% who achieved total remission in the placebo group.

Nearly 30% of participants treated with ketamine saw symptoms improve by at least 50% compared with 4% with placebo.

Dr. Loo wasn’t surprised to see a 20% remission rate, which she described as good enough for treatment-resistant depression.

The results here are actually very encouraging, Dr. Loo said. Even in people with depression at the high end of treatment resistance that were excluded from most previous studies, ketamine was still very effective, with an impressive 10 [times] difference from placebo.

In the future, researchers would like to conduct larger trials of generic ketamine over longer periods and continue to refine KSET.

Dr. David Mahjoubi, medical director of the Ketamine Healing Clinic in Los Angeles and Orange County who was not involved in this study, said MNT extension that trial looked at the administration of racemic ketamine via injections.

So it’s different from the IV [intravenous] shape so as not to enter that dissociative experience, which we believe contributes at least in some way to the therapeutic mechanism.
Dr. David Mahjoubi

Additionally, Dr. Mahjoubi noted that not all study participants received the same number of injections of racemic ketamine, [s]or this is a huge variable.

People with the same number of [injections] it should have been compared, advised Dr. Mahjoubi.

The doctor, who opened his first clinic eight years ago, has found that patients often don’t get the benefit of ketamine after their first or second infusion. It takes three or four infusions, he said.

He suggested that more participants could have seen their symptoms improve if they had received all eight injections.