Wednesday 19 July 2023

Ketamine offers hope for people with treatment-resistant depression


A new Australian study trialing the use of a low-cost variety of ketamine for treatment-resistant depression has shown promising results, opening the door to an effective, affordable treatment where other treatments have failed.

Major depressive disorder is a leading cause of disability globally. For around one-third of people with the condition, standard treatments are ineffective, and they’re deemed ‘treatment-resistant.' So, the hunt is always on for alternative, effective treatments.

Ketamine was first synthesized in 1962 and approved for medical use as an anesthetic by the FDA in 1970. Before long, ketamine made its way to the streets. Known as “Special K,” it gained popularity as a party drug in the ’70s and ’80s before the US made it a federally controlled drug in 1999 due to its potential for misuse or addiction. It wasn’t until the 2000s that researchers started exploring ketamine as a treatment for depression.

Now, a new Australian study led by researchers at the University of New South Wales trialing generic ketamine as a treatment for people with severe depression has provided some promising results.

Ketamine is what’s termed a dissociative anesthetic because it distorts a user’s perceptions of sight and sound and makes them feel detached or disassociated from pain and their environment.

The Ketamine for Adult Depression Study (KADS) was a four-week, randomized trial that recruited 176 participants from mood disorder centers in Australia and New Zealand. Participants had to have been diagnosed with a major depressive disorder for at least three months and had an insufficient response to antidepressant medication.

All of the participants were given either a generic form of ketamine that’s widely available in Australia, or a placebo. They received two injections a week in a clinic where they were monitored for two hours, until acute dissociative and sedative effects wore off. The treatment was continued for a month, and participants were asked to assess their mood at the end of the trial and one month later.

The trial was double-blind, meaning that neither the researchers nor the participants knew which patients received ketamine and which received the placebo. In this case, the placebo was midazolam, a benzodiazepine that also has a sedative effect. This was done to improve treatment masking and minimize the likelihood of bias.

“Because there are no subjective effects from the saline [used as a placebo], in previous studies it became obvious which people were receiving the ketamine and which people received placebo,” said Colleen Loo, the lead author of the study. “In using midazolam – which is not a treatment for depression, but does make you feel a bit woozy and out of it – you have much less chance of knowing whether you have received ketamine, which has similar acute effects.”

What also set the KADS trial apart from previous studies is that the researchers recruited participants who’d previously received electroconvulsive therapy (ECT) as a treatment for depression. ECT is a procedure performed under general anesthetic in which carefully controlled electric currents are passed through the brain, intentionally triggering a brief seizure. ECT causes changes in brain chemistry that may temporarily relieve severe depressive symptoms where other treatments have failed.

“People are recommended ECT treatment for their depression when all other treatments have been ineffective,” Loo said. “Most studies exclude people who have had ECT because it is very hard for a new treatment to work where ECT has not.”

And instead of administering ketamine intravenously, the researchers injected it under the skin (subcutaneously), reducing time, cost, and medical complexity.

The researchers found that more than one in five participants achieved total remission of their symptoms after a month of bi-weekly injections, while one-third had their symptoms improve by at least 50%. Ketamine was also well tolerated by the participants. These findings, the researchers say, are encouraging.

“For people with treatment-resistant depression – so those who have not benefitted from different modes of talk therapy, commonly prescribed antidepressants, or electroconvulsive therapy – 20% remission is actually quite good,” said Loo. “We found that in this trial, ketamine was clearly better than the placebo – with 20% reporting they no longer had clinical depression compared with only 2% in the placebo group. This is a huge and very obvious difference and brings definitive evidence to the field, which only had past smaller trials that compared ketamine with placebo.”

In Australia and the US, a patented version of ketamine called esketamine (sold as Spravato) is available as a nasal spray for treatment-resistant depression, to be used in combination with an oral antidepressant. However, for many, the cost of the medication is prohibitive. In the US, in 2020, the cost of esketamine was US$240 (AU$348) per dose. In Australia, the cost is around AU$800 (US$550) per dose. In both countries, users must use the drug in a clinical setting, which attracts an additional cost.

According to the researchers, the effects of ketamine wear off after a few days to weeks, so ongoing treatment is required. Which is why they are pushing for Medicare, Australia’s national health insurance program, to approve the use of generic ketamine, which costs as little as AU$5 (US$3.40), depending on the supplier.

The researchers will next undertake larger trials of generic ketamine over longer periods.

The study was published in the British Journal of Psychiatry.

Source: University of New South Wales/NewAtlas.

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