Slow-release ketamine can beat intractable depression

No dissociation required. Meanwhile, our ketamine funding paradox persists.

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A trial of slow-release oral ketamine for depression has shown not only the efficacy of a more convenient formulation, but also a robust antidepressant effect that does not depend on dissociation.  

The phase II study, published in JAMA Network Open, was conceived by New Zealand psychiatrist and clinical pharmacologist Professor Paul Glue, who collaborated with Douglas Pharmaceuticals to produce the extended-release oral formulation in a tablet that was hard to crush or misuse.  

Co-author Professor Colleen Loo told TMR there had long been “clues” that ketamine could improve mood independently from any psychedelic effects – in its history as an anaesthetic, for example.  

“We already had very good evidence that there’s something about ketamine that has very powerful effects in treating depression,” said Professor Loo, a professorial fellow at the Black Dog Institute and professor of psychiatry at the University of NSW.  

“[This study] shows that you can have antidepressant effects with ketamine without the dissociation.” 

The study used an enriched sample, a design previously used with Spravato, the nasal spray form of esketamine.  

A group of 231 people with treatment-resistant depression (screened from an initial 329) were first given 120mg tablets daily for five days. More than two-thirds (168) responded to the treatment (i.e. achieved at least a 50% reduction in their Montgomery-Asberg Depression Rating Scale (MADRS) score)  

Those that responded were then randomised to receive one of four dosages (30mg-180mg) or placebo for a further 12 weeks. Most of the dosing was done at home.  

All treatment groups showed a reduction in depression versus placebo, with the highest dose achieving the strongest effect, which was clinically and statistically significant.  

There was a relapse rate of 70% in the placebo group and 43% for the 180mg group.  

“Tolerability was excellent,” the authors reported, “with no changes in blood pressure, minimal reports of sedation and minimal dissociation.” 

The time to relapse was longer in the treatment groups and increased with dosage, but these results were not significant owing to the small numbers in each subgroup. Only 68 completed the trial across all subgroups, with 100 discontinuing, most for lack of efficacy.  

Professor Loo said the study protocol had anticipated and allowed for withdrawals, and that for a phase II study it was still sizeable.  

The drug didn’t work for everyone, she said – adding that this was true for most treatments for depression – and patients should have a detailed evaluation by a psychiatrist before they were considered for a course of ketamine.  

Nonetheless, the study’s results were “excellent” and laid a clear path for a larger phase III trial pitting one active dose (180mg) against placebo to show safety and efficacy.  

Professor Loo said while ketamine could be used simply as a powerful antidepressant drug, as in this study, it was also emerging in the US as an adjunct to psychotherapy, in the same way psilocybin is approved to be used here.  

She said the two drugs had many similarities, differing mainly in the duration of effect, which was much shorter for ketamine.  

“We’re looking at different ways of giving ketamine and different ways of using it to treat depression,” she said. “There’s another branch … using it combined with therapy to see whether you can get more lasting effects in treating depression.”  

While therapy and antidepressants were likely to remain the first-line treatments in most cases, for treatment-resistant depression Professor Loo said ketamine should ideally precede electroconvulsive therapy as a treatment.  

In fact, an RCT published at the same time in JAMA Network Open found that adults with nonpsychotic treatment-resistant major depression improved more on ketamine than with ECT.  

Thanks to a funding paradox, however, ECT is well subsidised in Australia while the cheaper ketamine is not.  

“There’s good evidence for Spravato and the generic form of ketamine,” she said. “The main problem is people can’t afford it. ECT has been around for eight decades, it’s recognised by Medicare and the private health funds. But ketamine is a new treatment that is not recognised by Medicare.” 

Professor Loo, who works with and researches ECT as well as running a ketamine clinic, said ECT was a powerful and effective treatment for the right patient, but it cost more, required general anaesthesia and was associated with more side effects such as memory loss.  

“The irony is that it would actually be cheaper for the government and the health services to treat people with ketamine than to treat them with ECT. Not only does it make sense clinically, but for the bean counters it would be saving money.  

“The treatment is distorted by this funding situation: they’re not having what is probably the more sensible stepwise treatment pathway, and it’s actually costing our society more to give people the treatment that’s not the best for them.” 

Ketamine also has the distinction of being both too expensive and too cheap. Spravato is not on the PBS; generic ketamine is cheap but not listed, and because it is cheap there is no financial incentive for any pharmaceutical company to sponsor its listing.  

That situation means Medicare cannot create an item number to cover ketamine treatment.  

“You can see why these rules came about, but you can also see that this is one of those situations where someone who has the authority needs to say: in this case the rule is actually preventing people from having more effective and cheaper care,” Professor Loo said.  

JAMA Network Open, 25 June, 2024