Ketamine for severe depression: 1 in 5 achieve remission after a month in ‘promising’ Aussie trial

A month-long course of ketamine injections may be an effective treatment for severe depression, say Australian doctors who found “promising” remission rates in their largest-of-its-kind trial.

One in five adults in the Ketamine for Adult Depression Study (KADS) achieved total remission from their symptoms after a month of twice-weekly subcutaneous ketamine injections, reported the UNSW Sydney–led team.

And nearly a third of the 179 participants with treatment-resistant depression in the placebo-controlled trial had a 50% reduction in symptom severity.

However, these benefits disappeared after treatment cessation, which the researchers said suggested a need for longer-term treatment to maintain the antidepressant effects.

Lead researcher Professor Colleen Loo told AusDoc that this result was “not unexpected”.

“The data to date on ketamine suggest significant risk of relapse when treatment is stopped,” the Sydney psychiatrist said.

“We don’t want to tell people they need to continue with treatment beyond four weeks unnecessarily, … but we now have good data that demonstrate this.

“Regardless of when the ketamine stops, follow-up is very important as that is when people are at risk of relapse.”

While researchers were yet to determine a set protocol for ongoing treatment, Professor Loo said the frequency of injections could be reduced to once weekly and then fortnightly before stopping completely, if possible.

“For many, ongoing treatment for weeks to months will be needed to maintain response and allow them to reclaim their lives.”

As part of the multi-centre trial, participants were randomly assigned to receive subcutaneous racemic ketamine or active control with midazolam, which has psychoactive properties (see protocol below).

They were then monitored in the clinic for two hours while the dissociative and sedative effects wore off.

The primary outcome was remission at the end of the treatment period and four weeks later, measured by the Montgomery–Åsberg Rating Scale for Depression (MADRS).

Overall, 20% of those given ketamine achieved remission at treatment cessation compared with 2% in the control group.

However, the remission rate in the ketamine group dropped to 8% versus 2% among midazolam recipients at four-week follow-up: a non-significant between-group difference of 6%.

“This supports other evidence that ongoing treatment is required to maintain antidepressant effects for most participants,” the authors wrote in the British Journal of Psychiatry.

They added that ketamine treatment was well tolerated with no major side effects.

Professor Loo said a key strength of the trial was the absence of an upper limit on depression severity among participants.

This meant even those with very high levels of treatment resistance were enrolled, including patients who had previously failed to respond to ECT.

The clinicians also highlighted the low cost of the generic ketamine used in the trial, which costs about $5 per dose compared with about $800 for the patented esketamine nasal spray currently in use.

Professor Loo said the Black Dog Institute had already made an application to the Medical Services Advisory Committee for an MBS item to fund the treatment, with a suggested cost of $350 for the monitoring at each treatment session.

“[If] you consider that many of these people might spend many months in hospital or be unable to work and are often quite suicidal, it is quite cost-effective when you see how incredibly quickly and powerfully [subcutaneous ketamine] works,” she said.

“We have seen people go back to work, study or leave hospital because of this treatment in a matter of weeks.”

She said future studies would be aimed at whether ketamine in combination with other therapies was also effective and how it compared with psilocybin-assisted therapy for treatment-resistant depression.

The study was the largest randomised controlled trial to date of racemic ketamine tested against placebo in patients with treatment-resistant depression.

The KADS method

The phase III trial recruited participants from six specialist mood disorder centres in Australia and one in New Zealand.

The inclusion criteria was:
– Aged over 18
– Major depressive disorder of at least three months’ duration and confirmed by the Structured Clinical – Interview for DSM-5 Research Version
– Insufficient response to at least two adequate trials of antidepressant medications
– Stable dose of any concurrent antidepressant medication for more than four weeks prior to and during the randomised controlled trial
– A score of greater than 20 on the MADRS

Ketamine and midazolam were given subcutaneously into the abdominal wall twice a week for four weeks, with at least three days between treatments.

The initial trial protocol involved fixed doses at 0.5mg/kg ketamine and 0.025mg/kg midazolam.

But a routine Data Safety Monitoring Board reviewing data from the first cohort recommended switching to flexible dosing as no participants had permitted and the safety profile was good.

For the second cohort, if participants had not improved by 50% from pre-treatment baseline in MADRS scores at session two, four and six, dose escalation steps were 0.6mg/kg, 0.75mg/kg and 0.9mg/kg ketamine and 0.03mg/kg, 0.0375mg/kg and 0.045mg/kg midazolam.

After the four-week treatment period, participants continued any antidepressant medications that were established prior to study entry, with dose unchanged prior to and during the trial.

Any patients who had relapsed at the second follow-up — week eight — were eligible to enter an open-label treatment phase.

More information: Br J Psychiatry 2023; 14 Jul.