Ketamine’s relief tends to last as long as the doses keep coming, and not always even then
STUDY: Vasudeva S et al, Psychiatry Research 2027
STUDY TYPE: Systematic review (43 studies)
FUNDING: Independent
Background
Ketamine and esketamine relieve treatment-resistant depression within hours, but a single course rarely lasts. Therapy may sustain its benefits, but most medications do not. This review asked how long the antidepressant effects keep up with repeated maintenance dosing.
The Study
- 43 studies of people with mood disorders who received at least 8 treatments or a month of ketamine or esketamine.
- Designs included 8 randomized trials and extensions, 4 open-label studies, 24 observational cohorts, and 7 case series.
- Routes ranged from intravenous to intranasal and oral. Follow-up ran from a few weeks to 6.5 years.
- Outcomes were sustained response, remission, and relapse, mostly on the clinician-rated MADRS or patient-rated PHQ-9.
Results
Continued dosing kept most responders well, and depression usually returned when the dose was stopped..
The strongest evidence comes from a phase 3 esketamine trial. Among patients who recovered fully, 27% relapsed on continued esketamine versus 45% who were switched to placebo (number needed to treat, NNT 6, a moderate effect).
Among responders who had not fully remitted after a course of esketamine, relapse was 26% versus 58% (NNT 4). That’s a bigger effect, suggesting people who don’t recover fully are more likely to need maintenance.
Other trials also suggest a continued benefit:
- Oral ketamine for 12 weeks at 180 mg twice weekly: 43% relapsed versus 71% on placebo.
- Intravenous ketamine for 4 weeks: 91% of responders held their response, but relapse was common within 2 to 3 weeks of stopping.
- An open-label esketamine extension followed patients up to 6.5 years, and only 4.5% stopped for lack of a continued benefit.
- Esketamine was slightly more effective than quetiapine in the long-term (32 weeks) head-to-head randomized ESCAPE-TRD trial (industry funded).
Real world studies were more mixed. Many saw stable or growing improvement over 6 to 12 months, while others saw the benefits fade despite ongoing doses. Four of the seven case series reported high relapse rates over time, suggesting no maintenance benefit.
Limitations
We have only one long-term, placebo controlled trial, which was industry funded. The evidence has gaps. Most observational studies had serious risk of bias. Bipolar depression was rarely analyzed on its own.
Practice Implications
- We haven’t found medications that replace ketamine, other than ketamine itself. Tolerance, while possible, is rare in these studies.
- When stretching intervals, step down gradually, from weekly to every other week, and stay on the schedule that keeps scores stable.
- Ideally, ketamine is paired with psychotherapy and behavioral change to extend its benefits. That is the strategy behind the Montreal model, described in Difficult to Treat Depression.
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
