Six months after a repeat ketamine course, only 17% still counted as responders

Much of the enthusiasm around ketamine for treatment-resistant depression rests on its dramatic short-term effects, but longer-term data on repeated courses, and on how prior ketamine exposure affects later treatment response, has been comparatively sparse. A study published this month in the British Journal of Psychiatry, an open-label extension of the KADS trial conducted across seven mood disorder centres in Australia and New Zealand, adds real-world duration to that picture — and the results are considerably more modest than ketamine's rapid-response reputation might suggest [s1].

The design

This open-label extension enrolled 130 participants from an earlier randomized controlled trial who still had significant depression (Montgomery-Åsberg Depression Rating Scale score of 20 or higher) at post-trial assessment [s1]. Participants initially received a fixed regimen of twice-weekly 0.5 mg/kg subcutaneous racemic ketamine for four weeks; following a Data Safety Monitoring Board recommendation partway through the study, dosing was revised to a "flexible regimen" of 0.5–0.9 mg/kg with response-guided dose increases [s1]. Of the 130 participants, 32 underwent the fixed regimen and 98 the flexible regimen [s1]. Depression and safety outcomes were tracked throughout treatment and at 4 weeks and 6 months afterward [s1].

What it found

At the end of the four-week treatment course, 30% of participants (36 of 116 assessed) had responded, defined as at least a 50% reduction in MADRS score [s1]. That response rate fell substantially by four weeks later: only 17% (19 of 110) still qualified as responders [s1]. Over half of all participants experienced less than a 25% reduction in depression symptoms at any point [s1]. There was no significant difference in depression response between the fixed and flexible dosing regimens at any timepoint [s1]. Participants who had received ketamine during the original randomized trial showed a transient, reduced response after their first extension-phase treatment, but not at any other assessment point [s1]. There were no reports of suicide or suicide-related hospital admission during the study, and only expected, previously documented side effects were observed [s1].

Why this population and this result matter for calibrating expectations

This trial specifically studied a "highly treatment-resistant sample" [s1] — participants who had already been through a prior randomized ketamine trial and still had significant depression afterward, meaning this cohort represents people for whom an initial course of ketamine hadn't already resolved their depression. A 30% response rate at treatment's end, falling to 17% a month later, in exactly this population is a materially more modest result than the striking short-term effect sizes reported in trials of less treatment-resistant populations (including, for instance, the separate JAMA Psychiatry meta-analysis published the same month reporting large effect sizes for ketamine's acute antidepressant impact) — a reminder that ketamine's benefit, like most psychiatric interventions, varies substantially by how treatment-resistant the population being studied actually is.

The declining response curve is the study's central, sobering finding

The drop from 30% response at treatment end to 17% just four weeks later illustrates a durability problem that a purely short-term trial wouldn't capture: whatever benefit repeated ketamine dosing produced in this population largely didn't hold. Combined with the finding that over half of participants never achieved even a 25% symptom reduction at any point, this data paints a considerably more tempered picture of repeated ketamine's effectiveness in a genuinely treatment-resistant population than headlines about rapid-acting antidepressants often convey.

What this doesn't establish

This is an open-label study — no placebo comparison group, no blinding — meaning the response rates reported can't be cleanly separated from expectation effects, natural symptom fluctuation, or the general benefits of engaged clinical monitoring, though this limitation is somewhat offset by the study's specific focus on describing what happens with continued treatment rather than on establishing efficacy versus placebo, which the original randomized trial was designed to test. The absence of a difference between fixed and flexible dosing regimens is informative but based on comparing 32 versus 98 participants, an uneven split that limits how confidently that specific comparison can be read.

What the authors conclude

The study's authors describe repeated subcutaneous ketamine as producing "short-term clinical benefit in a minority of participants, with response rates declining substantially after treatment cessation" in this highly treatment-resistant sample, while noting no unexpected safety concerns emerged [s1] — a summary that neither dismisses ketamine's value nor oversells its durability in this specific, difficult-to-treat population.

What to watch

Whether maintenance dosing protocols, rather than fixed treatment courses followed by cessation, can better sustain the response documented here, and how this treatment-resistant population's more modest outcomes compare against less resistant populations in future direct comparisons. This article describes off-label ketamine use in a clinical trial setting; it is not medical advice.

Sources

1. Effectiveness and safety of repeat dose subcutaneous ketamine for treatment-resistant depression, and the impact of prior ketamine treatment: open label extension of the KADS study — British Journal of Psychiatry, 6 July 2026