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
Nick Glozier, Richard W. Morris, Elizabeth Stratton, Andrew A Somogyi, Shanthi Sarma, Anthony Rodgers, Verònica Gálvez-Ortiz, Stevan Nikolin, Philip B Mitchell, Natalie T Mills, Donel Martin, Sean Hood, Dusan Hadzi-Pavlovic, Maree Hackett, Paul Glue, Vanessa Dong, Mary Lou Chatterton, Gregory Carter, Michael Berk, Adam Bayes, Bernhard T Baune, David Barton, A Gomez Alonzo, Colleen Loo
The British Journal of Psychiatry July 6, 2026 DOI: 10.1192/bjp.2026.10692 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Open label extension of a randomized controlled trial Open-label Peer reviewed |
|---|---|
| Sample size | 130 |
| Population | Adults with treatment-resistant depression from seven mood disorder centers in Australasia |
| Intervention | subcutaneous racemic ketamine |
| Dose | 0.5 mg/kg (fixed regimen) or 0.5-0.9 mg/kg (flexible regimen with response-guided increments) |
| Duration | 4-week intervention, with assessments at 4 weeks and 6 months after treatment end |
| Topics | Depression Ketamine Esketamine |
| Keywords | Dosing Depression economics Subcutaneous injection Randomized controlled trial Regimen Adverse effect Mood Anesthesia Clinical trial Open label Rating scale Clinical endpoint |
| Key findings | A 4-week course of subcutaneous racemic ketamine produced short-term clinical benefit in a minority of participants, with response rates declining substantially after treatment cessation and no unexpected safety concerns. |
Abstract
Background: Longer-term outcome and safety data of repeated subcutaneous racemic ketamine for treatment-resistant depression (TRD) is lacking, as is knowledge of the impact of prior ketamine treatment on subsequent response.
Aims: To evaluate the effectiveness and safety of a 4-week course of subcutaneous racemic ketamine over 6 months and investigate whether prior ketamine treatment influences treatment response.
Method: An open label extension (OLE) of a randomised controlled trial (RCT) was conducted at seven mood disorder centres in Australasia, enrolling consenting trial participants who had a Montgomery-Åsberg Depression Rating Scale (MADRS) score of ≥20 at post-trial assessment. Participants initially received twice-weekly 0.5 mg/kg subcutaneous racemic ketamine (fixed regimen) for 4 weeks. Dosing was revised after a Data Safety Monitoring Board recommendation, to a 'flexible regimen' (0.5-0.9 mg/kg with response-guided increments). Depression and safety outcomes were assessed throughout treatment, and 4 weeks and 6 months later.
Results: 130 RCT participants entered the OLE phase of whom 32 underwent the fixed OLE regimen and 98 the flexible regimen. At treatment end, 30% (36/116) had responded (MADRS reduction ≥50%), and 4 weeks later 17% (19/110) were 'responders'. Over 50% experienced <25% MADRS reduction. There was no difference in depression response at any time point between regimens. Those treated with ketamine during the RCT showed a transient reduced response after first OLE treatment but at no other assessment point. There were no reports of suicide or suicidal behaviour requiring admission and only expected side-effects observed.
Conclusions: In a highly treatment-resistant sample, a 4-week course of subcutaneous racemic ketamine produced short-term clinical benefit in a minority of participants, with response rates declining substantially after treatment cessation, and no unexpected safety concerns. Exploratory subgroup analyses showed no association between prior RCT ketamine exposure and OLE outcomes.
Trial Registration: ACTRN12616001096448 at www.anzctr.org.au.