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Oral prolonged-release ketamine showed minimal dissociation

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Research area:medicine-clinical

What the study found

The study found that KET01, an oral prolonged-release racemic ketamine tablet, caused little dissociation and few cardiovascular changes, but it did not meet its main antidepressant outcome at day 21 in treatment-resistant depression. The authors also observed early reductions in depression scores after the first dose.

Why the authors say this matters

The authors conclude that the antidepressant properties and tolerability profile of KET01, including minimal dissociation and cardiovascular effects, support further development of the oral KET01 formulation for at-home administration. Here, dissociation means a detached or altered state of awareness, and cardiovascular refers to heart and blood vessel effects.

What the researchers tested

The researchers ran two randomized clinical trials. KET01-03 was a phase 1 crossover study in healthy adult men comparing a single 240 mg dose of KET01 with intranasal esketamine, and KET01-02 was a phase 2 placebo-controlled study in adults with treatment-resistant depression testing 120 mg/day or 240 mg/day of KET01 added to standard therapy for 3 weeks.

What worked and what didn't

In KET01-03, intranasal esketamine produced significant dissociation within 24 hours, while KET01 did not. In KET01-02, the primary day 21 depression outcome was not met for 240 mg/day KET01 versus placebo, although lower depression scores were seen 7 hours after the first 240 mg dose and at days 4 and 7; the day 4 and day 7 differences were reported as nominally significant.

What to keep in mind

KET01-03 included only 26 healthy adult males at one site, so its findings are limited to that group. KET01-02 did not meet its primary endpoint, and the abstract does not describe other limitations beyond the study designs and sample sizes.

Key points

  • KET01 is an oral prolonged-release racemic ketamine tablet studied for treatment-resistant depression.
  • Intranasal esketamine caused significant dissociation in the phase 1 trial, while KET01 did not.
  • Pulse and blood pressure did not change markedly with KET01, unlike the rapid increases seen with intranasal esketamine in KET01-03.
  • The main depression outcome at day 21 was not met in the phase 2 trial.
  • Early reductions in MADRS depression scores were observed after the first 240 mg dose of KET01.
  • The authors say the findings support further development of oral KET01 for at-home administration.

Disclosure

Research title:
Oral prolonged-release ketamine showed minimal dissociation
Authors:
Martin Walter, Christine zu Eulenburg, Ani Damyanova, Karin Schmid, Isabel Schwienbacher, Evangelos Papanastasiou, Katarina Maiboe, Lars Arvastson, C. Strote, D. Gehrlach, Hans Eriksson
Institutions:
Boehringer Ingelheim (Germany), Develco Pharma (Switzerland), HolsboerMaschmeyer NeuroChemie (Germany), HolsboerMaschmeyer NeuroChemie (Germany), HolsboerMaschmeyer NeuroChemie (Germany), HolsboerMaschmeyer NeuroChemie (Germany), HolsboerMaschmeyer NeuroChemie (Germany), HolsboerMaschmeyer NeuroChemie (Germany), HolsboerMaschmeyer NeuroChemie (Germany), HolsboerMaschmeyer NeuroChemie (Germany), Jena University Hospital, Universität Hamburg, University Medical Center Hamburg-Eppendorf
Publication date:
2026-06-24
DOI:
10.1001/jamanetworkopen.2026.19121
OpenAlex record:
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AI provenance: This post was generated by gpt-5.4-mini (OpenAI). The original authors did not write or review this post.

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