Oral ketamine shows early promise without dissociation in treatment-resistant depression

Clinical Takeaway: Oral prolonged-release ketamine (KET01) demonstrated rapid but transient antidepressant effects with minimal dissociation or hemodynamic changes; however, it did not outperform placebo at 3 weeks, underscoring the need for further study before clinical adoption.

Current ketamine-based therapies for treatment-resistant depression (TRD) require in-clinic administration due to dissociation and cardiovascular risks. An effective oral option with improved tolerability could expand access and enable at-home treatment.

A prolonged-release oral ketamine tablet showed early signals of benefit in patients with treatment-resistant depression (TRD), while producing minimal dissociation and few acute cardiovascular effects in two randomized trials.

In a phase 2 trial of 122 adults with TRD, adjunctive KET01 240 mg/day reduced depression symptoms more than placebo at days 4 and 7. However, the benefit was not statistically significant at day 21, the study’s primary efficacy endpoint. By day 21, response occurred in 47.5% of patients receiving KET01 240 mg/day compared with 37.5% receiving placebo; remission occurred in 40.0% vs 25.0%, respectively.

The tolerability findings were notable. In a separate phase 1 crossover trial in 26 healthy male volunteers, intranasal esketamine caused clinically meaningful dissociation in nearly all participants, while single-dose KET01 240 mg did so in only 1 participant. KET01 also did not produce the rapid pulse and blood pressure increases seen with intranasal esketamine.

The phase 2 study tested once-daily KET01 120 mg or 240 mg, added to ongoing standard antidepressant therapy, against placebo for 3 weeks across 29 sites in Europe. The phase 1 study compared a single oral KET01 dose with intranasal esketamine.

Adverse events were common but generally manageable. Liver enzyme increases were seen in some KET01-treated patients and normalized after treatment ended. Longer studies are needed to clarify durability, hepatic safety, misuse risk, and whether early symptom improvements translate into sustained benefit.

“The antidepressant properties and tolerability profile of KET01 … support further development of oral KET01 formulation for at-home administration,” the authors concluded.

Source: Walter M, et al. 2026 June 24. JAMA Netw Open. Oral Prolonged-Release Ketamine for Treatment-Resistant Depression: Two Randomized Clinical Trials