Slow-release ketamine tablets caused little dissociation but missed their depression target

The question

Can a new oral, slow-release ketamine tablet (called KET01) ease treatment-resistant depression without the dissociation and blood pressure spikes seen with other forms of ketamine?

What they did

Two separate randomized, double-blind trials were run. The first, in Germany, gave 26 healthy adult men a single 240 mg dose of the tablet or 84 mg of intranasal esketamine, with each man trying both in turn. The second enrolled 122 adult outpatients with treatment-resistant depression at 29 sites in the Czech Republic, Germany and Poland, who took 120 mg or 240 mg of the tablet daily, or placebo, alongside their usual treatment for three weeks.

What they found

In the healthy-volunteer trial, intranasal esketamine produced marked dissociation (a feeling of detachment from body or surroundings) while the tablet did not: mean maximum change on the dissociation scale was 29.6 points versus 0.7 points. Peak ketamine levels in blood were lower with the tablet (39.1 ng/mL) than with esketamine (104.1 ng/mL), and pulse and blood pressure did not change markedly with the tablet. In the depression trial, the main outcome was not met: at day 21, the 240 mg tablet differed from placebo by only -1.82 points on the MADRS depression scale (95% CI, -6.21 to 2.57; P = .41). Smaller differences favouring the tablet appeared earlier, at day 4 (-3.66 points) and day 7 (-3.95 points), but these were secondary findings, and at four weeks of follow-up the difference (-3.35 points) was not statistically significant.

The fine print

The phase 1 trial included only 26 healthy men, so it says nothing about women or about people with depression. The phase 2 trial had 122 people and did not meet its primary endpoint; the early-day differences were nominal, meaning they were not adjusted for multiple comparisons and could be chance findings. Follow-up was short, and this summary is based on the abstract alone.

What it means

A slow-release ketamine tablet appears to avoid the dissociation and blood pressure effects of intranasal esketamine, but in this trial it did not beat placebo for depression at three weeks, so its benefit remains unproven.

Evidence grade: Moderate. Two randomized, double-blind trials, but both were small and early-phase, and the phase 2 trial missed its main depression outcome.

This summary is based on the study’s published abstract.