Intravenous arketamine for treatment-resistant depression: open-label pilot study

Over the past two decades, ketamine and its S(+)-enantiomer esketamine have been shown to produce rapid antidepressant effects in major depressive disorder (MDD), including in patients with treatment-resistant depression (TRD). Wider clinical use has been constrained by concerns about abuse potential, psychotomimetic and cardiovascular side-effects, and relatively short duration of benefit. Preclinical work has suggested that the R(-)-enantiomer of ketamine, arketamine, may produce more potent and longer-lasting antidepressant effects than either racemic ketamine or esketamine and with fewer psychotomimetic effects; limited human data from anaesthetic use and a small healthy volunteer study also suggested a favourable safety profile. Leal and colleagues therefore undertook an exploratory human study to evaluate whether a single intravenous infusion of arketamine produces rapid antidepressant effects in TRD and to characterise its acute safety and dissociative profile. The investigation is presented as a first-in-humans clinical evaluation of arketamine's antidepressant action in this population and intended to inform future controlled trials.

This was an open-label pilot trial conducted to guide future controlled studies. Subjects were recruited from local outpatient and inpatient psychiatric services and had to be aged 18–65 with a DSM-5 diagnosis of MDD, a Montgomery-Åsberg Depression Rating Scale (MADRS) score of at least 25 at screening, and failure to respond to at least two adequate antidepressant trials in the current episode. Key exclusions included current or past psychotic disorder, current substance use disorder, pregnancy, and unstable medical illness. Concomitant antidepressant medications were to be continued, with dosing stable for at least 15 days prior to infusion and through the one-week follow-up. All participants received a single intravenous infusion of arketamine at 0.5 mg/kg administered over 40 minutes. The study drug was manufactured from commercially available racemic ketamine hydrochloride via a three-step process to yield primarily (R)-ketamine hydrochloride, with reported enantiomeric purity above 99.0% and an R/S ratio > 99.5:0.5. Treatments and assessments took place at a university hospital in Salvador, Brazil. The protocol was approved by the local institutional review board and registered (UMIN000038347); participants provided written informed consent. Clinical assessments included MADRS performed immediately before infusion (baseline) and at 60, 120 and 240 minutes after infusion start, and at 1, 3 and 7 days post-infusion. The Clinician-Administered Dissociative States Scale (CADSS), which captures current dissociative symptoms using subject- and observer-rated items, was administered at baseline and at 40 minutes after infusion start and was repeated at 120 and 240 minutes if dissociative symptoms were present. Heart rate, blood pressure and peripheral oxygen saturation were monitored every 10 minutes during infusion and then at 60 and 240 minutes post-infusion. The primary outcome was the change in MADRS from baseline to 24 hours after infusion. Secondary endpoints included MADRS at other time-points, clinical response (≥50% decrease in baseline MADRS) and remission (MADRS ≤ 10). The extracted text does not clearly report a detailed statistical analysis plan beyond reporting mean differences with 95% confidence intervals and p-values for the primary outcome.

Seven subjects were enrolled, six from outpatient settings and one from the psychiatric ward. The extracted text does not provide a detailed table of baseline demographic or clinical characteristics within the body of the extraction, but later notes that all participants were female. On the primary endpoint, mean MADRS decreased from 30.7 at baseline to 10.4 at 24 hours, a mean difference of 20.3 points (95% CI 13.6–27.0; p < 0.001), corresponding to a 66% reduction from baseline. Reductions in mean MADRS were observed at all assessed time-points: a mean drop of 19.7 points at 60 minutes, 24.0 points at both 120 and 240 minutes, 20.3 points at day 3 and 16.7 points at day 7. Response and remission rates varied over time. The responder proportion (≥50% MADRS reduction) was 100% at 240 minutes, 71% at day 1 and 57% at day 7. Remission rates (MADRS ≤ 10) were 86% at 240 minutes, 57% at day 1 and 43% at day 7. Individual MADRS trajectories were reported in a figure in the extracted text but numerical individual-level data are not reproduced here. Physiological monitoring showed modest haemodynamic effects during infusion: mean systolic blood pressure change from baseline was +7.4 mmHg (range −8 to +15 mmHg) and mean diastolic change was +3.1 mmHg (range −3 to +7 mmHg). Heart rate and peripheral oxygen saturation remained stable during infusion. Dissociative symptoms were minimal: mean CADSS at 40 minutes was 1.1 (SD 1.7), with a maximum observed score of 5 and three participants scoring zero. The most commonly reported side effects were blurred vision (three subjects) and dizziness (two subjects); these events were described as mild and transient. No serious adverse events were reported in the extracted text.

Leal and colleagues interpret their findings as evidence that a single intravenous infusion of arketamine produced rapid and substantial antidepressant effects in this small TRD sample, with symptom improvement evident by 60 minutes and peaking at 240 minutes after infusion. They note that the magnitude of MADRS improvement and the rates of response and remission appeared, in this sample, to be larger than typically reported with racemic ketamine or esketamine, but the authors emphasise that cross-study comparisons are constrained and that the open-label design and small sample size limit firm conclusions. Safety and tolerability are highlighted as important features: arketamine induced only minimal dissociation on CADSS and small mean increases in blood pressure, which the authors contrast with larger haemodynamic changes and higher CADSS scores reported in some ketamine and esketamine trials. Participants reportedly described a subjective experience of serenity and inner peace after infusion. The authors suggest potential mechanistic explanations based on preclinical literature, proposing that arketamine's antidepressant-like effects may act independently of NMDA receptor antagonism and instead involve AMPA receptor activation and downstream BDNF–TrkB signalling; animal data are also cited to explain the apparently lower psychotomimetic liability via reduced dopamine release and lesser effects on parvalbumin-positive neurons compared with esketamine. Key limitations acknowledged by the investigators include the open-label design, the very small sample size, the absence of a placebo control preventing estimation of placebo contribution, lack of standardisation or washout of concomitant antidepressant medications (which the authors note reflects real-world conditions), and the fact that all participants were female, limiting generalisability to males. On the basis of these results, the authors conclude that larger, placebo-controlled trials are warranted to more definitively evaluate the clinical benefits and safety of arketamine for mood disorders.

The authors conclude that, in this small open-label pilot study, a single intravenous infusion of arketamine was associated with rapid and sustained antidepressant effects in patients with TRD and showed a favourable acute safety and dissociative profile. They state that these preliminary findings support the conduct of larger, placebo-controlled trials to establish efficacy and safety in a broader clinical population.