Andrii Lysenko/Adobe Stock
A novel agent selective for the NR2B subtype of the N-methyl-D-aspartate (NMDA) receptor demonstrated rapid improvement of treatment-resistant depression (TRD) with less dissociative effect than the nonspecific NMDA antagonist, ketamine, in a phase 2 “proof-of-concept” clinical trial.1
“This proof-of-concept trial demonstrates onfasprodil may be effective for the rapid reduction of depressive symptoms inpatients with TRD, with mild dissociative side effects that resolve rapidly,” reported lead author Richard Shelton, MD, Department of Psychiatry and Behavioral Neurobiology, Heersink School of Medicine, University of Alabama at Birmingham, and colleagues.
Shelton et al recount that onfasprodil, a negative allosteric modulator (NAM) selective for NR2B, followed development of another NAM targeting NR2B, traxoprodil, which had shown promise of therapeutic effect without dissociative reaction in lower dosages. That program was halted, however, when traxoprodil was found in clinical trials to exert QTc prolongation.
The current phase 2 trial with onfasprodil was conducted with adults experiencing persistent major depressive disorder (MDD) despite at least 2 different antidepressant regimens of adequate dose, at least 8 weeks duration, and with a Montgomery-Asberg Depression Rating Scale (MADRS) score of ≥24 at baseline.
Seventy participants completed the trial, from 72 initially randomized to one of the following 36-day treatment arms: onfasprodil 0.16 mg/kg infused once weekly; onfasprodil 0.16 mg/kg infused biweekly, alternating with biweekly placebo infusion; onfasprodil 0.32 mg/kg weekly; onfasprodil 0.32 mg/kg biweekly alternating with placebo; placebo weekly; and ketamine 0.5 mg/kg (not to exceed 40 mg) weekly. All infusions were completed over 40 minutes.
The primary outcome was change in MADRS total score from baseline to 24 hours after the first infusion. The key secondary outcomes were change in MADRS at 48 hours and at 6 weeks. The emergence of dissociative effects was assessed throughout the 6 weeks with the Clinical-Administered Dissociative States Scale (CADSS) questionnaire and the Dissociative Experiences Scale (DES).
The investigators reported adjusted mean differences of pooled results vs placebo in MADRS reduction from baseline for onfasprodil 0.16 mg/kg, 0.32 mg/kg and ketamine of -8.25, -5.71, and -5.67, respectively. At 48 hours, these were -7.06, -7.37, and -11.02, respectively, and at week 6, -5.78, -4.24, and -5.24, respectively. On analysis, the group receiving the lower dose of onfasprodil biweekly demonstrated the greatest overall MADRS benefit compared with placebo.
Shelton et al point out that although most patients had low scores in the MADRS suicidal category at baseline, there was a reduction measured 24 hours after the first dose which remained throughout the study.
“Therefore, onfasprodil may have the potential to improve suicidal symptoms, and further studies in MDD patients with serious suicidal ideation are needed to determine short- and long-term benefits, an effect that is consistent with literature reports for ketamine and esketamine,” they observed.
The most common treatment emergent adverse events in the onfasprodil groups were dizziness, transient amnesia, and somnolence. Dissociation was reported in 5 patients (23.8%) receiving onfasprodil 0.16 mg/kg, and in 5 (26.3%) receiving the higher dose.Dissociation was reported in 5 patients (50%) of those receiving ketamine. The maximum increase in CADSS total score was higher in the ketamine group than in the onfasprodil treatment groups (10.3 mean maximum change vs ≤5, respectively).
The investigators noted that treatment-related adverse events of interest resolved within a few hours after onset, and there were no clinically relevant changes in laboratory values, vital signs, or on ECG. They reported that, overall, “onfasprodil was well-tolerated across all dosing regimens.”
Shelton discussed the study and findings with Psychiatric Times, suggesting that onfasprodil could serve a role similar to intravenous (IV) ketamine or intranasal esketamine in rapid treatment of resistant depression. He indicated that it appeared as effective and rapidly acting as IV ketamine, while acknowledging that the trial was not sufficiently powered for that direct comparison.
“However, it has several significant advantages,” Shelton remarked. “There were fewer and less intense side effects, particularly with the lower dose (0.16 mg/kg), which was at least equivalent to the higher dose (0.32 mg), and perhaps slightly better.”
“Another advantage is that it can be administered no more than once per week, and the 0.16 mg dose given every other week seemed to be equally effective. Dosing every other week will be much more acceptable to patients than weekly or twice per week,” Shelton pointed out.
“I have treated hundreds of patients with IV ketamine or intranasal esketamine and participated as an investigator in the onfasprodil trial, [and] it seemed to be very well tolerated compared with ketamine products,” Shelton said.
Reference
1. Shelton RC, Litman RE, Hassman H, et al. Rapid onset and sustained efficacy of onfasprodil (MIJ821), a novel NR2B Negative allosteric modulator, in patients with treatment-resistant depression: a phase 2, randomized, placebo-controlled, proof-of-concept study. J Clin Psychiatry. 2025;86(3):23m15246.