A new direction in treatment-resistant depression
Treatment-resistant depression (TRD) is one of the most difficult challenges in psychiatry. Many patients do not improve even after trying multiple antidepressants. This has fueled interest in fast-acting therapies like ketamine and esketamine, but their use is limited by side effects such as dissociation. A new investigational drug, onfasprodil, is being studied as a potential alternative.
Onfasprodil works differently than traditional antidepressants. It targets a specific part of the NMDA receptor known as the NR2B subtype. This selective approach may explain why it seems to help patients quickly while producing fewer troubling side effects.
Results from the phase 2 trial
In a recent phase 2 clinical trial, researchers tested onfasprodil in adults with major depressive disorder who had not responded to at least two antidepressant treatments. Patients were randomly assigned to receive different doses of onfasprodil, ketamine, or placebo over a six-week period.
The main measure was change in depression severity using the Montgomery-Asberg Depression Rating Scale (MADRS). After just 24 hours, patients receiving onfasprodil showed significant improvement compared to placebo. The effect continued over time, especially in the group receiving the lower 0.16 mg/kg dose every other week.
Interestingly, this lower dose worked as well—or in some cases slightly better—than higher or more frequent doses, making it a practical option for patients and clinicians.
Comparing onfasprodil with ketamine
Ketamine is widely studied as a rapid-acting antidepressant, but it often causes dissociation, dizziness, and short-term memory problems. In this trial, dissociative symptoms were reported in about 50% of patients receiving ketamine, compared with only about a quarter of those receiving onfasprodil.
Other side effects with onfasprodil, such as mild dizziness or sleepiness, resolved within hours and did not lead to serious health concerns. This suggests that onfasprodil may provide a safer and more tolerable path to fast relief.
Impact on suicidal thoughts
Although most participants entered the study with relatively low levels of suicidal thoughts, researchers still observed a reduction in these symptoms within 24 hours of the first onfasprodil infusion. This effect persisted throughout the study, raising the possibility that onfasprodil could help patients at risk of suicide. Further research is needed to confirm these findings in high-risk populations.
Why this matters for the future
If confirmed in larger studies, onfasprodil could provide a new treatment option for patients who have exhausted standard antidepressants. Like ketamine and esketamine, it appears to act rapidly, but its ability to be given less frequently and with fewer side effects may improve both patient comfort and treatment accessibility.
Psychiatrists and researchers are now watching closely as more trials are launched to test its long-term safety and effectiveness. Onfasprodil represents an exciting step forward in the search for safer, faster, and more effective depression treatments.
References
- 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. Journal of Clinical Psychiatry. 2025;86(3):23m15246. https://pubmed.ncbi.nlm.nih.gov/40767837/
- 2) ClinicalTrials.gov. Proof of Concept Study Evaluating the Efficacy and Safety of MIJ821 in Patients With Treatment-Resistant Depression (NCT03756129). https://clinicaltrials.gov/study/NCT03756129