Psychedelics, Orexin Blockers, and More: Inside the Diverse New Pipeline for Depression

CONFERENCE REPORTER

A wave of investigational treatments spanning at least 6 distinct mechanisms is moving through mid- and late-stage trials for major depressive disorder (MDD), reported Jason Kellogg, MD, at the 2026 Southern California Psychiatry Conference in Huntington Beach, California. Kellogg, medical director at Progeny Psychiatric Clinics in Newport Beach, California, discussed the agents, which are classified as psychedelics, orexin antagonists, next-generation glutamatergic agents, sigma-1-active compounds, and neurosteroids.

The breadth of that pipeline matters because the unmet need remains substantial, he told attendees, as roughly one-third of patients with MDD do not respond to 2 or more antidepressants. He reminded attendees that the landmark STAR*D trial found the odds of remission fell to just 14% after 2 prior treatment attempts. The investigational agents are looking at novel mechanisms of action and ways to improve neuroplasticity, he said. Neuroplasticity and synaptic models that can provide rapid response are the current priority of these innovative investigative treatments, he reported.

“In psychiatry, we’re evolving to the point where we understand that not all depression is just serotonin,” Kellogg told attendees. He discussed an analogy one of his patients shared with him. “‘I feel like all the other humans out there, we all have noodles in our brain, and I feel like all the other humans, their noodles talk to each other. But I feel like my noodles don’t talk to each other.’ I thought that was brilliant. That’s a way of talking about neuroplasticity and connections,” Kellogg said.

Psychedelics: Moving Closer to Approval

Psilocybin, a psychedelic agent, is among the agents in the pipeline that addresses neuroplasticity, Kellogg told attendees. Head-to-head data comparing psilocybin with escitalopram found that psilocybin produced holistic well-being, with advantages seen in overall functioning, connectedness, anhedonia, and finding meaning in life. Although the trial’s primary outcome (change in Quick Inventory of Depressive Symptomatology scores) was not statistically significant, patients in the psilocybin group were fared better in those scores as well as remission and response rates (57% vs 28% and 70% vs 48%, respectively), he reported.

COMP360, a synthetic psilocybin compound that has shown efficacy when accompanied by psychotherapy, is among the most advanced psychedelics programs, Kellogg told attendees. He discussed the results from recent phase 3 results, which highlighted COMP360’s rapid and durable effect, having significantly reduced MADRS scores with antidepressant effects evident for 6 months after just 2 doses.^1,2 Such an effect excites Kellogg. “This is not taking Prozac every day for the rest of your life,” he said.

COMP360, which has a Breakthrough Therapy designation from the FDA, is expected to finalize its new drug application this year.

Orexin Antagonists Move Beyond Sleep

There is also interest in orexin and circadian targets, Kellogg told attendees. OX1 antagonists are anxiolytic and have potential for anti-stress, antidepressant augmentation, while OX2 antagonists can act as sleep normalizing antidepressant augmentation.

Seltorexant, a selective OX2 receptor antagonist, has multiple phase 2 and 3 studies demonstrating antidepressant signals and sleep improvement as an adjunctive agent, and it appears furthest along toward actual psychiatric use, according to Kellogg. For patients with insomnia or other sleep problems along with depression, it may address “pathologic hyperarousal” without the sedation typical of older sleep medications.

Tebideutorexant, a selective OX1 antagonist being studied for MDD with anxious distress, is also an agent of interest, he said. He noted early phase 2a data indicates potential for effectiveness and tolerability.

Next-Generation Glutamatergic Agents

Esketamine proved that a rapid-acting, non-monoamine antidepressant could work, but its dissociative side effects, the requirement that it be given in a monitored office setting, and open questions about how long its benefits last have pushed several companies to look for successors, Kellogg told attendees. “Wouldn’t it be nice to maybe have a medicine that works as well as esketamine, but you can do it at home,” he said, describing the goal behind several of these programs.

One candidate, ACP-211, is a chemically modified (deuterated) version of R-norketamine now in phase 2 testing as an oral glutamate blocker meant to match ketamine’s antidepressant effect without the sedation and dissociation. In an earlier phase 1 study, healthy volunteers tolerated high doses without sedation and with only minimal dissociation; a phase 2 trial is further exploring these effects in patients with MDD with a history of inadequate antidepressant response, according to Kellogg.

A separate strategy boosts signaling at the AMPA receptor instead of blocking NMDA receptors, he said. Furthest along in this class is osavampator (also known as NBI-1065845 or TAK-653) as a potential adjunctive agent for cognitive and depressive symptoms. In the SAVITRI phase 2 trial, osavampator hit its primary and secondary goals at both day 28 and day 56, and a phase 3 trial examining a 1-mg dose is underway. Although earlier AMPA receptor potentiators carried seizure risk, osavampator was selected due to its low direct agonistic activity, a molecule with weak direct receptor activity, aiming for a wider margin of safety, he said.

A third target sits downstream of both of those systems: mTORC1, a cellular growth-signaling pathway that researchers now believe ketamine switches on within hours by triggering BDNF release, Kellog explained.

“Remember, I mentioned earlier we want cell growth in our brains? We want our noodles to grow. We want them to talk to each other,” he told attendees, which is why this pathway is of interest.

NV-5138 represents a first in class oral compound that activates mTORC1 by acting on sestrin, a protein that normally holds that pathway in check when amino acid levels are low. After Yale researchers found that a single oral dose produced ketamine-like changes, the drug moved into phase 1 and phase 2a trials for treatment-resistant depression. “This could go nowhere, or this could be the future of depression,” Kellogg said of the approach.

Sigma-1 and Dextromethorphan Combinations

Because dextromethorphan simultaneously blocks NMDA receptors and activates sigma-1 receptors, it has already been paired with other drugs and brought to market, Kellogg noted. In the ASCEND trial, adults with moderate to severe depression who took dextromethorphan-bupropion (AXS-05; Auvelity) saw significantly larger drops in their MADRS scores than those on bupropion alone, and significantly greater remission rates.³

Fluvoxamine and the dextromethorphan-quinidine combination are the other 2 agents currently on the market with meaningful sigma-1 activity, Kellogg said. Blarcamesine, which acts on both sigma-1 and M1 muscarinic receptors, is being developed mainly for Alzheimer disease and Rett syndrome, although its mood effects are also of interest, he reported.

Neurosteroids, Monoamines, and Inflammation-Targeted Therapies and the Kappa Blockers

Although neurosteroids are of interest, they present a few obstacles, Kellogg told attendees. “As you all know, hormones are hard to get into our body via the GI via the oral route,” he explained. “So there are companies trying to find ways to get these meds into our system without needing to inject them.”

Even with all this movement away from monoamines, Kellogg noted that older-style mechanisms have not disappeared from development. For example, Ansofaxine (toludesvenlafaxine) is a triple reuptake inhibitor, acting on serotonin, norepinephrine, and dopamine; it is currently approved for MDD in China.⁴

Recognizing the potential role of inflammation in MDD, there is also interest in NLRP3, an intracellular immune signaling complex considered to drive neuroinflammation, he said.

Although there has been great successes, not every mechanism has panned out yet. Kellogg pointed to the 2 kappa-opioid receptor blockers meant to ease anhedonia, aticaprant and navacaprant, which came up short in late-stage depression trials.^5,6 Nonetheless, he noted both drugs were well tolerated, and their developers are exploring other paths forward for the compounds.

Great Potential Ahead

Kellogg is very excited about the pipeline and novel mechanisms of action as well as the evolution of treatment for MDD.

“Remember, the theme is we want neurons to talk to each other. And sometimes when you have a depressive episode, those neurons are on fire. You’re losing those neurons So let’s get in there and let’s get in there rapidly,” he said encouragingly.

For more information on the evolving pipeline in psychiatry, see Psychiatry’s Medication Pipeline in Motion, and to stay up to date on the latest clinical trial and approval information, follow our Drug Watch page.

References

1 Compass Pathways Announces Six-Month Data from Second Phase 3 Trial Confirming Rapid and Durable Profile. Press release. July 7, 2026. Accessed July 10, 2026.

2. Kuntz L. New 6-Month Data From Second Phase 3 Trial Confirms Rapid Effect of COMP360 for TRD. Psychiatric Times. July 7, 2026. Accessed July 10, 2026.

3. Kuntz L. Positive Results for Dextromethorphan-Bupropion ASCEND Phase 2 Clinical Trial. Psychiatric Times. May 19, 2022. Accessed July 10, 2026.

4. Mi W, Yang F, Li H, et al. Efficacy, Safety, and Tolerability of Ansofaxine (LY03005) Extended-Release Tablet for Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled, Dose-Finding, Phase 2 Clinical Trial. Int J Neuropsychopharmacol. 2022;25(3):252-260.

5. Johnson & Johnson Statement on VENTURA Program. March 6, 2025. Accessed July 10, 2026. https://www.jnj.com/media-center/press-releases/johnson-johnson-statement-on-ventura-program

6. Kuntz L. Navacaprant for Major Depressive Disorder Fails in Late-Stage Study. Psychiatric Times. January 2, 2025. Accessed July 10, 2026. https://www.psychiatrictimes.com/view/navacaprant-for-major-depressive-disorder-fails-in-late-stage-study