Psychiatry’s Medication Pipeline in Motion

It is an exciting time for us in psychiatry. A diverse pipeline is advancing with a significant number of candidates with new mechanisms of action.

This update provides a microcosm of the challenges involved in medication research and development. A tremendous amount of time, basic science research, innovation, preclinical development, clinical trials, and financial investment is required for a candidate medication to reach the point of filing a new drug application to the FDA, requesting approval for a specific indication. Then the waiting begins for the review that will culminate in a date with an expected decision from the FDA.

Agitation in Dementia: NMDA-Glutamate Antagonism/Sigma-1 Agonism

In individuals experiencing dementia, the 2 most common behavioral and psychological symptoms are agitation and psychosis.¹

Early in my career, when I treated agitation in patients with dementia, I drew from a large menu of off-label medications, in addition to behavioral and environmental modifications, in my attempts to present some degree of relief from the range of unpleasant consequences for the patient, caregivers, and others. Despite a plethora of clinical trials of wide-ranging medication classes, the antipsychotic brexpiprazole (Rexulti) became the first and only FDA-approved medication for the treatment of agitation associated with Alzheimer disease dementia in 2023. Now, an investigational agent leveraging a new pathway to address agitation may become a second option.

Dextromethorphan (DM) is a complex molecule with multiple mechanisms of action, including uncompetitive antagonism of the N-methyl-D-aspartate (NMDA) glutamate receptor, agonism of the sigma-1 receptor,² and inhibition of the serotonin transport pump. After the approval of DM hydrobromide and quinidine sulfate (Nuedexta) for the treatment of pseudobulbar affect, researchers found that the agent helped with agitation in patients who also had comorbid dementia.

Intrigued by DM’s multimodal mechanism, Axsome Therapeutics initiated clinical trials evaluating AXS-05’s effectiveness and safety for agitation in patients with Alzheimer disease and ultimately received breakthrough therapy designation for this indication. The comprehensive clinical research program included 4 randomized, double-blind, placebo-controlled phase 3 clinical trials and a long-term safety trial.^3-5 In the pivotal phase 2/3 ADVANCE-1 study, AXS-05 demonstrated a statistically significant mean reduction from baseline in the Cohen-Mansfield Agitation Inventory total score of 15.4 points compared with placebo of 11.5 points at week 5 (P = .010). This led to the recent FDA approval of AXS-05 for the treatment of Alzheimer disease agitation on April 30, 2026.

Clinical Significance

The treatment of agitation in individuals with dementia has remained elusive, and its burden is immense. A second option is a welcome respite for clinicians, their patients, and others caring for them.

ADHD: Norepinephrine, Dopamine, and Serotonin Reuptake Inhibitors

Currently, there are 3 medication classes approved by the FDA for the treatment of attention-deficit/hyperactivity disorder (ADHD): the Schedule 2 psychostimulants (formulations of the primary molecules methylphenidate and amphetamine); the unscheduled presynaptic α2-adrenergic receptor agonists (clonidine extended release [Kapvay] and guanfacine extended release [Intuniv]); and the unscheduled primarily norepinephrine reuptake inhibitors (NRIs; atomoxetine [Strattera] and viloxazine extended release [Qelbree]).

With a Prescription Drug User Fee Act date of July 24, 2026, centanafadine, a novel NRI described as a triple monoamine reuptake inhibitor, may soon be joining this third mechanistic subset. Centanafadine demonstrates secondary binding properties of antagonism of the dopamine reuptake inhibitor and serotonin reuptake inhibitor (SRI). As such, it is often referred to as a norepinephrine, dopamine, and serotonin reuptake inhibitor (NDSRI; or a triple monoamine reuptake inhibitor).

Centanafadine’s ADHD clinical developmental program has been comprehensive, with a phase 3 trial in children aged 4 to 12 years,⁶ a phase 3 trial in adolescents aged 13 to 17 years,⁷ and 2 phase 3 trials in adults aged 18 to 55 years.⁸ Results in all 4 trials demonstrated a significant improvement in ADHD symptoms as measured by the ADHD Rating Scale and the Adult ADHD Investigator Symptom Rating Scale.

Clinical Significance

The field of ADHD treatment continues to expand with increased appreciation for the heterogeneity of this disorder, and the presence of different phenotypes and longitudinal courses. Increasing the number of medications with differing mechanisms of action will provide much-needed choices to tailor treatment to symptoms and comorbidities.

MDD: Kappa-Opioid Receptor Antagonism

There has been ongoing investigation of candidate medications that antagonize the kappa-opioid receptor with the hope that this mechanism would improve symptoms of depression and anhedonia. Currently, navacaprant and aticaprant, both selective kappa-opioid receptor antagonists, are in phase 3 clinical trials but have uncertain futures.

Neumora Therapeutics’ navacaprant demonstrated improvement in depressive symptoms and anhedonia in patients with moderate to severe major depressive disorder (MDD) in an 8-week phase 2 study. This led to its KOASTAL Program, which included 3 phase 3 studies. Although KOASTAL-1 failed to meet its primary outcome, KOASTAL-2 and -3 are ongoing, with the anticipated combined readout expected sometime in 2026.

Johnson & Johnson’s aticaprant tells a similar tale. A phase 2 study of aticaprant 10 mg as an adjunct in adults with a moderate to severe episode of MDD who had not responded to an adequate trial of a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor found that aticaprant significantly improved depressive symptoms as compared with placebo. Aticaprant was also well tolerated, and further clinical trials were recommended.⁹ However, after the phase 3 trial failed to find sufficient efficacy, Johnson & Johnson discontinued the agent for MDD.¹⁰

Clinical Significance

Time will tell, but it appears likely that exclusive kappa-opioid receptor antagonism is not sufficient to provide a clinically meaningful antidepressant response. It may be that the complex opioid system requires multiple simultaneous subreceptor modulations to improve symptoms effectively.

MDD: AMPA Receptor Potentiator

Osavampator is a novel α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) glutamate receptor–positive allosteric modulator. It is hypothesized that glutamate activation of the AMPA postsynaptic receptors plays a pivotal intermediate role in the signaling cascade, which ultimately increases the levels of the mammalian target of rapamycin (mTOR), which is believed to be the final step in facilitating the synaptogenesis and neuroplasticity instrumental in improving depression.¹¹

Through positive allosteric modulation, osavampator is hypothesized to enhance the AMPA receptor’s sensitivity to glutamate in patients with depression, resulting in increased production of brain-derived neurotrophic factor, which ultimately facilitates the downstream production of mTOR.

The phase 2 SAVITRI study compared 2 doses of osavampator with placebo in change in depression severity from baseline to day 28 on the Montgomery–Åsberg Depression Rating Scale (MADRS). The 1-mg dose demonstrated a greater improvement in depression than the 3-mg dose. Both doses were well tolerated, with no clinically significant adverse events.¹² A phase 3 trial is under way.

Clinical Significance

Since 1995, a great deal of research has synthesized a hypothetical mechanism as to how antagonism of the NMDA receptor serves as a rapid-acting antidepressant to ultimately increase synaptogenesis and neuroplasticity. By directly increasing the activation of the AMPA receptors without affecting NMDA receptors, sedation, dissociation, transient hypertension, and potential abuse could be avoided. Understandably, this is an active area of research.

TRD: Psychedelics

The interest and explosion of research in the field of psychedelics is impressive. There are 278 registered clinical trials for psilocybin on ClinicalTrials.gov.¹³ It feels like the momentum is shifting toward the likelihood of an eventual FDA approval. The big question is: What will the structure and setting of psychedelic treatment look like if it crosses the evidence-based FDA approval threshold?

The compound closest to submitting a new drug application to the FDA is synthetic psilocybin COMP360 for treatment-resistant depression (TRD), which has been granted breakthrough therapy designation. Positive results recently came from a second phase 3 trial (COMP006), which demonstrated a highly statistically significant reduction in symptom severity (P < .001) and a clinically meaningful difference of 3.8 points in change at the primary end point.¹⁴ With 2 positive phase 3 studies, a new drug application is likely on the near horizon.¹⁵ Controversy exists among researchers in psychedelics about whether to dose it as a standalone treatment or if it should be part of a more comprehensive treatment integrated with psychotherapy. Comprehensive reviews on psilocybin share more on its mechanisms of action.^16-18

Clinical Significance

Slowly, but steadily, increasing scientific research demonstrating the neurobiology of psychedelics has brought us to the point where FDA approval of psilocybin appears plausible. The details and structure of treatments continue to be debated, and how the FDA will judge this research remains a big unknown.

Sleep and MDD: Orexin Receptor Antagonists and Agonists

The orexin system was identified in 1998 as a novel signaling pathway by 2 independent research groups and has been shown to play an important role in arousal and vigilance. Significant research on the human orexin system ultimately led to the FDA approval of suvorexant in 2014 for insomnia.¹⁹

As the understanding of the orexin system progressed, interest arose in the potential benefits of orexin receptor antagonists in the treatment of depressive symptoms. Orexin participates in regulating arousal, wakefulness, emotional response, reward-seeking behaviors, and appetite, which are all symptoms that can be dysregulated in depression. Additionally, preclinical research supports the hypothesis that orexin antagonists mitigate stress-induced dysregulation of the hypothalamic-pituitary-adrenal axis.

The selective orexin-2 receptor antagonist seltorexant has demonstrated antidepressant properties in phase 2 and 3 clinical trials as adjunctive therapy to antidepressants in patients with treatment-resistant MDD and insomnia, although it did not meet its primary end point.^20,21 On the other hand, orexin receptor agonists have been shown to improve symptoms in narcolepsy and hypersomnia.

The pipeline also includes 2 investigational medications of this variety. Deemed a breakthrough therapy by the FDA, oveporexton is an oral, highly selective orexin receptor 2 agonist developed by Takeda Pharmaceuticals to treat narcolepsy type 1. Studies have shown reduction in cataplexy and improvement in patient self-reported measures. An investigational, once-daily, oral, selective orexin 2 receptor agonist developed by Alkermes, alixorexton, also received breakthrough designation for narcolepsy type 1 based on positive phase 2 data demonstrating significant improvements in wakefulness. Alixorexton is also in phase 2 trials for narcolepsy type 2 and for idiopathic hypersomnia.

Clinical Significance

As our understanding of the orexin system progresses, increased clinical applications continue to emerge. The future appears bright with additional possible indications.

Schizophrenia: Muscarinic Cholinergic Receptor Agonists

A healthy pipeline of muscarinic receptor agonists and positive allosteric modulators at the muscarinic cholinergic type 1 (M1) and 4 (M4) receptors is feverishly occurring in clinical trials, following the approval of KarXT (Cobenfy) 19 months ago (Table 1²²).²³

Clinical Significance

It remains to be determined whether both M1 and M4 agonism are required to benefit the range of symptoms in schizophrenia, or if M4 alone can accomplish the same benefits with the absence of adverse effects from the peripheral M1 agonism.

Concluding Thoughts

The drums of psychiatric medication research and development continue to beat loudly with novel mechanisms of action, demonstrating that innovation and progress are alive and well in psychiatry. In addition to the novel agents, the industry continues to explore new formulations and delivery for existing medications. For instance, on February 20, 2026, the FDA accepted a new drug application for TEV-‘749, a long-acting, subcutaneous injectable olanzapine formulation for the once-monthly treatment of schizophrenia in adults. This article has merely scraped the surface; other medications are under investigation (Table 2), such as novel medications and medications currently approved for other indications.

Yet not all agents under investigation will reach our toolbox. In my previous review of the psychiatric medication pipeline in 2024, only 1 of 10 agents discussed, KarXT, crossed the finish line to FDA approval, with current active clinical usage beginning October 2024 (Table 3). What makes it into our armamentarium from this review remains to be seen.

References

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2. Miller JJ. The curious story of sigma-1 receptors. Psychiatric Times. 2026;43(4).

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9. Schmidt ME, Kezic I, Popova V, et al. Efficacy and safety of aticaprant, a kappa receptor antagonist, adjunctive to oral SSRI/SNRI antidepressant in major depressive disorder: results of a phase 2 randomized, double-blind, placebo-controlled study. Neuropsychopharmacology. 2024;49(9):1437-1447.

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

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13. Psilocybin. ClinicalTrials.gov. Accessed April 10, 2026. https://clinicaltrials.gov/search?intr=Psilocybin&viewType=Table

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17. Brudner RM, Kaczmarek E, Blainey MG, et al. Examining mystical experiences as a predictor of psilocybin-assisted psychotherapy for treatment-resistant depression. J Psychopharmacol. 2025;39(9):950-956.

18. Deutsch A, Contreras LE, Kratina S, Mayo LM. A scoping review of mystical-type experiences and mood symptom outcomes in psychedelic therapy clinical trials: comparing life-threatening disease and depressive populations. Ther Adv Psychopharmacol. 2026;16:1-15.

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23. Weiden PJ. From approval to practice: how has Cobenfy’s new mechanism of action impacted psychiatry? Psychiatric Times. 2026;3(1).

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