Emerging trends in antipsychotic and antidepressant drug development: Targeting nonmonoamine receptors and innovative mechanisms

Abstract The domain of psychiatric drug development is currently witnessing a notable transformation, with a paramount emphasis on targeting nonmonoamine receptors and exploring inventive mechanisms of action. This paper presents an overview of the ongoing advancements in antipsychotic and antidepressant drug development. Historically, antipsychotics predominantly targeted dopamine receptors, but there is now an escalating interest in drugs that act on alternative receptors, exemplified by the TAAR1 receptor. One noteworthy candidate is Ulotaront (SEP‐363856), an agent acting as a TAAR1 agonist with 5‐HT1A agonist activity, demonstrating promising outcomes in the treatment of schizophrenia, devoid of extrapyramidal symptoms or metabolic side‐effects. Similarly, MIN‐101 (Roluperidone) and KarXT are currently in development, with its focus on addressing the symptoms in schizophrenia. In the domain of antidepressants, novel therapeutic approaches have surfaced, such as Auvelity, a Food and Drug Administration (FDA)‐approved NMDA receptor antagonist synergistically combined with Bupropion to enhance its effects. Another notable candidate is Zuranolone, operating as a GABA A receptor‐positive allosteric modulator, showcasing efficacy in treating major depressive disorder (MDD) and postpartum depression. Additionally, TAK‐653 (NBI‐1065845) and MJI821 (Onfasprodil) have emerged as potential antidepressants targeting AMPA receptors and NMDA receptor 2B (NR2B) negative allosteric modulation, respectively. This paper underscores the transformative potential of these novel drug candidates in psychiatric treatment and their ability to address cases that were previously treatment‐resistant. By focusing on nonmonoamine receptors and introducing innovative mechanisms, these drugs offer a promising prospect of improved outcomes for individuals suffering from schizophrenia and MDD. Thus, sustained attention and dedication to the development of such drugs are essential to augmenting the therapeutic options available for psychiatric patients.


INTRODUCTION
While various treatments exist for psychiatric disorders, such as psychotherapy and neuromodulation therapy, drug treatment remains the predominant approach. 1,2Over the last approximately 50 years, these drugs have undergone significant development within their respective classes.Notably, antipsychotic medications were primarily used for schizophrenia but have recently found expanded clinical applications in bipolar disorder, autism, and agitation related to dementia.Similarly, antidepressants were primarily utilized for depression, but their indications have been broadened to include various anxiety disorders.Mechanistically, antipsychotics primarily act through dopamine blockade, supplemented with monoamines like serotonin, thus contributing to the reduction of adverse effects.Likewise, antidepressants exert their effects by modulating serotonin, noradrenaline, and other monoamines in the synaptic cleft.
Beyond these mechanisms, we are currently witnessing an exciting era of testing new drugs for marketing.In the following sections, we provide an overview of the two drug classes mentioned above and highlight some of the drugs anticipated to be launched in the near future.We have compiled a list-as exhaustive as possible-of drugs that have advanced to Phase 3 in major countries, with additional noteworthy drugs also in Phase 2.
These novel mechanisms of action hold the potential to revolutionize the treatment response for psychiatric disorders and offer therapeutic options for patients who have previously shown inadequate responses to conventional treatments.

SURVEY METHODOLOGY
In this survey, our primary focus was on two drug categoriesantipsychotics and antidepressantsaiming to assess the current state of drug development.The survey was conducted primarily by exploring the websites of pharmaceutical manufacturers, utilizing keywords such as "new drug development status," "pipeline," and "financial reports."We deliberately opted not to rely on articles from PubMed, which are commonly used for systematic reviews, as they might entail information delays due to the peer-review process.
Consequently, the data presented in this review have not undergone complete scientific verification and should be regarded solely as a point of reference.
We provide an overview of antipsychotic drugs currently in development (Table 1), encompassing a summary of drugs that have advanced to Phase 3 in major countries and Phase 2 drugs warranting attention.Furthermore, the review discusses specific antipsychotic drugs, such as SEP-363856 (Ulotaront) and MIN-101 (Roluperidone), that are likely to garner considerable attention in the future.Additionally, we include a similar analysis for antidepressants currently under development (Table 2), featuring drugs such as Auvelity and Zuranolone, which are poised to be significant contributors in the field.
T A B L E 1 Antipsychotic drugs in development.

MAJOR NEW ANTIPSYCHOTIC DRUG CANDIDATES SEP-363856 (Ulotaront)
Ulotaront is a promising antipsychotic candidate acting as a trace amine-associated receptor 1 (TAAR1) agonist with serotonin 5-HT1A agonist activity, while lacking dopamine D2 or serotonin TAAR1, the primary receptor targeted by the drug, is the sole endogenous receptor for trace amines like beta-phenylethylamine (phenylethylamine [PEA]) and tyramine, which exhibit lower blood levels in humans than dopamine and noradrenaline. 4TAAR1 is capable of reducing the firing rate of dopamine neurons and preventing a state of dopaminergic hyperactivity through direct activation of G proteincoupled inwardly rectifying potassium channels (GIRKs). 5,6The global anticipation of antipsychotic drugs that do not directly target dopamine has been steadily growing.
The drug is under codevelopment with Otsuka Pharmaceutical Negative symptoms represent a significant contributing factor to the impaired functional outcome observed in patients with schizophrenia. 8,9A vast majority of individuals meeting diagnostic criteria for schizophrenia experience negative symptoms, 10 which tend to persist throughout their lives. 11The severity of negative symptoms significantly influences the extent of social and occupational dysfunction in these patients. 12 for iloperidone 64 mg demonstrated a statistically significant decrease compared to placebo (p ≤ 0.044), albeit marginally, affirming the drug's effectiveness in alleviating negative symptoms. 13rXT KarXT, comprising xanomeline, a muscarinic agonist with a preference for M1/M4 receptors, and trospium, a nonselective muscarinic antagonist, represents a central-nervous-system-specific formulation.
It aims to harness the therapeutic potential of xanomeline while mitigating the adverse effects observed in initial investigations. 146][17][18][19][20] Trospium, due to its inability to penetrate the central nervous system, serves to decrease the peripheral cholinergic side-effects associated with xanomeline.the safety of the drug has been confirmed. 27ranolone has also undergone a Phase III randomized controlled trial for investigating its efficacy and safety in treating postpartum depression.The study showed remarkable improvement starting from Day 3 of treatment, with reductions observed in HAMD-17 and MADRS scores, which were sustained until the end of the study (Day 45).Notably, Zuranolone exhibited significant improvement compared to placebo at Day 45. 28 For postpartum depression, brexanolone, under the trade name Zulresso, has already obtained FDA approval in 2019.It is another drug developed by Sage Therapeutics Inc., the same company behind Zuranolone, and acts as a PAM of GABA receptors.The dosing regimen involves continuous intravenous infusion over a 2.5-day period. 29

TAK-653 (NBI-1065845)
TAK-653 is a promising oral tablet being developed for the treatment of MDD and treatment-resistant depression (TRD).[32] In collaboration with Neurocrine Biosciences Inc. and Takeda, TAK-653 is currently undergoing Phase 2 development in both the United States and Japan. 33This novel compound holds the potential to address MDD and TRD with its unique mechanism of action as a PAM of the AMPA receptor.

MIJ 821 (Onfasprodil)
MIJ 821, also known as Onfasprodil, is currently under development for the treatment of TRD and MDD.This drug is administered through intravenous and subcutaneous infusions.Its mechanism of action involves functioning as an NMDA receptor 2B (NR2B) negative allosteric modulator (NAM).Allosteric modulators act at a site distinct from the orthosteric site of action of the endogenous ligand and exhibit selective binding to receptor subtypes.While positive allosteric modulators enhance the strength of the receptor's signal to the cell, NAMs like MJI821 weaken the signal. 34rrently being developed by Novartis Inc., MIJ 821 is in Phase 2 of clinical trials. 35The results from a Phase II double-blind randomized controlled trial involving 70 patients with TRD showed that MIJ 821 at doses of 0.16 and 0.32 mg/kg, administered intravenously on a weekly or biweekly basis for 6 weeks, produced significant reductions in the MADRS total score at 24 h compared to placebo.Specifically, the MIJ 821 0.16 mg/kg pooled group exhibited a reduction of −15.51 (p = 0.0013), and the MIJ 821 0.32 mg/kg pooled group demonstrated a reduction of −12.98 (p = 0.0196). 36ese promising results suggest the potential of MIJ 821 as a treatment option for individuals with TRD and MDD.

CURRENT STATUS OF NEW DRUG DEVELOPMENT
The development of new antipsychotic agents for schizophrenia has primarily focused on drugs targeting dopamine D2 receptors, following the dopamine hypothesis. 37Additionally, efforts have been made to enhance cognitive function, increase anxiolytic and antidepressant effects, and minimize EPS and metabolic sideeffects by broadening the range of serotonin receptor affinities.
Notably, Aripiprazole, Brexpiprazole, and Lurasidone have received high evaluations, particularly in terms of safety. 38,39cently developed antipsychotic drugs have shifted their action towards TAAR1 receptors, sigma receptors, and α-adrenergic receptors, with a focus on receptors other than dopamine receptors.These novel agents are anticipated to yield different responses from the conventional pharmacological paradigm, potentially proving effective in patients previously considered resistant to conventional drug therapies.
Similarly, the development of novel antidepressant drugs remains a critical endeavor in managing MDD.Historically, antidepressants have been based on the monoamine hypothesis, 40 primarily targeting serotonin and noradrenaline.However, their slow onset of action poses challenges, particularly for patients at high risk of suicide and impulsive behavior. 41,42In recent times, agents acting on NMDA, sigma, and GABA receptors have emerged as an alternative mechanism of action compared to conventional antidepressants.
This difference in mechanism holds the potential to achieve clinical efficacy earlier in the treatment process.These advancements represent significant progress in the ongoing quest for more effective and efficient treatments for schizophrenia and MDD.
While these differently acting antipsychotics and antidepressants have the potential to bring new patient populations into therapeutic range, they may also cause side-effects due to their different framework.Therefore, Table 3  Looking ahead, continued attention and focus on the development of new antipsychotic and antidepressant drugs are warranted.
The potential breakthroughs in these areas can lead to improved treatment options and better outcomes for individuals living with schizophrenia and MDD.

AUTHOR CONTRIBUTION
Hitoshi Osaka and Tetsufumi Kanazawa made substantial contributions to the study concept, drafted the manuscript, approved the final version of the manuscript to be published, and agreed to be accountable for all aspects of the work.

ACKNOWLEDGMENTS
We express our sincere thanks to Dr. Keiichiro Nishida for his useful advice.This work was supported by JSPS KAKENHI Grant Numbers 22K07589, 22K07583-1, and 22K03148-1.

CONFLICT OF INTEREST STATEMENT
Tetsufumi Kanazawa is an Editorial Board member of Psychiatry and Clinical Neurosciences Reports and a co-author of this article.To minimize bias, they were excluded from all editorial decision-making T A B L E 3 Major adverse events from selected new antipsychotic/antidepressant drugs.Roluperidone MIN-101 adapted from Davidson et al. 13 KarXT adapted from Correll et al. 21uvelity adapted from Iosifescu et al. 24 Zuranolone adapted from Clayton et al. 25 MIJ821 adapted from the effects and safety of MIJ821 for people with treatment-resistant depression Trial No. CMIJ821X2201 by Novartis Clinical Results Summary. 43bbreviation: AE, adverse events.related to the acceptance of this article for publication.The authors declare no conflict of interest.
Abbreviation: PMDA, Pharmaceuticals and Medical Devices Agency.

and
Abbreviation: PMDA, Pharmaceuticals and Medical Devices Agency.
Currently, KARUNA is spearheading the development of KarXT, evaluating its efficacy in Phase 3 clinical trials, both as a standalone therapy and as an adjunctive treatment for schizophrenia and psychosis in Alzheimer's disease.In a 5-week randomized, double-blind, placebo-controlled Phase 2 trial involving inpatients with schizophrenia, 179 patients received at least one dose of either KarXT (n = 89) or placebo (n = 90).KarXT successfully achieved its primary efficacy endpoint and numerous secondary endpoints.Most procholinergic and anticholinergic adverse events associated with KarXT were mild and typically occurred during the initial 1-2 weeks of treatment.These symptoms were transient, with a median duration ranging from 1 day (vomiting) to 13 days (dry mouth).Notably, no patients in either treatment group discontinued the study due to procholinergic or anticholinergic adverse events.The incidence of somnolence/sedation adverse events with KarXT was low and comparable to that observed in the placebo group.20According to recently published results from the Phase 3 randomized, double-blind, placebo-controlled EMERGENT-2 trial, KarXT demonstrated a statistically significant and clinically meaningful reduction of 9.6 points (effect size = 0.61) in the PANSS total score from baseline to Week 5, in comparison to placebo.This significant improvement in PANSS total score was evident as early as Week 2 (the first postbaseline assessment) and persisted throughout the study.Rates of serious treatment-emergent adverse events were comparable between the KarXT and placebo groups, with none attributed to the drug.The most prevalent treatment-emergent adverse events (occurring in ≥5% of patients) were of mild to moderate severity and included constipation, indigestion, nausea, vomiting, headache, increased blood pressure, dizziness, gastroesophageal reflux disease, abdominal discomfort, and diarrhea.21MAJOR NEW ANTIDEPRESSANT CANDIDATES AuvelityAuvelity stands as the sole FDA-approved NMDA receptor antagonist for antidepressant use, presented as a sustainedrelease fixed-dose combination of Dextromethorphan hydrobromide and the antidepressant Bupropion.The ingenious design of Auvelity involves utilizing Bupropion, a CYP2D6 inhibitor, to elevate and prolong plasma concentrations of Dextromethorphan hydrobromide, a conventional NMDA receptor (ion channel glutamate receptor) antagonist and sigma 1 receptor agonist.Bupropion, beyond its CYP2D6 inhibition, also exhibits relatively weak inhibition of norepinephrine and dopamine neuronal reuptake, leading to additional anticipated antidepressant effects.Auvelity's mechanism of action involves the amelioration of GABA-mediated neuronal dysfunction and modulation of glutamatergic neurotransmission through direct interaction with postsynaptic NMDA receptors.22,23This drug, developed by Axsome Therapeutics Inc., obtained FDA approval in August 2022 for the treatment of major depressive disorder (MDD).In the GEMINI study, a Phase 3, double-blind, placebo-controlled trial, 327 patients with MDD were equally randomized to receive Auvelity or placebo, and their progress was assessed over 6 weeks.The study successfully achieved its primary endpoint, showcasing statistically significant improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Week 6. Auvelity demonstrated significant improvement in MADRS scores starting as early as Week 1 and maintaining this progress until Week 6.Additionally, Clinical Global Impression (CGI) scores reflected substantial symptom improvement at Week 1, sustaining this improvement through Week 6. Notably, CGI appears to exert a more immediate effect compared to prior antidepressants.Moreover, the percentage of patients achieving remission (MADRS total score of 10 or less) increased to 40% by Week 6.24 ZuranoloneZuranolone, a biweekly, once-daily oral treatment, is designed for individuals with MDD.As an oral neuroactive steroid (NAS), it acts as a GABA A receptor-positive allosteric modulator (PAM).GABA A receptors are crucial inhibitory signaling pathways in the brain and central nervous system, significantly influencing brain function regulation.25 Sage Therapeutics Inc., Biogen Inc., and Shionogi are collaboratively developing this drug, currently in Phase 3 trials in both the United States and Japan.Zuranolone has also garnered Breakthrough Therapy designation from the US FDA.26The WATERFALL Study, a Phase 3, double-blind, placebocontrolled trial, assessed the efficacy and safety of zuranolone in adults with MDD.Involving 543 patients, the study assigned participants randomly to receive either 50 mg of zuranolone or placebo once nightly for 2 weeks.The primary study endpoint was the change in the 17-item Hamilton Rating Scale for Depression (HAM-D) total score from baseline at Day 15.The results demonstrated that the administration of zuranolone 50 mg resulted in statistically significant and clinically meaningful reductions in depressive symptoms compared to placebo (p = 0.0141).Furthermore, Not feeling like themself 11% 19%Note: Ulotaront SEP-363856 adapted from Koblan et al.3