ulotaront (SEP-363856) / Sumitomo Pharma, Otsuka, PsychoGenics - LARVOL DELTA

A Trial of the Safety and Efficacy of SEP-363856 in the Treatment of Adults With Major Depressive Disorder (clinicaltrials.gov) - P2 | N=929 | Completed | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

A Long-term Administration Trial of SEP-363856 in Patients With Schizophrenia (clinicaltrials.gov) - P3 | N=100 | Not yet recruiting | Sponsor: Otsuka Pharmaceutical Co., Ltd.

New P3 trial • CNS Disorders • Psychiatry • Schizophrenia

Cortico-Striatal-Midbrain Circuit Dysregulation Underlying MK-801 Induced Impulsivity and the Ameliorative Effects of SEP. (PubMed, Adv Sci (Weinh)) - "Impulsivity is a core pathological feature of various psychiatric disorders including obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, and schizophrenia, which is conceptualized as dysregulated motivational and inhibitory processes. Furthermore, this work confirms that the application of the trace amine-associated receptor 1 agonist SEP-363856 could correct the abnormal responses of NAc neurons and behavioral deficits. These findings elucidate the neural basis of impulsivity and support the potential therapeutic effect of SEP."

Journal • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Mental Retardation • Mood Disorders • Obsessive-Compulsive Disorder • Psychiatry • Schizophrenia

The trace amine-associated receptor 1 regulates presynaptic dopamine function: evidence from preclinical studies and a phase 1b trial in patients with schizophrenia. (PubMed, Biol Psychiatry) - "TAAR1 regulates dopamine synthesis and release. Adjunctive ulotaront reduces presynaptic dopamine function and psychotic symptoms in schizophrenia. These findings support TAAR1 as a promising target for treating antipsychotic non-responsive schizophrenia and other dopaminergic disorders."

Journal • P1 data • Preclinical • CNS Disorders • Psychiatry • Schizophrenia

A double-blind study on ulotaront's impact on weight-related parameters in schizophrenia patients with metabolic syndrome and prediabetes: Part II. (PubMed, Diabetes Obes Metab) - "Despite the sample size constraints due to early study termination, all key endpoint trends and statistically significant differences favoured ulotaront over previous antipsychotics, lending support that ulotaront may improve antipsychotic-induced weight-associated markers. Liver fibro-inflammation may serve as a potential marker for antipsychotic-induced MetSyn and prediabetes, and possible treatment target. Further research is needed to build on these findings."

Journal • CNS Disorders • Hepatology • Inflammation • Metabolic Disorders • Psychiatry • Schizophrenia

An open-label study on ulotaront's effects on insulin-glucose regulation in schizophrenia patients with metabolic syndrome and prediabetes: Part I. (PubMed, Diabetes Obes Metab) - P1 | "Despite limited sample size, primary endpoints favoured ulotaront over prior antipsychotics with respect to a reduction trend in glucose, c-peptide and insulin. The insulin response after a solid meal was nominally significant, suggesting that semi-chronic twice-a-day dosing of ulotaront might improve insulin dynamics in schizophrenia patients at high diabetes risk."

Journal • CNS Disorders • Metabolic Disorders • Psychiatry • Schizophrenia • Type 2 Diabetes Mellitus

Trace Amine-associated Receptors (TAARs): Candidate Targets in the Treatment of Bipolar Disorders. (PubMed, Actas Esp Psiquiatr) - "Ulotaront is a TAAR1 agonist that has advanced to Phase III with Food and Drug Administration (FDA) breakthrough status in schizophrenia...This constitutes a theoretical basis for transdiagnostic applications. The evidence particularly favors the TAARs as novel targets in the treatment of bipolar disorders, thus warranting a dedicated effort at drug discovery."

Journal • Review • Bipolar Disorder • CNS Disorders • Depression • General Anxiety Disorder • Major Depressive Disorder • Mood Disorders • Psychiatry • Schizophrenia

A Trial of the Efficacy and Safety of SEP-363856 in Acutely Psychotic Participants With Schizophrenia (clinicaltrials.gov) - P3 | N=522 | Recruiting | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Trial completion date: Aug 2028 ➔ Oct 2026 | Trial primary completion date: Apr 2028 ➔ Oct 2026

Trial completion date • Trial primary completion date • CNS Disorders • Psychiatry • Schizophrenia

A Clinical Study That Will Measure How Well SEP-363856 Works and How Safe it is in Adults With Generalized Anxiety Disorder (clinicaltrials.gov) - P2/3 | N=434 | Completed | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • General Anxiety Disorder • Mood Disorders • Psychiatry

An Extension Study to a Clinical Study That Will Continue to Evaluate the Effectiveness and Safety of SEP-363856 in People With Schizophrenia That Switch to SEP-363856 From Their From Their Current Antipsychotic Medication (clinicaltrials.gov) - P3 | N=75 | Completed | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Enrolling by invitation ➔ Completed

Trial completion • CNS Disorders • Psychiatry • Schizophrenia

New Developments in the Treatments of Psychosis (WFSBP 2025) - "Objective: Despite the discovery of chlorpromazine over 70 years ago and substantial pharmacologic advances, postsynaptic dopamine blockade has remained the sole mechanism of action of approved drugs for schizophrenia... Newly/recently approved agents include vesicular monoamine transporter-2 inhibitors valbenazine and deutetrabenazine for tardive dyskinesia and, possibly, residual positive symptoms; olanzapine/samidorphan combination, lumateperone, new formulations, including subcutaneous injections, and ultra-long-acting injectable antipsychotics. Agents in development that have at least one positive phase 1B, 2 or 3 trial include the trace amine-associated receptor-1 (TAAR1) ulotaront, M1/M4 muscarinic agonist xanomeline plus peripherally restricted anticholinergic trospium, the M4 muscarinic positive allosteric modulator emraclidine, as well as multiple other muscarinic receptor modulators for total psychopathology, methylated amisulpride (LB-102), and evenamide, a..."

CNS Disorders • Movement Disorders • Psychiatry • Schizophrenia

A Clinical Study That Will Measure How Well SEP-363856 Works and How Safe it is in Adults With Generalized Anxiety Disorder (clinicaltrials.gov) - P2/3 | N=434 | Active, not recruiting | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Recruiting ➔ Active, not recruiting | Trial completion date: Feb 2026 ➔ Sep 2025 | Trial primary completion date: Feb 2026 ➔ Sep 2025

Enrollment closed • Trial completion date • Trial primary completion date • CNS Disorders • General Anxiety Disorder • Mood Disorders • Psychiatry

Trajectory of Efficacy and Safety Across Ulotaront Dose Levels in Schizophrenia: A Systematic Review and Dose-Response Meta-Analysis. (PubMed, Int J Neuropsychopharmacol) - "Ulotaront 100 mg appears greatest efficacy with favorable safety for acute schizophrenia. However, effect sizes were small, and higher ulotaront doses should be tested."

Clinical • Journal • Retrospective data • CNS Disorders • Mood Disorders • Psychiatry • Schizophrenia

A Trial of the Safety and Efficacy of SEP-363856 in the Treatment of Adults With Major Depressive Disorder (clinicaltrials.gov) - P2 | N=900 | Active, not recruiting | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Recruiting ➔ Active, not recruiting | Phase classification: P2/3 ➔ P2

Enrollment closed • Phase classification • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Trace amine-associated receptor 1 agonists differentially regulate dopamine transporter function. (PubMed, Mol Pharmacol) - "RO5166017, but not RO5256390 or ulotaront, increased amphetamine-induced dopamine efflux in a TAAR1-dependent manner. All 3 affected DAT transport and/or trafficking, with each exhibiting a unique profile of direct and heterologous effects, some of which were TAAR1-dependent. These issues should be considered with therapeutic design and clinical use of TAAR1 agonists."

Journal • CNS Disorders • Psychiatry • Schizophrenia

The role of trace amine-associated receptor 1 (TAAR1) in the pathophysiology and treatment of depression. (PubMed, Curr Neuropharmacol) - "In fact, Ulotaront (a TAAR1 agonist) is reported to be currently undergoing phase 2/3 clinical trials in order to test its safety and efficacy in the treatment of major depressive disorder (MDD)...Moreover, we briefly summarize the recent findings in the elucidation of behavioral and physiological properties of TAAR1 agonists both in clinical trials and preclinical animal studies. Collectively, these studies will provide a solid foundation for TAAR1 as a novel therapeutic target for depression."

Journal • CNS Disorders • Depression • Major Depressive Disorder • Mental Retardation • Mood Disorders • Psychiatry

A Trial of the Safety and Efficacy of SEP-363856 in the Treatment of Adults With Major Depressive Disorder (clinicaltrials.gov) - P2/3 | N=1030 | Recruiting | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Trial completion date: Nov 2025 ➔ Feb 2026 | Trial primary completion date: Nov 2025 ➔ Feb 2026

Trial completion date • Trial primary completion date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

A Trial of the Efficacy and Safety of SEP-363856 in Acutely Psychotic Participants With Schizophrenia (clinicaltrials.gov) - P3 | N=522 | Recruiting | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

New P3 trial • CNS Disorders • Psychiatry • Schizophrenia

Novel pharmaceutical treatment approaches for schizophrenia: a systematic literature review. (PubMed, Eur J Clin Pharmacol) - "Novel treatments for schizophrenia show promise in managing both positive and negative symptoms, with generally favorable safety profiles. Future studies should focus on large-scale, long-term trials to refine their efficacy, safety, and clinical applicability."

Journal • Review • CNS Disorders • Constipation • Gastroenterology • Gastrointestinal Disorder • Mental Retardation • Psychiatry • Schizophrenia

A Clinical Study That Will Measure How Well SEP-363856 Works and How Safe it is in Adults With Generalized Anxiety Disorder (clinicaltrials.gov) - P2/3 | N=434 | Recruiting | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Trial completion date: Feb 2025 ➔ Feb 2026 | Trial primary completion date: Feb 2025 ➔ Feb 2026

Trial completion date • Trial primary completion date • CNS Disorders • General Anxiety Disorder • Mood Disorders • Psychiatry

A Trial of the Safety and Efficacy of SEP-363856 in the Treatment of Adults With Major Depressive Disorder (clinicaltrials.gov) - P2/3 | N=1030 | Recruiting | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Trial completion date: May 2025 ➔ Nov 2025 | Trial primary completion date: May 2025 ➔ Nov 2025

Trial completion date • Trial primary completion date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Triangulating evidence from the GALENOS living systematic review on trace amine-associated receptor 1 (TAAR1) agonists in psychosis. (PubMed, Br J Psychiatry) - "This co-produced, international triangulation examined the available evidence and developed recommendations for future research and clinical applications for TAAR1 agonists in psychosis. Broader challenges included difficulties in assessing the risk of bias, reproducibility, translation and interpretability of animal models to clinical outcomes, and a lack of individual and clinical characteristics in the human data. The research will inform a separate, independent prioritisation process, led by lived experience experts, to prioritise directions for future research."

Journal • Review • CNS Disorders • Depression • Mood Disorders • Psychiatry • Schizophrenia

SEP-363856 attenuates CUMS-induced depression-like behaviours and reverses hippocampal neuronal injuries. (PubMed, World J Biol Psychiatry) - "The 10 mg/kg dosage of SEP-363856 and fluoxetine significantly improved depressive-like behaviours as assessed by the SPT, OFT, EPM, TST, and FST. The antidepressant-like effects of SEP-363856 are linked to increased hippocampal neurotrophic factors, decreased hippocampus neuronal lesions, and activation of the IGF-1Rβ/PI3K/AKT signalling pathway. The latter may serve as a novel drug target for the treatment of depression."

Journal • CNS Disorders • Depression • Psychiatry • IGF1 • SYP

Unlocking the secrets of trace amine-associated receptor 1 agonists: new horizon in neuropsychiatric treatment. (PubMed, Front Psychiatry) - "Recent cryogenic electron microscopic (cryo-EM) structures of human and mouse TAAR1 (hTAAR1 and mTAAR1, respectively) in complex with agonists and G proteins have revealed detailed atomic insights into the binding pockets, binding interactions and binding modes of several agonists including endogenous trace amines (β-phenylethylamine, 3-Iodothyronamine), psychostimulants (amphetamine, methamphetamine), clinical compounds (ulotaront, ralmitaront) and repurposed drugs (fenoldopam). The in vitro screening of drug libraries has also led to the discovery of novel TAAR1 agonists (asenapine, guanabenz, guanfacine) which can be used in clinical trials or further developed to treat different neuropsychiatric conditions...In this review, we discuss the emergence of structure-based approaches in the discovery of novel TAAR1 agonists through drug repurposing strategies and structure-guided designs. Additionally, we discuss the functional selectivity of TAAR1 signalling, which..."

Journal • Review • Bipolar Disorder • CNS Disorders • Cognitive Disorders • Depression • Mental Retardation • Mood Disorders • Psychiatry • Schizophrenia

Trace amine-associated receptor 1 agonists for the treatment of negative symptoms of schizophrenia: a review (ECNP 2024) - "Ulotaront (SEP-363856) and ralmitaront (RO6889450) are two TAAR1 agonists in clinical trials. Based on data from preclinical and clinical trials, TAAR1 agonists may be beneficial in reducing negative symptoms of schizophrenia. Placebo-controlled studies focusing on negative symptoms in appropriate patient populations are important to determine the place of ulotaront in the future treatment of schizophrenia."

Review • CNS Disorders • Mental Retardation • Psychiatry • Schizophrenia