A New Treatment Paradigm

Abstract

This continuing education supplement is jointly provided by Medical Education Resources and CMEology. The supplement is supported by an independent educational grant from Sunovion Pharmaceuticals Inc. It was edited and peer reviewed by the Journal of Clinical Psychopharmacology.After reviewing the learning objectives and reading the supplement, please complete the Activity Evaluation/Credit Request form online at https://www.cmesurvey.site/TAAR1.AbstractAll currently available antipsychotics work via essentially the same mechanism: by antagonizing the dopamine D2 receptor. However, schizophrenia is an extremely heterogeneous condition, and antipsychotics do not adequately control symptoms for all patients. Negative and cognitive symptoms are especially difficult to manage with existing medications. Therefore, antipsychotic agents with novel mechanisms of action are urgently needed. Recently, a phase 2 clinical trial and extension study demonstrated that, relative to placebo, the trace amine–associated receptor 1 (TAAR1) agonist ulotaront was effective at controlling the positive, negative, and cognitive symptoms of schizophrenia. In addition, ulotaront seems to lack the weight gain, metabolic issues, and extrapyramidal symptoms associated with traditional antipsychotics. This agent is currently undergoing multiple phase 3 trials for the treatment of schizophrenia. Another TAAR1 agonist, ralmitaront, is being investigated for the treatment of schizophrenia and schizoaffective disorders. Two phase 2 clinical trials are underway, evaluating ralmitaront both as a monotherapy and an add-on therapy to traditional antipsychotics. In this supplement, we review the biologic, preclinical, and clinical data available for TAAR1 agonists, so that if and when they are approved for the treatment of schizophrenia, psychiatry specialists will be ready to use them to optimize patient outcomes. We also briefly review other emerging therapies in late-stage development for the treatment of schizophrenia.

Canonical and Non-Canonical Antipsychotics’ Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia

“…Second, it could be questioned if and how non-canonical mechanisms can be pragmatically tackled for the development of novel therapeutic strategies that are needed for those conditions, such as TRS, that do not respond or respond poorly to the available antipsychotics. In this regard and concerning presynaptic dopamine regulation, at least two compounds are in an advanced phase of clinical development represented by TAAR1 agonist [ 174 , 582 , 583 , 584 , 585 ] and xanomeline + trospium [ 168 , 169 , 585 , 586 ], both involved in the regulation of dopamine release, though not through a primary dopamine-dependent receptor mechanism. Furthermore, regarding the modulation of synaptic proteins that are a significant non-canonical dopamine-dependent effect of antipsychotics, it should be acknowledged that despite the technical difficulties, there is a growing interest in the possibility of interfering with the PSD proteins’ function.…”

Structure-Based Design of Novel G-Protein-Coupled Receptor TAAR1 Agonists as Potential Antipsychotic Drug Candidates

“…Schizophrenia is a chronic, serious, and disabling brain disorder mainly characterized by positive and negative symptoms and cognitive impairments, and it typically occurs in late adolescence or early adulthood accompanied by multiple relapses. , Although lifetime schizophrenia is approximately affecting 24 million people worldwide, because of the chronicity and degree of associated functional impairment, the World Health Organization (WHO) believes that schizophrenia is ranked among the top 10 diseases that lead to global disability and economic burden. − Although pharmaceutical researchers have made significant efforts in the management of schizophrenia since the 1950s, the current antipsychotic therapy targeting the dopamine D2-receptor (D2R) or 5-hydroxytryptamine type 2A receptor (5-TH2AR) could cause plenty of serious side effects like extrapyramidal symptom (EPS), obesity, anhedonia, and cognitive impairment, as well as other types of adverse metabolism, which contribute to the high cardiovascular morbidity and mortality. − Given the unfavorable benefit −risk profile of schizophrenia patients, it is crucial to develop antipsychotic drugs (APDs) with novel mechanisms, improved efficacy, and few side effects.…”

“…1 H NMR (400 MHz, DMSO-d 6 ) δ 7.76 (d, J = 8 4. Hz, 2H, C 3 , C 5 −Ph-H), 7.65 (dt, J = 17.0, 8.4 Hz, 4H, C 2 , C 6 −Ph-H, C 2 , C 4 −Ph'-H), 7.45 (t, J = 7.8 Hz, 1H, C 5 −Ph'-H), 7.37 (d, J = 7.8 Hz, 1H, C 6 −Ph'-H), 3.46 (q, J = 7.0 Hz, 1H, CH), 1.24 (d, J = 6.9 Hz, 3H, CH 3 ).13 C NMR (125 MHz, DMSO-d 6 ) δ 175.54, 142.32, 139.52, 134.20, 133.55, 131.17, 127.57, 127.24, 126.35, 125.32, 119.94, 51.55, 21.87.…”

“…C 13 H 14 N 2 O 2(230.11). Yellow solid, 62% yield, mp: 118−120 °C 1. H NMR (400 MHz, DMSO-d 6 ) δ 7.75−7.67 (m, 3H, C 4 -furan-H, C 2 , C 6 −Ph-H), 7.64 (d, J = 8.5 Hz, , C 3 , C 5 −Ph-H), 6.83 (d, J = 3.4 Hz, 1H, C 2 -furan-H), 6.56 (dd, J = 3.3, 1.8 Hz, 1H, C 3 -furan-H), 3.47 (q, J = 6.9 Hz, 1H, CH), 1.23 (d, J = 6.8 Hz, 3H, CH 3 ).13 C NMR (125 MHz, DMSO-d 6 ) δ 175.15, 153.50, 142.85, 138.72, 125.90, 124.41, 119.81, 112.47, 105.21, 51.45, 21.68.…”

Protein Metabolism Changes and Alterations in Behavior of Trace Amine-Associated Receptor 1 Knockout Mice Fed a High-Fructose Diet

“…Furthermore, the AKT/GSK3 signaling pathway (not associated with the G protein-mediated D2 dopamine receptor signaling) was selectively activated, which is associated with the phosphorylation of AKT and GSK3β [ 21 ]. TAAR1 is being studied as a potential therapeutic target in the treatment of various mental disorders, such as schizophrenia [ 2 , 27 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ]. Ulotaront (SEP-363856) is a TAAR1 agonist with 5-HT1A receptor agonist activity, currently being tested in phase III clinical development, with very promising results from the phase II trials, which led to the FDA designation as a breakthrough therapy for the treatment of schizophrenia [ 26 , 27 , 28 , 29 , 30 , 40 , 47 , 48 , 49 , 50 , 51 , 52 ].…”