Trace Amine-Associated Receptor 1 as a Target for the Development of New Antipsychotics: Current Status of Research and Future Directions

Kantrowitz, Joshua T.

doi:10.1007/s40263-021-00864-3

Cited by 13 publications

(13 citation statements)

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“…9,15,[28][29][30] TAAR1 is found throughout the central nervous system as well as in peripheral tissues, and its expression in key areas of the brain makes it an attractive target for a number of neurologic disorders. 28,29,31 TAAR1 agonists represent a novel drug class for treating schizophrenia as they do not block D2 receptors. 10,12,23,25 TAAR1 agonism has been shown to help inhibit firing of a subset of neurons in the ventral tegmental area of the midbrain and play a role in regulating dopamine and glutamate activity.…”

Section: Introductionmentioning

confidence: 99%

“…10,23,28,32,33 More specifically, it modulates midbrain dopaminergic hyperactivity and cortical glutamatergic hypoactivity. 9,28,30,31 Additionally, TAAR1 agonism has demonstrated the potential to treat a wider range of schizophrenia symptoms due to its effect on prefrontal cortical activity, and has shown no increased risk of the metabolic and motor side effects associated with the traditional first-line antipsychotic drugs currently available for schizophrenia. 27,28,31 Preclinical studies have demonstrated the potential of TAAR1 agonism in the improvement of positive, negative, and cognitive symptoms of schizophrenia, as well as a possible role in the management of mood and anxiety-related behaviours.…”

Section: Introductionmentioning

confidence: 99%

“…9 Two TAAR1 agonists are currently in clinical development for the treatment of schizophrenia (Table 1). 9,28,31,[34][35][36] Ulotaront is both a TAAR1 and 5-hydroxytryptamine 1A receptor agonist (5-hydroxytryptamine 1A receptor agonists also have a potential role in schizophrenia treatment), with no activity at 5-hydroxytryptamine 2A, and is administered orally once daily. 9,10,[23][24][25]37 Animal research demonstrated that ulotaront does not produce significant D2 receptor occupancy at clinically relevant doses, suggesting that its therapeutic effect is not dependent on this mechanism of action.…”

Section: Introductionmentioning

confidence: 99%

“…10,38 Ralmitaront is another TAAR1 agonist and is also administered orally once daily. 9,11,31,35,36 These 2 drugs differ in that ralmitaront is a TAAR1 partial agonist, whereas ulotaront is a TAAR1 full agonist. 31,38…”

Section: Introductionmentioning

confidence: 99%

“…9,11,31,35,36 These 2 drugs differ in that ralmitaront is a TAAR1 partial agonist, whereas ulotaront is a TAAR1 full agonist. 31,38…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Trace Amine-Associated Receptor 1 Agonists for Schizophrenia

Vannabouathong¹,

Picheca²,

Dyrda³

2022

cjht

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TAAR1 agonists are an emerging drug class in the treatment of schizophrenia as they may offer a novel mechanism of action for symptom management without blocking dopamine D2 receptors, unlike currently available antipsychotic medications that act primarily via D2 binding. Two TAAR1 agonists are currently in clinical development for schizophrenia. The first is ulotaront, a TAAR1 full agonist with 5-hydroxytryptamine 1A agonist activity that is administered orally once daily, and the other is ralmitaront, a TAAR1 partial agonist that is also administered orally once daily. The published clinical trial evidence on TAAR1 agonists currently only pertains to ulotaront, which includes a 4-week, phase II, placebo-controlled randomized trial on patients with acute exacerbation of schizophrenia and a 26-week, open-label extension study of this same trial. These studies demonstrated improvements across disease-specific and global impression scales following treatment with ulotaront, with statistically significant differences compared to placebo, and no increased risk of the side effects (extrapyramidal symptoms and metabolic changes) associated with traditional D2-binding antipsychotic therapies. There is currently no cost information available for TAAR1 agonists. Ulotaront is currently undergoing phase III trials and, though it is not currently approved in any country and the date of Health Canada licensing and marketing in Canada is not yet known, it is expected to be the first TAAR1 agonist for schizophrenia in the Canadian market. Ulotaront received Breakthrough Therapy designation from the FDA in 2019 to expedite its development and the drug’s manufacturer is planning to file a New Drug Application with the FDA in 2023. Ralmitaront is currently in phase II trials, which are expected to be completed in 2023.

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Section: Introductionmentioning

confidence: 99%