Skip to main content

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

Abstract

Schizophrenia is a mental illness associated with an array of symptoms that often result in disability. The primary treatments for schizophrenia are termed antipsychotics. Although antipsychotics modulate a number of different receptor types and subtypes, all currently regulatory agency-approved antipsychotics share in common direct or functional antagonism at the dopamine type 2 receptor (D2R). The majority of people with schizophrenia do not achieve full resolution of their symptoms with antipsychotics, suggesting the need for alternative or complementary approaches. The primary focus of this review is to assess the evidence for the role of the trace amine-associated receptor 1 (TAAR-1) in schizophrenia and the role of TAAR-1 modulators as novel-mechanism antipsychotics. Topics include an overview of TAAR-1 physiology and pathophysiology in schizophrenia, interaction with other neurotransmitter systems, including the dopaminergic, glutamatergic and serotonergic system, and finally, a review of investigational TAAR-1 compounds that have reached Phase II clinical studies in schizophrenia: SEP-363856 (ulotaront) and RO6889450 (ralmitaront). Thus far, results are publicly available only for ulotaront in a relatively young (18–40 years) and acutely exacerbated cohort. These results showed positive effects for overall schizophrenia symptoms without significant tolerability concerns. An ongoing study of ralmitaront will assess specific efficacy in patients with persistent negative symptoms. If trials of TAAR-1 modulators, and other novel-mechanism targets for schizophrenia that are under active study, continue to show positive results, the definition of an antipsychotic may need to be expanded beyond the D2R target in the near future.

This is a preview of subscription content, access via your institution.

References

  1. 1.

    Kantrowitz JT. Managing negative symptoms of schizophrenia: how far have we come? CNS Drugs. 2017;31(5):373–88.

    PubMed  Article  PubMed Central  Google Scholar 

  2. 2.

    Strauss GP, Bartolomeo LA, Harvey PD. Avolition as the core negative symptom in schizophrenia: relevance to pharmacological treatment development. NPJ Schizophr. 2021;7(1):16.

    PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Galderisi S, Mucci A, Dollfus S, Nordentoft M, Falkai P, Kaiser S, et al. EPA guidance on assessment of negative symptoms in schizophrenia. Eur Psychiatry. 2021;64(1):e23.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Kantrowitz JT. How do we address treating the negative symptoms of schizophrenia pharmacologically? Expert Opin Pharmacother. 2021;16:1–3.

    Article  CAS  Google Scholar 

  5. 5.

    Kurtz MM, Moberg JP, Ragland JD, Gur RC, Gur RE. Symptoms versus neurocognitive test performance as predictors of psychosocial status in schizophrenia: a 1- and 4-year prospective study. Schizophr Bull. 2005;31:167–74.

    PubMed  Article  PubMed Central  Google Scholar 

  6. 6.

    Kirkpatrick B, Buchanan RW, Ross DE, Carpenter WT Jr. A separate disease within the syndrome of schizophrenia. Arch Gen Psychiatry. 2001;58(2):165–71.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  7. 7.

    Keefe RS, Haig GM, Marder SR, Harvey PD, Dunayevich E, Medalia A, et al. Report on ISCTM consensus meeting on clinical assessment of response to treatment of cognitive impairment in schizophrenia. Schizophr Bull. 2016;42(1):19–33.

    PubMed  PubMed Central  Google Scholar 

  8. 8.

    Mucci A, Galderisi S, Gibertoni D, Rossi A, Rocca P, Bertolino A, et al. Factors associated with real-life functioning in persons with schizophrenia in a 4-year follow-up study of the Italian network for research on psychoses. JAMA Psychiat. 2021;78(5):550–9.

    Article  Google Scholar 

  9. 9.

    Fleischhacker WW, Podhorna J, Groschl M, Hake S, Zhao Y, Huang S, et al. Efficacy and safety of the novel glycine transporter inhibitor BI 425809 once daily in patients with schizophrenia: a double-blind, randomised, placebo-controlled phase 2 study. Lancet Psychiatry. 2021;8(3):191–201.

    PubMed  Article  PubMed Central  Google Scholar 

  10. 10.

    Shen WW. A history of antipsychotic drug development. Compr Psychiatry. 1999;40(6):407–14.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  11. 11.

    Lawrence RE, Appelbaum PS, Lieberman JA. A historical review of placebo-controlled, relapse prevention trials in schizophrenia: The loss of clinical equipoise. Schizophr Res. 2021;229:122–31.

    PubMed  Article  PubMed Central  Google Scholar 

  12. 12.

    Taylor M, Jauhar S. Are we getting any better at staying better? The long view on relapse and recovery in first episode nonaffective psychosis and schizophrenia. Therap Adv Psychopharmacol. 2019;9:2045125319870033.

    Article  Google Scholar 

  13. 13.

    Jaaskelainen E, Juola P, Hirvonen N, McGrath JJ, Saha S, Isohanni M, et al. A systematic review and meta-analysis of recovery in schizophrenia. Schizophr Bull. 2013;39(6):1296–306.

    PubMed  Article  PubMed Central  Google Scholar 

  14. 14.

    Kantrowitz JT. Additional perspective on cariprazine and negative symptoms. Exp Opin Pharmacotherapy. 2021;2:1–2.

    Google Scholar 

  15. 15.

    Meftah AM, Deckler E, Citrome L, Kantrowitz JT. New discoveries for an old drug: a review of recent olanzapine research. Postgrad Med. 2020;132(1):80–90.

    PubMed  Article  PubMed Central  Google Scholar 

  16. 16.

    Huhn M, Nikolakopoulou A, Schneider-Thoma J, Krause M, Samara M, Peter N, et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet. 2019;394(10202):939–51.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209–23.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  18. 18.

    Seeman P, Lee T. Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science. 1975;188(4194):1217–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  19. 19.

    Wong DF, Wagner HN Jr, Tune LE, Dannals RF, Pearlson GD, Links JM, et al. Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics. Science. 1986;234(4783):1558–63.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. 20.

    Kapur S, Remington G. Dopamine D(2) receptors and their role in atypical antipsychotic action: still necessary and may even be sufficient. Biol Psychiatry. 2001;50(11):873–83.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  21. 21.

    Gomes FV, Grace AA. Beyond dopamine receptor antagonism: new targets for schizophrenia treatment and prevention. Int J Mol Sci. 2021;22(9):4467.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Kozak R, Kiss T, Dlugolenski K, Johnson DE, Gorczyca RR, Kuszpit K, et al. Characterization of PF-6142, a novel, non-catecholamine dopamine receptor D1 agonist, in murine and nonhuman primate models of dopaminergic activation. Front Pharmacol. 2020;11:1005.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Bitter I, Lieberman JA, Gaudoux F, Sokoloff P, Groc M, Chavda R, et al. Randomized, double-blind, placebo-controlled study of F17464, a preferential D3 antagonist, in the treatment of acute exacerbation of schizophrenia. Neuropsychopharmacology. 2019;44(11):1917–24.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    de la Garrigue N, Glasser J, Sehatpour P, Iosifescu DV, Dias E, Carlson M, et al. Grant report on d-serine augmentation of neuroplasticity-based auditory learning in schizophrenia (dagger). J Psychiatr Brain Sci. 2020;5:4.

    Google Scholar 

  25. 25.

    Davidson M, Saoud J, Staner C, Noel N, Luthringer E, Werner S, et al. Efficacy and safety of MIN-101: a 12-week randomized, double-blind, placebo-controlled trial of a new drug in development for the treatment of negative symptoms in schizophrenia. Am J Psychiatry. 2017;174(12):1195–202.

    PubMed  Article  PubMed Central  Google Scholar 

  26. 26.

    Kantrowitz JT. Targeting serotonin 5-HT2A receptors to better treat schizophrenia: rationale and current approaches. CNS Drugs. 2020;34(9):947–59.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. 27.

    Kantrowitz JT, Grinband J, Goff DC, Lahti AC, Marder SR, Kegeles LS, et al. Proof of mechanism and target engagement of glutamatergic drugs for the treatment of schizophrenia: RCTs of pomaglumetad and TS-134 on ketamine-induced psychotic symptoms and pharmacoBOLD in healthy volunteers. Neuropsychopharmacology. 2020;45(11):1842–50.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Brannan SK, Sawchak S, Miller AC, Lieberman JA, Paul SM, Breier A. Muscarinic cholinergic receptor agonist and peripheral antagonist for schizophrenia. N Engl J Med. 2021;384(8):717–26.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Koblan KS, Kent J, Hopkins SC, Krystal JH, Cheng H, Goldman R, et al. A non-D2-receptor-binding drug for the treatment of schizophrenia. N Engl J Med. 2020;382(16):1497–506.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  30. 30.

    Berry MD, Gainetdinov RR, Hoener MC, Shahid M. Pharmacology of human trace amine-associated receptors: therapeutic opportunities and challenges. Pharmacol Ther. 2017;180:161–80.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    Dodd S, Puri BK, Maes M, Bortolasci CC, Morris G, et al. Trace amine-associated receptor 1 (TAAR1): a new drug target for psychiatry? Neurosci Biobehav Rev. 2021;120:537–41.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  32. 32.

    Pei Y, Asif-Malik A, Canales JJ. Trace amines and the trace amine-associated receptor 1: pharmacology, neurochemistry, and clinical implications. Front Neurosci. 2016;10:148.

    PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Rutigliano G, Accorroni A, Zucchi R. The case for TAAR1 as a modulator of central nervous system function. Front Pharmacol. 2017;8(987):987.

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Schwartz MD, Canales JJ, Zucchi R, Espinoza S, Sukhanov I, Gainetdinov RR. Trace amine-associated receptor 1: a multimodal therapeutic target for neuropsychiatric diseases. Expert Opin Ther Targets. 2018;22(6):513–26.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  35. 35.

    Branchek TA, Blackburn TP. Trace amine receptors as targets for novel therapeutics: legend, myth and fact. Curr Opin Pharmacol. 2003;3(1):90–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  36. 36.

    Nair PC, Miners JO, McKinnon RA, Langmead CJ, Gregory KJ, Copolov D, et al. Binding of SEP-363856 within TAAR1 and the 5HT1A receptor: implications for the design of novel antipsychotic drugs. Mol Psychiatry. 2021;2:2.

    Google Scholar 

  37. 37.

    Boulton AA. Letter: amines and theories in psychiatry. Lancet. 1974;2(7871):52–3.

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Borowsky B, Adham N, Jones KA, Raddatz R, Artymyshyn R, Ogozalek KL, et al. Trace amines: identification of a family of mammalian G protein-coupled receptors. Proc Natl Acad Sci U S A. 2001;98(16):8966–71.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Bunzow JR, Sonders MS, Arttamangkul S, Harrison LM, Zhang G, Quigley DI, et al. Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor. Mol Pharmacol. 2001;60(6):1181–8.

    CAS  Article  Google Scholar 

  40. 40.

    Grandy DK. Trace amine-associated receptor 1-Family archetype or iconoclast? Pharmacol Ther. 2007;116(3):355–90.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Wainscott DB, Little SP, Yin T, Tu Y, Rocco VP, He JX, et al. Pharmacologic characterization of the cloned human trace amine-associated receptor1 (TAAR1) and evidence for species differences with the rat TAAR1. J Pharmacol Exp Ther. 2007;320(1):475–85.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42.

    Boulton AA. Trace amines and mental disorders. Can J Neurol Sci. 1980;7(3):261–3.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  43. 43.

    Sandler M, Reynolds GP. Does phenylethylamine cause schizophrenia? Lancet. 1976;1(7950):70–1.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  44. 44.

    Potkin SG, Karoum F, Chuang LW, Cannon-Spoor HE, Phillips I, Wyatt RJ. Phenylethylamine in paranoid chronic schizophrenia. Science. 1979;206(4417):470–1.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  45. 45.

    Shirkande S, O’Reilly R, Davis B, Durden D, Malcom D. Plasma phenylethylamine levels of schizophrenic patients. Can J Psychiatry. 1995;40(4):221.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  46. 46.

    Rutigliano G, Zucchi R. Molecular variants in human trace amine-associated receptors and their implications in mental and metabolic disorders. Cell Mol Neurobiol. 2020;40(2):239–55.

    PubMed  Article  PubMed Central  Google Scholar 

  47. 47.

    Alexandrov V, Brunner D, Hanania T, Leahy E. High-throughput analysis of behavior for drug discovery. Eur J Pharmacol. 2015;5(750):82–9.

    Article  CAS  Google Scholar 

  48. 48.

    Lindemann L, Meyer CA, Jeanneau K, Bradaia A, Ozmen L, Bluethmann H, et al. Trace amine-associated receptor 1 modulates dopaminergic activity. J Pharmacol Exp Ther. 2008;324(3):948–56.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  49. 49.

    Bradaia A, Trube G, Stalder H, Norcross RD, Ozmen L, Wettstein JG, et al. The selective antagonist EPPTB reveals TAAR1-mediated regulatory mechanisms in dopaminergic neurons of the mesolimbic system. Proc Natl Acad Sci U S A. 2009;106(47):20081–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Leo D, Mus L, Espinoza S, Hoener MC, Sotnikova TD, Gainetdinov RR. Taar1-mediated modulation of presynaptic dopaminergic neurotransmission: role of D2 dopamine autoreceptors. Neuropharmacol. 2014;81:283–91.

    CAS  Article  Google Scholar 

  51. 51.

    Siemian JN, Zhang Y, Li JX. Trace amine-associated receptor 1 agonists RO5263397 and RO5166017 attenuate quinpirole-induced yawning but not hypothermia in rats. Behav Pharmacol. 2017;28(7):590–3.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Gainetdinov RR, Sotnikova TD, Grekhova TV, Rayevsky KS. In vivo evidence for preferential role of dopamine D3 receptor in the presynaptic regulation of dopamine release but not synthesis. Eur J Pharmacol. 1996;308(3):261–9.

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Espinoza S, Salahpour A, Masri B, Sotnikova TD, Messa M, Barak LS, et al. Functional interaction between trace amine-associated receptor 1 and dopamine D2 receptor. Mol Pharmacol. 2011;80(3):416–25.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Harmeier A, Obermueller S, Meyer CA, Revel FG, Buchy D, Chaboz S, et al. Trace amine-associated receptor 1 activation silences GSK3beta signaling of TAAR1 and D2R heteromers. Eur Neuropsychopharmacol. 2015;25(11):2049–61.

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Espinoza S, Ghisi V, Emanuele M, Leo D, Sukhanov I, Sotnikova TD, et al. Postsynaptic D2 dopamine receptor supersensitivity in the striatum of mice lacking TAAR1. Neuropharmacol. 2015;93:308–13.

    CAS  Article  Google Scholar 

  56. 56.

    Wolinsky TD, Swanson CJ, Smith KE, Zhong H, Borowsky B, Seeman P, et al. The Trace Amine 1 receptor knockout mouse: an animal model with relevance to schizophrenia. Genes Brain Behav. 2007;6(7):628–39.

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Kapur S, Mamo D. Half a century of antipsychotics and still a central role for dopamine D2 receptors. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27(7):1081–90.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  58. 58.

    Urban JD, Vargas GA, von Zastrow M, Mailman RB. Aripiprazole has functionally selective actions at dopamine D2 receptor-mediated signaling pathways. Neuropsychopharmacology. 2007;32(1):67–77.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  59. 59.

    Kantrowitz JT. The potential role of lumateperone-something borrowed? something new? JAMA Psychiat. 2020;77(4):343–4.

    Article  Google Scholar 

  60. 60.

    Vanover KE, Davis RE, Zhou Y, Ye W, Brasic JR, Gapasin L, et al. Dopamine D2 receptor occupancy of lumateperone (ITI-007): a positron emission tomography study in patients with schizophrenia. Neuropsychopharmacology. 2019;44(3):598–605.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  61. 61.

    Asif-Malik A, Hoener MC, Canales JJ. Interaction between the trace amine-associated receptor 1 and the dopamine D2 receptor controls cocaine’s neurochemical actions. Sci Rep. 2017;7(1):13901.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  62. 62.

    Liu JF, Seaman R Jr, Siemian JN, Bhimani R, Johnson B, Zhang Y, et al. Role of trace amine-associated receptor 1 in nicotine’s behavioral and neurochemical effects. Neuropsychopharmacology. 2018;43(12):2435–44.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    Sukhanov I, Dorofeikova M, Dolgorukova A, Dorotenko A, Gainetdinov RR. Trace amine-associated receptor 1 modulates the locomotor and sensitization effects of nicotine. Front Pharmacol. 2018;9:329.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  64. 64.

    Gemechu JM, Sharma A, Yu D, Xie Y, Merkel OM, Moszczynska A. Characterization of dopaminergic system in the striatum of young adult Park2(-/-) knockout rats. Sci Rep. 2018;8(1):1517.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  65. 65.

    Cisneros IE, Ghorpade A. Methamphetamine and HIV-1-induced neurotoxicity: role of trace amine associated receptor 1 cAMP signaling in astrocytes. Neuropharmacol. 2014;85:499–507.

    CAS  Article  Google Scholar 

  66. 66.

    Revel FG, Moreau JL, Pouzet B, Mory R, Bradaia A, Buchy D, et al. A new perspective for schizophrenia: TAAR1 agonists reveal antipsychotic- and antidepressant-like activity, improve cognition and control body weight. Mol Psychiatry. 2013;18(5):543–56.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  67. 67.

    Revel FG, Moreau JL, Gainetdinov RR, Bradaia A, Sotnikova TD, Mory R, et al. TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity. Proc Natl Acad Sci U S A. 2011;108(20):8485–90.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Espinoza S, Lignani G, Caffino L, Maggi S, Sukhanov I, Leo D, et al. TAAR1 modulates cortical glutamate NMDA receptor function. Neuropsychopharmacology. 2015;40(9):2217–27.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Egerton A, Broberg BV, Van Haren N, Merritt K, Barker GJ, Lythgoe DJ, et al. Response to initial antipsychotic treatment in first episode psychosis is related to anterior cingulate glutamate levels: a multicentre (1)H-MRS study (OPTiMiSE). Mol Psychiatry. 2018;23(11):2145–55.

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Mouchlianitis E, Bloomfield MA, Law V, Beck K, Selvaraj S, Rasquinha N, et al. Treatment-resistant schizophrenia patients show elevated anterior cingulate cortex glutamate compared to treatment-responsive. Schizophr Bull. 2016;42(3):744–52.

    PubMed  Article  PubMed Central  Google Scholar 

  71. 71.

    Jauhar S, McCutcheon R, Borgan F, Veronese M, Nour M, Pepper F, et al. The relationship between cortical glutamate and striatal dopamine in first-episode psychosis: a cross-sectional multimodal PET and magnetic resonance spectroscopy imaging study. Lancet Psychiatry. 2018;5(10):816–23.

    PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Merritt K, McGuire PK, Egerton A, Investigators HMiS, Aleman A, Block W, , et al. Association of age, antipsychotic medication, and symptom severity in schizophrenia with proton magnetic resonance spectroscopy brain glutamate level: a mega-analysis of individual participant-level data. JAMA Psychiat. 2021;2:2.

    Google Scholar 

  73. 73.

    Kokkinou M, Ashok AH, Howes OD. The effects of ketamine on dopaminergic function: meta-analysis and review of the implications for neuropsychiatric disorders. Mol Psychiatry. 2018;23(1):59–69.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  74. 74.

    Kokkinou M, Irvine EE, Bonsall DR, Natesan S, Wells LA, Smith M, et al. Reproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: a translational imaging study with ketamine. Mol Psychiatry. 2020;2:2.

    Google Scholar 

  75. 75.

    Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS, et al. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci U S A. 2000;97(14):8104–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76.

    Aleksandrov AA, Knyazeva VM, Volnova AB, Dmitrieva ES, Polyakova NV, Gainetdinov RR. Trace amine-associated receptor 1 agonist modulates mismatch negativity-like responses in mice. Front Pharmacol. 2019;10:470.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77.

    Kantrowitz JT. N-methyl-d-aspartate-type glutamate receptor modulators and related medications for the enhancement of auditory system plasticity in schizophrenia. Schizophr Res. 2019;207:70–9.

    PubMed  Article  PubMed Central  Google Scholar 

  78. 78.

    Kantrowitz JT, Swerdlow NR, Dunn W, Vinogradov S. Auditory system target engagement during plasticity-based interventions in schizophrenia: a focus on modulation of N-methyl-D-aspartate-type glutamate receptor function. Biol Psychiatry Cognit Neurosci Neuroimaging. 2018;3(7):581–90.

    Article  Google Scholar 

  79. 79.

    Greenwood LM, Leung S, Michie PT, Green A, Nathan PJ, Fitzgerald P, et al. The effects of glycine on auditory mismatch negativity in schizophrenia. Schizophr Res. 2018;191:61–9.

    PubMed  Article  PubMed Central  Google Scholar 

  80. 80.

    Kantrowitz JT, Epstein ML, Beggel O, Rohrig S, Lehrfeld JM, Revheim N, et al. Neurophysiological mechanisms of cortical plasticity impairments in schizophrenia and modulation by the NMDA receptor agonist D-serine. Brain. 2016;139(Pt 12):3281–95.

    PubMed  PubMed Central  Article  Google Scholar 

  81. 81.

    Kantrowitz JT, Epstein ML, Lee M, Lehrfeld N, Nolan KA, Shope C, et al. Improvement in mismatch negativity generation during d-serine treatment in schizophrenia: Correlation with symptoms. Schizophr Res. 2018;191:70–9.

    PubMed  Article  PubMed Central  Google Scholar 

  82. 82.

    Lavoie S, Murray MM, Deppen P, Knyazeva MG, Berk M, Boulat O, et al. Glutathione precursor, N-acetyl-cysteine, improves mismatch negativity in schizophrenia patients. Neuropsychopharmacology. 2008;33(9):2187–99.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  83. 83.

    Umbricht D, Javitt D, Novak G, Bates J, Pollack S, Lieberman J, et al. Effects of risperidone on auditory event-related potentials in schizophrenia. Int J Neuropsychopharmcol. 1999;2(4):299–304.

    CAS  Article  Google Scholar 

  84. 84.

    Sehatpour P, Javitt DC, De Baun HM, Carlson M, Margolin DH, Brice N, et al. Mismatch negativity as an index of target engagement for excitation/inhibition-based treatment development: A double-blind, placebo-controlled, randomized, single-dose cross-over study of the serotonin type-3 receptor antagonist CVN058. Res Square (preprint). 2021;2:2.

    Google Scholar 

  85. 85.

    Sehatpour P, Javitt DC, De Baun HM, Carlson M, Belobordova A, Margolin DH, et al. Mismatch negativity as an index of target engagement for excitation/inhibition-based treatment development: a double-blind, placebo-controlled, randomized, single-dose cross-over study of the serotonin type-3 receptor antagonist CVN058. Neuropsychopharmacol. 2021;2:2.

    Google Scholar 

  86. 86.

    Razakarivony O, Newman-Tancredi A, Zimmer L. Towards in vivo imaging of functionally active 5-HT1A receptors in schizophrenia: concepts and challenges. Transl Psychiatry. 2021;11(1):22.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. 87.

    Dedic N, Jones PG, Hopkins SC, Lew R, Shao L, Campbell JE, et al. SEP-363856, a novel psychotropic agent with a unique, non-D2 receptor mechanism of action. J Pharmacol Exp Ther. 2019;371(1):1–14.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  88. 88.

    De Gregorio D, Comai S, Posa L, Gobbi G. d-lysergic acid diethylamide (LSD) as a model of psychosis: mechanism of action and pharmacology. Int J Mol Sci. 2016;23(17):11.

    Google Scholar 

  89. 89.

    Rickli A, Luethi D, Reinisch J, Buchy D, Hoener MC, Liechti ME. Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs). Neuropharmacol. 2015;99:546–53.

    CAS  Article  Google Scholar 

  90. 90.

    Rickli A, Moning OD, Hoener MC, Liechti ME. Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens. Eur Neuropsychopharmacol. 2016;26(8):1327–37.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  91. 91.

    Correll CU, Koblan KS, Hopkins SC, Kent J, Cheng H, Goldman R, et al. Safety and effectiveness of sep-363856 in schizophrenia: results of a 6-month, Open-Label Extension Study. CNS Spectr. 2021;26(2):148–9.

    PubMed  Article  PubMed Central  Google Scholar 

  92. 92.

    Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261–76.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Aleksandrov AA, Dmitrieva ES, Volnova AB, Knyazeva VM, Gainetdinov RR, Polyakova NV. Effect of trace amine-associated receptor 1 agonist RO5263397 on sensory gating in mice. NeuroReport. 2019;30(15):1004–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  94. 94.

    Dorotenko A, Tur M, Dolgorukova A, Bortnikov N, Belozertseva IV, Zvartau EE, et al. The action of TAAR1 agonist RO5263397 on executive functions in rats. Cell Mol Neurobiol. 2020;40(2):215–28.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  95. 95.

    Espinoza S, Leo D, Sotnikova TD, Shahid M, Kaariainen TM, Gainetdinov RR. Biochemical and functional characterization of the trace amine-associated receptor 1 (TAAR1) agonist RO5263397. Front Pharmacol. 2018;9:645.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  96. 96.

    Ferragud A, Howell AD, Moore CF, Ta TL, Hoener MC, Sabino V, et al. The trace amine-associated receptor 1 agonist RO5256390 blocks compulsive, Binge-like eating in rats. Neuropsychopharmacology. 2017;42(7):1458–70.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  97. 97.

    Wu R, Liu J, Wang K, Huang Y, Zhang Y, Li JX. Effects of a trace amine-associated receptor 1 agonist RO 5263397 on ethanol-induced behavioral sensitization. Behav Brain Res. 2020;390:112641.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Joshua T. Kantrowitz.

Ethics declarations

Funding

No funding was received specifically for the preparation of this article.

Availability of data and material

Not applicable.

Code availability

Not applicable.

Conflicts of interest

Dr. Kantrowitz reports having received consulting payments within the last 24 months from Alphasights, Charles River Associates, Medscape, Putnam, techspert.io, Third Bridge, MEDACorp, Parexel, GroupH, ECRI Institute, ExpertConnect, Parexel, Schlesinger Group, CelloHealth, Acsel Health, Antheum, Strafluence, Guidepoint, L.E.K., SmartAnalyst, and System Analytic. He has served on the MedinCell Psychiatry and the Karuna Mechanism of Action (MOA) Advisory Boards. He has conducted clinical research supported by the NIMH, Sunovion, Roche, Alkermes, Cerevance, Corcept, Takeda, Taisho, Boehringer Ingelheim, NeuroRX, and Teva within the last 24 months. He owns a small number of shares of common stock from GSK.

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Author's contribution

Dr. Kantrowitz was responsible for all aspects of the drafting and revision of the review, and agrees to be accountable for the work.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kantrowitz, J.T. Trace Amine-Associated Receptor 1 as a Target for the Development of New Antipsychotics: Current Status of Research and Future Directions. CNS Drugs 35, 1153–1161 (2021). https://doi.org/10.1007/s40263-021-00864-3

Download citation