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image of Clinical Effects of Recently Developed Antipsychotic Drugs in Schizophrenia

Abstract

Introduction

Schizophrenia and schizoaffective disorder are generally treated with second-generation antipsychotic drugs. These drugs are mostly dopaminergic (D2) and serotonergic (5-HT2A) antagonists. They sufficiently improve positive schizophrenia symptoms; however, they ameliorate negative symptoms and cognitive functions only to a limited extent.

Material and Methods

We review novel antipsychotic drugs that exert partial agonism at dopaminergic and serotonergic receptors, such as cariprazine, brexpiprazole, and lumateperone. In addition, the mechanisms of action of non-dopaminergic antipsychotic drugs are described. Updated neural network models are used to explain the mechanisms of action of muscarinic (M4 and M1) receptor agonists (, xanomeline combined with trospium) and trace-amine-associated receptor 1 (TAAR1) agonists (, ulotaront). Phase 3 clinical trials of new third-generation antipsychotic drugs are also presented.

Results

Novel antipsychotic drugs with partial agonism at D2 and D3 receptors improve positive and negative schizophrenia symptoms, as well as cognitive symptoms, more effectively than second-generation antipsychotic drugs. They are also well tolerated. M4 and M1 receptor agonists (, xanomeline combined with trospium or emraclidine) and TAAR1 agonists (, ulotaront) substantially improve negative schizophrenia symptoms and cognitive functions. These new non-dopaminergic antipsychotic drugs better ameliorate negative symptoms and improve cognitive functions compared with second-generation antipsychotic drugs.

Discussion

Results from phase 3 clinical studies indicate the clinical efficacy of new third-generation antipsychotic drugs.

Conclusion

Promising new antipsychotic drugs include cariprazine, brexpiprazole, lumateperone, ulotaront, and xanomeline combined with trospium. Phase 3 clinical studies have shown therapeutic effects superior to those achieved with second-generation antipsychotic drugs.

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2026-01-21
2026-02-27

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References

  1. Werner F.M. Coveñas R. Classical neurotransmitters and neuropeptides involved in schizoaffective disorder: Focus on prophylactic medication. Sharjah Bentham Science Publishers 2016
    [Google Scholar]
  2. Correll C.U. Arango C. Fagerlund B. Galderisi S. Kas M.J. Leucht S. Identification and treatment of individuals with childhood-onset and early-onset schizophrenia. Eur. Neuropsychopharmacol. 2024 82 57 71 10.1016/j.euroneuro.2024.02.005 38492329
    [Google Scholar]
  3. Pahwa M. Sleem A. Elsayed O.H. Good M.E. El-Mallakh R.S. New antipsychotic medications in the last decade. Curr. Psychiatry Rep. 2021 23 12 87 10.1007/s11920‑021‑01298‑w 34843030
    [Google Scholar]
  4. Werner F.M. Coveñas R. Updated neural networks in schizophrenia and novel antipsychotic drugs. Clin. Neurophysiol. 2023 148 e1 e7
    [Google Scholar]
  5. de Bartolomeis A. Ciccarelli M. Vellucci L. Fornaro M. Iasevoli F. Barone A. Update on novel antipsychotics and pharmacological strategies for treatment-resistant schizophrenia. Expert Opin. Pharmacother. 2022 23 18 2035 2052 10.1080/14656566.2022.2145884 36368055
    [Google Scholar]
  6. Correll CU Abi-Dargham A Howes O Emerging treatments in schizophrenia. J. Clin. Psych 2022 83 1 U21024IP1 10.4088/JCP.SU21024IP1 35172048
    [Google Scholar]
  7. Tandon R. Gaebel W. Barch D.M. Bustillo J. Gur R.E. Heckers S. Malaspina D. Owen M.J. Schultz S. Tsuang M. Van Os J. Carpenter W. Definition and description of schizophrenia in the DSM-5. Schizophr. Res. 2013 150 1 3 10 10.1016/j.schres.2013.05.028 23800613
    [Google Scholar]
  8. Okubo R. Okada M. Motomura E. Dysfunction of the NMDA receptor in the pathophysiology of schizophrenia and/or the pathomechanisms of treatment-resistant schizophrenia. Biomolecules 2024 14 9 1128 10.3390/biom14091128 39334894
    [Google Scholar]
  9. Siafis S. Wu H. Wang D. Burschinski A. Nomura N. Takeuchi H. Schneider-Thoma J. Davis J.M. Leucht S. Antipsychotic dose, dopamine D2 receptor occupancy and extrapyramidal side-effects: A systematic review and dose-response meta-analysis. Mol. Psychiatry 2023 28 8 3267 3277 10.1038/s41380‑023‑02203‑y 37537284
    [Google Scholar]
  10. Mauri M.C. Paletta S. Di Pace C. Reggiori A. Cirnigliaro G. Valli I. Altamura A.C. Clinical pharmacokinetics of atypical antipsychotics: An update. Clin. Pharmacokinet. 2019 58 9 1219 1220 10.1007/s40262‑019‑00797‑7 31214940
    [Google Scholar]
  11. Werner F.M. Coveñas R. Safety of antipsychotic drugs: Focus on therapeutic and adverse effects. Expert Opin. Drug Saf. 2014 13 8 1031 1042 10.1517/14740338.2014.935761 24975932
    [Google Scholar]
  12. Orzelska-Górka J. Mikulska J. Wiszniewska A. Biała G. New atypical antipsychotics in the treatment of schizophrenia and depression. Int. J. Mol. Sci. 2022 23 18 10624 10.3390/ijms231810624 36142523
    [Google Scholar]
  13. Mohr P. Masopust J. Kopeček M. Dopamine receptor partial agonists: Do they differ in their clinical efficacy? Front. Psychiatry 2022 12 781946 10.3389/fpsyt.2021.781946 35145438
    [Google Scholar]
  14. Wu H. Siafis S. Hamza T. Schneider-Thoma J. Davis J.M. Salanti G. Leucht S. Antipsychotic-induced weight gain: Dose-response meta-analysis of randomized controlled trials. Schizophr. Bull. 2022 48 3 643 654 10.1093/schbul/sbac001 35137229
    [Google Scholar]
  15. Schneider-Thoma J. Chalkou K. Dörries C. Bighelli I. Ceraso A. Huhn M. Siafis S. Davis J.M. Cipriani A. Furukawa T.A. Salanti G. Leucht S. Comparative efficacy and tolerability of 32 oral and injectable long-acting antipsychotics for the maintenance treatment of adults with schizophrenia: A systematic review and network meta-analysis. Lancet 2022 399 824 836 10.1016/S0140‑6736(21)01997‑8 35219395
    [Google Scholar]
  16. Dean B. Scarr E. Muscarinic M1 and M4 receptors: Hypothesis driven drug development for schizophrenia. Psychiatry Res. 2020 288 112989 10.1016/j.psychres.2020.112989 32315882
    [Google Scholar]
  17. Yang A.C. Tsai S-J. New targets for schizophrenia treatment beyond the dopamine hypothesis. Int. J. Mol. Sci. 2017 18 8 1689 10.3390/ijms18081689 28771182
    [Google Scholar]
  18. Heffernan M.L.R. Herman L.W. Brown S. Jones P.G. Shao L. Hewitt M.C. Campbell J.E. Dedic N. Hopkins S.C. Koblan K.S. Xie L. Ulotaront: A TAAR1 agonist for the treatment of schizophrenia. ACS Med. Chem. Lett. 2021 13 1 92 98 10.1021/acsmedchemlett.1c00527 35047111
    [Google Scholar]
  19. Caccia S. Invernizzi R.W. Nobili A. Pasina L. A new generation of antipsychotics: Pharmacology and clinical utility of cariprazine in schizophrenia. Ther. Clin. Risk Manag. 2013 9 319 328 10.2147/TCRM.S35137 23966785
    [Google Scholar]
  20. Werner F.M. Coveñas R. New developments in the management of schizophrenia and bipolar disorder: Potential use of cariprazine. Ther. Clin. Risk Manag. 2015 11 1657 1661 10.2147/TCRM.S64915 26586950
    [Google Scholar]
  21. Laszlovszky I. Barabássy Á. Németh G. Cariprazine, a broad-spectrum antipsychotic for the treatment of schizophrenia: Pharmacology, efficacy and safety. Adv. Ther. 2021 38 7 3652 3673 10.1007/s12325‑021‑01797‑5 34091867
    [Google Scholar]
  22. Grossberg G.T. Kohegyi E. Mergel V. Josiassen M.K. Meulien D. Hobart M. Slomkowski M. Baker R.A. McQuade R.D. Cummings J.L. Efficacy and safety of brexpiprazole for the treatment of agitation in Alzheimer’s dementia: Two 12-week, randomized, double-blind, placebo-controlled trials. Am. J. Geriatr. Psychiatry 2020 28 4 383 400 10.1016/j.jagp.2019.09.009 31708380
    [Google Scholar]
  23. Ishigooka J. Iwashita S. Higashi K. Liew E.L. Tadori Y. Pharmacokinetics and safety of brexpiprazole following multiple-dose administration to Japanese patients with schizophrenia. J. Clin. Pharmacol. 2018 58 1 74 80 10.1002/jcph.979 28750151
    [Google Scholar]
  24. Greig S.L. Brexpiprazole: First global approval. Drugs 2015 75 14 1687 1697 10.1007/s40265‑015‑0462‑2 26310190
    [Google Scholar]
  25. Edinoff A. Wu N. deBoisblanc C. Feltner C.O. Norder M. Tzoneva V. Kaye A.M. Cornett E.M. Kaye A.D. Viswanath O. Urits I. Lumateperone for the treatment of schizophrenia. Psychopharmacol. Bull. 2020 50 4 32 59 [PMID: 33012872
    [Google Scholar]
  26. Werner F.M. Coveñas R. The novel antipsychotic drug cariprazine and cognition enhancing drugs: Indications for their use as the add-on therapy in schizophrenia. Curr. Pharm. Des. 2021 27 39 4033 4038 10.2174/1381612826666201210123229 33302854
    [Google Scholar]
  27. Blair H.A. Lumateperone: First Approval. Drugs 2020 80 4 417 423 10.1007/s40265‑020‑01271‑6 32060882
    [Google Scholar]
  28. Snyder G.L. Vanover K.E. Davis R.E. Li P. Fienberg A. Mates S. A review of the pharmacology and clinical profile of lumateperone for the treatment of schizophrenia. Adv. Pharmacol. 2021 90 253 276 10.1016/bs.apha.2020.09.001 33706936
    [Google Scholar]
  29. Dodd S. Carvalho F. A.; Puri, B.K.; Maes, M.; Bortolasci, C.C.; Morris, G.; Berk, M. Trace Amine-Associated Receptor 1 (TAAR1): A new drug target for psychiatry? Neurosci. Biobehav. Rev. 2021 120 537 541 10.1016/j.neubiorev.2020.09.028 33031817
    [Google Scholar]
  30. Koblan K.S. Kent J. Hopkins S.C. Krystal J.H. Cheng H. Goldman R. Loebel A. A non-D2-receptor-binding drug for the treatment of schizophrenia. N. Engl. J. Med. 2020 382 16 1497 1506 10.1056/NEJMoa1911772 32294346
    [Google Scholar]
  31. Dean B. Muscarinic M1 and M4 receptor agonists for schizophrenia: Promising candidates for the therapeutic arsenal. Expert Opin. Investig. Drugs 2023 32 12 1113 1121 10.1080/13543784.2023.2288074 37994870
    [Google Scholar]
  32. Kaul I. Sawchak S. Correll C.U. Kakar R. Breier A. Zhu H. Miller A.C. Paul S.M. Brannan S.K. Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline–trospium) in schizophrenia (EMERGENT-2) in the USA: Results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial. Lancet 2024 403 10422 160 170 10.1016/S0140‑6736(23)02190‑6 38104575
    [Google Scholar]
  33. Jones C.K. Byun N. Bubser M. Muscarinic and nicotinic acetylcholine receptor agonists and allosteric modulators for the treatment of schizophrenia. Neuropsychopharmacology 2012 37 1 16 42 10.1038/npp.2011.199 21956443
    [Google Scholar]
  34. Jones C.K. Eberle E.L. Shaw D.B. McKinzie D.L. Shannon H.E. Pharmacologic interactions between the muscarinic cholinergic and dopaminergic systems in the modulation of prepulse inhibition in rats. J. Pharmacol. Exp. Ther. 2005 312 3 1055 1063 10.1124/jpet.104.075887 15574685
    [Google Scholar]
  35. Thomsen M. Wess J. Fulton B.S. Fink-Jensen A. Caine S.B. Modulation of prepulse inhibition through both M1 and M4 muscarinic receptors in mice. Psychopharmacology 2010 208 3 401 416 10.1007/s00213‑009‑1740‑z 20013114
    [Google Scholar]
  36. Thorn C.A. Popiolek M. Stark E. Edgerton J.R. Effects of M1 and M4 activation on excitatory synaptic transmission in CA1. Hippocampus 2017 27 7 794 810 10.1002/hipo.22732 28422371
    [Google Scholar]
  37. Crook J.M. Tomaskovic-Crook E. Copolov D.L. Dean B. Decreased muscarinic receptor binding in subjects with schizophrenia: A study of the human hippocampal formation. Biol. Psychiatry 2000 48 5 381 388 10.1016/S0006‑3223(00)00918‑5 10978721
    [Google Scholar]
  38. Werner F. Coveñas R. New, not anti-dopaminergic antipsychotic drugs in the treatment of schizophrenia, M4 or M1 receptor agonists and TAAR1 agonists. Clin. Neurophysiol. 2024 159 e13 10.1016/j.clinph.2023.12.038
    [Google Scholar]
  39. Krystal J.H. Kane J.M. Correll C.U. Walling D.P. Leoni M. Duvvuri S. Patel S. Chang I. Iredale P. Frohlich L. Versavel S. Perry P. Sanchez R. Renger J. Emraclidine, a novel positive allosteric modulator of cholinergic M4 receptors, for the treatment of schizophrenia: A two-part, randomised, double-blind, placebo-controlled, phase 1b trial. Lancet 2022 400 10369 2210 2220 10.1016/S0140‑6736(22)01990‑0 36528376
    [Google Scholar]
  40. Corponi F. Fabbri C. Bitter I. Montgomery S. Vieta E. Kasper S. Pallanti S. Serretti A. Novel antipsychotics specificity profile: A clinically oriented review of lurasidone, brexpiprazole, cariprazine and lumateperone. Eur. Neuropsychopharmacol. 2019 29 9 971 985 10.1016/j.euroneuro.2019.06.008 31255396
    [Google Scholar]
  41. Citrome L. Activating and sedating adverse effects of second-generation antipsychotics in the treatment of schizophrenia and major depressive disorder. J. Clin. Psychopharmacol. 2017 37 2 138 147 10.1097/JCP.0000000000000665 28141623
    [Google Scholar]
  42. Barman R. Majumder P. Doifode T. Kablinger A. Newer antipsychotics: Brexpiprazole, cariprazine, and lumateperone: A pledge or another unkept promise? World J. Psychiatry 2021 11 12 1228 1238 10.5498/wjp.v11.i12.1228 35070772
    [Google Scholar]
  43. Edinoff A. Ruoff M.T. Ghaffar Y.T. Rezayev A. Jani D. Kaye A.M. Cornett E.M. Kaye A.D. Viswanath O. Urits I. Cariprazine to treat schizophrenia and bipolar disorder in adults. Psychopharmacol. Bull. 2020 50 4 83 117 [PMID: 33012874
    [Google Scholar]
  44. Breier A. Brannan S.K. Paul S.M. Miller A.C. Evidence of trospium’s ability to mitigate cholinergic adverse events related to xanomeline: Phase 1 study results. Psychopharmacology 2023 240 5 1191 1198 10.1007/s00213‑023‑06362‑2 37036495
    [Google Scholar]
  45. Grant M.K.O. Noetzel M.J. De Lorme K.C. Jakubík J. Doležal V. El-Fakahany E.E. Pharmacological evaluation of the long-term effects of xanomeline on the M(1) muscarinic acetylcholine receptor. PLoS One 2010 5 12 e15722 10.1371/journal.pone.0015722 21203415
    [Google Scholar]
  46. Russell J.K. Ingram S.M. Teal L.B. Lindsley C.W. Jones C.K.M. 1 /M 4 -Preferring muscarinic cholinergic receptor agonist xanomeline reverses wake and arousal deficits in nonpathologically aged mice. ACS Chem. Neurosci. 2023 14 3 435 457 10.1021/acschemneuro.2c00592 36655909
    [Google Scholar]
  47. Németh G. Laszlovszky I. Czobor P. Szalai E. Szatmári B. Harsányi J. Barabássy Á. Debelle M. Durgam S. Bitter I. Marder S. Fleischhacker W.W. Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: A randomised, double-blind, controlled trial. Lancet 2017 389 10074 1103 1113 10.1016/S0140‑6736(17)30060‑0 28185672
    [Google Scholar]
  48. McIntyre R.S. Daniel D.G. Vieta E. Laszlovszky I. Goetghebeur P.J. Earley W.R. Patel M.D. The efficacy of cariprazine on cognition: A post hoc analysis from phase II/III clinical trials in bipolar mania, bipolar depression, and schizophrenia. CNS Spectr. 2023 28 3 319 330 10.1017/S109285292200013X 35193729
    [Google Scholar]
  49. Hishimoto A. Yasui-Furukori N. Sekine D. Matsukawa M. Yamada S. Treatment discontinuation among patients with schizophrenia treated with brexpiprazole and other oral atypical antipsychotics in Japan: A retrospective observational study. Adv. Ther. 2022 39 9 4299 4314 10.1007/s12325‑022‑02252‑9 35904721
    [Google Scholar]
  50. Correll C.U. Davis R.E. Weingart M. Saillard J. O’Gorman C. Kane J.M. Lieberman J.A. Tamminga C.A. Mates S. Vanover K.E. Efficacy and safety of lumateperone for treatment of schizophrenia. A ramomized clinical trial. JAMA Psychiatry 2020 77 4 349 358 10.1001/jamapsychiatry.2019.4379 31913424
    [Google Scholar]
  51. Luca M. Luca A. Serretti A. A clinically oriented review of new antipsychotics for schizophrenia. Neuropsychiatr. Dis. Treat. 2024 20 2637 2649 10.2147/NDT.S501560 39741904
    [Google Scholar]
  52. Ye N. Wang Q. Li Y. Zhen X. Current emerging therapeutic targets and clinical investigational agents for schizophrenia: Challenges and opportunities. Med. Res. Rev. 2025 45 2 755 787 10.1002/med.22086 39300769
    [Google Scholar]
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Clinical Effects of Recently Developed Antipsychotic Drugs in Schizophrenia
Bentham Science Publishers ; https://doi.org/10.2174/0118715249384914251122074130
/content/journals/cnsamc/10.2174/0118715249384914251122074130
/content/journals/cnsamc/10.2174/0118715249384914251122074130
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  • Article Type:     Review Article
Keywords: positive schizophrenia symptom ; negative schizophrenia symptom ; xanomeline ; M4 and M1 receptor agonist ; schizoaffective disorder ; schizophrenia ; trace-amine-associated receptor 1 agonist ; trospium ; dopamine ; Antipsychotic drug

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