Download PDF
Pharmacopsychiatry 2024; 57(05): 221-231
DOI: 10.1055/a-2307-6484
Review

Advancements in Non-Dopaminergic Treatments for Schizophrenia: A Systematic Review of Pipeline Developments

Yuki Komatsu   ‡
1   Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
2   Department of Psychiatry, Tokyo Metropolitan Matsuzawa Hospital, Tokyo, Japan
,
Moe Takehara   ‡
3   Division of Drug Informatics, Keio University Faculty of Pharmacy, Tokyo, Japan
,
Xenia Hart   ‡
1   Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
4   Department of Molecular Neuroimaging, Medical Faculty Mannheim, Central Institute of Mental Health, Heidelberg University, Mannheim, Germany
,
Yuna Takahashi
3   Division of Drug Informatics, Keio University Faculty of Pharmacy, Tokyo, Japan
,
Satoko Hori
3   Division of Drug Informatics, Keio University Faculty of Pharmacy, Tokyo, Japan
,
Fumihiko Ueno
1   Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
5   Brain Health Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
6   Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
,
Hiroyuki Uchida
1   Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
› Author Affiliations Funding Japan Society for the Promotion of Science — http://dx.doi.org/10.13039/501100001691; JP19H03587 and JP20K20603 Overseas Research Fellow Award This work was supported by JSPS KAKENHI, Grant Numbers JP19H03587 and JP20K20603 (H. Uchida). Dr. Hart was supported by an Overseas Research Fellow Award from the Japan Society for the Promotion of Science.
› Further Information
Also available at
   Permissions and Reprints

Abstract

Introduction Conventional antipsychotic drugs that attenuate dopaminergic neural transmission are ineffective in approximately one-third of patients with schizophrenia. This necessitates the development of non-dopaminergic agents.

Methods A systematic search was conducted for completed phase II and III trials of compounds for schizophrenia treatment using the US Clinical Trials Registry and the EU Clinical Trials Register. Compounds demonstrating significant superiority over placebo in the primary outcome measure in the latest phase II and III trials were identified. Collateral information on the included compounds was gathered through manual searches in PubMed and press releases.

Results Sixteen compounds were identified; four compounds (ulotaront, xanomeline/trospium chloride, vabicaserin, and roluperidone) were investigated as monotherapy and the remaining 12 (pimavanserin, bitopertin, BI 425809, encenicline, tropisetron, pregnenolone, D-serine, estradiol, tolcapone, valacyclovir, cannabidiol, and rimonabant) were examined as add-on therapy. Compared to the placebo, ulotaront, xanomeline/trospium chloride, vabicaserin, bitopertin, estradiol, cannabidiol, rimonabant, and D-serine showed efficacy for positive symptoms; roluperidone and pimavanserin were effective for negative symptoms; and encenicline, tropisetron, pregnenolone, tolcapone, BI 425809, and valacyclovir improved cognitive function.

Discussion Compounds that function differently from existing antipsychotics may offer novel symptom-specific therapeutic strategies for patients with schizophrenia.

Keywords

antipsychotic. schizophrenia - pipeline - non-dopaminergic

‡ These authors contributed equally to this work: Yuki Komatsu, Moe Takehara, Xenia Hart




Publication History

Received: 28 January 2024
Received: 30 March 2024

Accepted: 05 April 2024

Article published online:
06 May 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 McGrath J, Saha S, Chant D. et al. Schizophrenia: A concise overview of incidence, prevalence, and mortality. Epidemiol Rev 2008; 30: 67-76
    CrossrefPubMedSearch in Google Scholar
  • 2 Zhu Y, Krause M, Huhn M. et al. Antipsychotic drugs for the acute treatment of patients with a first episode of schizophrenia: A systematic review with pairwise and network meta-analyses. Lancet Psychiatry 2017; 4: 694-705
    CrossrefPubMedSearch in Google Scholar
  • 3 Ceraso A, Lin JJ, Schneider-Thoma J. et al. Maintenance treatment with antipsychotic drugs in schizophrenia: A Cochrane systematic review and meta-analysis. Schizophr Bull 2022; 48: 738-740
    CrossrefPubMedSearch in Google Scholar
  • 4 Suzuki T, Remington G, Mulsant BH. et al. Treatment resistant schizophrenia and response to antipsychotics: A review. Schizophr Res 2011; 133: 54-62
    CrossrefPubMedSearch in Google Scholar
  • 5 Siskind D, Siskind V, Kisely S. Clozapine response rates among people with treatment-resistant schizophrenia: Data from a systematic review and meta-analysis. Can J Psychiatry 2017; 62: 772-777
    CrossrefPubMedSearch in Google Scholar
  • 6 Uchida H, Takeuchi H, Graff-Guerrero A. et al. Dopamine D2 receptor occupancy and clinical effects: A systematic review and pooled analysis. J Clin Psychopharmacol 2011; 31: 497-502
    CrossrefPubMedSearch in Google Scholar
  • 7 Ray WA, Chung CP, Murray KT. et al. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med 2009; 360: 225-235
    CrossrefPubMedSearch in Google Scholar
  • 8 Sakurai H, Bies RR, Stroup ST. et al. Dopamine D2 receptor occupancy and cognition in schizophrenia: Analysis of the CATIE data. Schizophr Bull 2013; 39: 564-574
    CrossrefPubMedSearch in Google Scholar
  • 9 Adrianzén C, Arango-Dávila C, Araujo DM. et al. Relative association of treatment-emergent adverse events with quality of life of patients with schizophrenia: Post hoc analysis from a 3-year observational study. Hum Psychopharmacol 2010; 25: 439-447
    CrossrefPubMedSearch in Google Scholar
  • 10 Haddaway NR, Page MJ, Pritchard CC. et al. PRISMA2020: An R package and Shiny app for producing PRISMA 2020-compliant flow diagrams, with interactivity for optimised digital transparency and Open Synthesis. Campbell Systematic Reviews 2022; 18: e1230
    CrossrefPubMedSearch in Google Scholar
  • 11 Koblan KS, Kent J, Hopkins SC. et al. A non-D2-receptor-binding drug for the treatment of schizophrenia. N Engl J Med 2020; 382: 1497-1506
    CrossrefPubMedSearch in Google Scholar
  • 12 Dedic N, Jones PG, Hopkins SC. et al. SEP-363856, a novel psychotropic agent with a unique, non-D2 receptor mechanism of action. J Pharmacol Exp Ther 2019; 371: 1-14
    CrossrefPubMedSearch in Google Scholar
  • 13 Shannon HE, Bymaster FP, Calligaro DO. et al. Xanomeline: A novel muscarinic receptor agonist with functional selectivity for M1 receptors. J Pharmacol Exp Ther 1994; 269: 271-281
    PubMedSearch in Google Scholar
  • 14 Brannan SK, Sawchak S, Miller AC. et al. Muscarinic cholinergic receptor agonist and peripheral antagonist for schizophrenia. N Engl J Med 2021; 384: 717-726
    CrossrefPubMedSearch in Google Scholar
  • 15 Shen JH, Zhao Y, Rosenzweig-Lipson S. et al. A 6-week randomized, double-blind, placebo-controlled, comparator referenced trial of vabicaserin in acute schizophrenia. J Psychiatr Res 2014; 53: 14-22
    CrossrefPubMedSearch in Google Scholar
  • 16 Dunlop J, Watts SW, Barrett JE. et al. Characterization of vabicaserin (SCA-136), a selective 5-hydroxytryptamine 2C receptor agonist. J Pharmacol Exp Ther 2011; 337: 673-680
    CrossrefPubMedSearch in Google Scholar
  • 17 Davidson M, Saoud J, Staner C. 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: 1195-1202
    CrossrefPubMedSearch in Google Scholar
  • 18 Bugarski-Kirola D, Arango C, Fava M. et al. Pimavanserin for negative symptoms of schizophrenia: Results from the ADVANCE phase 2 randomised, placebo-controlled trial in North America and Europe. Lancet Psychiatry 2022; 9: 46-58
    CrossrefPubMedSearch in Google Scholar
  • 19 Vanover KE, Weiner DM, Makhay M. et al. Pharmacological and behavioral profile of N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel 5-hydroxytryptamine(2A) receptor inverse agonist. J Pharmacol Exp Ther 2006; 317: 910-918
    CrossrefPubMedSearch in Google Scholar
  • 20 Alberati D, Moreau JL, Lengyel J. et al. Glycine reuptake inhibitor RG1678: A pharmacologic characterization of an investigational agent for the treatment of schizophrenia. Neuropharmacology 2012; 62: 1152-1161
    CrossrefPubMedSearch in Google Scholar
  • 21 Bugarski-Kirola D, Iwata N, Sameljak S. et al. Efficacy and safety of adjunctive bitopertin versus placebo in patients with suboptimally controlled symptoms of schizophrenia treated with antipsychotics: Results from three phase 3, randomised, double-blind, parallel-group, placebo-controlled, multicentre studies in the SearchLyte clinical trial programme. Lancet Psychiatry 2016; 3: 1115-1128
    CrossrefPubMedSearch in Google Scholar
  • 22 Rosenbrock H, Desch M, Kleiner O. et al. Evaluation of pharmacokinetics and pharmacodynamics of BI 425809, a novel GlyT1 inhibitor: Translational studies. Clin Transl Sci 2018; 11: 616-623
    CrossrefPubMedSearch in Google Scholar
  • 23 Fleischhacker WW, Podhorna J, Groschl M. 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: 191-201
    CrossrefPubMedSearch in Google Scholar
  • 24 Keefe RS, Meltzer HA, Dgetluck N. et al. Randomized, double-blind, placebo-controlled study of encenicline, an alpha7 nicotinic acetylcholine receptor agonist, as a treatment for cognitive impairment in schizophrenia. Neuropsychopharmacology 2015; 40: 3053-3060
    CrossrefPubMedSearch in Google Scholar
  • 25 Prickaerts J, van Goethem NP, Chesworth R. et al. EVP-6124, a novel and selective alpha7 nicotinic acetylcholine receptor partial agonist, improves memory performance by potentiating the acetylcholine response of alpha7 nicotinic acetylcholine receptors. Neuropharmacology 2012; 62: 1099-1110
    CrossrefPubMedSearch in Google Scholar
  • 26 Macor JE, Gurley D, Lanthorn T. et al. The 5-HT3 antagonist tropisetron (ICS 205-930) is a potent and selective alpha7 nicotinic receptor partial agonist. Bioorg Med Chem Lett 2001; 11: 319-321
    CrossrefPubMedSearch in Google Scholar
  • 27 Shiina A, Shirayama Y, Niitsu T. et al. A randomised, double-blind, placebo-controlled trial of tropisetron in patients with schizophrenia. Ann Gen Psychiatry 2010; 9: 27
    CrossrefPubMedSearch in Google Scholar
  • 28 Marx CE, Lee J, Subramaniam M. et al. Proof-of-concept randomized controlled trial of pregnenolone in schizophrenia. Psychopharmacology (Berl) 2014; 231: 3647-3662
    CrossrefPubMedSearch in Google Scholar
  • 29 Kantrowitz JT, Epstein ML, Lee M. et al. Improvement in mismatch negativity generation during d-serine treatment in schizophrenia: Correlation with symptoms. Schizophr Res 2018; 191: 70-79
    CrossrefPubMedSearch in Google Scholar
  • 30 Kulkarni J, Gavrilidis E, Wang W. et al. Estradiol for treatment-resistant schizophrenia: A large-scale randomized-controlled trial in women of child-bearing age. Mol Psychiatry 2015; 20: 695-702
    CrossrefPubMedSearch in Google Scholar
  • 31 Zürcher G, Colzi A, Da Prada M. Ro 40-7592: inhibition of COMT in rat brain and extracerebral tissues. J Neural Transm Suppl 1990; 32: 375-380
    CrossrefPubMedSearch in Google Scholar
  • 32 Prasad KM, Eack SM, Keshavan MS. et al. Antiherpes virus-specific treatment and cognition in schizophrenia: A test-of-concept randomized double-blind placebo-controlled trial. Schizophr Bull 2013; 39: 857-866
    CrossrefPubMedSearch in Google Scholar
  • 33 McGuire P, Robson P, Cubala WJ. et al. Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: A multicenter randomized controlled trial. Am J Psychiatry 2018; 175: 225-231
    CrossrefPubMedSearch in Google Scholar
  • 34 Atalay S, Jarocka-Karpowicz I, Skrzydlewska E. Antioxidative and anti-inflammatory properties of cannabidiol. Antioxidants (Basel) 2019; 9
    CrossrefPubMedSearch in Google Scholar
  • 35 Kelly DL, Gorelick DA, Conley RR. et al. Effects of the cannabinoid-1 receptor antagonist rimonabant on psychiatric symptoms in overweight people with schizophrenia: A randomized, double-blind, pilot study. J Clin Psychopharmacol 2011; 31: 86-91
    CrossrefPubMedSearch in Google Scholar