Psychiatric Pharmacy Essentials: Major Clinical Trials in Schizophrenia/Psychosis

Antipsychotics are used in the management of schizophrenia and other psychiatric disorders. Several major trials have been conducted examining the use of antipsychotics in treatment of schizophrenia, including examining effectiveness, side effect profile, and pharmacoeconomic differences. These major trials help guide the treatment of individuals with psychosis.

Essential Questions and References

How do antipsychotics compare in regard to effectiveness?1-6

Is there a clinical difference between typical antipsychotics and atypical antipsychotics?1

How do antipsychotics differ as far as side effect profile?7-8

Can antipsychotics be used for treatment of non-schizophreniform disorders?9-16

How does antipsychotic selection affect quality of life?17-20

Have any antipsychotics been shown to aid in decreasing suicidality?21

How is first-episode psychosis managed?22

How does schizophrenia impact life expectancy?23-25

What evidence is there regarding the safety and or efficacy of dual antipsychotic usage?26-30

Reviewer 1: Bridgette Gleisner, PharmD, BCPP
Reviewer 2: Amanda Campbell, PharmD, BCPP
2025-2026 AAPP Resident and New Practitioner Committee

  1. Lieberman JA, Stroup TS, McEvoy JP, et al.  Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209-23. [PubMed]
  2. Stroup TS, Lieberman JA, McEvoy JP, et al.  Effectiveness of olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia after discontinuing perphenazine: a CATIE study. Am J Psychiatry. 2007;164(3):415-27. [PubMed]
  3. Stroup TS, Lieberman JA, McEvoy JP, et al.  Effectiveness of olanzapine, quetiapine, risperidone, and ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic. Am J Psychiatry. 2006;163(4):611-22. [PubMed]
  4. McEvoy JP, Lieberman JA, Stroup TS, et al.  Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry. 2006;163(4):600-10. [PubMed]
  5. Stroup TS, Lieberman JA, McEvoy JP, et al.  Results of phase 3 of the CATIE schizophrenia trial. Schizophr Res. 2009;107(1):1-12. [PubMed]
  6. Huhn M, Nikolakopoulou A, Schneider-Thoma J, 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):939-951. [Weblink]
  7. Patel JK, Buckley PF, Woolson S, et al.  Metabolic profiles of second-generation antipsychotics in early psychosis: findings from the CAFE study. Schizophr Res. 2009 Jun;111(1-3):9-16. [PubMed]
  8. Leucht S., Cipriani A., Spineli L., et al. Comparative efficacy and tolerability of 15 antipsyhcotic drugs for schizophrenia: a meta analysis. Lancet. 2013;382(9896):951-962. [PubMed]
  9. Schneider LS, Tariot PN, Dagerman KS, et al.  Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease. N Engl J Med. 2006;355(15):1525-38. [PubMed]
  10. Kahn RS, Fleischhhacker WW, Boter H, et al.  Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet. 2008;371(9618):1085-97. [PubMed]
  11. Mohamed S, Johnson GR, Chen P, et al. Effect of antidepressant switching vs augmentation on remission among patients with major depressive disorder unresponsive to antidepressant treatment: The VAST-D randomized clinical trial. JAMA. 2017;318(2):132-45. [PubMed]
  12. Calabrese JR, Keck PE, Macfadden W, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry. 2005;162(7):1351-60. [PubMed]
  13. Thase ME, Macfadden W, Weisler RH, et al. Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebo-controlled study (BOLDER II study). J Clin Psychopharmacol. 2006;26(6):600-9. [PubMed]
  14. Young AH, McElroy SL, Bauer M, et al. A double-blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression (EMBOLDEN I). J Clin Psychiatry. 2010;71(2):150-62.  [PubMed]
  15. McElroy SL, Weisler RH, Chang W, et al. A double-blind, placebo-controlled study of quetiapine and paroxetine as monotherapy in adults with bipolar depression (EMBOLDEN II). J Clin Psychiatry. 2010;71(2):163-74. [PubMed]
  16. DeVane CL, Charles JM, Abramson RK, et al. Pharmacotherapy of autism spectrum disorder: results from the randomized BAART clinical trial. Pharmacotherapy. 2019;39(6):626-35. [PubMed]
  17. Jones PB, Barnes TR, Davies L, et al.  Randomized controlled trial of the effect on Quality of Life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry. 2006 Oct;63(10):1079-87. [PubMed]
  18. Knapp M, Windmeijer F, Brown J, et al.  Cost-utility analysis of treatment with olanzapine compared with other antipsychotic treatments in patients with schizophrenia in the pan-European SOHO study. Pharmacoeconomics. 2008;26(4):341-58. [PubMed]
  19. Haro JM, Novick D, Suarez D, et al.  Remission and relapse in the outpatient care of schizophrenia: three-year results from the Schizophrenia Outpatient Health Outcomes study.  J Clin Psychopharmacol. 2006;26(6):571-8. [PubMed]
  20. Sampogna G, Di Vincenzo M, Giuliani L, et al. A systematic review of antipsychotic drugs on the quality of life of patients with schizophrenia. Brain Sci. 2023;13(11):1577. [Weblink]
  21. Meltzer HY, Alphs L, Green AI, et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry. 2003;60(1):82-91. [PubMed]
  22. Kane JM, Robinson DG, Schooler NR, et al. Comprehensive Versus Usual Community Care for First-Episode Psychosis: 2-Year Outcomes From the NIMH RAISE Early Treatment Program. Am J Psychiatry. 2016 Apr 1;173(4):362-72. [PubMed]
  23. Gardner-Sood P, Lally J, Smith S, et al. Cardiovascular risk factors and metabolic syndrome in people with established psychotic illnesses: baseline data from the IMPaCT randomized controlled trial. Psychol Med. 2015; 45(12):2619-2629. [Weblink]
  24. Brown S, Inskip H, Barraclough B. Causes of the excess mortality in schizophrenia. Br J Psychiatry. 2000;177:212-217. [Weblink]
  25. Taipale H, Tanskanen A, Mehtala J, Vattulainen P, Correll CU, Tiihonen J. 20-year follow-up study of physical morbidity and mortality in relationship to antipsychotic treatment in a nationwide cohort of 62,250 patients with schizophrenia (FIN20). World Psychiatry. 2020;19(1):61-8. [PubMed]
  26. Correll CU., et al. Efficacy of 42 pharmacologic cotreatment strategies added to antipsychotic monotherapy in schizophrenia; systematic overview and quality appraisal of the meta-analytic evidence. JAMA Psychiatry. 2017;74(7):675-684. [PubMed]
  27. Calvin N., Minischetti L., Salanon F., et al. Combination of two long-acting injectable antipsychotics in treatment-resistant schizophrenia: a retrospective 12-month mirror image study. [PubMed]
  28. Tihonen J., Taipale H., Mahtala J., et al. Association of antipsychotic polypharmacy vs monotherapy with psychiatric rehospitalization among adults with schizophrenia. JAMA Psychiatry. 2019;76(5):499-507. [PubMed]
  29. Weiser M, Davis JM, Brown CH, et al. Differences in antipsychotic treatment discontinuation among veterans with schizophrenia in the U.S. Department of Veterans Affairs. Am J Psychiatry. 2021;178(10):932-940. [Weblink]
  30. Taipale H, Tankanen A, Tihonen J. Safety of antipsychotic polypharmacy versus monotherapy in a nationwide cohort of 61,889 patients with schizophrenia. Am J Psychiatry. 2023;180(5):377-385. [Weblink]