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?1-8

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

How do antipsychotics differ as far as side effect profile?7-10

Can antipsychotics be used for treatment of non-schizophreniform disorders?11-18

How does antipsychotic selection affect quality of life?19-22

Have any antipsychotics been shown to aid in decreasing suicidality?23-24

How is first-episode psychosis managed?25

How does schizophrenia impact life expectancy?26-27

What evidence is there regarding the safety and or efficacy of dual antipsychotic usage?28-32

Reviewer 1: Christine Sun, PharmD, BCPP
Reviewer 2: Angeleki Zecopoulos, PharmD
2026-2027 AAPP Resident and New Practitioner Committee

  1. Lieberman JA. Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia. J Clin Psychiatry. 2007 Feb 15;68(02):e04. Physicians Postgraduate Press, Inc. DOI: 10.4088/jcp.0207e04.
  2. Stroup TS, Lieberman JA, McEvoy JP, Swartz MS, Davis SM, Capuano GA, et al. Effectiveness of olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia after discontinuing perphenazine: a CATIE study.. Am J Psychiatry. 2007 Mar;164(3):415-27. DOI: 10.1176/ajp.2007.164.3.415; PubMed PMID: 17329466.
  3. Stroup TS, Lieberman JA, McEvoy JP, Swartz MS, Davis SM, Rosenheck RA, et al. Effectiveness of Olanzapine, Quetiapine, Risperidone, and Ziprasidone in Patients With Chronic Schizophrenia Following Discontinuation of a Previous Atypical Antipsychotic. FOC. 2006 Sep;4(4):539-552. American Psychiatric Association Publishing. DOI: 10.1176/foc.4.4.539.
  4. McEvoy JP, Lieberman JA, Stroup TS, Davis SM, Meltzer HY, Rosenheck RA, et al. Effectiveness of Clozapine Versus Olanzapine, Quetiapine, and Risperidone in Patients With Chronic Schizophrenia Who Did Not Respond to Prior Atypical Antipsychotic Treatment. AJP. 2006 Apr;163(4):600-610. American Psychiatric Association Publishing. DOI: 10.1176/ajp.2006.163.4.600.
  5. Stroup TS, Lieberman JA, McEvoy JP, Davis SM, Swartz MS, Keefe RSE, et al. Results of phase 3 of the CATIE schizophrenia trial. Schizophrenia Res. 2009 Jan;107(1):1-12. Elsevier BV. DOI: 10.1016/j.schres.2008.10.011.
  6. 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. FOC. 2020 Oct;18(4):443-455. American Psychiatric Association Publishing. DOI: 10.1176/appi.focus.18306.
  7. Zhao G, Sun Y, Zhang Y, Lu T, Lu Z, Kang Z, et al. Efficacy and Tolerability of Seven Antipsychotic Drugs in Acutely Ill Patients With Schizophrenia: A Randomized, Multicenter, Assessor-Blinded Trial. AJP. 2026 Feb;183(2):112-123. American Psychiatric Association Publishing. DOI: 10.1176/appi.ajp.20250111.
  8. Schneider-Thoma J, Zhu Y, Qin M, Dong Y, Guan S, Wang J, et al. Comparative efficacy and tolerability of antidopaminergic and muscarinic antipsychotics for acute schizophrenia: a network meta-analysis of randomised controlled trials indexed in international English and Chinese databases. Lancet. 2026 Feb;407(10531):876-891. Elsevier BV. DOI: 10.1016/s0140-6736(25)02365-7.
  9. Patel JK, Buckley PF, Woolson S, Hamer RM, McEvoy JP, Perkins DO, et al. Metabolic profiles of second-generation antipsychotics in early psychosis: Findings from the CAFE study. Schizophrenia Res. 2009 Jun;111(1-3):9-16. Elsevier BV. DOI: 10.1016/j.schres.2009.03.025.
  10. Leucht S, Cipriani A, Spineli L, Mavridis D, Örey D, Richter F, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013 Sep;382(9896):951-962. Elsevier BV. DOI: 10.1016/s0140-6736(13)60733-3.
  11. Schneider LS, Tariot PN, Dagerman KS, Davis SM, Hsiao JK, Ismail MS, et al. Effectiveness of Atypical Antipsychotic Drugs in Patients with Alzheimer's Disease. N Engl J Med. 2006 Oct 12;355(15):1525-1538. Massachusetts Medical Society. DOI: 10.1056/nejmoa061240.
  12. Kahn RS, Fleischhacker WW, Boter H, Davidson M, Vergouwe Y, Keet IP, et al. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet. 2008 Mar;371(9618):1085-1097. Elsevier BV. DOI: 10.1016/s0140-6736(08)60486-9.
  13. Mohamed S, Johnson GR, Chen P, Hicks PB, Davis LL, Yoon J, et al. Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment. JAMA. 2017 Jul 11;318(2):132. American Medical Association (AMA). DOI: 10.1001/jama.2017.8036.
  14. Calabrese JR, Keck PE, Macfadden W, Minkwitz M, Ketter TA, Weisler RH, et al. A Randomized, Double-Blind, Placebo-Controlled Trial of Quetiapine in the Treatment of Bipolar I or II Depression. AJP. 2005 Jul 1;162(7):1351-1360. American Psychiatric Association Publishing. DOI: 10.1176/appi.ajp.162.7.1351.
  15. Thase ME. BOLDER II study of quetiapine therapy for bipolar depression. Futur Neurol. 2007 Jun 20;2(4):373-377. Informa UK Limited. DOI: 10.2217/14796708.2.4.373.
  16. Young AH, McElroy SL, Bauer M, Philips N, Chang W, Olausson B, 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 Feb 15;71(02):150-162. Physicians Postgraduate Press, Inc. DOI: 10.4088/jcp.08m04995gre.
  17. McElroy SL, Weisler RH, Chang W, Olausson B, Paulsson B, Brecher M, 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 Feb 15;71(02):163-174. Physicians Postgraduate Press, Inc. DOI: 10.4088/jcp.08m04942gre.
  18. DeVane CL, Charles JM, Abramson RK, Williams JE, Carpenter LA, Raven S, et al. Pharmacotherapy of Autism Spectrum Disorder: Results from the Randomized BAART Clinical Trial. Pharmacotherapy. 2019 Jun;39(6):626-635. Wiley. DOI: 10.1002/phar.2271.
  19. Jones PB, Barnes TRE, Davies L, Dunn G, Lloyd H, Hayhurst KP, et al. Randomized Controlled Trial of the Effect on Quality of Life of Second- vs First-Generation Antipsychotic Drugs in Schizophrenia. Arch Gen Psychiatry. 2006 Oct 1;63(10):1079. American Medical Association (AMA). DOI: 10.1001/archpsyc.63.10.1079.
  20. Knapp M, Windmeijer F, Brown J, Kontodimas S, Tzivelekis S, Haro JM, 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):341-358. Springer Science and Business Media LLC. DOI: 10.2165/00019053-200826040-00006.
  21. Gasquet I, Haro JM, Tcherny-Lessenot S, Chartier F, Lépine JP. Remission in the outpatient care of schizophrenia: 3-Year results from the Schizophrenia Outpatients Health Outcomes (SOHO) Study in France. Eur psychiatr. 2008 Oct;23(7):491-496. Cambridge University Press (CUP). DOI: 10.1016/j.eurpsy.2008.03.012.
  22. Sampogna G, Di Vincenzo M, Giuliani L, Menculini G, Mancuso E, Arsenio E, et al. A Systematic Review on the Effectiveness of Antipsychotic Drugs on the Quality of Life of Patients with Schizophrenia. Brain Sci. 2023 Nov 10;13(11):1577. MDPI AG. DOI: 10.3390/brainsci13111577.
  23. Meltzer HY. Clozapine Treatment for Suicidality in Schizophrenia<subtitle>International Suicide Prevention Trial (InterSePT)</subtitle>. Arch Gen Psychiatry. 2003 Jan 1;60(1):82. American Medical Association (AMA). DOI: 10.1001/archpsyc.60.1.82.
  24. Kozhevnikova S, Emilian C, Scola G, Chang Z, Yukhnenko D, Fazel S. Effect of psychotropic medications on suicide-related outcomes: a systematic review and meta-analysis of observational studies. eClinicalMedicine. 2026 Mar;93:103800. Elsevier BV. DOI: 10.1016/j.eclinm.2026.103800.
  25. Kane JM, Robinson DG, Schooler NR, Mueser KT, Penn DL, Rosenheck RA, et al. Comprehensive Versus Usual Community Care for First-Episode Psychosis: 2-Year Outcomes From the NIMH RAISE Early Treatment Program. AJP. 2016 Apr 1;173(4):362-372. American Psychiatric Association Publishing. DOI: 10.1176/appi.ajp.2015.15050632.
  26. Gardner-Sood P, Lally J, Smith S, Atakan Z, Ismail K, Greenwood KE, 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 Sep;45(12):2619-2629. Cambridge University Press (CUP). DOI: 10.1017/s0033291715000562.
  27. Taipale H, Tanskanen A, Mehtälä 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 Feb;19(1):61-68. Wiley. DOI: 10.1002/wps.20699.
  28. Correll CU, Rubio JM, Inczedy-Farkas G, Birnbaum ML, Kane JM, Leucht S. Efficacy of 42 Pharmacologic Cotreatment Strategies Added to Antipsychotic Monotherapy in Schizophrenia. JAMA Psychiatry. 2017 Jul 1;74(7):675. American Medical Association (AMA). DOI: 10.1001/jamapsychiatry.2017.0624.
  29. Calvin N, Minischetti L, Salanon F, Llorca PM, Pouchon A, Polosan M, et al. Combination of two long-acting injectable antipsychotics in treatment-resistant schizophrenia: A retrospective 12-month mirror-image study. Asian J Psychiatry. 2023 Feb;80:103402. Elsevier BV. DOI: 10.1016/j.ajp.2022.103402.
  30. Tiihonen J, Taipale H, Mehtälä J, Vattulainen P, Correll CU, Tanskanen A. Association of Antipsychotic Polypharmacy vs Monotherapy With Psychiatric Rehospitalization Among Adults With Schizophrenia.. JAMA Psychiatry. 2019 May 1;76(5):499-507. DOI: 10.1001/jamapsychiatry.2018.4320; PubMed PMID: 30785608; PubMed Central PMCID: PMC6495354.
  31. Weiser M, Davis JM, Brown CH, Slade EP, Fang LJ, Medoff DR, et al. Differences in Antipsychotic Treatment Discontinuation Among Veterans With Schizophrenia in the U.S. Department of Veterans Affairs. AJP. 2021 Oct 1;178(10):932-940. American Psychiatric Association Publishing. DOI: 10.1176/appi.ajp.2020.20111657.
  32. Taipale H, Tanskanen A, Tiihonen J. Safety of Antipsychotic Polypharmacy Versus Monotherapy in a Nationwide Cohort of 61,889 Patients With Schizophrenia. AJP. 2023 May 1;180(5):377-385. American Psychiatric Association Publishing. DOI: 10.1176/appi.ajp.20220446.