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Drug treatments for schizophrenia: pragmatism in trial design shows lack of progress in drug design

Part of: Special Articles

Published online by Cambridge University Press:  07 February 2013

F. Cheng  and
P. B. Jones
F. Cheng*
Affiliation:
Department of Psychiatry, University of Cambridge, Cambridge, UK
P. B. Jones
Affiliation:
Department of Psychiatry, University of Cambridge, Cambridge, UK
*
*Address for correspondence: Professor F. Cheng, Department of Psychiatry, University of Cambridge, Box 189, Cambridge Biomedical Campus, Cambridge CB2 2QQ, UK. (Email: pbj21@cam.ac.uk)
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Abstract

Aims.

The introduction of second generation antipsychotic (SGA) medication over a decade ago led to changes in prescribing practices; these drugs have eclipsed their predecessors as treatments for schizophrenia. However, the metabolic side effects of these newer antipsychotics have been marked and there are increasing concerns as to whether these novel drugs really are superior to their predecessors in terms of the balance between risks and benefits. In this article, we review the literature regarding comparisons between first generation antipsychotic (FGA) and SGA in terms of clinical effectiveness.

Methods.

Large (n > 150) randomized-controlled trials (RCTs) comparing the effectiveness (efficacy and side effects) of FGA and SGA medications other than clozapine were reviewed, as were meta-analyses that included smaller studies.

Results.

The superiority in efficacy and reduced extrapyramidal side effects (EPSE) of SGAs is modest, especially when compared with low-dose FGAs. However, the high risk of weight gain and other metabolic disturbances associated with certain SGAs such as olanzapine is markedly higher than the risk with FGAs at the doses used in the trials.

Conclusions.

The efficacy profiles of various FGAs and SGAs are relatively similar, but their side effects vary between and within classes. Overall, large pragmatic trials of clinical effectiveness indicate that the care used in prescribing and managing drug treatments to ensure tolerability may be more important than the class of drug used.

Keywords

antipsychotic drugsclinical effectivenessschizophreniarandomized controlled trials
Type
Special Article
Information
Epidemiology and Psychiatric Sciences , Volume 22 , Issue 3 , September 2013 , pp. 223 - 233
Copyright
Copyright © Cambridge University Press 2013 

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References

American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; and North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes (2004). Journal of Clinical Psychiatry 65, 267–272.CrossRefGoogle Scholar
Brown, S (1997). Excess mortality of schizophrenia. A meta-analysis. British Journal of Psychiatry 171, 502–508.Google Scholar
Cheng, F, Jones, PB (2010). Second-generation atypical versus first-generation conventional antipsychotic drug treatment in schizophrenia: another triumph of hope over experience? In Therapeutic Strategies in Schizophrenia (ed. Mortimer, AM and McKenna, PJ), pp. 193–206. Clinical Publishing: Oxford, UK.Google ScholarPubMed
Chen, CK, Chen, YC, Huang, YS (2009). Effects of a 10-week weight control program on obese patients with schizophrenia or schizoaffective disorder: a 12-month follow up. Psychiatry and Clinical Neurosciences 63, 17–22.Google Scholar
Citrome, L (2011a). Iloperidone: a clinical overview. Journal of Clinical Psychiatry 72 (Suppl. 1), 19–23.Google ScholarPubMed
Citrome, L (2011b). Lurasidone for schizophrenia: a review of the efficacy and safety profile for this newly approved second-generation antipsychotic. International Journal of Clinical Practice 65, 189–210.Google Scholar
Davis, JM, Chen, N, Glick, ID (2003). A meta-analysis of the efficacy of second-generation antipsychotics. Archives of General Psychiatry 60, 553–564.Google Scholar
Ernst, E, Canter, PH (2005). Limitations of “pragmatic” trials. Postgraduate Medical Journal 81, 203.CrossRefGoogle ScholarPubMed
Geddes, J, Freemantle, N, Harrison, P, Bebbington, P (2000). Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis. British Medical Journal 321, 1371–1376.CrossRefGoogle ScholarPubMed
Healy, D (2002). The Creation of Psychopharmacology. Harvard University Press: Cambridge, MA.Google Scholar
Hotopf, M, Churchill, R, Lewis, G (1999). Pragmatic randomised controlled trials in psychiatry. British Journal of Psychiatry 175, 217–223.Google Scholar
Jones, PB, Barnes, TR, Davies, L, Dunn, G, Lloyd, H, Hayhurst, KP, Murray, RM, Markwick, A, Lewis, SW (2006). 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). Archives of General Psychiatry 63, 1079–1087.Google Scholar
Kahn, RS, Fleischhacker, WW, Boter, H, Davidson, M, Vergouwe, Y, Keet, IP, Gheorghe, MD, Rybakowski, JK, Galderisi, S, Libiger, J, Hummer, M, Dollfus, S, Lopez-Ibor, JJ, Hranov, LG, Gaebel, W, Peuskens, J, Lindefors, N, Riecher-Rossler, A, Grobbee, DE (2008). Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet 371, 1085–1097.Google Scholar
Kane, J, Honigfeld, G, Singer, J, Meltzer, H (1988). Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Archives of General Psychiatry 45, 789–796.Google Scholar
Klemp, M, Tvete, IF, Skomedal, T, Gaasemyr, J, Natvig, B, Aursnes, I (2011). A review and Bayesian meta-analysis of clinical efficacy and adverse effects of 4 atypical neuroleptic drugs compared with haloperidol and placebo. Journal of Clinical Psychopharmacology 31, 698–704.Google Scholar
Leucht, S, Pitschel-Walz, G, Abraham, D, Kissling, W (1999). Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A meta-analysis of randomized controlled trials. Schizophrenia Research 35, 51–68.Google Scholar
Leucht, S, Wahlbeck, K, Hamann, J, Kissling, W (2003). New generation antipsychotics versus low-potency conventional antipsychotics: a systematic review and meta-analysis. Lancet 361, 1581–1589.CrossRefGoogle ScholarPubMed
Leucht, S, Corves, C, Arbter, D, Engel, RR, Li, C, Davis, JM (2009). Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 373, 31–41.Google Scholar
Lewis, SW, Barnes, TR, Davies, L, Murray, RM, Dunn, G, Hayhurst, KP, Markwick, A, Lloyd, H, Jones, PB (2006). Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Schizophrenia Bulletin 32, 715–723.CrossRefGoogle ScholarPubMed
Lieberman, J, Jody, D, Geisler, S, Alvir, J, Loebel, A, Szymanski, S, Woerner, M, Borenstein, M (1993). Time course and biologic correlates of treatment response in first-episode schizophrenia. Archives of General Psychiatry 50, 369–376.Google Scholar
Lieberman, JA, Stroup, TS, McEvoy, JP, Swartz, MS, Rosenheck, RA, Perkins, DO, Keefe, RS, Davis, SM, Davis, CE, Lebowitz, BD, Severe, J, Hsiao, JK (2005). Clinical Antipsychotic Trials of Intervention Effectivness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. New England Journal of Medicine 353, 1209–1223.Google Scholar
Malla, AK, Norman, RM, Scholten, DJ, Zirul, S, Kotteda, V (2001). A comparison of long-term outcome in first-episode schizophrenia following treatment with risperidone or a typical antipsychotic. Journal of Clinical Psychiatry 62, 179–184.Google Scholar
Marder, S, Jones, PB (2008). Pharmacological treatments for schizophrenia. In Cambridge Textbook of Effective Treatments in Schizophrenia (ed. Tyrer, P and Silk, R), Cambridge University Press: Cambridge.Google Scholar
Marder, SR, Essock, SM, Miller, AL, Buchanan, RW, Casey, DE, Davis, JM, Kane, JM, Lieberman, JA, Schooler, NR, Covell, N, Stroup, S, Weissman, EM, Wirshing, DA, Hall, CS, Pogach, L, Pi-Sunyer, X, Bigger, JT Jr., Friedman, A, Kleinberg, D, Yevich, SJ, Davis, B, Shon, S (2004). Physical health monitoring of patients with schizophrenia. American Journal of Psychiatry 161, 1334–1349.Google Scholar
Marson, A, Kadir, Z, Chadwick, D (1997). Large pragmatic randomised studies of new antiepileptic drugs are needed. British Medical Journal 314, 1764.Google Scholar
McEvoy, JP, Lieberman, JA, Stroup, TS, Davis, SM, Meltzer, HY, Rosenheck, RA, Swartz, MS, Perkins, DO, Keefe, RS, Davis, CE, Severe, J, Hsiao, JK (2006). Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. American Journal of Psychiatry 163, 600–610.CrossRefGoogle Scholar
McEvoy, JP, Lieberman, JA, Perkins, DO, Hamer, RM, Gu, H, Lazarus, A, Sweitzer, D, Olexy, C, Weiden, P, Strakowski, SD (2007). Efficacy and tolerability of olanzapine, quetiapine, and risperidone in the treatment of early psychosis: a randomized, double-blind 52-week comparison. American Journal of Psychiatry 164, 1050–1060.Google Scholar
Patil, ST, Zhang, L, Martenyi, F, Lowe, SL, Jackson, KA, Andreev, BV, Avedisova, AS, Bardenstein, LM, Gurovich, IY, Morozova, MA, Mosolov, SN, Neznanov, NG, Reznik, AM, Smulevich, AB, Tochilov, VA, Johnson, BG, Monn, JA, Schoepp, DD (2007). Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nature Medicine 13, 1102–1107.Google Scholar
Peluso, MJ, Lewis, SW, Barnes, TR, Jones, PB (2012). Extrapyramidal motor side-effects of first- and second-generation antipsychotic drugs. British Journal of Psychiatry 200, 387–392.Google Scholar
Practice parameter for the assessment and treatment of children and adolescents with schizophrenia. American Academy of Child and Adolescent Psychiatry (2001). Journal of the American Academy of Child and Adolescent Psychiatry 40, 4S–23S.Google Scholar
Robinson, DG, Woerner, MG, Alvir, JM, Geisler, S, Koreen, A, Sheitman, B, Chakos, M, Mayerhoff, D, Bilder, R, Goldman, R, Lieberman, JA (1999). Predictors of treatment response from a first episode of schizophrenia or schizoaffective disorder. American Journal of Psychiatry 156, 544–549.Google Scholar
Rosenheck, RA (2008). Pharmacotherapy of first-episode schizophrenia. Lancet 371, 1048–1049.CrossRefGoogle ScholarPubMed
Schoemaker, J, Naber, D, Vrijland, P, Panagides, J, Emsley, R (2010). Long-term assessment of asenapine vs. olanzapine in patients with schizophrenia or schizoaffective disorder. Pharmacopsychiatry 43, 138–146.CrossRefGoogle ScholarPubMed
Schooler, N, Rabinowitz, J, Davidson, M, Emsley, R, Harvey, PD, Kopala, L, McGorry, PD, Van Hove, I, Eerdekens, M, Swyzen, W, De Smedt, G (2005). Risperidone and haloperidol in first-episode psychosis: a long-term randomized trial. American Journal of Psychiatry 162, 947–953.Google Scholar
Sikich, L, Frazier, JA, McClellan, J, Findling, RL, Vitiello, B, Ritz, L, Ambler, D, Puglia, M, Maloney, AE, Michael, E, De Jong, S, Slifka, K, Noyes, N, Hlastala, S, Pierson, L, McNamara, NK, Delporto-Bedoya, D, Anderson, R, Hamer, RM, Lieberman, JA (2008). Double-blind comparison of first- and second-generation antipsychotics in early-onset schizophrenia and schizo-affective disorder: findings from the treatment of early-onset schizophrenia spectrum disorders (TEOSS) study. American Journal of Psychiatry 165, 1420–1431.Google Scholar
Stoner, SC, Pace, HA (2012). Asenapine: a clinical review of a second-generation antipsychotic. Clinical Therapeutics 34, 1023–1040.CrossRefGoogle ScholarPubMed
Tiihonen, J, Lonnqvist, J, Wahlbeck, K, Klaukka, T, Niskanen, L, Tanskanen, A, Haukka, J (2009). 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet 374, 620–627.CrossRefGoogle ScholarPubMed
Tunis, SR, Stryer, DB, Clancy, CM (2003). Practical clinical trials: increasing the value of clinical research for decision making in clinical and health policy. Journal of the American Medical Association 290, 1624–1632.Google Scholar
Turner, T (2007). Chlorpromazine: unlocking psychosis. British Medical Journal 334 (Suppl. 1), s7.Google Scholar
Zarin, DA, Young, JL, West, JC (2005). Challenges to evidence-based medicine: a comparison of patients and treatments in randomized controlled trials with patients and treatments in a practice research network. Social Psychiatry and Psychiatric Epidemiology 40, 27–35.Google Scholar
Zhang-Wong, J, Zipursky, RB, Beiser, M, Bean, G (1999). Optimal haloperidol dosage in first-episode psychosis. Canadian Journal of Psychiatry 44, 164–167.CrossRefGoogle ScholarPubMed
Zwarenstein, M, Treweek, S, Gagnier, JJ, Altman, DG, Tunis, S, Haynes, B, Oxman, AD, Moher, D (2008). Improving the reporting of pragmatic trials: an extension of the CONSORT statement. British Medical Journal 337, a2390.Google Scholar