CNS Drugs

, Volume 21, Issue 9, pp 699–714 | Cite as

Conceptual and Methodological Issues in the Design of Clinical Trials of Antipsychotics for the Treatment of Schizophrenia

  • William G. Honer
  • Allen E. Thornton
  • Megan Sherwood
  • G. William MacEwan
  • Tom S. Ehmann
  • Richard Williams
  • Lili C. Kopala
  • Ric Procyshyn
  • Alasdair M. Barr
Current Opinion


Schizophrenia is one of the most severe and disabling psychiatric disorders. Antipsychotic drugs offer considerable benefits in controlling symptoms and preventing relapse. The strategy for the present review of clinical trials was to ask ‘What are the features of schizophrenia and the existing treatments of the illness that have implications for future clinical trials’ ? Six key facts were identified.

First, schizophrenia is genetically ‘complex’. Trials may benefit from designs including genetically related illnesses, by focussing on cross-cutting aspects of the phenotype such as psychosis or cognitive dysfunction, and by collecting information on possible moderators and mediators of treatment response.

Second, schizophrenia affects multiple neurotransmitter systems. Mutiple signalling pathways may need to be considered, with different time courses of response. Outcome measures from clinical trials could be collected at more frequent intervals, particularly in the early phase of response.

Third, the clinical features used to define the illness are a mix of symptoms and social-occupational dysfunction, yet treatment response is often defined only by changes in symptoms. Multiple measures of functioning need to be collected at baseline and at the endpoint of trials. Consensus definitions for response, remission, relapse, recovery and recurrence need to be developed.

Fourth, schizophrenia is often highly disabling. Linking treatment response in clinical trials to measures of quality-adjusted life-years will allow comparison with other medical illnesses using common metrics.

Fifth, the general health and care of individuals with schizophrenia is often poor. ‘Complex’ interventions, which include, but are not limited to, antipsychotic medications, need to be designed and tested for the problems facing these patients.

Finally, large gaps exist between clinical trials, practice guidelines and patterns of practice. Trials need to be designed to investigate widely used approaches such as antipsychotic polypharmacy, where actual practice diverges from evidence-based guidelines.


Schizophrenia Clozapine Risperidone Antipsychotic Drug Negative Symptom 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Support was provided by the Michael Smith Foundation for Health Research and the BC Mental Health and Addictions Services.

Dr Honer reports receiving consulting or advisory board fees from In Silico, Janssen, AstraZeneca and Solvay; lecture fees from AstraZeneca and Janssen; and grant support from Eli Lilly, Janssen and AstraZeneca.

Drs Thornton, Sherwood and Barr have no financial ties to the industry.

Dr MacEwan reports receiving consulting or advisory board fees from AstraZeneca, Janssen, Eli Lilly and Novartis; lecture fees from GlaxoSmithKline; and grant support from AstraZeneca.

Dr Ehmann reports receiving grant support from Pfizer.

Dr Williams reports receiving consulting or advisory board fees from AstraZeneca, GenPharm, Janssen, Eli Lilly and Prestwick Pharmaceuticals; lecture fees from AstraZeneca, GenPharm, Janssen, Eli Lilly, Novartis, Pfizer and Prestwick Pharmaceuticals; and grant funding from AstraZeneca, Janssen and Pfizer.

Dr Kopala reports receiving consulting or advisory board fees from AstraZeneca, Pfizer, Solvay and Janssen; and receiving lecture fees as well as grant support from AstraZeneca and Janssen.

Dr Procyshyn reports receiving consulting or advisory board fees and lecture fees from AstraZeneca, Janssen, Eli Lilly and GlaxoSmithKline.


  1. 1.
    Murray CJL, Lopez AD. Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study. Lancet 1997; 349: 1498–504PubMedCrossRefGoogle Scholar
  2. 2.
    Murray CJL, Lopez AD. The global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries and risk factors in 1990 and projected to 2020. Cambridge (MA): Harvard School of Public Health, 1996Google Scholar
  3. 3.
    Stroup TS, Alves WM, Hamer RM, et al. Clinical trials for antipsychotic drugs: design conventions, dilemmas and innovations. Nat Rev Drug Discovery 2006; 5: 133–46CrossRefGoogle Scholar
  4. 4.
    Leucht S. Translating research into clinical practice: critical interpretation of clinical trials in schizophrenia. Int Clin Psychopharmacol 2006; 21Suppl. 2: S1–10PubMedCrossRefGoogle Scholar
  5. 5.
    Pajonk F-G. Clinical trial design in schizophrenia: implications for clinical decisions. Curr Opin Psychiatry 2005; 18: 692–9PubMedCrossRefGoogle Scholar
  6. 6.
    Thornley B, Adams C. Content and quality of 2000 controlled trials in schizophrenia over 50 years. BMJ 1998; 317: 1181–4PubMedCrossRefGoogle Scholar
  7. 7.
    Wyatt RJ, Alexander RC, Egan MF, et al. Schizophrenia, just the facts. Schizophr Res 1988; 1: 3–18PubMedCrossRefGoogle Scholar
  8. 8.
    Sawa A, Snyder SH. Schizophrenia: diverse approaches to a complex disease. Science 2002; 296: 692–5PubMedCrossRefGoogle Scholar
  9. 9.
    Vicsek T. The bigger picture. Nature 2002; 418: 131PubMedCrossRefGoogle Scholar
  10. 10.
    Harrison PJ, Owen MJ. Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet 2003; 361: 417–9PubMedCrossRefGoogle Scholar
  11. 11.
    Risch N. Linkage strategies for genetically complex traits: I. Multilocus models. Am J Hum Geneti 1990; 46: 222–8Google Scholar
  12. 12.
    Owen MJ, Craddock N, O’Donovan MC. Schizophrenia: genes at last? Trends Genet 2005; 21: 518–25PubMedCrossRefGoogle Scholar
  13. 13.
    Kennedy JL, Farrer LA, Andreasen NC, et al. The genetics of adult-onset neuropsychiatric disease: complexities and conundra? Science 2003; 302: 822–6PubMedCrossRefGoogle Scholar
  14. 14.
    Maziade M, Roy MA, Chagnon YC, et al. Shared and specific susceptibility loci for schizophrenia and bipolar disorder: a dense genome scan in Eastern Quebec families. Mol Psychiatry 2005; 10: 486–99PubMedCrossRefGoogle Scholar
  15. 15.
    Park N, Juo SH, Cheng R, et al. Linkage analysis of psychosis in bipolar pedigrees suggests novel putative loci for bipolar disorder and shared susceptibility with schizophrenia. Mol Psychiatry 2004; 9: 1091–9PubMedCrossRefGoogle Scholar
  16. 16.
    Craddock N, O’Donovan MC, Owen MJ. Genes for schizophrenia and bipolar disorder: implications for psychiatric nosology. Schizophr Bull 2006; 32: 9–16PubMedCrossRefGoogle Scholar
  17. 17.
    Williams NM, Green EK, Macgregor S, et al. Variation at the DAOA/G30 locus influences susceptibility to major mood episodes but not psychosis in schizophrenia and bipolar disorder. Arch Gen Psychiatry 2006; 63: 366–73PubMedCrossRefGoogle Scholar
  18. 18.
    Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 2003; 160: 636–45PubMedCrossRefGoogle Scholar
  19. 19.
    John B, Lewis KR. Chromosome variability and geographic distribution in insects. Science 1966; 152: 711–21PubMedCrossRefGoogle Scholar
  20. 20.
    Roses AD, Saunders AM, Huang Y, et al. Complex disease-associated pharmacogenetics: drug efficacy, drug safety, and confirmation of a pathogenetic hypothesis (Alzheimer’s disease). Pharmacogenomics J 2007; 7: 10–28PubMedCrossRefGoogle Scholar
  21. 21.
    McGrath J, Saha S, Welham J, et al. A systematic review of the incidence of schizophrenia: the distribution of rates and the influence of sex, urbanicity, migrant status and methodology. BMC Med 2004; 2: 13PubMedCrossRefGoogle Scholar
  22. 22.
    Jablensky A. Epidemiology of schizophrenia: the global burden of disease and disability. Eur Arch Psychiatry Clin Neurosci 2000; 250: 274–85PubMedCrossRefGoogle Scholar
  23. 23.
    Mortensen PB, Pedersen CB, Westergaard T, et al. Effects of family history and place and season of birth on the risk of schizophrenia. N Engl J Med 1999; 340: 603–8PubMedCrossRefGoogle Scholar
  24. 24.
    Pedersen CB, Mortensen PB. Evidence of a dose-response relationship between urbanicity during upbringing and schizophrenia risk. Arch Gen Psychiatry 2001; 58: 1039–46PubMedCrossRefGoogle Scholar
  25. 25.
    Smith GN, Boydell J, Murray RM, et al. The incidence of schizophrenia in European immigrants to Canada. Schizophr Res 2006; 87: 205–11PubMedCrossRefGoogle Scholar
  26. 26.
    Cantor-Graae E, Pedersen CB, McNeil TF, et al. Migration as a risk factor for schizophrenia: a Danish population-based cohort study. Br J Psychiatry 2003; 182: 117–22PubMedCrossRefGoogle Scholar
  27. 27.
    Pedersen CB, Mortensen PB. Are the cause(s) responsible for urban-rural diferences in schizophrenia risk roted in families or in individuals? Am J Epidemiol 2006; 163: 971–8PubMedCrossRefGoogle Scholar
  28. 28.
    Van Os J, Hanssen M, Bak M, et al. Do urbanicity and familial liability coparticipate in causing psychosis? Am J Psychiatry 2003; 160: 477–82PubMedCrossRefGoogle Scholar
  29. 29.
    AbdelMalik P, Husted J, Chow EWC, et al. Childhood head injury and expression of schizophrenia in multiply affected families. Arch Gen Psychiatry 2003; 60: 231–6PubMedCrossRefGoogle Scholar
  30. 30.
    Malaspina D, Goetz RR, Friedman JH, et al. Traumatic brain injury and schizophrenia in members of schizophrenia and bipolar pedigrees. Am J Psychiatry 2001; 158: 440–6PubMedCrossRefGoogle Scholar
  31. 31.
    Caspi A, Moffitt TE, Cannon M, et al. Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction. Biol Psychiatry 2005; 57: 1117–27PubMedCrossRefGoogle Scholar
  32. 32.
    Kraemer HC, Wilson GT, Fairburn CG, et al. Mediators and moderators of treatment efects in randomized clinical trials. Arch Gen Psychiatry 2002; 59: 877–83PubMedCrossRefGoogle Scholar
  33. 33.
    Kraemer HC, Kupfer DJ. Size of treatment effects and their importance to clinical research and practice. Biol Psychiatry 2006; 59: 990–6PubMedCrossRefGoogle Scholar
  34. 34.
    Dickerson FB, Boronow JJ, Stallings C, et al. Association of serum antibodies to herpes simplex virus 1 with cognitive deficits in individuals with schizophrenia. Arch Gen Psychiatry 2003; 60: 466–72PubMedCrossRefGoogle Scholar
  35. 35.
    Dickerson KB, Boronow JJ, Stallings C, et al. Infection with herpes simplex virus type 1 is associated with cognitive deficits in bipolar disorder. Biol Psychiatry 2004; 55: 588–93PubMedCrossRefGoogle Scholar
  36. 36.
    Dickerson FB, Boronow JJ, Stallings CR, et al. Reduction of symptoms by valacyclovir in cytomegalovirus-seropositive individuals with schizophrenia. Am J Psychiatry 2003; 160: 2234–6PubMedCrossRefGoogle Scholar
  37. 37.
    Dawson GR, Goodwin G. Experimental medicine in psychiatry. J Psychopharmacol 2005; 19: 565–6PubMedCrossRefGoogle Scholar
  38. 38.
    Mayeux R. Biomarkers: potential uses and limitations. NeuroRx 2004; 1: 182–8PubMedCrossRefGoogle Scholar
  39. 39.
    Katz R. Biomarkers and surrogate markers: an FDA perspective. NeuroRx 2004; 1: 189–95PubMedCrossRefGoogle Scholar
  40. 40.
    Feigin A. Evidence from biomarkers and surrogate endpoints. NeuroRx 2004; 1: 323–30PubMedCrossRefGoogle Scholar
  41. 41.
    Wang TJ, Gona P, Larson MG, et al. Multiple biomarkers for the prediction of first major cardiovascular events and death. New Engl J Med 2006; 355: 2631–9PubMedCrossRefGoogle Scholar
  42. 42.
    Freedman R. Drug therapy: schizophrenia. New Engl J Med 2003; 349: 1738–49PubMedCrossRefGoogle Scholar
  43. 43.
    Lewis DA, Hashimoto T, Volk DW. Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 2005; 6: 312–24PubMedCrossRefGoogle Scholar
  44. 44.
    Fishman MC, Porter JA. A new grammar for drug discovery. Nature 2005; 437: 491–3PubMedCrossRefGoogle Scholar
  45. 45.
    Hahn C-G, Wang H-Y, Cho D-S, et al. Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nat Med 2006; 12: 824–8PubMedCrossRefGoogle Scholar
  46. 46.
    Agid O, Kapur S, Arenovich T, et al. Delayed-onset hypothesis of antipsychotic action: a hypothesis tested and rejected. Arch Gen Psychiatry 2003; 60: 1228–35PubMedCrossRefGoogle Scholar
  47. 47.
    Leucht S, Busch R, Hamann J, et al. Early-onset hypothesis of drug action: a hypothesis tested, confirmed and extended. Biol Psychiatry 2005; 57: 1543–9PubMedCrossRefGoogle Scholar
  48. 48.
    Sherwood M, Thornton AE, Honer WG. A meta-analysis of profile and time-course of symptom change in acute schizophrenia treated with atypical antipsychotics. Int J Neuropsychopharmacol 2005; 9: 1–10CrossRefGoogle Scholar
  49. 49.
    Leucht S, Kane JM, Etschel E, et al. Linking the PANSS, BPRS, and CGI: clinical implications. Neuropsychopharmacol 2006; 31: 2318–25CrossRefGoogle Scholar
  50. 50.
    Elkes J, Elkes C. Effect of chlorpromazine on the behaviour of chronically overactive psychotic patients. BMJ 1954; 2: 560–5PubMedCrossRefGoogle Scholar
  51. 51.
    Gunduz-Bruce H, McMeniman M, Robinson DG, et al. Duration of untreated psychosis and time to treatment response for delusions and hallucinations. Am J Psychiatry 2005; 162: 1966–9PubMedCrossRefGoogle Scholar
  52. 52.
    Emsley R, Rabinowitz J, Medori R. Time course for antipsychotic treatment response in first-episode schizophrenia. Am J Psychiatry 2006; 163: 743–5PubMedCrossRefGoogle Scholar
  53. 53.
    Bird EG, Goss JD, Denber HCB. Chlorpromazine in the treatment of mental illness: a study of 750 patients. Am J Psychiatry 1955; 111: 930PubMedGoogle Scholar
  54. 54.
    Cares RM, Asrican E, Fenichel M, et al. Therapeutic and toxic effects of chlorpromazine among 3,014 hospitalized cases. Am J Psychiatry 1957; 114: 318–27PubMedGoogle Scholar
  55. 55.
    Winkelman NW. Chlorpromazine in the treatment of neuropsychiatric disorders. JAMA 1954; 155: 18–21CrossRefGoogle Scholar
  56. 56.
    Leucht S, Busch R, Kissling W, et al. Early prediction of antipsychotic nonresponse among patients with schizophrenia. J Clin Psychiatry 2007; 68: 352–60PubMedCrossRefGoogle Scholar
  57. 57.
    Laruelle M, Abi-Dargham A, Gil R, et al. Increased dopmine transmission in schizophrenia: relationship to illness phase. Biol Psychiatry 1999; 46: 56–72PubMedCrossRefGoogle Scholar
  58. 58.
    Heinrich K, Klieser E, Lehmann E, et al. Risperidone versus clozapine in the treatment of schizophrenic patients with acute symptoms: a double blind, randomized trial. Prog Neuropsychopharmacol Biol Psychiatry 1994; 18: 129–37PubMedCrossRefGoogle Scholar
  59. 59.
    Lieberman JA, Phillips M, Gu H, et al. Atypical and conventional antipsychotic drugs in treatment-naive first-episode schizophrenia: a 52-week randomized trial of clozapine vs chlorpromazine. Neuropsychopharmacol 2003; 28: 995–1003Google Scholar
  60. 60.
    Woerner MG, Robinson DG, Alvir JM, et al. Clozapine as a first treatment for schizophrenia. Am J Psychiatry 2003; 160: 1514–6PubMedCrossRefGoogle Scholar
  61. 61.
    Wyatt R, Torgow J. A comparison of equivalent clinical potencies of neuroleptics as used to treat schizophrenia and affective disorders. J Psychiatr Res 1976; 13: 91–8CrossRefGoogle Scholar
  62. 62.
    Klein DF. The importance of psychiatric diagnosis in prediction of clinical drug effects. Arch Gen Psychiatry 1967; 16: 118–26PubMedCrossRefGoogle Scholar
  63. 63.
    Fleischhacker WW, Czobor P, Hummer M, et al. Placebo or active control trials of antipsychotic drugs? Arch Gen Psychiatry 2003; 60: 458–64PubMedCrossRefGoogle Scholar
  64. 64.
    Kemmler G, Hummer M, Widschwendter C, et al. Dropout rates in placebo-controlled and active-control clinical trials of antipsychotic drugs. Arch Gen Psychiatry 2005; 62: 1305–12PubMedCrossRefGoogle Scholar
  65. 65.
    Woods SW, Gueorguieva RV, Baker B, et al. Control group bias in randomized atypical antipsychotic medication trials for schizophrenia. Arch Gen Psychiatry 2005; 62: 961–70PubMedCrossRefGoogle Scholar
  66. 66.
    Leucht S, Davis JM, Engel RR, et al. Defining “response” in antipsychotic drug trials: recommendations for the use of scale-derived cutoffs. Neuropsychopharmacol. In pressGoogle Scholar
  67. 67.
    Leucht S, Kane JM, Kissling W, et al. Clinical implications of Brief Psychiatric Rating Scale scores. Br J Psychiatry 2005; 187: 366–71PubMedCrossRefGoogle Scholar
  68. 68.
    Leucht S, Kane JM, Kissling W, et al. What does the PANSS mean? Schizophr Res 2005; 79: 231–8PubMedCrossRefGoogle Scholar
  69. 69.
    Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. New Engl J Med 2005; 353: 1209–23PubMedCrossRefGoogle Scholar
  70. 70.
    Csernansky JG, Mahmoud R, Brenner R. A comparison of risperidone and haloperidol for the prevention of relapse in patients with schizophrenia. New Engl J Med 2002; 346: 16–22PubMedCrossRefGoogle Scholar
  71. 71.
    Remington G, Kapur S. Remission: what’s in a name? Am J Psychiatry 2005; 162: 2393–4PubMedCrossRefGoogle Scholar
  72. 72.
    Andreasen NC, Carpenter WT, Kane JM, et al. Remission in schizophrenia: proposed criteria and rationale for consensus. Am J Psychiatry 2005; 162: 441–9PubMedCrossRefGoogle Scholar
  73. 73.
    Frank E, Prien RF, Jarrett RB, et al. Conceptualization and rationale for consensus terms in major depressive disorder: remission, recovery, relapse and recurrence. Arch Gen Psychiatry 1991; 48: 851–5PubMedCrossRefGoogle Scholar
  74. 74.
    Keller MB. Past, present, and future directions for defining optimal treatment outcome in depression. JAMA 2003; 289: 3152–60PubMedCrossRefGoogle Scholar
  75. 75.
    Green MF. What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 1996; 153: 321–30PubMedGoogle Scholar
  76. 76.
    Norman RM, Malla AK, McLean T, et al. The relationship of symptoms and level of functioning in schizophrenia to general wellbeing and the Quality of Life Scale. Acta Psychiat Scand 2000; 102: 303–9PubMedCrossRefGoogle Scholar
  77. 77.
    Buchanan RW, Davis M, Goff D, et al. A summary of the FDA-NIMH-MATRICS workshop on clinical trial design for neurocognitive drugs for schizophrenia. Schizophr Bull 2005; 31: 5–19PubMedCrossRefGoogle Scholar
  78. 78.
    Kirkpatrick B, Fenton WS, Carpenter WT, et al. The NIMH-MATRICS consensus statement on negative symptoms. Schizophr Bull 2006; 32: 214–9PubMedCrossRefGoogle Scholar
  79. 79.
    Gueorguieva R, Krystal JH. Progress in analyzing repeated-measures data and its reflection in papers published in the Arch Gen Psychiatry. Arch Gen Psychiatry 2004; 61: 310–7PubMedCrossRefGoogle Scholar
  80. 80.
    Lagakos SW. The challenge of subgroup analyses-reporting without distorting. New Engl J Med 2006; 354: 1667–9PubMedCrossRefGoogle Scholar
  81. 81.
    Rossler W, Salize HJ, Van Os J, et al. Size of burden of schizophrenia and psychotic disorders. Eur Neuropsychopharmacol 2005; 15: 399–409PubMedCrossRefGoogle Scholar
  82. 82.
    Harwood RH, Sayer AA, Hirschfeld M. Current and future worldwide prevalence of dependency, its relationship to total population, and dependency ratios. Bull World Health Org 2004; 82: 251–8PubMedGoogle Scholar
  83. 83.
    Ustun TB, Rehm J, Chatterji S, et al. Multiple-informant ranking of the disabling effects of different health conditions in 14 countries. Lancet 1999; 354: 111–5PubMedCrossRefGoogle Scholar
  84. 84.
    Lohr K, Skillman S. Glossary: health outcomes methodology. Med Care 2000; 38(SII): 7–13Google Scholar
  85. 85.
    Weiss AP. Measuring the imapct of medical research: moving from outputs to outcomes. Am J Psychiatry 2007; 164: 204–14Google Scholar
  86. 86.
    Lenert LA, Sturley AP, Rapaport MH, et al. Public preferences for health states with schizophrenia and a mapping function to estimate utilities from positive and negative symptom scale scores. Schizophr Res 2004; 71: 155–65PubMedCrossRefGoogle Scholar
  87. 87.
    Lenert LA, Ziegler J, Lee T, et al. Differences in health values among patients, family members, and providers for outcomes in schizophrenia. Med Care 2000; 38: 1011–21PubMedCrossRefGoogle Scholar
  88. 88.
    Chouinard G, Albright PS. Economic and health state utility determinations for schizophrenic patients treated with risperidone or haloperidol. J Clin Psychopharmacol 1997; 17: 298–307PubMedCrossRefGoogle Scholar
  89. 89.
    Mohr PE, Cheng CM, Claxton K, et al. The heterogeneity of schizophrenia in disease states. Schizophr Res 2004; 71: 83–95PubMedCrossRefGoogle Scholar
  90. 90.
    Rosenheck RA, Leslie DL, Sindelar J, et al. Cost-effectiveness of second-generation antipsychotics and perphenazine in a randomized trial of treatment for chronic schizophrenia. Am J Psychiatry 2006; 163: 2080–9PubMedCrossRefGoogle Scholar
  91. 91.
    Almond S, O’Donnell O. Cost analysis of the treatment of schizophrenia in the UK: a comparison of olanzapine and haloperidol. Pharmacoeconomics 1998; 13: 575–88PubMedCrossRefGoogle Scholar
  92. 92.
    Almond S, O’Donnell O. Cost analysis of the treatment of schizophrenia in the UK: a simulation model comparing olanzapine, risperidone and haloperidol. Pharmacoeconomics 2000; 17: 383–9PubMedCrossRefGoogle Scholar
  93. 93.
    Basu A, Meltzer HY, Dukic V. Estimating transitions between symptom severity states over time in schizophrenia: a Bayesian meta-analytic approach. Stat Med 2006; 25: 551–5CrossRefGoogle Scholar
  94. 94.
    James GM, Sugar CA, Desai R, et al. A comparison of outcomes among patients with schizophrenia in two mental health systems: a health state approach. Schizophr Res 2006; 86: 309–20PubMedCrossRefGoogle Scholar
  95. 95.
    Osborn DP, Levy G, Nazareth I, et al. Relative risk of cardiovascular and cancer mortality in people with severe mental illness from the United Kingdom’s general practice research database. Arch Gen Psychiatry 2007; 64: 242–9PubMedCrossRefGoogle Scholar
  96. 96.
    Goff DC, Cather C, Evins AE, et al. Medical morbidity and mortality in schizophrenia: guidelines for psychiatrists. J Clin Psychiatry 2005; 66: 183–94PubMedCrossRefGoogle Scholar
  97. 97.
    McEvoy JP, Meyer JM, Goff DC, et al. Prevalence of the metabolic syndrome in patients with schizophrenia: baseline results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial and comparison with national estimates from NHANES III. Schizophr Res 2005; 80: 19–32PubMedCrossRefGoogle Scholar
  98. 98.
    Gaebel W, Weinmann S, Sartorius N, et al. Schizophrenia practice guidelines: international survey and comparison. Br J Psychiatry 2005; 187: 248–55PubMedCrossRefGoogle Scholar
  99. 99.
    Weinmann S, Janssen B, Gaebel W. Guideline adherence in medication management of psychotic disorders: an observational multisite hospital study. Acta Psychiat Scand 2005; 112: 18–25PubMedCrossRefGoogle Scholar
  100. 100.
    Lehman AF, Steinwachs DM. Patterns of usual care for schizophrenia: initial results from the Schizophrenia Patient Outcomes Research Team (PORT) client survey. Schizophr Bull 1998; 24: 11–20PubMedCrossRefGoogle Scholar
  101. 101.
    West JC, Wilk JE, Olfson M, et al. Patterns and quality of treatment for patients with schizophrenia in routine psychiatric practice. Psychiatric Serv 2005; 56: 283–91CrossRefGoogle Scholar
  102. 102.
    Patrick V, Schleifer SJ, Nurenberg JR, et al. An initiative to curtail the use of antipsychotic polypharmacy in a State psychiatric hospital. Psychiatric Serv 2006; 57: 21–3CrossRefGoogle Scholar
  103. 103.
    Edlinger M, Hausmann A, Kemmler G, et al. Trends in the pharmacological treatment of patients with schizophrenia over a 12 year observation period. Schizophr Res 2005; 77: 25–34PubMedCrossRefGoogle Scholar
  104. 104.
    Stahl SM, Grady MM. High-cost use of second-generation antipsychotics under California’s Medicaid program. Psychiatr Serv 2006; 57: 127–9PubMedCrossRefGoogle Scholar
  105. 105.
    Sim K, Su A, Leong JY, et al. High dose antipsychotic use in schizophrenia: findings of the REAP (Research on East Asia psychotropic Prescriptions) study. Pharmacopsychiatry 2004; 37: 175–9PubMedCrossRefGoogle Scholar
  106. 106.
    Centorrino F, Eakin M, Bahk W-M, et al. Inpatient antipsychotic drug use in 1998, 1993, and 1989. Am J Psychiatry 2002; 159: 1932–5PubMedCrossRefGoogle Scholar
  107. 107.
    Procyshyn RM, Thompson B. Patterns of antipsychotic utilization in a tertiary care psychiatric institution. Pharmacopsychiatry 2004; 37: 12–7PubMedGoogle Scholar
  108. 108.
    Paton C, Lelliott P, Harrington M, et al. Patterns of antipsychotic and anticholinergic prescribing for hospital inpatients. J Psychopharmacol 2003; 17: 223–9PubMedCrossRefGoogle Scholar
  109. 109.
    Humberstone V, Wheeler A, Lambert T. An audit of outpatient antipsychotic usage in the three health sectors of Auckland, New Zealand. Aust N Z J Psychiatry 2004; 38: 240–5PubMedCrossRefGoogle Scholar
  110. 110.
    Citrome L, Jaffe A, Levine J. Monotherapy versus polypharmacy for hospitalized psychiatric patients [letter]. Am J Psychiatry 2005; 162: 631PubMedCrossRefGoogle Scholar
  111. 111.
    Tapp A, Wood AE, Secrest L, et al. Combination antipsychotic therapy in clinical practice. Psychiatr Serv 2003; 54: 55–9PubMedCrossRefGoogle Scholar
  112. 112.
    Ganguly R, Kotzan JA, Miller S, et al. Prevalence, trends, and factors associated with antipsychotic polypharmacy among medicaid-eligible schizophrenia patients, 1998–2000. J Clin Psychiatry 2004; 65: 1377–88PubMedCrossRefGoogle Scholar
  113. 113.
    Kreyenbuhl J, Valenstein M, McCarthy JF, et al. Long-term combination antipsychotic treatment in VA patients with schizophrenia. Schizophr Res 2006; 84: 90–9PubMedCrossRefGoogle Scholar
  114. 114.
    Faries D, Ascher-Svanum H, Zhu B, et al. Antipsychotic monotherapy and polypharmacy in the naturalistic treatment of schizophrenia with atypical antipsychotics. BMC Psychiatry 2005; 5: 26PubMedCrossRefGoogle Scholar
  115. 115.
    Stahl SM. Antipsychotic polypharmacy: evidence-based prescribing or prescribing-based evidence? Int J Neuropsychopharmacol 2004; 7: 113–6PubMedCrossRefGoogle Scholar
  116. 116.
    Freudenreich O, Goff DC. Antipsychotic combination therapy in schizophrenia. Acta Psychiat Scand 2002; 106: 323–30PubMedCrossRefGoogle Scholar
  117. 117.
    Sernyak MJ, Rosenheck R. Clinicians’ reasons for antipsychotic coprescribing. J Clin Psychiatry 2004; 65: 1597–600PubMedCrossRefGoogle Scholar
  118. 118.
    Ito H, Koyama A, Higuchi T. Polypharmacy and excessive dosing: psychiatrists’ perceptions of antipsychotic drug prescription. Br J Psychiatry 2005; 187: 243–7PubMedCrossRefGoogle Scholar
  119. 119.
    Shiloh R, Zemishlany Z, Aizenberg D, et al. Sulpiride augmentation in people with schizophrenia partially responsive to clozapine. Br J Psychiatry 1997; 171: 569–73PubMedCrossRefGoogle Scholar
  120. 120.
    Josiassen RC, Joseph A, Kohegyi E, et al. Clozapine augmented with risperidone in the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry 2005; 162: 130–6PubMedCrossRefGoogle Scholar
  121. 121.
    Anil Yagcioglu AE, Kivircik Akdede BB, Turgut TI, et al. A double-blind controlled study of adjunctive treatment with risperidone in schizophrenic patients partially responsive to clozapine: efficacy and safety. J Clin Psychiatry 2005; 66: 63–72PubMedCrossRefGoogle Scholar
  122. 122.
    Honer WG, Thornton AE, Chen EYH, et al. Clozapine alone versus clozapine and risperidone with refractory schizophrenia. New Engl J Med 2006; 354: 472–82PubMedCrossRefGoogle Scholar
  123. 123.
    Freudenreich O, Henderson DC, Walsh JP, et al. Risperidone augmentation for schizophrenia partially responsive to clozapine: a double-blind, placebo-controlled trial. Schizophr Res 2007; 92: 90–4PubMedCrossRefGoogle Scholar
  124. 124.
    Rubinow DR. Treatment strategies after SSRI failure: good news and bad news. New Engl J Med 2006; 345: 1305–7CrossRefGoogle Scholar
  125. 125.
    Davis JM. The choice of drugs for schizophrenia. New Engl J Med 2006; 354: 518–20PubMedCrossRefGoogle Scholar
  126. 126.
    Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. New Engl J Med 2006; 354: 1231–42PubMedCrossRefGoogle Scholar
  127. 127.
    Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. New Engl J Med 2006; 354: 1243–52PubMedCrossRefGoogle Scholar
  128. 128.
    Centorrino F, Goren JL, Hennen J, et al. Multiple versus single antipsychotic agents for hospitalized psychiatric patients: case-control study of risks versus benefits. Am J Psychiatry 2004; 161: 700–6PubMedCrossRefGoogle Scholar
  129. 129.
    Taylor D, Young C, Esop R, et al. Testing for diabetes in hospitalised patients prescribed antipsychotic drugs. Br J Psychiatry 2004; 185: 152–6PubMedCrossRefGoogle Scholar
  130. 130.
    Correll CU, Frederickson AM, Kane JM, et al. Does antipsychotic polypharmacy increase the risk for metabolic syndrome? Schizophr Res 2007; 89: 91–100PubMedCrossRefGoogle Scholar
  131. 131.
    Kivircik Akdede BB, Anil Yagcioglu AE, et al. A double-blind study of combination of clozapine with risperidone in patients with schizophrenia: effects on cognition. J Clin Psychiatry 2006; 67: 1912–9CrossRefGoogle Scholar
  132. 132.
    Hori H, Noguchi H, Hashimoto R, et al. Antipsychotic medication and cognitive function in schizophrenia. Schizophr Res 2006; 86: 138–46PubMedCrossRefGoogle Scholar
  133. 133.
    Kawai N, Yamakawa Y, Baba A, et al. High-dose of multiple antipsychotics and cognitive function in schizophrenia: the effect of dose-reduction. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 1009–14PubMedCrossRefGoogle Scholar
  134. 134.
    Suzuki T, Uchida H, Tanaka KF, et al. Revising polypharmacy to a single antipsychotic regimen for patients with chronic schizophrenia. Int J Neuropsychopharmacol 2004; 7: 133–42PubMedCrossRefGoogle Scholar
  135. 135.
    Waddington JL, Youssef HA, Kinsella A. Antipsychotic polypharmacy and absence of adjunctive anticholinergics over the course of a 10-year prospective study. Br J Psychiatry 1998; 173: 325–9PubMedCrossRefGoogle Scholar
  136. 136.
    Joukamaa M, Heliovaara M, Knekt P, et al. Schizophrenia, neuroleptic medication and mortality. Br J Psychiatry 2006; 188: 122–7PubMedCrossRefGoogle Scholar
  137. 137.
    Lewis SW, Barnes TRE, Davies L, et al. Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Schizophr Bull 2006; 32: 715–23PubMedCrossRefGoogle Scholar
  138. 138.
    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: 600–10PubMedCrossRefGoogle Scholar
  139. 139.
    Chakos M, Lieberman J, Hoffman E, et al. Effectiveness of second-generation antipsychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of randomized trials. Am J Psychiatry 2001; 158: 518–26PubMedCrossRefGoogle Scholar
  140. 140.
    Taylor DM, Young C, Paton C. Prior antipsychotic prescribing in patients currently receiving clozapine: a case note review. J Clin Psychiatry 2003; 64: 30–4PubMedCrossRefGoogle Scholar
  141. 141.
    Jones PB, Barnes TRE, Davies L, 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; 63: 1079–87PubMedCrossRefGoogle Scholar
  142. 142.
    Perlis RH, Ganz DA, Avorn J, et al. Pharmacogenetic testing in the clinical management of schizophrenia. J Clin Psychopharmacol 2005; 25: 427–34PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2007

Authors and Affiliations

  • William G. Honer
    • 1
    • 2
  • Allen E. Thornton
    • 2
    • 3
  • Megan Sherwood
    • 1
    • 4
  • G. William MacEwan
    • 1
    • 4
  • Tom S. Ehmann
    • 1
    • 4
  • Richard Williams
    • 1
  • Lili C. Kopala
    • 1
  • Ric Procyshyn
    • 1
    • 2
  • Alasdair M. Barr
    • 1
  1. 1.Department of PsychiatryUniversity of British ColumbiaVancouverCanada
  2. 2.Riverview HospitalCoquitlamCanada
  3. 3.Department of PsychologySimon Fraser UniversityBurnabyCanada
  4. 4.Department of PsychiatrySt Paul’s HospitalVancouverCanada

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