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CNS Drugs

, Volume 25, Issue 5, pp 383–399 | Cite as

Antipsychotic Polypharmacy in Schizophrenia

Benefits and Risks
  • Thomas R. E. BarnesEmail author
  • Carol Paton
Review Article

Abstract

Antipsychotic polypharmacy refers to the co-prescription of more than one antipsychotic drug for an individual patient. Surveys of prescribing in psychiatric services internationally have identified the relatively frequent and consistent use of combined antipsychotics, usually for people with established schizophrenia, with a prevalence of up to 50% in some clinical settings. A common reason for prescribing more than one antipsychotic is to gain a greater or more rapid therapeutic response than has been achieved with antipsychotic monotherapy. However, the evidence on the risks and benefits for such a strategy is equivocal, and not generally considered adequate to warrant a recommendation for its use in routine clinical practice in psychiatry. Combined antipsychotics are a major contributor to high-dose prescribing, associated with an increased adverse effect burden, and of limited value in helping to establish the optimum maintenance regimen for a patient.

The relatively widespread use of antipsychotic polypharmacy identified in cross-sectional surveys reflects not only the addition of a second antipsychotic to boost therapeutic response, but also the use of as-required antipsychotic medication (mainly to treat disturbed behaviour), gradual cross-titration while switching from one antipsychotic to another, and augmentation of clozapine with a second antipsychotic where the illness has failed to respond adequately to an optimized trial of clozapine. This review addresses the clinical trial data and other evidence for each of these pharmacological approaches. Also reviewed are examples of systematic, practice-based interventions designed to reduce the prevalence of antipsychotic polypharmacy, most of which have met with only modest success.

Guidelines generally agree that if combined antipsychotics are prescribed to treat refractory psychotic illness, this should be after other, evidence-based, pharmacological treatments such as clozapine have been exhausted. Further, their prescription for each patient should be in the context of an individual trial, with monitoring of the clinical response and adverse effects, and appropriate physical health monitoring.

Keywords

Clozapine Risperidone Aripiprazole Ziprasidone Amisulpride 
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.

Notes

Acknowledgements

No sources of funding were used to prepare this review. Thomas R.E. Barnes has acted as an advisor to Johnson & Johnson, Servier and Bristol-Myers Squibb. Carol Paton has been an advisor to Eli-Lilly, Janssen-Cilag and Bristol-Myers Squibb with regard to antipsychotic medications.

References

  1. 1.
    Gaebel W, Weinmann S, Sartorius N, et al. Schizophrenia practice guidelines: international survey and comparison. Br J Psychiatry 2005; 187: 248–55PubMedCrossRefGoogle Scholar
  2. 2.
    Royal Australian and New Zealand College of Psychiatrists. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the treatment of schizophrenia and related disorders. Aust N Z J Psychiatry 2005; 39: 1–30CrossRefGoogle Scholar
  3. 3.
    National Institute for Health and Clinical Excellence. Schizophrenia: core interventions in the treatment and management of schizophrenia in adults in primary and secondary care. Clinical guideline 82, 2009 [online]. Available from URL: http://guidance.nice.org.uk/CG82 [Accessed 2010 Aug 26]
  4. 4.
    Taylor D, Paton C, Kapur S. The Maudsley prescribing guidelines. 10th ed.London: Informa Healthcare, 2009Google Scholar
  5. 5.
    Miller AL. PORT treatment recommendations. Schizophr Bull 2004; 30: 601–4PubMedCrossRefGoogle Scholar
  6. 6.
    Sheppard C, Collins L, Fiorentino D, et al. Polypharmacyin psychiatric treatment: incidence at a state hospital. Curr Ther Res 1969; 11: 765–74PubMedGoogle Scholar
  7. 7.
    Keks NA, Alston K, Hope J, et al. Use of antipsychosis and adjunctive medications by an inner urban community psychiatric service. Aust N Z J Psychiatry 1999; 33: 896–901PubMedCrossRefGoogle Scholar
  8. 8.
    Ito C, Kubota Y, Sato M. A prospective survey on drug choice for prescriptions for admitted patients with schizophrenia. Psychiatry Clin Neurosci 1999; 53 Suppl. : S35–40PubMedCrossRefGoogle Scholar
  9. 9.
    Centorrino F, Goren JL, Hennen J, et al. Multiple versus single antipsychotic agents for hospitalised psychiatric patients: case-control study of risks versus benefits. Am J Psychiatry 2004; 161: 700–6PubMedCrossRefGoogle Scholar
  10. 10.
    McCue RE, Waheed R, Urcuyo L. Polypharmacy in patients with schizophrenia. J Clin Psychiatry 2003; 64: 984–9PubMedCrossRefGoogle Scholar
  11. 11.
    Gilmer TP, Dolder CR, Folsom DP, et al. Antipsychotic polypharmacy trends among medical beneficiaries with schizophrenia in San Diego County, 1999–2004. Psychiatr Serv 2007; 58: 1007–10PubMedCrossRefGoogle Scholar
  12. 12.
    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
  13. 13.
    Marchand J, Grignon S. A case-control study of patients with resistant schizophrenia after clozapine discontinuation. J Clin Psychopharmacol 2007; 27: 90–2PubMedCrossRefGoogle Scholar
  14. 14.
    Fenton WS, Blyler CR, Heinssen RK. Determinants ofmedication compliance in schizophrenia: empirical and clinical findings. Schizophr Bull 1997; 23: 637–51PubMedCrossRefGoogle Scholar
  15. 15.
    Milton J, Lawton J, Smith M, et al. Hidden high-dose antipsychotic prescribing: effects of p.r.n doses. Psych Bull 1998; 22: 675–7CrossRefGoogle Scholar
  16. 16.
    Tibaldi G, Munizza C, Bollini P, et al. Utilization of neuroleptic drugs in Italian mental health services: a survey in Piedmont. Psychiatr Serv 1997; 48: 213–7PubMedGoogle Scholar
  17. 17.
    Harrington M, Lelliott C, Paton C, et al. The results of a multicentre audit of the prescribing of antipsychotic drugs for inpatients in the UK. Psychiatr Bull 2002; 26: 414–8CrossRefGoogle Scholar
  18. 18.
    Paton C, Barnes TRE, Cavanagh MR, et al. High-dose and combination antipsychotic prescribing in acute adult wards in the UK: the challenges posed by p.r.n. prescribing. Br J Psychiatry 2008; 192: 435–9CrossRefGoogle Scholar
  19. 19.
    Hung GBK, Cheung HK. Predictors of high-dose antipsychotic prescription in psychiatric patients in Hong Kong. Hong Kong Med J 2008; 14: 35–9PubMedGoogle Scholar
  20. 20.
    Davis JM, Chen N. Dose response and dose equivalence of antipsychotics. J Clin Psychopharmacol 2004; 24: 192–208PubMedCrossRefGoogle Scholar
  21. 21.
    Royal College of Psychiatrists. Revised consensus statement on high dose antipsychotic medication (council report CR138). London: Royal College of Psychiatrists, 2006Google Scholar
  22. 22.
    Taylor D, Atkinson J, Fischetti C, et al. A prospective 6-month analysis of the naturalistic use of aripiprazole: factors predicting favourable outcome. Acta Psychiatr Scand 2007; 116: 461–6PubMedCrossRefGoogle Scholar
  23. 23.
    Kinon BJ, Volavka J, Stauffer V, et al. Standard and higher dose of olanzapine in patients with schizophrenia or schizoaffective disorder: a randomized, double-blind, fixed-dose study. J Clin Psychopharmacol 2008; 28: 392–400PubMedCrossRefGoogle Scholar
  24. 24.
    Sparshatt A, Taylor D, Patel MX, et al. Amisulpride-dose, plasma concentration, occupancy and response: implications for therapeutic drug monitoring. Acta Psychiatr Scand 2009; 120: 416–28PubMedCrossRefGoogle Scholar
  25. 25.
    Paton C, Lelliott P, Harrington M, et al. Patterns of antipsychotic and anticholinergic prescribing for hospital inpatients. J Psychopharmacol 2003; 17: 223–9PubMedCrossRefGoogle Scholar
  26. 26.
    Correll CU, Frederickson AM, Kane JM, et al. Does antipsychotic polypharmacy increase the risk for metabolic syndrome? Schizophr Res 2007; 89: 91–100PubMedCrossRefGoogle Scholar
  27. 27.
    Weinmann S, Read J, Aderhold V. Influence of antipsychotics on mortality in schizophrenia: systematic review. Schiz Res 2009; 113: 1–11CrossRefGoogle Scholar
  28. 28.
    Joukamaa M, Heliovaara M, Knekt P, et al. Schizophrenia, neuroleptic medication and mortality. Br J Psychiatry 2006; 188: 122–7PubMedCrossRefGoogle Scholar
  29. 29.
    Baandrup L, Gasse C, Jensen VD, et al. Antipsychotic polypharmacy and risk of death from natural causes in patients with schizophrenia: a population-based nested case-control study. J Clin Psychiatry 2010; 71: 103–8PubMedCrossRefGoogle Scholar
  30. 30.
    Hori H, Noguchi H, Hashimoto R, et al. Antipsychoticmedication and cognitive function in schizophrenia. Schizophr Res 2006; 86: 138–46PubMedCrossRefGoogle Scholar
  31. 31.
    Chakos MH, Glick ID, Miller AL, et al. Baseline use of concomitant psychotropic medications to treat schizophrenia in the CATIE trial. Psychiatr Serv 2006; 57: 1094–101PubMedCrossRefGoogle Scholar
  32. 32.
    Élie D, Poirier M, Chianetta JM, et al. Cognitive effects of antipsychotic dosage and polypharmacy: a study with the BACS in patients with the BACS in patients with schizophrenia and schizoaffective disorder. J Psychopharmacol 2010; 24: 1037–44PubMedCrossRefGoogle Scholar
  33. 33.
    Pope A, Adams C, Paton C, et al. Assessment of adverse effects in clinical studies of antipsychotic medication: survey of methods used. Br J Psychiatry 2010; 197: 67–72PubMedCrossRefGoogle Scholar
  34. 34.
    Freudenreich O, Goff DC. Antipsychotic combination therapy in schizophrenia: a review of efficacy and risks of current combinations. Acta Psychiatr Scand 2002; 106: 23–30CrossRefGoogle Scholar
  35. 35.
    Pandurangi AK, Dalkilic A. Polypharmacy with second-generation antipsychotics: a review of evidence. J Psychiatric Pract 2008; 14: 345–67CrossRefGoogle Scholar
  36. 36.
    Miller AL, Craig CS. Combination antipsychotics: pros, cons, and questions. Schiz Bull 2002; 28: 105–9CrossRefGoogle Scholar
  37. 37.
    Shim JC, Shin JG, Kelly DL, et al. Adjunctive treatment with a dopamine partial agonist, aripiprazole, for antipsychotic-induced hyperprolactinemia: a placebo-controlled trial. Am J Psychiatry 2007; 164: 1404–10PubMedCrossRefGoogle Scholar
  38. 38.
    Hoffer ZS, Roth RL, Mathews M. Evidence for the partial dopamine-receptor agonist aripiprazole as a first-line treatment of psychosis in patients with iatrogenic or tumorogenic hyperprolactinemia. Psychosomatics 2009; 50: 317–24PubMedCrossRefGoogle Scholar
  39. 39.
    Fleischhacker WW, Heikkinen ME, Olié JP, et al. Effects of adjunctive treatment with aripiprazole on body weight and clinical efficacy in schizophrenia patients treated with clozapine: a randomized, double-blind, placebo-controlled trial. Int J Neuropsychopharmacol 2010; 13: 1115–25PubMedCrossRefGoogle Scholar
  40. 40.
    Masopust J, Tůma I, Libiger J. Adjunctive aripiprazole decreased metabolic side effects of clozapine treatment. Neuro Endocrinol Lett 2008; 29: 435–7PubMedGoogle Scholar
  41. 41.
    Henderson DC, Kunkel L, Nguyen DD, et al. An exploratory open-label trial of aripiprazole as an adjuvant to clozapine therapy in chronic schizophrenia. Acta Psychiatr Scand 2006; 113: 142–7PubMedCrossRefGoogle Scholar
  42. 42.
    Kreyenbuhl J, Marcus SC, West JC, et al. Adding or switching antipsychotic medications in treatment-refractory schizophrenia. Psychiatr Serv 2007; 58: 983–90PubMedCrossRefGoogle Scholar
  43. 43.
    Bitter I, Treuer T, Dyachkova Y, et al. Antipsychotic prescription patterns in outpatient settings: 24-month results from the Intercontinental Schizophrenia Outpatient Health Outcomes (IC-SOHO) study. Eur Neuropsychopharmacol 2008; 18: 170–80PubMedCrossRefGoogle Scholar
  44. 44.
    Stahl SM. Antipsychotic polypharmacy, part 1: therapeutic option or dirty little secret? J Clin Psychiatry 1999; 60: 425–6PubMedCrossRefGoogle Scholar
  45. 45.
    Kingsbury SJ, Yi D, Simpson GM. Psychopharmacology: rational and irrational polypharmacy. Psychiatr Serv 2001; 52: 1033–6PubMedCrossRefGoogle Scholar
  46. 46.
    Langan J, Shajahan P. Antipsychotic polypharmacy: review of mechanisms, mortality and management. Psychiatrist 2010; 34: 58–62CrossRefGoogle Scholar
  47. 47.
    Curson DA, Barnes TRE, Bamber RW, et al. Long-term depot maintenance of chronic schizophrenic out-patients: the seven year follow-up of the Medical Research Council fluphenazine/placebo trial. II. The incidence of compliance problems, side-effects, neurotic symptoms and depression. Br J Psychiatry 1985; 146: 469–74Google Scholar
  48. 48.
    Barnes TRE, Shingleton-Smith A, Paton C. Treatment of schizophrenia by long-acting depot injections in the UK. Br J Psychiatry 2009; 195 Suppl. 52: s37–42CrossRefGoogle Scholar
  49. 49.
    Taylor D, Mir S, Mace S, et al. Co-prescribing of atypical and typical antipsychotics-prescribing sequence and documented outcome. Psychiatr Bull 2002; 26: 170–2CrossRefGoogle Scholar
  50. 50.
    Nielsen J, Dahm M, Lublin H, et al. Psychiatrists’ attitude towards and knowledge of clozapine treatment. J Psychopharmacol 2010; 24: 965–71PubMedCrossRefGoogle Scholar
  51. 51.
    Prescribing Observatory for Mental Health. Topic 3 report 3b: prescribing of high-dose and combined antipsychotics for patients on forensic wards — re-audit. CRTU060, 2008. (Data on file)Google Scholar
  52. 52.
    TREC Collaborative Group. Rapid tranquillisation for agitated patients in emergency psychiatric rooms: a randomised trial of midazolam versus haloperidol plus promethazine. BMJ 2003; 327: 708–13CrossRefGoogle Scholar
  53. 53.
    Alexander J, Tharyan P, Adams C, et al. Rapid tranquillisation of violent or agitated patients in a psychiatric emergency setting: pragmatic randomized trial of intramuscular lorazepam v haloperidol plus promethazine. Br J Psychiatry 2004; 185: 63–9PubMedCrossRefGoogle Scholar
  54. 54.
    Whicher E, Morrison M, Douglas-Hall P. ‘As required’ medication regimens for seriously mentally ill people in hospital (review). Cochrane Database Syst Rev 2002; (3): CD003441Google Scholar
  55. 55.
    Usher K, Lindsay D, Sellen J. Mental health nurses’ PRN psychotropic medication administration practices. J Psychiatr Mental Health Nurs 2001; 8: 383–90CrossRefGoogle Scholar
  56. 56.
    Usher L, Luck L. Psychotropic PRN: a model for best practice management of acute psychotic behavioural disturbance in inpatient psychiatric settings. Int J Mental Health Nurs 2004; 13: 18–21CrossRefGoogle Scholar
  57. 57.
    Baker JA, Lovell K, Harris N. Mental health professionals’ psychotropic pro re nata (p.r.n.) medication practices in acute inpatient mental health care: a qualitative study. Gen Hosp Psychiatry 2007; 29: 163–8PubMedCrossRefGoogle Scholar
  58. 58.
    Ito A, Koyama A, Higuchi T. Polypharmacy and excessivedosing: psychiatrists’ perceptions of antipsychotic drug prescription. Br J Psychiatry 2005; 187: 243–7PubMedCrossRefGoogle Scholar
  59. 59.
    Ito H, Koyama A, Higuchi T. Polypharmacy and excessive dosing: psychiatrists’ perceptions of antipsychotic drug prescription. Br J Psychiatry 2006; 187: 243–7CrossRefGoogle Scholar
  60. 60.
    Geffen J, Cameron A, Sorensen L, et al. Pro re nata medication for psychoses: the knowledge and beliefs of doctors and nurses. Aust NZ J Psychiatry 2002; 36: 642–8CrossRefGoogle Scholar
  61. 61.
    Volavka J, Citrome L. Heterogeneity of violence in schizophrenia and implications for long-term treatment. Int J Clin Pract 2008; 62: 1237–45PubMedCrossRefGoogle Scholar
  62. 62.
    Swanson JW, Swartz NS, Van Dorn RA, et al. Comparison of antipsychotic effects on reducing violence in people with schizophrenia. Br J Psychiatry 2008; 193: 37–43PubMedCrossRefGoogle Scholar
  63. 63.
    Citrome L, Volavka J, Czobar P, et al. Effect of clozapine, olanzapine, risperidone and haloperidol on hostility among people with schizophrenia. Psychiatr Serv 2001; 52: 1510–4PubMedCrossRefGoogle Scholar
  64. 64.
    Krakowski MI, Czobor P, Citrome L, et al. Atypical antipsychotic agents in the treatment of violent patients with schizophrenia and schizoaffective disorder. Arch Gen Psych 2006; 63: 622–9CrossRefGoogle Scholar
  65. 65.
    Mortimer AM, Singh P, Shepherd CJ, et al. Clozapine for treatment-resistant schizophrenia: National Institute of Clinical Excellence (NICE) guidance in the real world. Clin Schizophr Relat Psychoses 2010; 4: 49–55PubMedCrossRefGoogle Scholar
  66. 66.
    Chan J, Sweeting MJ. Combination therapy with nonclozapine atypical antipsychotic medication: a review of current evidence. J Psychopharmacol 2007; 21: 657–64PubMedCrossRefGoogle Scholar
  67. 67.
    Pae CU, Chiesa A, Mandelli L, et al. Predictors of early worsening after switch to aripiprazole: a randomized, controlled, open-label study. Clin Drug Investig 2010; 30: 187–93PubMedCrossRefGoogle Scholar
  68. 68.
    Kane JM, Correll CU, Goff DC, et al. A multicenter, randomized, double-blind, placebo-controlled, 16-week study of adjunctive aripiprazole for schizophrenia or schizoaffective disorder inadequately treated with quetiapine or risperidone monotherapy. J Clin Psychiatry 2009; 70: 1348–57PubMedCrossRefGoogle Scholar
  69. 69.
    Suzuki T, Uchida H, Watanabe K, et al. Effectiveness of antipsychotic polypharmacy for patients with treatment refractory schizophrenia: an open-label trial of olanzapine plus risperidone for those who failed to respond to a sequential treatment with olanzapine, quetiapine and risperidone. Hum Psychopharmacol 2008; 23: 455–63PubMedCrossRefGoogle Scholar
  70. 70.
    Correll CU, Rummel-Kluge C, Corves C, et al. Antipsychotic combinations vs monotherapy in schizophrenia: a meta-analysis of randomized controlled trials. Schizophr Bull 2009; 35: 443–57PubMedCrossRefGoogle Scholar
  71. 71.
    Kreyenbuhl JA, Valenstein M, McCarthy JF, et al. Long-term antipsychotic polypharmacy in the VA health system: patient characteristics and treatment patterns. Psychiatr Serv 2007; 58: 489–95PubMedCrossRefGoogle Scholar
  72. 72.
    Godleski LS, Kerler R, Barber JW, et al. Multiple versus single antipsychotic drug treatment in chronic psychosis. J Nerv Ment Dis 1989; 177: 686–9PubMedCrossRefGoogle Scholar
  73. 73.
    Yuzda MSK. Combination antipsychotics: what is the evidence? J Inform Pharmacother 2000; 2: 300–5Google Scholar
  74. 74.
    Gören JL, Parks JJ, Ghinassi FA, et al. When is antipsychotic polypharmacy supported by research evidence? Implications for QI. Jt Comm J Qual Patient Saf 2008; 34: 571–82PubMedGoogle Scholar
  75. 75.
    Tranulis C, Skalli L, Lalonde P, et al. Benefits and risks of antipsychotic polypharmacy: an evidence-based review of the literature. Drug Saf 2008; 31: 7–20PubMedCrossRefGoogle Scholar
  76. 76.
    Buchanan RW, Kreyenbuhl J, Kelly DL, et al. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schiz Bull 2010; 36: 71–93CrossRefGoogle Scholar
  77. 77.
    Lerner V, Libov I, Kotler M, et al. Combination of ‘atypical’ antipsychotic medication in the management of treatment-resistant schizophrenia and schizoaffective disorder. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28: 89–98PubMedCrossRefGoogle Scholar
  78. 78.
    Chakos M, Lieberman J, Hoffman E, et al. Effectiveness ofsecond-generation antipsychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of randomized trials. Am J Psychiatry 2001; 158: 518–26PubMedCrossRefGoogle Scholar
  79. 79.
    Pani L, Villagrán JM, Kontaxakis VP, et al. Practical issues with amisulpride in the management of patients with schizophrenia. Clin Drug Investig 2008; 28: 465–77PubMedCrossRefGoogle Scholar
  80. 80.
    Kontaxakis VP, Ferentinos PP, Havaki-Kontaxaki BJ, et al. Randomized controlled augmentation trials in clozapine-resistant schizophrenic patients: a critical review. Eur Psychiatry 2005; 20: 409–15PubMedCrossRefGoogle Scholar
  81. 81.
    Genç Y, Taner E, Candansayar S. Comparison of clozapine-amisulpride and clozapine-quetiapine combinations for patients with schizophrenia who are partially responsive to clozapine: a single-blind randomized study. Adv Ther 2007; 24: 1–13PubMedCrossRefGoogle Scholar
  82. 82.
    Josiassen RC, Ashok J, 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
  83. 83.
    Yagcioglu AEA, Akdede BBK, 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: 63–72CrossRefGoogle Scholar
  84. 84.
    Weiner E, Conley RR, Ball MP, et al. Adjunctive risperidone for partially responsive people with schizophrenia treated with clozapine. Neuropsychopharmacology 2010; 35(10): 2274–83PubMedCrossRefGoogle Scholar
  85. 85.
    Honer WG, Thornton AE, Chen EYH, et al. Clozapine alone versus clozapine and risperidone with refractory schizophrenia. N Engl J Med 2006; 354: 472–82PubMedCrossRefGoogle Scholar
  86. 86.
    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
  87. 87.
    Shiloh R, Zemishlany Z, Aizenberg D, et al. Sulpiride augmentation in people with schizophrenia partially responsive to clozapine: a double-blind, placebo-controlled study. Br J Psychiatry 1997; 171: 569–73PubMedCrossRefGoogle Scholar
  88. 88.
    Assion HJ, Reinbold H, Lemanski S, et al. Amisulpride augmentation in patients with schizophrenia partially responsive or unresponsive to clozapine: a randomized, double-blind, placebo-controlled trial. Pharmacopsychiatry 2008 Jan; 41(1): 24–8PubMedCrossRefGoogle Scholar
  89. 89.
    Chang JS, Ahn YM, Park HJ, et al. Aripiprazole augmentation in clozapine-treated patients with refractory schizophrenia: an 8-week, randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2008; 69: 720–31PubMedCrossRefGoogle Scholar
  90. 90.
    Fleischhacker WW, Heikkinen ME, Olié JP, et al. Effects of adjunctive treatment with aripiprazole on body weight and clinical efficacy in schizophrenia patients treated with clozapine: a randomized, double-blind, placebo-controlled trial. Int J Neuropsychopharmacol 2010; 13(8): 1115–25PubMedCrossRefGoogle Scholar
  91. 91.
    Ziegenbein M, Kropp S, Kuenzel HE. Combination of clozapine and ziprasidone in treatment-resistant schizophrenia: an open clinical study. Clin Neuropharmacol 2005; 28: 220–4PubMedCrossRefGoogle Scholar
  92. 92.
    Henderson DC, Fan X, Copeland PM, et al. Ziprasidone as an adjuvant for clozapine- or olanzapine-associated medical morbidity in chronic schizophrenia. Hum Psychopharmacol 2009; 24: 225–32PubMedGoogle Scholar
  93. 93.
    Cipriani A, Boso M, Barbui C. Clozapine combined with different antipsychotic drugs for treatment resistant schizophrenia. Cochrane Database Syst Rev 2009; (3): CD006324Google Scholar
  94. 94.
    Wang J, Omori IM, Fenton M, et al. Sulpiride augmentation for schizophrenia. Cochrane Database Syst Rev 2010; (1): CD008125Google Scholar
  95. 95.
    Paton C, Whittington C, Barnes TRE. Augmentation with a second antipsychotic in patients with schizophrenia who partially respond to clozapine: a meta-analysis. J Clin Psychopharmacol 2007; 27: 198–204PubMedCrossRefGoogle Scholar
  96. 96.
    Taylor DM, Smith L. Augmentation of clozapine with a second antipsychotic: a meta-analysis of randomized, placebo-controlled studies. Acta Psychiatr Scand 2009; 119: 419–25PubMedCrossRefGoogle Scholar
  97. 97.
    Barbui C, Signoretti A, Mulè S, et al. Does the addition of a second antipsychotic drug improve clozapine treatment? Schizophr Bull 2009; 35: 458–68PubMedCrossRefGoogle Scholar
  98. 98.
    Godleski LS, Sernyak MJ. Agranulocytosis after addition of risperidone to clozapine treatment. Am J Psychiatry 1996; 153: 735–6PubMedGoogle Scholar
  99. 99.
    Chong SA, Tan CH, Lee HS. Atrial ectopics with clozapine-risperidone combination. J Clin Psychopharmacol 1997; 17: 130–1PubMedCrossRefGoogle Scholar
  100. 100.
    Kontaxakis VP, Havaki-Kontaxaki BJ, Stamouli SS, et al. Toxic interaction between risperidone and clozapine: a case report. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26: 407–9PubMedCrossRefGoogle Scholar
  101. 101.
    Marder SR, Essock SM, Miller AL, et al. The Mount Sinaiconference on the pharmacotherapy of schizophrenia. Schizophr Bull 2002; 28: 5–16PubMedCrossRefGoogle Scholar
  102. 102.
    Kiivet RA, Llerena A, Dahl M-L, et al. Patterns of drug treatment of schizophrenic patients in Estonia, Spain and Sweden. Br J Clin Pharmacol 1995; 40: 467–76PubMedCrossRefGoogle Scholar
  103. 103.
    Lehman AF, Lieberman JA, Dixon LB, et al. Practice guideline for the treatment of patients with schizophrenia. 2nd ed. Am J Psychiatry 2004; 161(2 Suppl. ): 1–56PubMedGoogle Scholar
  104. 104.
    Clark RE, Bartels SJ, Mellman TA, et al. Recent trends in antipsychotic combination therapy of schizophrenia and schizoaffective disorder: implications for state mental health policy. Schizophr Bull 2002; 28: 75–84PubMedCrossRefGoogle Scholar
  105. 105.
    Stahl SM. Antipsychotic polypharmacy: squandering precious resources? J Clin Psychiatry 2002; 63: 93–4PubMedCrossRefGoogle Scholar
  106. 106.
    Stahl SM. Focus on antipsychotic polypharmacy: evidence-based prescribing or prescribing-based evidence? Int J Neuropsychopharmacol 2004; 7: 113–6PubMedCrossRefGoogle Scholar
  107. 107.
    Canales PL, Olsen J, Miller AL, et al. Role of antipsychotic polypharmacotherapy in the treatment of schizophrenia. CNS Drugs 1999; 12: 179–88CrossRefGoogle Scholar
  108. 108.
    Jaffe AB, Levine J. Antipsychotic medication coprescribing in a large state hospital system. Pharmacoepidemiol Drug Saf 2003; 12: 41–8PubMedCrossRefGoogle Scholar
  109. 109.
    De Hert M, Wampers M, Peuskens J. Pharmacological treatment of hospitalised schizophrenic patients in Belgium. Int J Psychiatry Clin Pract 2006; 10: 285–90CrossRefGoogle Scholar
  110. 110.
    Procyshyn RM, Kennedy NB, Tse G, et al. Antipsychotic polypharmacy: a survey of discharge prescriptions from a tertiary care psychiatric institution. Can J Psychiatry 2001; 46: 334–9PubMedGoogle Scholar
  111. 111.
    Hemminki E. Polypharmacy among psychiatric patients. Acta Psychiatr Scand 1977; 56: 347–56PubMedCrossRefGoogle Scholar
  112. 112.
    Bret P, Bonnet F, Bret MC, et al. Use of atypical antipsychotics in Charles Perrens psychiatric hospital (Bordeaux): analysis of prescribing practices for amisulpride, clozapine, olanzapine and risperidone. Encephale 2002; 28: 329–42PubMedGoogle Scholar
  113. 113.
    Bret P, Bret MC, Queuille E. Prescribing patterns of antipsychotics in 13 French psychiatric hospitals. Encephale 2009; 35: 129–38PubMedCrossRefGoogle Scholar
  114. 114.
    Hamann J, Ruppert A, Auby P, et al. Antipsychotic prescribing patterns in Germany: a retrospective analysis using a large outpatient prescription database. Int Clin Psychopharmacol 2003; 18: 237–42PubMedCrossRefGoogle Scholar
  115. 115.
    Yosselson-Superstine S, Sternik D, Liebenzon D. Prescribing patterns in psychiatric hospitals in Israel. Acta Psychiatr Scand 1979; 60: 477–82PubMedCrossRefGoogle Scholar
  116. 116.
    Biancosino B, Barbui C, Marmai L, et al. Determinants of antipsychotic polypharmacy in psychiatric inpatients: a prospective study. Int Clin Psychopharmacol 2005; 20: 305–9PubMedCrossRefGoogle Scholar
  117. 117.
    Yoshimura R, Okamoto T, Nakamura J, et al. Prescription pattern of antipsychotic drugs for schizophrenic inpatients in Japan: research on East Asia Psychotropic Prescription Pattern-Antipsychotics study. Psychiatry Clin Neurosci 2006; 60: 778–9PubMedCrossRefGoogle Scholar
  118. 118.
    Yip K, Ungvari G, Lau S. A survey of antipsychotic reatment for schizophrenia in Hong Kong. Chin Med J (Engl) 1997; 110: 792–6Google Scholar
  119. 119.
    Chong S-A, Sachdev P, Mahendran R, et al. Neuroleptic and anticholinergic drug use in Chinese patients with schizophrenia resident in a state psychiatric hospital in Singapore. Aust NZ J Psychiatry 2000; 34: 988–91CrossRefGoogle Scholar
  120. 120.
    Sim K, Su A, Fujii S, et al. Antipsychotic polypharmacy in patients with schizophrenia: a multicentre comparative study in East Asia. Br J Clin Pharmacol 2004; 58: 178–83PubMedCrossRefGoogle Scholar
  121. 121.
    Broekema WJ, de Groot IW, van Harten PN. Simultaneous prescribing of atypical antipsychotics, conventional antipsychotics and anticholinergics: a European study. Pharm World Sci 2007; 29: 126–30PubMedCrossRefGoogle Scholar
  122. 122.
    Remington G, Shammi CM, Sethna R, et al. Antipsychotic dosing patterns for schizophrenia in three treatment settings. Psychiatr Serv 2001; 52: 96–8PubMedCrossRefGoogle Scholar
  123. 123.
    Covell NH, Jackson CT, Evans AC, et al. Antipsychotic prescribing practices in Connecticut’s public mental health system: rates of changing medications and prescribing styles. Schizophr Bull 2002; 28: 17–29PubMedCrossRefGoogle Scholar
  124. 124.
    Tapp A, Wood AE, Secrest L, et al. Combination antipsychotic therapy in clinical practice. Psychiatr Serv 2003; 54: 55–9PubMedCrossRefGoogle Scholar
  125. 125.
    Essock SM, Covell NH, Leckman-Westin E, et al. Identifying clinically questionable psychotropic prescribing practices for medicaid recipients in New York State. Psychiatr Serv 2009; 60: 1595–602PubMedCrossRefGoogle Scholar
  126. 126.
    Tungaraza TE, Gupta S, Jones J, et al. Polypharmacy and high-dose antipsychotic regimes in the community. Psychiatrist 2010; 34: 44–6CrossRefGoogle Scholar
  127. 127.
    Hermann RC, Yang D, Ettner SL, et al. Prescription of antipsychotic drugs by office-based physicians in the United States, 1989–1997. Psychiatr Serv 2002; 53: 425–30PubMedCrossRefGoogle Scholar
  128. 128.
    Ganguly R, Kotzan JA, Miller LS, 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
  129. 129.
    Prescribing Observatory for Mental Health. Using the Prescribing Observatory for Mental Health to generate data on prescribing practices relating to people with schizophrenia and bipolar disorder. MHRN commissioned report, 2009. (Data on file)Google Scholar
  130. 130.
    Prescribing Observatory for Mental Health. Topic 1e supplementary report: prescribing of high-dose and combination antipsychotics on adult acute and intensive care wards. CRTU088, 2010. (Data on file)Google Scholar
  131. 131.
    Prescribing Observatory for Mental Health. Topic 2 report 2b: screening for metabolic side effects of antipsychotic drugs in patients treated by assertive outreach teams. 12-month re-audit, 2007. (Data on file)Google Scholar
  132. 132.
    McCombs JS, Nichol MB, Johnstone BM, et al. Antipsychotic drug use patterns and the cost of treating schizophrenia. Psychiatr Serv 2000; 51: 525–7PubMedCrossRefGoogle Scholar
  133. 133.
    Fleischhacker WW. New developments in the pharmacotherapy of schizophrenia. J Neural Transm 2003; 64 Suppl. : 105–17Google Scholar
  134. 134.
    Weissman EM. Antipsychotic prescribing practices in the Veterans Healthcare Administration: New York metropolitan region. Schizophr Bull 2002; 28: 31–42PubMedCrossRefGoogle Scholar
  135. 135.
    Sohler NL, Walkup J, McAlpine D, et al. Antipsychotic dosage at hospital discharge and outcomes among persons with schizophrenia. Psychiatr Serv 2003; 54: 1258–63PubMedCrossRefGoogle Scholar
  136. 136.
    Benson PR. Factors associated with antipsychotic drug prescribing by southern psychiatrists. Med Care 1983; 21: 639–54PubMedCrossRefGoogle Scholar
  137. 137.
    Diaz FJ, De Leon J. Excessive antipsychotic dosing in 2 U.S. State hospitals. J Clin Psychiatry 2002; 63: 998–1003Google Scholar
  138. 138.
    Herlihy D, Chatterjee A, Gwenzi S, et al. Low violence rates on PICU despite reduction in use of combination or high-dose antipsychotic prescribing [abstract]. J Psychopharmacol 2010; 24(3 Suppl. ): A14Google Scholar
  139. 139.
    Sernyak MJ, Dausey D, Desai R, et al. Prescribers’ nonadherence to treatment guidelines for schizophrenia when prescribing neuroleptics. Psychiatr Serv 2003; 54: 246–8PubMedCrossRefGoogle Scholar
  140. 140.
    Falzer PR, Garman DM, Moore BA. Examining the influence of clinician decision making on adherence to a clinical guideline. Psychiatr Serv 2009; 60: 698–701PubMedCrossRefGoogle Scholar
  141. 141.
    Chilvers R, Harrison G, Sipos A, et al. Evidence into practice: application of psychological models of change in evidence-based implementation. Br J Psychiatry 2002; 181: 99–101PubMedGoogle Scholar
  142. 142.
    Drake RE, Bond GR, Essock SM. Implementing evidence-based practices for people with schizophrenia. Schizophr Bull 2009; 35: 704–13PubMedCrossRefGoogle Scholar
  143. 143.
    Bero LA, Grilli R, Grimshaw JM, et al. Getting research findings into practice: closing the gap between research and practice — an overview of systematic reviews of interventions to promote the implementation of research findings. BMJ 1998; 317: 465–8PubMedCrossRefGoogle Scholar
  144. 144.
    Moore TA, Buchanan RW, Buckley PF, et al. The Texas Medication Algorithm Project antipsychotic algorithm for schizophrenia: 2006 update. J Clin Psychiatry 2007; 68: 1751–62PubMedCrossRefGoogle Scholar
  145. 145.
    Toprac MG, Dennehy EB, Carmody TJ, et al. Implementation of the Texas Medication Algorithm Project Patient and Family Education Program. J Clin Psychiatry 2006; 67: 1362–72PubMedCrossRefGoogle Scholar
  146. 146.
    Miller AL, Hall CS, Buchanan RW, et al. The Texas Medication Algorithm Project antipsychotic algorithm for schizophrenia: 2003 update. J Clin Psychiatry 2004; 65: 500–8PubMedCrossRefGoogle Scholar
  147. 147.
    Constantine RJ, Andel R, Tandon R. Trends in adult antipsychotic polypharmacy: progress and challenges in Florida’s Medicaid program. Community Ment Health J 2010; 46(6): 523–30PubMedCrossRefGoogle Scholar
  148. 148.
    Patrick V, Schleifer SJ, Nurenberg JR, et al. An initiative to curtail the use of antipsychotic polypharmacy in a state psychiatric hospital. Psychiatr Serv 2006; 57: 21–3PubMedCrossRefGoogle Scholar
  149. 149.
    Chong S-A, Ravichandran N, Poon L-Y, et al. Reducing polypharmacy through the introduction of a treatment algorithm: use of a treatment algorithm on the impact on polypharmacy. Ann Acad Med Singapore 2006; 35: 457–60PubMedGoogle Scholar
  150. 150.
    Thompson A, Sullivan SA, Barley M, et al. The DEBIT trial: an intervention to reduce antipsychotic polypharmacy prescribing in adult psychiatry wards — a cluster randomized controlled trial. Psychol Med 2008; 38: 705–15PubMedCrossRefGoogle Scholar
  151. 151.
    Thompson A, Sullivan S, Barley M, et al. Effectiveness of a cognitive behavioural workbook for changing beliefs about antipsychotic polypharmacy: analysis from a cluster randomized controlled trial. J Eval Clin Pract 2010; 16: 520–8PubMedCrossRefGoogle Scholar
  152. 152.
    Bowden MF. Audit: prescription of ‘as required’ (p.r.n.) medication in an in-patient setting. Psychiatr Bull 1999; 23: 413–6CrossRefGoogle Scholar
  153. 153.
    Thapa PB, Palmer SL, Owen RR, et al. PRN (as needed) orders and exposure of psychiatric inpatients to unnecessary psychotropic medications. Psychiatr Serv 2003; 54: 1282–6PubMedCrossRefGoogle Scholar
  154. 154.
    Donat DC. Impact of a clinical-administrative review procedure on reducing reliance on psychotropic PRN medication. Psychiatr Rehab J 2006; 29: 215–8CrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2011

Authors and Affiliations

  1. 1.Centre for Mental Health, Division of Experimental MedicineImperial College London, Charing Cross CampusLondonUK

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