Skip to main content
NCBI home page
CADTH Technology Overviews logoLink to CADTH Technology Overviews
. 2012 Sep 1;2(3):e2301.

Combination and High-Dose Atypical Antipsychotic Therapy in Patients with Schizophrenia: Systematic Review

PMCID: PMC3442617  PMID: 23002379

Introduction

Schizophrenia is a mental illness that requires lifelong treatment1 and is associated with symptoms that include hallucinations, delusions, cognitive impairment, disorganized thoughts, social withdrawal, and low motivation.2 Antipsychotic medications are effective at relieving the symptoms of schizophrenia, and they form the foundation of treatment.3 These medications fall into two classes: the typical, or first-generation, antipsychotics (TAPs); and the atypical, or second-generation, antipsychotics (AAPs). At the time of this review, seven AAPs were available in Canada:

  • aripiprazole

  • clozapine

  • olanzapine

  • paliperidone

  • quetiapine

  • risperidone

  • ziprasidone.

Approximately one-third of patients with schizophrenia have a poor response to antipsychotic medications.4 Although not recommended in most clinical practice guidelines,5 the use of AAPs at doses higher than recommended or combination of an AAP with another antipsychotic medication are strategies that are sometimes used in clinical practice to treat patients who have an inadequate response to standard doses of a single AAP. These strategies may be associated with increased risks for adverse effects, as well as increased costs. Annual expenditures on antipsychotics in Canada by 11 publicly funded drug plans in 2009 were approximately C$421.9 million, while C$62.3 million was spent by privately funded drug plans. The Canadian Agency for Drugs and Technologies in Health’s (CADTH’s) analysis of current utilization data found that combination therapy and high dose AAP monotherapy accounted for 20% to 38% of total antipsychotic expenditures in 2009.6

Objective

The objective of this study was to assess the efficacy and safety of AAP combination therapy and high-dose treatment strategies in adolescents and adults with schizophrenia.

The following research questions were addressed:

  1. What is the comparative clinical effectiveness (including clinical benefits and harms) of using combination therapy with AAPs (i.e., more than one AAP or AAP[s] plus TAP[s]) compared with AAP monotherapy for the treatment of adolescents and adults with schizophrenia for whom treatment with a single AAP or typical antipsychotic at recommended doses is inadequate?

  2. What is the comparative clinical effectiveness (including clinical benefits and harms) of using high-dose AAP therapy compared with standard dose antipsychotic therapy for the treatment of adolescents and adults with schizophrenia for whom treatment with an AAP or TAP at recommended doses is inadequate?

Following careful evaluation of the evidence, the COMPUS Expert Review Committee (CERC) produced four recommendations on the use of AAP combination and high-dose treatment strategies in adolescents and adults with schizophrenia inadequately controlled on standard-dose antipsychotic monotherapy (recommendation report)7 to guide Canadian health-care providers and policy-makers. CADTH also studied current practice (current practice report)8 and current utilization6 related to the prescribing of AAPs for patients with schizophrenia to guide knowledge exchange efforts around this work.

Methods

The project protocol9 presents, in detail, the methodology for the systematic review.

The population of interest for this review was adolescents (aged 13 to 17 years) and adults (aged 18 years and older) with schizophrenia or schizoaffective disorder who were inadequately managed with one or more AAPs at recommended doses. For the systematic review, a literature search was conducted on June 16, 2010 in medical databases and restricted to English or French publications. Monthly alerts were monitored until publication of the report. A search of grey literature (literature that is not commercially published) was also conducted. Studies were selected independently, by two reviewers, based on set criteria, with discrepancies resolved through discussion or the judgment of a third reviewer. Ultimately, the systematic review encompassed 30 unique randomized controlled trials (RCTs).

Meta-analyses were performed, where appropriate, to obtain pooled estimates of effect. Monthly RCT alerts were maintained until May of 2011. Four studies meeting the inclusion criteria were identified via these alerts, but sensitivity analyses incorporating the new data from these trials did not significantly affect the results of the analyses.

Results

The selected RCTs studied the following treatment strategies:

  • Dual antipsychotic therapy involving either one or two AAPs (compared with AAP monotherapy); these included trials of clozapine-based combination therapy versus clozapine monotherapy, and non-clozapine AAP combinations versus AAP monotherapy. No trials were identified comparing non-clozapine combination therapy with clozapine monotherapy.

  • High-dose, non-clozapine AAP therapy (compared with standard-dose clozapine and non-clozapine antipsychotics).

Of the 30 included RCTs, only one10 was conducted in adolescents (aged 10 to 18 years). Baseline duration of illness for the adult studies ranged from 711 to 2212 years (weighted mean [SD] 15.6 [4.8]). A broad range of antipsychotic doses were used in the included trials. Common outcome measures included schizophrenia symptom scales (e.g., Positive and Negative Symptoms Scale [PANSS], Brief Psychiatric Rating Scale [BPRS] scores, Clinical Global Impression [CGI]), response rate, cognition, withdrawals, and serious adverse events. No evidence was available for relapse or remission rates.

Combination Treatment Strategies

a). Clozapine-based antipsychotic combination therapy versus standard dose clozapine-monotherapy

Eleven RCTs13–24 compared combination therapy involving clozapine (CLZ) versus CLZ monotherapy. There were no statistical differences between groups for any outcome, with the exception of the Clinical Global Impression Improvement (CGI-I) scale, where slightly greater improvement was seen in the CLZ combination arm compared with CLZ monotherapy at 16 weeks.

The four studies that reported efficacy scores (PANSS-total score) were inconsistent in their findings. One study17 showed a small, statistically significant benefit with CLZ monotherapy, whereas another study14 showed a small, statistically significant benefit with CLZ combination therapy. The other two studies16,20 did not show a statistically significant difference between CLZ combination therapy and CLZ monotherapy.

More serious adverse events occurred with CLZ combination therapy compared with CLZ monotherapy (11/216 versus 0/194). For the majority of other harms outcomes, there were no statistically significant differences between groups, although withdrawal due to adverse events (8/200 versus 4/180) and akathisia (6/138 versus 0/113) occurred numerically more frequently in the CLZ combination arm.

Regarding body weight, four trials comparing either risperidone16,17,21 or aripiprazole13 combined with clozapine with clozapine alone did not show a statistically significant difference. However, one study20 of patients who had gained more than 2.5 kg on CLZ monotherapy prior to the start of the trial reported a significant difference in body weight reduction with aripiprazole combined with CLZ, despite similar clozapine doses between arms. Total cholesterol was statistically significantly lower with CLZ combination than CLZ monotherapy, as was low-density lipoprotein or LDL cholesterol.

Five studies reported prolactin levels: three trials17,19,25 reported statistically lower prolactin levels with CLZ monotherapy, while two trials13,21 indicated a non-significant difference.

b). Non-clozapine antipsychotic combination therapy versus non-clozapine monotherapy

One RCT26 lasting 16 weeks compared risperidone or quetiapine plus aripiprazole with risperidone or quetiapine plus placebo.

There were no statistically significant differences between groups for any efficacy-related outcomes for this comparison. Regarding harms, there were fewer serious adverse events in patients using combination therapy (8/169 versus 19/153), and prolactin levels showed a statistically significant decrease from baseline with combination therapy, compared with monotherapy. No significant differences were observed for other harms outcomes.

High-Dose AAP Treatment Strategies

c). High-dose non-clozapine AAP therapy versus standard-dose clozapine

Eight RCTs10,25,27–38 compared high-dose non-clozapine AAP therapy with standard-dose clozapine therapy.

In pooled analyses, there were no statistically significant differences in efficacy between groups except for Global Assessment of Functioning (GAF) scores, which were improved with standard-dose CLZ compared with high-dose AAPs. One trial39 reported significantly improved BPRS scores in the standard-dose clozapine arm compared with high-dose risperidone, whereas there was no significant difference between high-dose olanzapine and standard-dose clozapine in the second trial.29 Regarding harms, there were no statistically significant differences between groups for most outcomes. High-dose non-clozapine AAPs was associated with fewer cases of parkinsonism (two RCTs29,35), as well as fewer withdrawals due to adverse events (six RCTs25,29,32,35,36,39). Patients on high-dose non-CLZ AAPs had a higher incidence of extrapyramidal symptoms (two RCTs36,39) and higher prolactin levels (two RCTs29,36) compared with standard-dose CLZ. There was no overlap between studies reporting total extrapyramidal symptoms36,39 and those reporting parkinsonism,29,35 which may explain the apparent discrepancy in the direction of effects for these outcomes.

d). High-dose non-clozapine AAP therapy versus standard-dose non-clozapine antipsychotic drugs

Two RCTs40,41 compared high-dose non-clozapine AAP therapy with standard-dose non-clozapine antipsychotic drugs.

There were no statistically significant differences between groups in efficacy or harms outcomes. Data for PANSS-total and PANSS-positive from the two included studies40,41 were not pooled due to a high degree of heterogeneity. For PANSS-total, a trial40 comparing high-dose risperidone with standard-dose haloperidol found significantly greater improvement with high-dose risperidone, while a trial41 comparing high-dose quetiapine with standard-dose quetiapine did not find a significant difference. Similarly, PANSS-positive was significantly improved when high-dose risperidone was compared with standard-dose haloperidol,40 but not when high-dose quetiapine was compared with standard dose.41

Limitations

Limitations of this systematic review include lack of and low quality of available evidence. Of the 30 included RCTs, 27 were rated as being of “poor” methodological quality. The trials were of short duration and had inadequate study power, particularly for safety outcomes.

It was difficult to compare across trials because of differences in dosing and because the RCTs included patients with various treatment histories — often, dosing levels and treatment history were not reported. There was also heterogeneity in reported outcomes (e.g., different definitions for inadequate control) and lack of data on many clinically important outcomes. In particular, there was insufficient evidence available for mortality, hospitalizations, relapse rates, suicidality, health-related quality of life, level of function, and long-term adverse effects of combination or high-dose antipsychotic use. PANSS and CGI were the primary efficacy outcomes reported in the majority of included RCTs; however, the relationship between the change in PANSS score and long-term clinical outcomes has not been well-established.42

Conclusions

The systematic review showed no clinically significant improvements in efficacy with combination or high-dose AAP treatment strategies when compared with standard-dose monotherapy. The evidence regarding harms was inconclusive, but there were signals for increased harm with high dose and combination strategies in some comparisons. Despite the heterogeneity in trial populations, studies were consistent in reporting that combination and high-dose strategies were not more efficacious than standard dose monotherapy; therefore, the results of this review are largely applicable to patients in Canada with schizophrenia.

Longer-term studies of sufficient methodological quality and sample size are required to determine with more certainty the clinical value, if any, of combination or high-dose treatment strategies. Considering that clozapine serves as the standard of care for treatment-resistant patients, further comparative trials of this drug with high dose and combination therapies may be of particular value in guiding optimal treatment strategies for patients with schizophrenia.

Adapted from A Systematic Review of Combination and High-Dose Atypical Antipsychotic Therapy in Patients with Schizophrenia [CADTH Optimal Use Report; Volume 1, Issue 1B]. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2011.

For more information on this project, visit http://www.cadth.ca/en/products/optimal-use/atypical-antipsychotics-for-schizophrenia.

References

  • 1.Kasper S, Lerman MN, McQuade RD, Saha A, Carson WH, Ali M, et al. Efficacy and safety of aripiprazole vs. haloperidol for long-term maintenance treatment following acute relapse of schizophrenia. Int J Neuropsychopharmacol. 2003 Dec;6(4):325–37. doi: 10.1017/S1461145703003651. [DOI] [PubMed] [Google Scholar]
  • 2.Health Canada . A report on mental illnesses in Canada. Ottawa: Health Canada; 2002. Schizophrenia [Internet] Chapter 3 [cited 2012 Jun 12]. Available from: http://www.phac-aspc.gc.ca/publicat/miic-mmac/pdf/men_ill_e.pdf. [Google Scholar]
  • 3.Diagnostic and statistical manual of mental disorders: DSM-IV-TR. 4th ed, text revision. Washington: American Psychiatric Association; 2000. [Google Scholar]
  • 4.National Institute for Health and Clinical Excellence . London: NICE; 2009. Mar, Schizophrenia: core interventions in the treatment and management of schizophrenia in adults in primary and secondary care [Internet] [cited 2012 Jun 12]. (NICE clinical guideline 82). Available from: http://www.nice.org.uk/nicemedia/pdf/CG82NICEGuideline.pdf. [Google Scholar]
  • 5.Canadian Psychiatric Association Clinical practice guidelines. Treatment of schizophrenia. Can J Psychiatry [Internet] 2005 Nov;50(13 Suppl 1):7S–57S. [cited 2012 Jun 12] Available from: https://ww1.cpa-apc.org/Publications/Clinical_Guidelines/schizophrenia/november2005/cjp-cpg-suppl1-05_full_spread.pdf. [PubMed] [Google Scholar]
  • 6.Canadian Agency for Drugs and Technologies in Health . Current utilization of antipsychotic agents for schizophrenia: combination and high dose therapies. Ottawa: CADTH; 2011. (CADTH optimal use report). Forthcoming. [PubMed] [Google Scholar]
  • 7.Canadian Agency for Drugs and Technologies in Health . Optimal use recommendations for atypical antipsychotics: combination and high-dose treatment strategies in adolescents and adults with schizophrenia [Internet] Ottawa: CADTH; 2011. [cited 2012 Jun 12]. (CADTH optimal use report; vol. 1, no. 1c). Available from: http://www.cadth.ca/media/pdf/H0503_AAP_rec-report_e.pdf. [PubMed] [Google Scholar]
  • 8.Canadian Agency for Drugs and Technologies in Health . Atypical antipsychotics for schizophrenia: combination therapy, high doses, and clozapine - current pracitce study. Ottawa: CADTH; 2011. (CADTH optimal use report). Forthcoming. [PubMed] [Google Scholar]
  • 9.Canadian Agency for Drugs and Technologies in Health . Atypical antipsychotics for schizophrenia: combination therapy and high doses -- project protocol [Internet] Ottawa: CADTH; 2011. [cited 2011 Sep 7]. (CADTH optimal use report; vol. 1, no. 1a). Available from: http://www.cadth.ca/media/pdf/H0503_atypical_antipsych_protocol_o-u_e.pdf. [PubMed] [Google Scholar]
  • 10.Kumra S, Kranzler H, Gerbino-Rosen G, Kester HM, De Thomas C, Kafantaris V, et al. Clozapine and “high-dose” olanzapine in refractory early-onset schizophrenia: a 12-week randomized and double-blind comparison. Biol Psychiatry. 2008 Mar 1;63(5):524–9. doi: 10.1016/j.biopsych.2007.04.043. [DOI] [PubMed] [Google Scholar]
  • 11.Shafti SS. Augmentation of olanzapine by fluphenazine decanoate in poorly responsive schizophrenia. Clin Schizophr Relat Psychoses. 2009;3(2):97–102. [Google Scholar]
  • 12.Josiassen RC, Joseph A, Kohegyi E, Stokes S, Dadvand M, Paing WW, et al. Clozapine augmented with risperidone in the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry. 2005 Jan;162(1):130–6. doi: 10.1176/appi.ajp.162.1.130. [DOI] [PubMed] [Google Scholar]
  • 13.Chang JS, Ahn YM, Park HJ, Lee KY, Kim SH, Kang UG, et al. Aripiprazole augmentation in clozapine-treated patients with refractory schizophrenia: an 8-week, randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2008 May;69(5):720–31. doi: 10.4088/jcp.v69n0505. [DOI] [PubMed] [Google Scholar]
  • 14.Freudenreich O, Henderson DC, Walsh JP, Culhane MA, Goff DC. Risperidone augmentation for schizophrenia partially responsive to clozapine: a double-blind, placebo-controlled trial. Schizophr Res. 2007 May;(1–3):92. 90–4. doi: 10.1016/j.schres.2006.12.030. [DOI] [PubMed] [Google Scholar]
  • 15.Akdede BB, Anil Yagcioglu AE, Alptekin K, Turgut TI, Tumuklu M, Yazici MK, et al. A double-blind study of combination of clozapine with risperidone in patients with schizophrenia: effects on cognition. J Clin Psychiatry. 2006 Dec;67(12):1912–9. [PubMed] [Google Scholar]
  • 16.Honer WG, Thornton AE, Chen EY, Chan RC, Wong JO, Bergmann A, et al. Clozapine alone versus clozapine and risperidone with refractory schizophrenia. N Engl J Med [Internet] 2006 Feb 2;354(5):472–82. doi: 10.1056/NEJMoa053222. [cited 2010 Jun 25] Available from: http://content.nejm.org/cgi/reprint/354/5/472.pdf. [DOI] [PubMed] [Google Scholar]
  • 17.Anil Yagcioglu AE, Kivircik Akdede BB, Turgut TI, Tumuklu M, Yazici MK, Alptekin K, 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 Jan;66(1):63–72. doi: 10.4088/jcp.v66n0109. [DOI] [PubMed] [Google Scholar]
  • 18.Assion HJ, Reinbold H, Lemanski S, Basilowski M, Juckel G. Amisulpride augmentation in patients with schizophrenia partially responsive or unresponsive to clozapine. A randomized, double-blind, placebo-controlled trial. Pharmacopsychiatry. 2008 Jan;41(1):24–8. doi: 10.1055/s-2007-993209. [DOI] [PubMed] [Google Scholar]
  • 19.Shiloh R, Zemishlany Z, Aizenberg D, Radwan M, Schwartz B, Dorfman-Etrog P, et al. Sulpiride augmentation in people with schizophrenia partially responsive to clozapine. A double-blind, placebo-controlled study. Br J Psychiatry. 1997 Dec;171:569–73. doi: 10.1192/bjp.171.6.569. [DOI] [PubMed] [Google Scholar]
  • 20.Fleischhacker WW, Heikkinen ME, Olie JP, Landsberg W, Dewaele P, McQuade RD, 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 Sep;13(8):1115–25. doi: 10.1017/S1461145710000490. [DOI] [PubMed] [Google Scholar]
  • 21.Weiner E, Conley RR, Ball MP, Feldman S, Gold JM, Kelly DL, et al. Adjunctive risperidone for partially responsive people with schizophrenia treated with clozapine. Neuropsychopharmacology [Internet] 2010 Oct;35(11):2274–83. doi: 10.1038/npp.2010.101. [cited 2011 Jul 15] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2939921/ [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Mossaheb N, Sacher J, Wiesegger G, Klein N, Spindelegger CJ, Asenbaum S, et al. Haloperidol in combination with clozapine in treatment-refractory patients with schizophrenia [abstract] Eur Neuropsychopharmacol. 2006;16(Suppl 4):S416. [Google Scholar]
  • 23.Millar H, Felter C, Landsberg W. The effects of aripiprazole in combination with clozapine: patient functioning results from a double-blind, 16-week study in patients with schizophrenia (CN138-170) [abstract] J Psychopharmacol. 2008;22(5):A17. [Google Scholar]
  • 24.Richardson CM, Feldman S, Kelly DL, Ball MP, Boggs DL, Weiner E, et al. Metabolic side effects of combined antipsychotic treatment: results from a double blind trial of adjunctive risperidone in clozapine treated people with treatment-resistant schizophrenia [abstract] Schizophr Bull. 2009;35(Suppl 1):38–9. [Google Scholar]
  • 25.Kelly DL, Conley RR, Richardson CM, Tamminga CA, Carpenter WT., Jr Adverse effects and laboratory parameters of high-dose olanzapine vs. clozapine in treatment-resistant schizophrenia. Ann Clin Psychiatry. 2003 Sep;15(3–4):181–6. doi: 10.1023/b:acli.0000008171.90644.f8. [DOI] [PubMed] [Google Scholar]
  • 26.Kane JM, Correll CU, Goff DC, Kirkpatrick B, Marder SR, Vester-Blokland E, 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 Oct;70(10):1348–57. doi: 10.4088/JCP.09m05154yel. [DOI] [PubMed] [Google Scholar]
  • 27.Meltzer HY, Bobo WV, Roy A, Jayathilake K, Chen Y, Ertugrul A, et al. A randomized, double-blind comparison of clozapine and high-dose olanzapine in treatment-resistant patients with schizophrenia. J Clin Psychiatry. 2008 Feb;69(2):274–85. doi: 10.4088/jcp.v69n0214. [DOI] [PubMed] [Google Scholar]
  • 28.Kelly DL, Richardson CM, Yu Y, Conley RR. Plasma concentrations of high-dose olanzapine in a double-blind crossover study. Hum Psychopharmacol. 2006 Aug;21(6):393–8. doi: 10.1002/hup.781. [DOI] [PubMed] [Google Scholar]
  • 29.Tollefson GD, Birkett MA, Kiesler GM, Wood AJ. Double-blind comparison of olanzapine versus clozapine in schizophrenic patients clinically eligible for treatment with clozapine. Biol Psychiatry. 2001;49(1):52–63. doi: 10.1016/s0006-3223(00)01026-x. [DOI] [PubMed] [Google Scholar]
  • 30.Volavka J, Czobor P, Cooper TB, Sheitman B, Lindenmayer JP, Citrome L, et al. Prolactin levels in schizophrenia and schizoaffective disorder patients treated with clozapine, olanzapine, risperidone, or haloperidol. J Clin Psychiatry. 2004 Jan;65(1):57–61. doi: 10.4088/jcp.v65n0109. [DOI] [PubMed] [Google Scholar]
  • 31.Lindenmayer JP, Czobor P, Volavka J, Citrome L, Sheitman B, McEvoy JP, et al. Changes in glucose and cholesterol levels in patients with schizophrenia treated with typical or atypical antipsychotics. Am J Psychiatry [Internet] 2003 Feb;160(2):290–6. doi: 10.1176/appi.ajp.160.2.290. [cited 2011 Jul 15] Available from: http://ajp.psychiatryonline.org/cgi/reprint/160/2/290. [DOI] [PubMed] [Google Scholar]
  • 32.Volavka J, Czobor P, Sheitman B, Lindenmayer JP, Citrome L, McEvoy JP, et al. Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder. Am J Psychiatry [Internet] 2002 Feb;159(2):255–62. doi: 10.1176/appi.ajp.159.2.255. [cited 2011 Jul 15] Available from: http://ajp.psychiatryonline.org/cgi/reprint/159/2/255. [DOI] [PubMed] [Google Scholar]
  • 33.Citrome L, Volavka J, Czobor P, Sheitman B, Lindenmayer JP, McEvoy J, et al. Effects of clozapine, olanzapine, risperidone, and haloperidol on hostility among patients with schizophrenia. Psychiatr Serv [Internet] 2001 Nov;52(11):1510–4. doi: 10.1176/appi.ps.52.11.1510. [cited 2010 Aug 4] Available from: http://ps.psychiatryonline.org/cgi/reprint/52/11/1510. [DOI] [PubMed] [Google Scholar]
  • 34.Wirshing DA, Marshall BD, Jr, Green MF, Mintz J, Marder SR, Wirshing WC. Risperidone in treatment-refractory schizophrenia. Am J Psychiatry [Internet] 1999 Sep;156(9):1374–9. doi: 10.1176/ajp.156.9.1374. [cited 2011 Jul 15] Available from: http://ajp.psychiatryonline.org/cgi/reprint/156/9/1374. [DOI] [PubMed] [Google Scholar]
  • 35.Bondolfi G, Dufour H, Patris M, May JP, Billeter U, Eap CB, et al. Risperidone versus clozapine in treatment-resistant chronic schizophrenia: a randomized double-blind study. The Risperidone Study Group. Am J Psychiatry [Internet] 1998 Apr;155(4):499–504. doi: 10.1176/ajp.155.4.499. [cited 2011 Jul 15] Available from: http://ajp.psychiatryonline.org/cgi/reprint/155/4/499. [DOI] [PubMed] [Google Scholar]
  • 36.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. Am J Psychiatry [Internet] 2006 Apr;163(4):600–10. doi: 10.1176/ajp.2006.163.4.600. [cited 2010 Aug 19] Available from: http://ajp.psychiatryonline.org/cgi/content/full/163/4/600. [DOI] [PubMed] [Google Scholar]
  • 37.Czobor P, Volavka J, Sheitman B, Lindenmayer JP, Citrome L, McEvoy J, et al. Antipsychotic-induced weight gain and therapeutic response: a differential association. J Clin Psychopharmacol. 2002 Jun;22(3):244–51. doi: 10.1097/00004714-200206000-00003. [DOI] [PubMed] [Google Scholar]
  • 38.Conley RR, Kelly DL, Richardson CM, Tamminga CA, Carpenter WT. The efficacy of high-dose olanzapine versus clozapine in treatment-resistant schizophrenia: a double-blind, crossover study. J Clin Psychopharmacol. 2003;23(6):668–71. doi: 10.1097/01.jcp.0000096246.29231.73. [DOI] [PubMed] [Google Scholar]
  • 39.Azorin JM, Spiegel R, Remington G, Vanelle JM, Pere JJ, Giguere M, et al. A double-blind comparative study of clozapine and risperidone in the management of severe chronic schizophrenia. Am J Psychiatry [Internet] 2001 Aug;158(8):1305–13. doi: 10.1176/appi.ajp.158.8.1305. [cited 2011 Jul 15] Available from: http://ajp.psychiatryonline.org/cgi/reprint/158/8/1305. [DOI] [PubMed] [Google Scholar]
  • 40.Claus A, Bollen J, DeCuyper H, Eneman M, Malfroid M, Peuskens J, et al. Risperidone versus haloperidol in the treatment of chronic schizophrenic inpatients: a multicentre double-blind comparative study. Acta Psychiatr Scand. 1992 Apr;85(4):295–305. doi: 10.1111/j.1600-0447.1992.tb01473.x. [DOI] [PubMed] [Google Scholar]
  • 41.Honer WG, MacEwan GW, Gendron A, Stip E, Labelle A, Williams R, et al. A randomized, double blind, placebo-controlled study of the safety and tolerability of high-dose quetiapine in patients with persistent symptoms of schizophrenia or schizoaffective disorder. J Clin Psychiatry. 2011 Jun 14; doi: 10.4088/JCP.10m06194. Epub ahead of print. [DOI] [PubMed] [Google Scholar]
  • 42.Leucht S, Kane JM, Kissling W, Hamann J, Etschel E, Engel RR. What does the PANSS mean? Schizophr Res. 2005 Nov 15;79(2–3):231–8. doi: 10.1016/j.schres.2005.04.008. [DOI] [PubMed] [Google Scholar]

Articles from CADTH Technology Overviews are provided here courtesy of Canadian Agency for Drugs and Technologies in Health

RESOURCES