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Figure 1.
PRISMA Diagram
PRISMA Diagram

The diagram illustrates the process of review and exclusion of studies.

Figure 2.
Network Plot for Mean Change in Overall Symptoms of Schizophrenia
Network Plot for Mean Change in Overall Symptoms of Schizophrenia

The size of the nodes corresponds to the number of trials that study the treatments. Directly comparable treatments are linked with a line; the thickness of the line corresponds to the number of trials that assess the comparison.

Figure 3.
Primary Outcome of Mean Score Reduction in Overall Symptoms of Schizophrenia
Primary Outcome of Mean Score Reduction in Overall Symptoms of Schizophrenia

Pairwise (upper right portion) and network (lower left portion) meta-analytic results are shown for the primary outcome. Drugs are reported in order of efficacy ranking, and outcomes are expressed as standardized mean differences (SMDs) (95% credible intervals). For the pairwise meta-analyses, SMDs of less than 0 indicate that the treatment specified in the row is more efficacious. For the network meta-analysis (NMA), SMDs of less than 0 indicate that the treatment specified in the column is more efficacious. Bold results indicate statistical significance. The overall heterogeneity (τ) is 0.11 for pairwise results and 0.08 for NMA results. To obtain SMDs for comparisons in the opposite direction, negative values should be converted into positive values and vice versa.

Figure 4.
Secondary Outcome of Response Rates
Secondary Outcome of Response Rates

Pairwise (upper right portion) and network (lower left portion) meta-analytic results are shown for the secondary outcome. Drugs are reported in order of efficacy ranking, and outcomes are expressed as odds ratios (ORs) (95% credible intervals). For the pairwise meta-analyses, ORs of greater than 1 indicate that the treatment specified on the row has more responders. For the network meta-analysis (NMA), ORs of greater than 1 indicate that the treatment specified in the column has more responders than the treatment on the row. Bold results indicate statistical significance. The overall heterogeneity (τ) is 0.27 for pairwise results and 0.30 for NMA results. To obtain ORs for comparisons in the opposite direction, reciprocals should be taken.

Figure 5.
Pairwise Meta-analysis of All Clozapine Trials per Comparator Drug
Pairwise Meta-analysis of All Clozapine Trials per Comparator Drug

The size of squares reflects the weight attributed to each study for every separate pairwise meta-analysis (per drug) and not vs all drugs combined. The diamonds illustrate the summary effect sizes (per separate drug and vs all drugs combined). The middle of each diamond sits on the value for the summary effect size, and the width of the diamond depicts the width of the overall CI. The last comparison (combined) presents the summary effect size for the pairwise meta-analysis of clozapine vs all other antipsychotics. Error bars indicate 95% CI; SMD, standardized mean difference.

1.
Hasan  A, Falkai  P, Wobrock  T,  et al; World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Treatment Guidelines for Schizophrenia.  World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance.  World J Biol Psychiatry. 2012;13(5):318-378.PubMedGoogle ScholarCrossref
2.
Barnes  TR; Schizophrenia Consensus Group of British Association for Psychopharmacology.  Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology.  J Psychopharmacol. 2011;25(5):567-620.PubMedGoogle ScholarCrossref
3.
Lehman  AF, Lieberman  JA, Dixon  LB,  et al; American Psychiatric Association; Steering Committee on Practice Guidelines.  Practice guideline for the treatment of patients with schizophrenia, second edition.  Am J Psychiatry. 2004;161(2)(suppl):1-56.PubMedGoogle Scholar
4.
Buchanan  RW, Kreyenbuhl  J, Kelly  DL,  et al; Schizophrenia Patient Outcomes Research Team (PORT).  The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements.  Schizophr Bull. 2010;36(1):71-93.PubMedGoogle ScholarCrossref
5.
Kane  JM, Honigfeld  G, Singer  J, Meltzer  H.  Clozapine in treatment-resistant schizophrenics.  Psychopharmacol Bull. 1988;24(1):62-67.PubMedGoogle Scholar
6.
Kane  J, Honigfeld  G, Singer  J, Meltzer  H.  Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine.  Arch Gen Psychiatry. 1988;45(9):789-796.PubMedGoogle ScholarCrossref
7.
Buchanan  RW, Breier  A, Kirkpatrick  B, Ball  P, Carpenter  WT  Jr.  Positive and negative symptom response to clozapine in schizophrenic patients with and without the deficit syndrome.  Am J Psychiatry. 1998;155(6):751-760.PubMedGoogle Scholar
8.
Rosenheck  R, Cramer  J, Xu  W,  et al; Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia.  A comparison of clozapine and haloperidol in hospitalized patients with refractory schizophrenia.  N Engl J Med. 1997;337(12):809-815.PubMedGoogle ScholarCrossref
9.
Chakos  M, Lieberman  J, Hoffman  E, Bradford  D, Sheitman  B.  Effectiveness of second-generation antipsychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of randomized trials.  Am J Psychiatry. 2001;158(4):518-526.PubMedGoogle ScholarCrossref
10.
Wahlbeck  K, Cheine  M, Essali  A, Adams  C.  Evidence of clozapine’s effectiveness in schizophrenia: a systematic review and meta-analysis of randomized trials.  Am J Psychiatry. 1999;156(7):990-999.PubMedGoogle Scholar
11.
Essali  A, Al-Haj Haasan  N, Li  C, Rathbone  J.  Clozapine versus typical neuroleptic medication for schizophrenia.  Cochrane Database Syst Rev. 2009;(1):CD000059.PubMedGoogle Scholar
12.
Leucht  S, Cipriani  A, Spineli  L,  et al.  Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis.  Lancet. 2013;382(9896):951-962.PubMedGoogle ScholarCrossref
13.
Asenjo Lobos  C, Komossa  K, Rummel-Kluge  C,  et al.  Clozapine versus other atypical antipsychotics for schizophrenia.  Cochrane Database Syst Rev. 2010;(11):CD006633.PubMedGoogle Scholar
14.
Leucht  S, Corves  C, Arbter  D, Engel  RR, Li  C, Davis  JM.  Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis.  Lancet. 2009;373(9657):31-41.PubMedGoogle ScholarCrossref
15.
Davis  JM, Chen  N, Glick  ID.  A meta-analysis of the efficacy of second-generation antipsychotics.  Arch Gen Psychiatry. 2003;60(6):553-564.PubMedGoogle ScholarCrossref
16.
McEvoy  JP, Lieberman  JA, Stroup  TS,  et al; CATIE Investigators.  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(4):600-610.PubMedGoogle ScholarCrossref
17.
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: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUTLASS 1).  Arch Gen Psychiatry. 2006;63(10):1079-1087.PubMedGoogle ScholarCrossref
18.
Higgins  JP, Welton  NJ.  Network meta-analysis: a norm for comparative effectiveness?  Lancet. 2015;386(9994):628-630.PubMedGoogle ScholarCrossref
19.
Cipriani  A, Higgins  JP, Geddes  JR, Salanti  G.  Conceptual and technical challenges in network meta-analysis.  Ann Intern Med. 2013;159(2):130-137.PubMedGoogle ScholarCrossref
20.
Leucht  S, Komossa  K, Rummel-Kluge  C,  et al.  A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia.  Am J Psychiatry. 2009;166(2):152-163.PubMedGoogle ScholarCrossref
21.
Elbourne  DR, Altman  DG, Higgins  JP, Curtin  F, Worthington  HV, Vail  A.  Meta-analyses involving cross-over trials: methodological issues.  Int J Epidemiol. 2002;31(1):140-149.PubMedGoogle ScholarCrossref
22.
Divine  GW, Brown  JT, Frazier  LM.  The unit of analysis error in studies about physicians’ patient care behavior.  J Gen Intern Med. 1992;7(6):623-629.PubMedGoogle ScholarCrossref
23.
Higgins  JPT, Green  S.  Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0. Chichester, England: Wiley & Sons; 2011.
24.
Bian  ZX, Li  YP, Moher  D,  et al.  Improving the quality of randomized controlled trials in Chinese herbal medicine, part I: clinical trial design and methodology.  Zhong Xi Yi Jie He Xue Bao. 2006;4(2):120-129.PubMedGoogle ScholarCrossref
25.
Wu  T, Li  Y, Bian  Z, Liu  G, Moher  D.  Randomized trials published in some Chinese journals: how many are randomized?  Trials. 2009;10:46.PubMedGoogle ScholarCrossref
26.
Kay  SR, Fiszbein  A, Opler  LA.  The Positive and Negative Syndrome Scale (PANSS) for schizophrenia.  Schizophr Bull. 1987;13(2):261-276.PubMedGoogle ScholarCrossref
27.
Overall  JE, Gorham  DR.  The Brief Psychiatric Rating Scale.  Psychol Rep. 1962;10:799-812.Google ScholarCrossref
28.
Guy  W.  ECDEU Assessment Manual for Psychopharmacology–Revised. Rockville, MD: US Dept of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute of Mental Health, Psychopharmacology Research Branch, Division of Extramural Research Programs; 1976:218-222. DHEW Publication ADM 76-338.
29.
Levine  SZ, Rabinowitz  J, Engel  R, Etschel  E, Leucht  S.  Extrapolation between measures of symptom severity and change: an examination of the PANSS and CGI.  Schizophr Res. 2008;98(1-3):318-322.PubMedGoogle ScholarCrossref
30.
Leucht  S, Kane  JM, Etschel  E, Kissling  W, Hamann  J, Engel  RR.  Linking the PANSS, BPRS, and CGI: clinical implications.  Neuropsychopharmacology. 2006;31(10):2318-2325.PubMedGoogle Scholar
31.
Leucht  S, Davis  JM, Engel  RR, Kane  JM, Wagenpfeil  S.  Defining ‘response’ in antipsychotic drug trials: recommendations for the use of scale-derived cutoffs.  Neuropsychopharmacology. 2007;32(9):1903-1910.PubMedGoogle ScholarCrossref
32.
DerSimonian  R, Laird  N.  Meta-analysis in clinical trials.  Control Clin Trials. 1986;7(3):177-188.PubMedGoogle ScholarCrossref
33.
Caldwell  DM, Ades  AE, Higgins  JP.  Simultaneous comparison of multiple treatments: combining direct and indirect evidence.  BMJ. 2005;331(7521):897-900.PubMedGoogle ScholarCrossref
34.
Dias  S, Sutton  AJ, Ades  AE, Welton  NJ.  Evidence synthesis for decision making 2: a generalized linear modeling framework for pairwise and network meta-analysis of randomized controlled trials.  Med Decis Making. 2013;33(5):607-617.PubMedGoogle ScholarCrossref
35.
Lunn  DJ, Thomas  A, Best  N, Spiegelhalter  D.  WinBUGS—a Bayesian modelling framework: concepts, structure, and extensibility.  Stat Comput. 2000;10:325-337.Google ScholarCrossref
36.
Higgins  JP, Green  S, Scholten  RJ. Maintaining reviews: updates, amendments and feedback. In: Higgins  JP, Green  S, eds.  Cochrane Handbook for Systematic Reviews of Interventions. Chichester, England: John Wiley & Sons Ltd; 2008:31-49.
37.
Salanti  G, Ades  AE, Ioannidis  JP.  Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial.  J Clin Epidemiol. 2011;64(2):163-171.PubMedGoogle ScholarCrossref
38.
Salanti  G.  Indirect and mixed-treatment comparison, network, or multiple-treatments meta-analysis: many names, many benefits, many concerns for the next generation evidence synthesis tool.  Res Synth Methods. 2012;3(2):80-97.PubMedGoogle ScholarCrossref
39.
Jansen  JP, Naci  H.  Is network meta-analysis as valid as standard pairwise meta-analysis? it all depends on the distribution of effect modifiers.  BMC Med. 2013;11:159.PubMedGoogle ScholarCrossref
40.
Chaimani  A, Higgins  JP, Mavridis  D, Spyridonos  P, Salanti  G.  Graphical tools for network meta-analysis in STATA.  PLoS One. 2013;8(10):e76654.PubMedGoogle ScholarCrossref
41.
Dias  S, Welton  NJ, Sutton  AJ, Caldwell  DM, Lu  G, Ades  AE.  Evidence synthesis for decision making 4: inconsistency in networks of evidence based on randomized controlled trials.  Med Decis Making. 2013;33(5):641-656.PubMedGoogle ScholarCrossref
42.
Song  F, Altman  DG, Glenny  AM, Deeks  JJ.  Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses.  BMJ. 2003;326(7387):472.PubMedGoogle ScholarCrossref
43.
Veroniki  AA, Vasiliadis  HS, Higgins  JP, Salanti  G.  Evaluation of inconsistency in networks of interventions.  Int J Epidemiol. 2013;42(1):332-345.PubMedGoogle ScholarCrossref
44.
Higgins  JPT, Jackson  D, Barrett  JK, Lu  G, Ades  AE, White  IR.  Consistency and inconsistency in network meta-analysis: concepts and models for multi-arm studies.  Res Synth Methods. 2012;3(2):98-110.PubMedGoogle ScholarCrossref
45.
Jackson  D, Barrett  JK, Rice  S, White  IR, Higgins  JP.  A design-by-treatment interaction model for network meta-analysis with random inconsistency effects.  Stat Med. 2014;33(21):3639-3654.PubMedGoogle ScholarCrossref
46.
White  IR, Barrett  JK, Jackson  D, Higgins  JPT.  Consistency and inconsistency in network meta-analysis: model estimation using multivariate meta-regression.  Res Synth Methods. 2012;3(2):111-125.PubMedGoogle ScholarCrossref
47.
Gardner  DM, Murphy  AL, O’Donnell  H, Centorrino  F, Baldessarini  RJ.  International consensus study of antipsychotic dosing.  Am J Psychiatry. 2010;167(6):686-693.PubMedGoogle ScholarCrossref
48.
Leucht  S, Samara  M, Heres  S,  et al.  Dose equivalents for second-generation antipsychotic drugs: the classical mean dose method.  Schizophr Bull. 2015;41(6):1397-1402.PubMedGoogle ScholarCrossref
49.
Leucht  S, Samara  M, Heres  S, Patel  MX, Woods  SW, Davis  JM.  Dose equivalents for second-generation antipsychotics: the minimum effective dose method.  Schizophr Bull. 2014;40(2):314-326.PubMedGoogle ScholarCrossref
50.
Chaimani  A, Salanti  G.  Using network meta-analysis to evaluate the existence of small-study effects in a network of interventions.  Res Synth Methods. 2012;3(2):161-176.PubMedGoogle ScholarCrossref
51.
Kane  JM, Meltzer  HY, Carson  WH  Jr, McQuade  RD, Marcus  RN, Sanchez  R; Aripiprazole Study Group.  Aripiprazole for treatment-resistant schizophrenia: results of a multicenter, randomized, double-blind, comparison study versus perphenazine.  J Clin Psychiatry. 2007;68(2):213-223.PubMedGoogle ScholarCrossref
52.
Howard  JS  III.  Haloperidol for chronically hospitalized psychotics: a double-blind comparison with thiothixene and placebo: a follow-up open evaluation.  Dis Nerv Syst. 1974;35(10):458-463.PubMedGoogle Scholar
53.
Honigfeld  G, Patin  J, Singer  J.  Clozapine: antipsychotic activity in treatment-resistant schizophrenics.  Adv Ther. 1984;1(2):77-97.Google Scholar
54.
Hall  WB, Vestre  ND, Schiele  BC, Zimmermann  R.  A controlled comparison of haloperidol and fluphenazine in chronic treatment-resistant schizophrenics.  Dis Nerv Syst. 1968;29(6):405-408.PubMedGoogle Scholar
55.
Browne  FWA, Cooper  SJ, Wilson  R, King  DJ.  Serum haloperidol levels and clinical response in chronic, treatment-resistant schizophrenic patients.  J Psychopharmacol. 1988;2(2):94-103.PubMedGoogle ScholarCrossref
56.
Azorin  JM, Spiegel  R, Remington  G,  et al.  A double-blind comparative study of clozapine and risperidone in the management of severe chronic schizophrenia.  Am J Psychiatry. 2001;158(8):1305-1313.PubMedGoogle ScholarCrossref
57.
Hong  CJ, Chen  JY, Chiu  HJ, Sim  CB.  A double-blind comparative study of clozapine versus chlorpromazine on Chinese patients with treatment-refractory schizophrenia.  Int Clin Psychopharmacol. 1997;12(3):123-130.PubMedGoogle ScholarCrossref
58.
Kane  JM, Marder  SR, Schooler  NR,  et al.  Clozapine and haloperidol in moderately refractory schizophrenia: a 6-month randomized and double-blind comparison.  Arch Gen Psychiatry. 2001;58(10):965-972.PubMedGoogle ScholarCrossref
59.
Volavka  J, Czobor  P, Sheitman  B,  et al.  Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder.  Am J Psychiatry. 2002;159(2):255-262.PubMedGoogle ScholarCrossref
60.
Bitter  I, Dossenbach  MR, Brook  S,  et al; Olanzapine HGCK Study Group.  Olanzapine versus clozapine in treatment-resistant or treatment-intolerant schizophrenia.  Prog Neuropsychopharmacol Biol Psychiatry. 2004;28(1):173-180.PubMedGoogle ScholarCrossref
61.
Conley  RR, Kelly  DL, Richardson  CM, Tamminga  CA, Carpenter  WT  Jr.  The efficacy of high-dose olanzapine versus clozapine in treatment-resistant schizophrenia: a double-blind crossover study.  J Clin Psychopharmacol. 2003;23(6):668-671.PubMedGoogle ScholarCrossref
62.
Meltzer  HY, Bobo  WV, Roy  A,  et al.  A randomized, double-blind comparison of clozapine and high-dose olanzapine in treatment-resistant patients with schizophrenia.  J Clin Psychiatry. 2008;69(2):274-285.PubMedGoogle ScholarCrossref
63.
Moresco  RM, Cavallaro  R, Messa  C,  et al.  Cerebral D2 and 5-HT2 receptor occupancy in schizophrenic patients treated with olanzapine or clozapine.  J Psychopharmacol. 2004;18(3):355-365.PubMedGoogle ScholarCrossref
64.
Naber  D, Riedel  M, Klimke  A,  et al.  Randomized double blind comparison of olanzapine vs. clozapine on subjective well-being and clinical outcome in patients with schizophrenia.  Acta Psychiatr Scand. 2005;111(2):106-115.PubMedGoogle ScholarCrossref
65.
Tollefson  GD, Birkett  MA, Kiesler  GM, Wood  AJ; Lilly Resistant Schizophrenia Study Group.  Double-blind comparison of olanzapine versus clozapine in schizophrenic patients clinically eligible for treatment with clozapine.  Biol Psychiatry. 2001;49(1):52-63.PubMedGoogle ScholarCrossref
66.
Bondolfi  G, Dufour  H, Patris  M,  et al; Risperidone Study Group.  Risperidone versus clozapine in treatment-resistant chronic schizophrenia: a randomized double-blind study.  Am J Psychiatry. 1998;155(4):499-504.PubMedGoogle ScholarCrossref
67.
Breier  AF, Malhotra  AK, Su  TP,  et al.  Clozapine and risperidone in chronic schizophrenia: effects on symptoms, parkinsonian side effects, and neuroendocrine response.  Am J Psychiatry. 1999;156(2):294-298.PubMedGoogle Scholar
68.
McGurk  SR, Carter  C, Goldman  R,  et al.  The effects of clozapine and risperidone on spatial working memory in schizophrenia.  Am J Psychiatry. 2005;162(5):1013-1016.PubMedGoogle ScholarCrossref
69.
Wahlbeck  K, Cheine  M, Tuisku  K, Ahokas  A, Joffe  G, Rimón  R.  Risperidone versus clozapine in treatment-resistant schizophrenia: a randomized pilot study.  Prog Neuropsychopharmacol Biol Psychiatry. 2000;24(6):911-922.PubMedGoogle ScholarCrossref
70.
Sacchetti  E, Galluzzo  A, Valsecchi  P, Romeo  F, Gorini  B, Warrington  L; MOZART Study Group.  Ziprasidone vs clozapine in schizophrenia patients refractory to multiple antipsychotic treatments: the MOZART study [published correction appears in Schizophr Res. 2010;121(1-3)281].  Schizophr Res. 2009;113(1):112-121.PubMedGoogle ScholarCrossref
71.
Altamura  AC, Velonà  I, Curreli  R, Mundo  E, Bravi  D.  Is olanzapine better than haloperidol in resistant schizophrenia? a double-blind study in partial responders.  Int J Psychiatry Clin Pract. 2002;6(2):107-111.PubMedGoogle ScholarCrossref
72.
AstraZeneca Clinical Trials. A multicentre, double-blind, randomised comparison of quetiapine (Seroquel) and chlorpromazine in the treatment of subjects with treatment-resistant schizophrenia. 5077IL/0031. http://www.astrazenecaclinicaltrials.com/Submission/View?id=988. Verified November 2013. Accessed March 14, 2014.
73.
AstraZeneca Clinical Trials. A multicentre, double-blind, randomised trial to compare the effects of seroquel and chlorpromazine in patients with treatment resistant schizophrenia [TRESS]. 5077IL/0054. http://www.astrazenecaclinicaltrials.com/Submission/View?id=994. Verified November 2013. Accessed March 14, 0214.
74.
Breier  A, Hamilton  SH.  Comparative efficacy of olanzapine and haloperidol for patients with treatment-resistant schizophrenia.  Biol Psychiatry. 1999;45(4):403-411.PubMedGoogle ScholarCrossref
75.
Buchanan  RW, Ball  MP, Weiner  E,  et al.  Olanzapine treatment of residual positive and negative symptoms.  Am J Psychiatry. 2005;162(1):124-129.PubMedGoogle ScholarCrossref
76.
Chen  JJ, Chan  HY, Chen  CH, Gau  SS, Hwu  HG.  Risperidone and olanzapine versus another first generation antipsychotic in patients with schizophrenia inadequately responsive to first generation antipsychotics.  Pharmacopsychiatry. 2012;45(2):64-71.PubMedGoogle ScholarCrossref
77.
Conley  RR, Tamminga  CA, Bartko  JJ,  et al.  Olanzapine compared with chlorpromazine in treatment-resistant schizophrenia.  Am J Psychiatry. 1998;155(7):914-920.PubMedGoogle ScholarCrossref
78.
Daniel  DG, Goldberg  TE, Weinberger  DR,  et al.  Different side effect profiles of risperidone and clozapine in 20 outpatients with schizophrenia or schizoaffective disorder: a pilot study.  Am J Psychiatry. 1996;153(3):417-419.PubMedGoogle ScholarCrossref
79.
Emsley  RA, Raniwalla  J, Bailey  PJ, Jones  AM; PRIZE Study Group.  A comparison of the effects of quetiapine (‘seroquel’) and haloperidol in schizophrenic patients with a history of and a demonstrated, partial response to conventional antipsychotic treatment.  Int Clin Psychopharmacol. 2000;15(3):121-131.PubMedGoogle ScholarCrossref
80.
Kane  JM, Khanna  S, Rajadhyaksha  S, Giller  E.  Efficacy and tolerability of ziprasidone in patients with treatment-resistant schizophrenia.  Int Clin Psychopharmacol. 2006;21(1):21-28.PubMedGoogle ScholarCrossref
81.
Kane  JM, Potkin  SG, Daniel  DG, Buckley  PF.  A double-blind, randomized study comparing the efficacy and safety of sertindole and risperidone in patients with treatment-resistant schizophrenia.  J Clin Psychiatry. 2011;72(2):194-204.PubMedGoogle ScholarCrossref
82.
Kinon  BJ, Kane  JM, Johns  C,  et al.  Treatment of neuroleptic-resistant schizophrenic relapse.  Psychopharmacol Bull. 1993;29(2):309-314.PubMedGoogle Scholar
83.
See  RE, Fido  AA, Maurice  M, Ibrahim  MM, Salama  GM.  Risperidone-induced increase of plasma norepinephrine is not correlated with symptom improvement in chronic schizophrenia.  Biol Psychiatry. 1999;45(12):1653-1656.PubMedGoogle ScholarCrossref
84.
Sirota  P, Pannet  I, Koren  A, Tchernichovsky  E.  Quetiapine versus olanzapine for the treatment of negative symptoms in patients with schizophrenia.  Hum Psychopharmacol. 2006;21(4):227-234.PubMedGoogle ScholarCrossref
85.
Smith  RC, Infante  M, Singh  A, Khandat  A.  The effects of olanzapine on neurocognitive functioning in medication-refractory schizophrenia.  Int J Neuropsychopharmacol. 2001;4(3):239-250.PubMedGoogle ScholarCrossref
86.
Wirshing  DA, Marshall  BD  Jr, Green  MF, Mintz  J, Marder  SR, Wirshing  WC.  Risperidone in treatment-refractory schizophrenia.  Am J Psychiatry. 1999;156(9):1374-1379.PubMedGoogle Scholar
87.
Conley  RR, Kelly  DL, Nelson  MW,  et al.  Risperidone, quetiapine, and fluphenazine in the treatment of patients with therapy-refractory schizophrenia.  Clin Neuropharmacol. 2005;28(4):163-168.PubMedGoogle ScholarCrossref
88.
US Department of Health and Human Services Food and Drug Administration Office of Regulatory Affairs. Guidance for industry: guideline for the monitoring of clinical investigations. http://www.ahc.umn.edu/img/assets/19826/Clinical%20monitoring.pdf. Published January 1988. Accessed October 24, 2014.
89.
Brunoni  AR, Tadini  L, Fregni  F.  Changes in clinical trials methodology over time: a systematic review of six decades of research in psychopharmacology.  PLoS One. 2010;5(3):e9479.PubMedGoogle ScholarCrossref
90.
Kane  JM, Correll  CU.  Past and present progress in the pharmacologic treatment of schizophrenia.  J Clin Psychiatry. 2010;71(9):1115-1124.PubMedGoogle ScholarCrossref
91.
Cohen  J.  Statistical Power Analysis for the Behavioral Sciences. 2nd ed. Hillsdale, NJ: Erlbaum; 1988.
92.
Essock  SM, Frisman  LK, Covell  NH, Hargreaves  WA.  Cost-effectiveness of clozapine compared with conventional antipsychotic medication for patients in state hospitals.  Arch Gen Psychiatry. 2000;57(10):987-994.PubMedGoogle ScholarCrossref
93.
Agid  O, Siu  CO, Potkin  SG,  et al.  Meta-regression analysis of placebo response in antipsychotic trials, 1970-2010.  Am J Psychiatry. 2013;170(11):1335-1344.PubMedGoogle ScholarCrossref
94.
Leucht  S, Arbter  D, Engel  RR, Kissling  W, Davis  JM.  How effective are second-generation antipsychotic drugs? a meta-analysis of placebo-controlled trials.  Mol Psychiatry. 2009;14(4):429-447.PubMedGoogle ScholarCrossref
95.
Rutherford  BR, Pott  E, Tandler  JM, Wall  MM, Roose  SP, Lieberman  JA.  Placebo response in antipsychotic clinical trials: a meta-analysis.  JAMA Psychiatry. 2014;71(12):1409-1421.PubMedGoogle ScholarCrossref
96.
Lewis  SW, Barnes  TR, 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(4):715-723.PubMedGoogle ScholarCrossref
97.
Nyakyoma  K, Morriss  R.  Effectiveness of clozapine use in delaying hospitalization in routine clinical practice: a 2 year observational study.  Psychopharmacol Bull. 2010;43(2):67-81.PubMedGoogle Scholar
98.
Ciudad  A, Haro  JM, Alonso  J,  et al.  The Schizophrenia Outpatient Health Outcomes (SOHO) study: 3-year results of antipsychotic treatment discontinuation and related clinical factors in Spain.  Eur Psychiatry. 2008;23(1):1-7.PubMedGoogle ScholarCrossref
99.
Schneider  C, Papachristou  E, Wimberley  T,  et al.  Clozapine use in childhood and adolescent schizophrenia: a nationwide population-based study.  Eur Neuropsychopharmacol. 2015;25(6):857-863.PubMedGoogle ScholarCrossref
100.
Tiihonen  J, Lönnqvist  J, Wahlbeck  K,  et al.  11-Year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study).  Lancet. 2009;374(9690):620-627.PubMedGoogle ScholarCrossref
101.
Ringbäck Weitoft  G, Berglund  M, Lindström  EA, Nilsson  M, Salmi  P, Rosén  M.  Mortality, attempted suicide, re-hospitalisation and prescription refill for clozapine and other antipsychotics in Sweden: a register-based study.  Pharmacoepidemiol Drug Saf. 2014;23(3):290-298.PubMedGoogle ScholarCrossref
102.
Davis  JM, Chen  N.  Dose response and dose equivalence of antipsychotics.  J Clin Psychopharmacol. 2004;24(2):192-208.PubMedGoogle ScholarCrossref
103.
Kinon  BJ, Ahl  J, Stauffer  VL, Hill  AL, Buckley  PF.  Dose response and atypical antipsychotics in schizophrenia.  CNS Drugs. 2004;18(9):597-616.PubMedGoogle ScholarCrossref
104.
Simpson  GM, Josiassen  RC, Stanilla  JK,  et al.  Double-blind study of clozapine dose response in chronic schizophrenia.  Am J Psychiatry. 1999;156(11):1744-1750.PubMedGoogle Scholar
105.
Thompson  SG, Higgins  JP.  How should meta-regression analyses be undertaken and interpreted?  Stat Med. 2002;21(11):1559-1573.PubMedGoogle ScholarCrossref
106.
Zhang  JP, Gallego  JA, Robinson  DG, Malhotra  AK, Kane  JM, Correll  CU.  Efficacy and safety of individual second-generation vs first-generation antipsychotics in first-episode psychosis: a systematic review and meta-analysis.  Int J Neuropsychopharmacol. 2013;16(6):1205-1218.PubMedGoogle ScholarCrossref
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    1 Comment for this article
    EXPAND ALL
    Other Atypicals are Not Equivalent to Clozapine
    Jeffrey A. Mattes, M.D. | Psychopharmacology Research Association of Princeton
    “First do no harm”. But the article by Samara et al (1) suggesting that clozapine may be no better than some other atypicals may do great harm to patients who might benefit from clozapine. At a time when many prominent psychiatrists are decrying inadequate use of clozapine in the U.S. (2), this article is counterproductive.

    The authors mention many caveats regarding their study, however, some issues they don’t discuss sufficiently invalidate their conclusions:

    1) Companies making other atypicals have at times attempted to show that their drugs are better than typical neuroleptics for
    refractory patients (references are in the Samara article). Unlike with clozapine, these studies did not show benefit, which is why clozapine is the only drug FDA approved for treatment refractory illness.

    2) Companies also tried to show that clozapine was not better than their atypicals. To do a study of this type “properly”, one would have a group assigned to a typical neuroleptic, in addition to groups assigned to clozapine and the other atypical. This would establish “assay sensitivity” since, for the study to be meaningful, it would have to show (as has been shown before) that clozapine is better than the typical agent (similarly, new antidepressants are typically compared both to a standard antidepressant and to placebo; for the study to be meaningful, the standard antidepressant has to be better than placebo). Admittedly, such studies are difficult to do, but a study without a typical neuroleptic, is not particularly meaningful. Apparent (but not true) equivalence can be caused by many factors, e.g., if patients studied are not truly treatment refractory, or if ratings are not sufficiently reliable. High dropout rates, poor compliance, and a multitude of other factors would all tend to increase the chance of finding no difference between groups. A study only comparing clozapine to another atypical which shows equivalence, especially if it is funded by a drug company making the other atypical, should be given little credence. D’Agostino et al. (3) and Kaul et al. (4) discuss the difficulties in interpreting non-inferiority trials.

    3) The authors don’t mention the many reports of attempts to change patients from clozapine to other atypicals, which document how difficult this change is, with frequent relapses (5).

    4) This article should not be justification for psychiatrists not using clozapine because “there’s no evidence that it’s better than some other atypicals”. Refractory patients should be tried on clozapine.

    Sincerely,

    Jeffrey A. Mattes, M.D.


    References:

    (1) Samara MT, Dold M, Gianatsi M, et al. Efficacy, Acceptability, and Tolerability of
    Antipsychotics in Treatment-Resistant Schizophrenia. JAMA Psychiatry. 2016;73(3):199-210.

    (2) Stroup TS, Gerhard T, Crystal S, et al. Geographic and Clinical Variation in Clozapine Use in
    the United States. Psychiatric Services. 2014 Feb;65(2):186-192.

    (3) Agostino RB, Massaro JM, Sullivan LM. Non-inferiority trials: design concepts and issues – the encounters of academic consultants in statistics. Statist. Med. 2003;22:169-186.

    (4) Kaul S, Diamond GA, Weintraub WS. Trials and Tribulations of Non-Inferiority. J Am Coll
    Cardiol. 2005;46(11):1986-1995.

    (5) Atkinson JM, Douglas-Hall P, Fischetti C, et al. Outcome following clozapine discontinuation: a retrospective analysis. J Clin Psychiatry. 2007 Jul;68(7):1027-30.

    CONFLICT OF INTEREST: None Reported
    READ MORE
    Original Investigation
    Meta-analysis
    March 2016

    Efficacy, Acceptability, and Tolerability of Antipsychotics in Treatment-Resistant Schizophrenia: A Network Meta-analysis

    Author Affiliations
    • 1Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany
    • 2Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria
    • 3Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
    • 4Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
    • 5Berner Institut für Hausarztmedizin, University of Bern, Bern, Switzerland
    • 6CTU Bern (Clinical Trials Unit), Department of Clinical Research, University of Bern, Bern, Switzerland
    JAMA Psychiatry. 2016;73(3):199-210. doi:10.1001/jamapsychiatry.2015.2955
    Abstract

    Importance  In treatment-resistant schizophrenia, clozapine is considered the standard treatment. However, clozapine use has restrictions owing to its many adverse effects. Moreover, an increasing number of randomized clinical trials (RCTs) of other antipsychotics have been published.

    Objective  To integrate all the randomized evidence from the available antipsychotics used for treatment-resistant schizophrenia by performing a network meta-analysis.

    Data Sources  MEDLINE, EMBASE, Biosis, PsycINFO, PubMed, Cochrane Central Register of Controlled Trials, World Health Organization International Trial Registry, and clinicaltrials.gov were searched up to June 30, 2014.

    Study Selection  At least 2 independent reviewers selected published and unpublished single- and double-blind RCTs in treatment-resistant schizophrenia (any study-defined criterion) that compared any antipsychotic (at any dose and in any form of administration) with another antipsychotic or placebo.

    Data Extraction and Synthesis  At least 2 independent reviewers extracted all data into standard forms and assessed the quality of all included trials with the Cochrane Collaboration’s risk-of-bias tool. Data were pooled using a random-effects model in a Bayesian setting.

    Main Outcomes and Measures  The primary outcome was efficacy as measured by overall change in symptoms of schizophrenia. Secondary outcomes included change in positive and negative symptoms of schizophrenia, categorical response to treatment, dropouts for any reason and for inefficacy of treatment, and important adverse events.

    Results  Forty blinded RCTs with 5172 unique participants (71.5% men; mean [SD] age, 38.8 [3.7] years) were included in the analysis. Few significant differences were found in all outcomes. In the primary outcome (reported as standardized mean difference; 95% credible interval), olanzapine was more effective than quetiapine (−0.29; −0.56 to −0.02), haloperidol (−0. 29; −0.44 to −0.13), and sertindole (−0.46; −0.80 to −0.06); clozapine was more effective than haloperidol (−0.22; −0.38 to −0.07) and sertindole (−0.40; −0.74 to −0.04); and risperidone was more effective than sertindole (−0.32; −0.63 to −0.01). A pattern of superiority for olanzapine, clozapine, and risperidone was seen in other efficacy outcomes, but results were not consistent and effect sizes were usually small. In addition, relatively few RCTs were available for antipsychotics other than clozapine, haloperidol, olanzapine, and risperidone. The most surprising finding was that clozapine was not significantly better than most other drugs.

    Conclusions and Relevance  Insufficient evidence exists on which antipsychotic is more efficacious for patients with treatment-resistant schizophrenia, and blinded RCTs—in contrast to unblinded, randomized effectiveness studies—provide little evidence of the superiority of clozapine compared with other second-generation antipsychotics. Future clozapine studies with high doses and patients with extremely treatment-refractory schizophrenia might be most promising to change the current evidence.

    Introduction

    As many as one-third of patients with schizophrenia experience persistent psychotic symptoms despite adequate treatment with antipsychotics.1 At present, clozapine is considered the standard treatment for patients with refractory forms of schizophrenia, which has been codified in international guidelines.1-4 Unanimity concerning the superiority of clozapine is based mainly on the landmark study by Kane et al5,6 that resulted in an impressive effect size of clozapine compared with chlorpromazine hydrochloride and led to clozapine’s reintroduction in clinical practice. Although subsequent comparisons7,8 with first-generation antipsychotics (FGAs) showed smaller effect sizes than the dramatic superiority in the study by Kane et al,5,6 the superiority of clozapine compared with FGAs for treatment-resistant schizophrenia has been corroborated by an early meta-analysis of 12 trials9 and a Cochrane review.10,11 Moreover, researchers12 found that clozapine was the most efficacious antipsychotic in a network meta-analysis (NMA) of trials for treatment of nonrefractory schizophrenia, but the superiority was again driven by old comparisons with FGAs. Indeed, in a Cochrane review using a simple pairwise meta-analysis,13 clozapine was not more efficacious than the second-generation antipsychotics (SGAs) olanzapine, risperidone, or ziprasidone.

    The reintroduction of clozapine led to the development of numerous other SGAs, some of which showed superior efficacy in meta-analyses not restricted to patients with treatment-resistant disease.12,14,15 Moreover, effectiveness studies suggested that some older agents, such as perphenazine16 or sulpiride,17 might be as efficacious as SGAs, but their effects in treatment-resistant schizophrenia are unknown. Given the restrictions of clozapine use owing to its many adverse effects, such as agranulocytosis, metabolic problems, or sedation, and in light of a continuously increasing number of randomized clinical trials (RCTs) of other SGAs, a new systematic review and meta-analysis on the effects of the various antipsychotics in treatment-resistant schizophrenia appeared to be necessary.

    Quiz Ref IDIn an attempt to integrate all the evidence from the available antipsychotics in treatment-resistant schizophrenia, we performed simple pairwise meta-analyses and an NMA (also called a multiple-treatments meta-analysis), a technique that allows the comparison of the relative effectiveness among all antipsychotics that have been examined in at least 1 trial. A particular advantage of this technique is that one can obtain an effect estimate for the relative effectiveness between 2 interventions, even if they have not been compared directly in any trial, as long as they are part of a connected network.18,19 This technique uses indirect comparison of the 2 treatments of interest via 1 or more intermediate comparators. Moreover, even when outcome data for a particular comparison exist, the use of all available information, direct and indirect, renders the effect estimate more precise than the pairwise meta-analysis counterpart. Such advantages have established NMA as a powerful evidence synthesis tool, and its use is crucial in health care areas where many drugs are available, such as in treatment-resistant schizophrenia.

    Box Section Ref ID

    Key Points

    • Question: What is the most effective and acceptable antipsychotic for treatment-resistant schizophrenia?

    • Findings: A certain pattern of superiority was found for olanzapine, clozapine, and risperidone in various efficacy outcomes, such as mean change in overall and positive symptoms, response rates, and dropouts owing to inefficacy, but treatment efficacy differences were not definitive and clozapine was no more efficacious than most other second-generation antipsychotics. Although substantial evidence was available for clozapine, haloperidol, olanzapine, and risperidone, data on the other included antipsychotics were limited.

    • Meaning: Insufficient evidence exists on which antipsychotic is more efficacious for patients with treatment-resistant schizophrenia.

    Methods
    Participants and Interventions

    An a priori written study protocol can be found in eAppendix 1 in the Supplement. Quiz Ref IDOur analysis included all single- and double-blind RCTs of adult patients with a treatment-resistant form of schizophrenia, schizophreniform disorder, or schizoaffective disorder. We planned a subgroup analysis a priori based on the degree of treatment resistance (discussed below in the Statistical Analysis subsection). All worldwide available antipsychotics, at any dose and in any form of administration that were compared with another antipsychotic or placebo, were included if the antipsychotics were used as monotherapy. Minimum duration of RCTs was set at 3 weeks. Institutional review board approval was not necessary for this review.

    Search Strategy and Selection Criteria

    We identified RCTs in patients with treatment-resistant schizophrenia through a comprehensive, systematic literature search in MEDLINE, EMBASE, Biosis, PsycINFO, PubMed, Cochrane Central Register of Controlled Trials, World Health Organization International Trial Registry, and clinicaltrials.gov up to June 30, 2014 (eAppendix 2 in the Supplement). Moreover, we inspected the reference lists of the included studies and previous reviews on antipsychotics in general schizophrenia.12,13,15,20 We included published and unpublished blinded RCTs because unblinded trials systematically favored SGAs in a previous analysis.14 In the case of crossover studies, we only used the first crossover phase to avoid the problem of carryover effects.21 We excluded cluster-randomized trials.22 Furthermore, studies that demonstrated a high risk for bias for sequence generation or allocation concealment were excluded.23 If a trial was described as double-blind but randomization was not explicitly mentioned, we assumed that study participants were randomized, and we excluded the trial in a sensitivity analysis. Study quality was independently assessed by 2 reviewers (M.D. and B.H.), who used the Cochrane Collaboration’s risk-of-bias tool.23

    We excluded studies from mainland China to avoid a systematic bias because many of these studies do not use appropriate randomization procedures and do not report their methods.24,25 We sent emails to the first and corresponding authors of all included studies to ask for missing data.

    Outcome Measures and Data Extraction

    The primary outcome was the mean change from baseline to end point in overall symptoms of schizophrenia as measured by the Positive and Negative Syndrome Scale (PANSS),26 the Brief Psychiatric Rating Scale,27 or any other validated scale for the assessment of overall schizophrenia symptoms. If change data were not available, we used the mean score at study end point of these scales. Intention-to-treat data sets were used whenever available.

    Secondary outcome was a clinically important response to treatment that was defined primarily as at least a 20% reduction of PANSS or Brief Psychiatric Rating Scale score or at least minimal improvement on the Clinical Global Impressions Scale.28,29 In patients with treatment-resistant schizophrenia, even a slight improvement might represent a clinically significant effect, justifying the use of the 20% cutoff, which roughly corresponds to at least minimal improvement on the Clinical Global Impressions Scale.30 For the typical patient with acute schizophrenia, the 50% cutoff, corresponding to much improvement on the Clinical Global Impressions Scale, might be preferable.31 Other secondary outcomes were the mean change in positive and negative symptoms of schizophrenia, dropouts owing to any reason (all-cause discontinuation), dropouts owing to inefficacy of treatment, the occurrence of important adverse effects (ie, weight gain, extrapyramidal symptoms, and sedation), quality of life, ability to work, and economic outcomes.

    Study selection and data extraction were performed independently by at least 2 reviewers (M.T.S., M.D., B.H., and S.L.). Missing SDs were estimated from P values or substituted by the mean SD of the other included studies.

    Statistical Analysis

    Data were analyzed from October 13, 2014, to March 3, 2015. We performed pairwise meta-analyses and NMA in a Bayesian setting using WinBUGs.32-35 We used the random-effects model and assumed common heterogeneity across all comparisons. For continuous outcomes, the effect sizes were calculated as Hedges adjusted g standardized mean differences (SMDs).36 For binary outcomes, the effect sizes were calculated as odds ratios (ORs). Both types of effect sizes were presented along with their 95% credible intervals (CRIs). To enhance understandability, SMDs were also transformed in original units and ORs in numbers needed to benefit (NNTB) and numbers needed to harm (NNTH), which were estimated with the mean occurrence of an outcome as the baseline risk. The NMA combined direct and indirect evidence of all relative treatment effects, provided estimates with maximum power, and allowed the ranking of the various antipsychotics based on the surface under the cumulative ranking and the mean ranks.37

    The assumption underlying the performance of NMA is transitivity, which suggests that all pairwise comparisons in the network do not differ with respect to the distribution of effect modifiers.19,38,39 Important intransitivity might be manifested in the data as inconsistency between direct and indirect evidence. Consistency was assessed by calculating the difference between direct and indirect treatment effects in all closed loops and assuming loop-specific heterogeneity.40-43 The magnitude of inconsistency factors and their respective P values were used to examine the presence of inconsistency in each loop; we judged loops to be inconsistent with a significant disagreement between direct and indirect evidence (P < .10). To assess the evidence of inconsistency in the entire network, we used the design-by-treatment model,44-46 which enabled us to examine the presence of loop and design inconsistency.

    To assess the effect of potential moderator and quality variables on the primary outcome, we planned several metaregression, subgroup, and sensitivity analyses in advance. In separate network metaregression models, the variables’ publication date, quality of randomization and allocation concealment, dose of antipsychotics in chlorpromazine equivalents,47 and severity of illness at baseline were included as covariates. Other analyses were added post hoc, including the dose of antipsychotics using 2 alternative methods to calculate chlorpromazine equivalents,48,49 dose of clozapine, trial duration, and study sponsorship.

    The definition of treatment resistance varied across studies. In a preplanned subgroup analysis, the included studies were classified into the following 3 groups according to the applied criteria for defining treatment resistance: (1) no response to 1 previous antipsychotic, (2) no response to at least 2 retrospective periods of antipsychotic treatment, and (3) no response to a combination of retrospective and prospective criteria for treatment resistance.

    In preplanned sensitivity analyses, we used the fixed-effect model, and we excluded trials with only completer data, trials that included patients who previously demonstrated treatment intolerance, trials that did not apply operationalized criteria to diagnose schizophrenia, and single-blind trials. In a post hoc sensitivity analysis, we performed pairwise meta-analyses and NMA for the primary outcome that included 5 studies published before 1990 that had to be excluded from the main analysis because they led to inconsistency (described in the Consistency of the Network subsection of the Results). The motivation underlying this sensitivity analysis was to show the full evidence of antipsychotic efficacy and to justify that the decision to exclude studies conducted before 1990 in the main analysis did not introduce bias. Other post hoc sensitivity analyses involved the exclusion of trials with a high risk for attrition bias and those with a high risk for reporting bias.

    We investigated the presence of small-study effects for the primary outcome to assess whether important differences in treatment effect estimates were found between precise and imprecise studies. We produced 2 comparison-adjusted funnel plots; comparisons have been directed according to the age and effectiveness of the treatments, assuming that newer and more effective treatments, respectively, are favored in small trials.40,50 Potential asymmetry would indicate a form of small-study effects depending on the defined direction, whereas symmetry in the funnel plot would indicate a lack of evidence of small-study effects.

    Results
    Description of Included Studies

    We identified 40 unique blinded RCTs 6-8,51-87 with 5172 unique participants published from 1968 to March 2012 through the literature search. The PRISMA flowchart is shown in Figure 1 and with details of all included studies in eAppendix 3 in the Supplement. Of 4813 patients with sex indicated, 3442 were men (71.5%). The mean (SD) age of participants was 38.8 (3.7) years; the mean (SD) duration of illness, 16.2 (4.3) years; and the mean (SD) number of previous hospitalizations, 6.9 (3.1). The median trial duration was 11 weeks. The assessment of risk for bias is presented in eAppendix 4 in the Supplement. Overall, the trial reports often did not provide details about randomization procedures and allocation concealment; 4 studies69,76,78,84 were single-blind and the remaining were double-blind. The mean dropout rate was 30.2% for the studies included in our analysis, and we found some indication of selective reporting in 18 studies (45.0%). Figure 2 shows the network of eligible comparisons for the primary outcome; network plots for secondary outcomes are presented in eAppendix 5 in the Supplement. The mean dose of the 12 antipsychotics included in the analysis was 794 mg/d in chlorpromazine equivalents.47 The drug involved in most comparisons was clozapine (20 of 40 trials), followed by haloperidol (15 of 40 trials), olanzapine (14 of 40 trials), and risperidone (12 of 40 trials), whereas few trials were available for most other drugs. Three antipsychotics (aripiprazole, perphenazine, and thiothixene hydrochloride), although included in the systematic review, were not included in the meta-analysis because one of the 2 relevant studies was not connected to the network51 and the other52 did not provide usable data (further explanations can be found in eAppendix 3 in the Supplement).

    Consistency of the Network

    When we integrated the evidence from all trials in the NMA, we found a severe inconsistency between direct and indirect evidence (eAppendix 6 in the Supplement). Inspection of the data showed that the inconsistency was owing to 3 loops that included 2 older studies published before 1990.5,6,53 Because the methods of antipsychotic trials changed greatly88-90 after the study by Kane et al,5,6 cohort effects were the most likely explanation (explained in detail below in the Discussion section). Because consistency (transitivity) is a central assumption of NMA, we had to remove the 5 trials published5,6,52-55 before 1990 from the network of all outcomes post hoc, which resolved the inconsistency in all outcomes (P > .10). Assessment of inconsistency is presented in detail in eAppendix 7 in the Supplement. Moreover, we performed a sensitivity analysis of the primary outcome, including all trials (described in the Sensitivity Analyses of the Primary Outcome subsection below and eAppendix 6 in the Supplement).

    Primary Outcome

    The results of the pairwise meta-analysis and the NMA for the primary outcome, mean change in overall symptoms, are summarized in Figure 3. The surface under the cumulative ranking is given in eAppendix 8 in the Supplement. Drugs are reported in Figure 3 in order of their efficacy ranking. As a rule of thumb, Cohen91 recommended that an SMD of –0.20 is small, −0.50 is medium, and −0.80 is large. Few statistically significant differences were found. In the simple pairwise meta-analytic comparisons, only olanzapine was significantly better than haloperidol (SMD, −0.29, corresponding to −6.08 PANSS points; 95% CRI, −0.53 to −0.06) based on 4 studies59,71,74,75 (693 participants). Quiz Ref IDIn the NMA, olanzapine was significantly more effective than quetiapine fumarate (SMD, −0.29, corresponding to −6.08 PANSS points; CRI, −0.56 to −0.02), haloperidol (SMD, −0. 29, corresponding to −6.08 PANSS points; CRI, −0.44 to −0.13), and sertindole (SMD, −0.46, corresponding to −9.64 PANSS points; 95% CRI, −0.80 to −0.06); clozapine was significantly more effective than haloperidol (SMD, −0.22, corresponding to −4. 61 PANSS points; 95% CRI, −0.38 to −0.07) and sertindole (SMD, −0.40, corresponding to −8.39 PANSS points; 95% CRI, −0.74 to −0.04); and risperidone was significantly more effective than sertindole (SMD, −0.32, corresponding to −6.71 PANSS points; 95% CRI, −0.63 to −0.01). In terms of rankings, olanzapine was ranked first, followed by ziprasidone and clozapine, but results for ziprasidone were based on only 2 studies70,80 (n = 453) and did not show a significant difference compared with any other antipsychotic (Figure 3).

    Positive and Negative Symptoms

    Results for the secondary outcome, reduction in positive symptoms, are shown in eAppendix 9 in the Supplement. In pairwise comparisons, only risperidone was statistically significantly better than fluphenazine hydrochloride and quetiapine (SMDs, −0.73 [95% CRI, −1.48 to −0.02] and −0.93 [95% CRI, −1.72 to −0.11], respectively; corresponding to −5.16 and −6.57 PANSS points, respectively) based on a single small trial with 38 participants.87 In the NMA, risperidone, clozapine, and olanzapine were significantly more efficacious than quetiapine (SMDs, −0.43 [95% CRI, −0.81 to −0.09], −0.40 [95% CRI, −0.75 to −0.09], and −0.33 [95% CRI, −0.67 to −0.01], respectively, corresponding to −3.04, −2.83, and −2.33 PANSS points, respectively). In addition, risperidone and clozapine were significantly more efficacious than haloperidol (SMDs, −0.29 [95% CRI, −0.54 to −0.07] and −0.27 [95% CRI, −0.46 to −0.09], respectively, corresponding to −2.05 and −1.91 PANSS points, respectively).

    Results for the secondary outcome, reduction in negative symptoms, are shown in eAppendix 9 in the Supplement. In pairwise comparisons, olanzapine was significantly more efficacious than risperidone (SMD, −0.43, corresponding to −2.42 PANSS points; 95% CRI, −0.84 to −0.02) and haloperidol (SMD, −0.26, corresponding to −1.46 PANSS points; 95% CRI, −0.50 to −0.02). In the NMA, olanzapine was better than clozapine (SMD, −0.14, corresponding to −0.79 PANSS points; 95% CRI, -0.30 to -0.01), risperidone (SMD, −0.24, corresponding to −1.35 PANSS points; 95% CRI, −0.44 to −0.02), haloperidol (SMD, −0.24, corresponding to −1.35 PANSS points; 95% CRI, −0.40 to −0.04), chlorpromazine (SMD, −0.26, corresponding to −1.46 PANSS points; 95% CRI, −0.51 to −0.02), and sertindole (SMD, −0.44, corresponding to −2.48 PANSS points; 95% CRI, −0.81 to −0.08). Ziprasidone was better than chlorpromazine (SMD, −0.26, corresponding to −1.46 PANSS points; 95% CRI, −0.53 to −0.04) and sertindole (SMD, −0.44, corresponding to −2.48 PANSS points; 95% CRI, −0.88 to −0.01).

    Categorical Response to Treatment

    The ORs for the secondary outcome, categorical response to treatment, are presented in Figure 4. In the pairwise comparisons, findings were significantly better for risperidone (OR, 9.68; 95% CRI, 1.11-183.46) and clozapine (OR 1.86; 95% CRI, 1.01-4.00) compared with haloperidol. Quiz Ref IDIn the network comparisons, significantly better results were found for risperidone (OR, 2.27; 95% CRI, 1.11-4.73), clozapine (OR, 2.09; 95% CRI, 1.26-3.82), and olanzapine (OR, 2.00; 95% CRI, 1.16-3.76) compared with haloperidol (NNTBs, 7, 8, and 8, respectively).

    Discontinuation

    Treatment discontinuation owing to all causes was used as a measure of acceptability. Results are shown in eAppendix 9 in the Supplement. In pairwise comparisons, only olanzapine was better than haloperidol (OR, 0.52; 95% CRI, 0.24-0.97). In the NMA, no difference among antipsychotics was found apart from olanzapine being better than haloperidol (OR, 0.56; 95% CRI, 0.33-0.87; NNTH, 9) and fluphenazine (OR, 0.24; 95% CRI, 0.03-0.87; NNTH, 5).

    In pairwise comparisons of discontinuation owing to inefficacy, clozapine was better than risperidone (OR, 0.32; 95% CRI, 0.14-0.81) and haloperidol (OR, 0.18; 95% CRI, 0.08-0.46), and olanzapine was better than haloperidol (OR, 0.32; 95% CRI, 0.10-0.99). In the NMA, clozapine was better than risperidone, quetiapine, haloperidol, and fluphenazine (OR range, 0.44 [95% CRI, 0.19-0.91] to 0.08 [95% CRI, 0.01-0.35]; NNTH range, 6-10); chlorpromazine and olanzapine were better than haloperidol and fluphenazine (OR range, 0.04 [95% CRI, 0.01-0.76] to 0.27 [95% CRI, 0.11-0.60]; NNTH range, 5-7); and risperidone was better than fluphenazine (OR, 0.19; 95% CRI, 0.02-0.81; NNTH, 7) (eAppendix 9 in the Supplement).

    Adverse Events

    Few significant differences were found in terms of adverse events (eAppendix 9 in the Supplement). As expected, the patterns were generally consistent with the previous NMA12 in patients with non–treatment-resistant schizophrenia, but fewer findings were statistically significant, which may be attributed to the lower number of included participants.

    Other Outcomes

    Only 5 studies8,51,72,75,87 provided data on quality of life. The pairwise meta-analysis did not indicate any significant difference among antipsychotics (eAppendix 9 in the Supplement), whereas conducting an NMA was not feasible. No data were available for ability to work and economic outcomes.

    Sensitivity Analyses of the Primary Outcome

    The most important sensitivity analysis was the inclusion of the 5 old studies5,6,52-55 that were excluded from the primary analysis owing to a violation of the consistency assumption. Including these trials did not change the results much (eAppendix 6 in the Supplement). The only change in pairwise comparisons was that clozapine was now significantly better than chlorpromazine (sensitivity analysis SMD, −0.74 [95% CRI, −0.99 to −0.49] vs main analysis SMD, −0.44 [95% CRI, −1.10 to 0.22]). In the NMA, the main change was a few differences in terms of statistical significance. Olanzapine was ranked first as in the main analysis, whereas clozapine was ranked second compared with third in the main analysis, but clozapine was still not significantly superior to all other SGAs. In the remaining sensitivity analyses, SMDs and rankings did not change considerably, or so few studies remained that hardly any result was significant (eAppendix 10 in the Supplement).

    Subgroup and Metaregression Analyses for the Primary Outcome

    For the degree of treatment resistance, the 3 subgroups of studies based on the criteria for defining treatment resistance (described in the Statistical Analysis subsection of the Methods section) were formed. No significant efficacy difference was shown among antipsychotics in any of these subgroups, probably because the available data per group were less than that of the main analysis (eAppendix 10 in the Supplement). Similar results were obtained when all trials, irrespective of their publication date, were included in this subgroup analysis (eAppendix 6 in the Supplement).

    Moreover, we found no significant effects in metaregressions examining the impact of the possible effect modifiers (eAppendix 10 in the Supplement), but these analyses also had limited statistical power, and any interpretation should be made with great caution.

    Small-Study Effects, Original Units, NNTBs, and NNTHs

    We found no evidence of small-study effects for the primary outcome (eAppendix 11 in the Supplement). The SMDs back transformed to original units, and NNTBs, and NNTHs can be found in eAppendices 12 and 13 in the Supplement.

    Discussion

    We compared the effects of all antipsychotics in patients with treatment-resistant schizophrenia using pairwise meta-analyses and NMA. Olanzapine, clozapine, and risperidone were found to be significantly better than some other antipsychotics in various efficacy outcomes, but the results were not consistent and the effect sizes were usually small. The most surprising finding was that clozapine was not significantly more efficacious than most other drugs.

    Clozapine’s superiority was originally demonstrated in a pivotal study5,6 in which it was clearly superior to chlorpromazine in treatment-resistant schizophrenia. Although some subsequent comparisons with FGAs were also statistically significant8,92 and although the superiority to FGAs has been confirmed by meta-analyses,9-11 the effect size of the original study by Kane et al5,6 (−0.88) has never been replicated. Quiz Ref IDFigure 5 presents the results of all single-comparison clozapine trials5-8,53,56-70 and illustrates that, of 21 comparisons, only 2 old studies compared with chlorpromazine,5,6,53 1 study compared with haloperidol,8 and 1 study compared with risperidone56 showed a significant superiority; thus, the failure to find clozapine superior is not an artifact of NMA. The 2 old studies5,6,53 led to a high inconsistency in the NMA, violating a key assumption of the method. We speculate that the inconsistency is in part owing to cohort effects in terms of the periods when these studies were performed because some evidence suggests that the clinical trial quality of psychopharmacologic studies changed significantly after 1990.89,90 This finding is also evident, among others, by an increasing placebo response93 and smaller drug-placebo differences.94,95 Nevertheless, when all trials, irrespective of their publication date, were included, results of the NMA did not substantially differ (eAppendix 6 in the Supplement).

    Owing to several limitations, our NMA is not definitive. Clozapine was superior in 3 large effectiveness studies16,92,96 that could not be included. Essock et al92 published a large cost-effectiveness study in which clozapine was superior to the group of FGAs in many measures of effectiveness, but the study was unblinded. Similarly, in phase 2 of the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE),16 clozapine was shown to be more effective than risperidone and quetiapine, but clozapine was the only open-label treatment arm. In the Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study Band 2 (CUTLASS 2),96 clozapine was found to be more effective than other SGAs as a group, but again the trial was unblinded and comparisons with individual SGAs were not presented. One could claim that, in open-label studies, expectation bias could be a reason for clozapine’s superiority, but results from real-world observational studies97,98 and population-based register studies99-101 confirm this finding, even regarding hard end points such as hospitalization and number of inpatient days. In these studies, better monitoring of patients receiving clozapine (eg, regular blood tests) is a possible bias. Therefore, another possible explanation for not finding clozapine superior to other SGAs is that patients who could benefit from clozapine the most (patients with the most treatment-resistant disease) are rarely included in a blinded RCT, which causes sampling bias.

    The same explanation could apply to clozapine’s dramatic superiority found in the study by Kane et al.5,6 At the time of their study, clozapine was off the market owing to agranulocytosis, so only patients considered “beyond the reach of conventional therapy”6 were recruited. In our analysis, most included studies were conducted at a time when less severely ill patients were generally enrolled in blinded RCTs, with more onerous consenting procedures and commercialization of the research conduct. Therefore, the criteria of treatment resistance varied from partial nonresponse to high levels of treatment resistance, and synthesizing this evidence could be problematic. For example, most trials examining olanzapine applied a more liberal definition of treatment resistance than clozapine trials, highlighting the shortcomings when comparing both compounds in a meta-analysis. The subgroup analysis based on the degree of treatment resistance failed to detect any significant efficacy difference among the various antipsychotics, but the data per group were very limited, which increased the possibility of failing to detect a difference, although it might be present (type II error).

    Furthermore, some evidence shows clozapine having a dose-related efficacy at as much as 600 mg/d in patients with treatment-resistant schizophrenia.102-104 Also, recent guidelines1,4 underline the importance of adequate plasma concentrations of clozapine (>350 ng/mL; to convert to micromoles per liter, multiply by 0.003) and treatment duration (≥8 weeks) in patients failing to respond to clozapine. Clozapine plasma concentrations were not examined in most clozapine studies included in our analysis, but clozapine titration speed was high and similar to that of each comparator used. The mean clozapine dose in studies comparing clozapine with an SGA was 392 mg/d, which was significantly lower than the mean clozapine dose (511 mg/d) in studies using an FGA as a comparator (P = .03). The metaregression analyses using the antipsychotic dose and trial duration as moderator variables did not show any effect on treatment efficacy, but the statistical power of these metaregressions was again markedly weak.105 Therefore, the dose schedule in clozapine trials and especially the likely underdosing in industry-funded trials could constitute a serious problem that could have affected the results.

    Finally, results from a meta-analysis cannot be better than those of the studies included. In our NMA, attrition and reporting bias were present in a considerable number of studies, and the issue of resistance to specific antipsychotics that might be used subsequently as comparators in the included trials (another form of sampling bias) could not be addressed directly. In addition, NMA is a relatively new method that has been criticized even more than conventional meta-analysis because it includes indirect evidence, which adds another level of complexity and assumptions. Indeed, the trials in the network were not as well linked (Figure 2) as in the previous NMA of patients with nonrefractory schizophrenia.12 Enough studies examined clozapine, olanzapine, risperidone, and haloperidol, but, for drugs such as fluphenazine, sertindole, and ziprasidone, the body of evidence was small and conclusions on them are not robust. Therefore, more trials are needed to provide clearer answers. Moreover, many other antipsychotics, including SGAs, had no available RCT. Nevertheless, the parallel that olanzapine and risperidone were also superior to some other antipsychotics in nonrefractory schizophrenia12 and even first-episode schizophrenia106 is noteworthy. In addition, the lack of statistically significant differences calls into question the hierarchies found by the NMA, so we prefer to emphasize the effect sizes between individual drugs (of which few were significant) rather than the rankings as presented in Figures 3 and 4 and in eAppendices 9 and 14 in the Supplement. However, the fact that, even in conventional pairwise meta-analyses and in the individual trials (Figure 5), hardly any significant differences were found clearly shows that the lack of consistent superiority of clozapine is not simply owing to methodologic limitations of NMA.

    Conclusions

    At present, insufficient blinded evidence exists on which antipsychotic is more efficacious for patients with treatment-resistant schizophrenia. Clozapine’s superiority over the FGAs has been demonstrated repeatedly, which establishes clozapine as the standard treatment in this specific population, but evidence from blinded RCTs for the comparison of clozapine with other SGAs is lacking. Our analysis suggests that more trials comparing clozapine with other SGAs in patients with more severe illness and using high clozapine doses are warranted. Moreover, the evidence on antipsychotics other than clozapine, haloperidol, olanzapine, and risperidone is scarce, and their results can change if further studies become published.

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    Article Information

    Corresponding Author: Stefan Leucht, MD, Department of Psychiatry and Psychotherapy, Technische Universität München, Klinikum rechts der Isar, Ismaningerstrasse 22, 81675 Munich, Germany (stefan.leucht@lrz.tum.de).

    Submitted for Publication: July 8, 2015; final revision received October 19, 2015; accepted November 15, 2015.

    Published Online: February 3, 2016. doi:10.1001/jamapsychiatry.2015.2955.

    Author Contributions: Drs Samara and Leucht had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Study concept and design: Dold, Leucht.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Samara, Leucht.

    Critical revision of the manuscript for important intellectual content: Samara, Dold, Gianatsi, Nikolakopoulou, Helfer, Salanti.

    Statistical analysis: Samara, Dold, Gianatsi, Nikolakopoulou, Salanti, Leucht.

    Obtained funding: Leucht.

    Administrative, technical, or material support: Samara, Dold, Helfer, Leucht.

    Study supervision: Samara, Salanti, Leucht.

    Conflict of Interest Disclosures: In the past 3 years, Dr Leucht reports receiving honoraria for lectures from Eli Lilly, Lundbeck (Institute), Pfizer, Janssen, BMS, Johnson and Johnson, Otsuka, Roche, Sanofi, ICON, AbbVie, AOP Orphan, and Servier; for consulting/advisory boards from Roche, Janssen, Lundbeck, Eli Lilly, Otsuka, and TEVA; and for the preparation of educational material and publications from Lundbeck Institute and Roche. Eli Lilly has provided medication for a clinical trial led by Dr Leucht as the principal investigator. No other disclosures were reported.

    Funding/Support: This study was supported by grant FKZ 01KG1214 from the German Federal Ministry of Education and Research.

    Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Additional Contributions: Samantha Roberts, Nottinghamshire Healthcare NHS Foundation Trust, conducted the literature search and received compensation for this role. Carlo Altamura, MD, Department of Mental Health, Psychiatry Clinic, University of Milan, Istvan Bitter, PhD, Department of Psychiatry and Psychotherapy, Semmelweis University, Robert W. Buchanan, MD, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Hung-Yu Chan, PhD, Department of General Psychiatry, Taoyuan Mental Hospital, Taoyuan, Department of Psychology, Chung Yuan Christian University, Chung-Li, and Department of General Psychiatry, National Taiwan University Hospital and College of Medicine, Robin Emsley, MD, University of Stellenbosch, Tygerberg, Deanna L. Kelly, PharmD, Maryland Psychiatric Research Center, University of Maryland, Bruce Kinon, MD, US Therapeutic Area Head, Psychosis, Lundbeck, LLC, Rosa Maria Moresco, MSc, Institute of Molecular Bioimaging and Physiology, National Research Council, Tecnomed Foundation and Department of Health Sciences, University of Milan-Bicocca, and Experimental Imaging Center, Institute for Research, Hospitalization and Health Care San Raffaele Scientific Institute, Susan McGurk, PhD, Center of Psychiatric Rehabilitation and Department of Occupational Therapy, Boston University, Dieter Naber, MD, PhD, Department of Psychiatry and Psychotherapy, University of Hamburg, Pierre Baumann, PhD, Département de Psychiatrie, Département de Psychiatrie, Centre Hospitalier Universitaire Vaudois, Robert Rosenheck, MD, Department of Psychiatry, Yale University School of Medicine, Emilio Sacchetti, MD, University of Brescia, School of Medicine, and Department of Mental Health, Spedali Civili Hospital, Ronald E. See, PhD, Department of Neurosciences, Medical University of South Carolina, Robert C. Smith, MD, PhD, Nathan Kline Institute for Psychiatric Research, and Department of Psychiatry, New York University Medical School, Jan Volavka, MD, PhD, Department of Psychiatry, New York University School of Medicine, and William C. Wirshing, MD, UCLA Medical Center, assisted by replying to our requests. None of these contributors received compensation for this role.

    References
    1.
    Hasan  A, Falkai  P, Wobrock  T,  et al; World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Treatment Guidelines for Schizophrenia.  World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance.  World J Biol Psychiatry. 2012;13(5):318-378.PubMedGoogle ScholarCrossref
    2.
    Barnes  TR; Schizophrenia Consensus Group of British Association for Psychopharmacology.  Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology.  J Psychopharmacol. 2011;25(5):567-620.PubMedGoogle ScholarCrossref
    3.
    Lehman  AF, Lieberman  JA, Dixon  LB,  et al; American Psychiatric Association; Steering Committee on Practice Guidelines.  Practice guideline for the treatment of patients with schizophrenia, second edition.  Am J Psychiatry. 2004;161(2)(suppl):1-56.PubMedGoogle Scholar
    4.
    Buchanan  RW, Kreyenbuhl  J, Kelly  DL,  et al; Schizophrenia Patient Outcomes Research Team (PORT).  The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements.  Schizophr Bull. 2010;36(1):71-93.PubMedGoogle ScholarCrossref
    5.
    Kane  JM, Honigfeld  G, Singer  J, Meltzer  H.  Clozapine in treatment-resistant schizophrenics.  Psychopharmacol Bull. 1988;24(1):62-67.PubMedGoogle Scholar
    6.
    Kane  J, Honigfeld  G, Singer  J, Meltzer  H.  Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine.  Arch Gen Psychiatry. 1988;45(9):789-796.PubMedGoogle ScholarCrossref
    7.
    Buchanan  RW, Breier  A, Kirkpatrick  B, Ball  P, Carpenter  WT  Jr.  Positive and negative symptom response to clozapine in schizophrenic patients with and without the deficit syndrome.  Am J Psychiatry. 1998;155(6):751-760.PubMedGoogle Scholar
    8.
    Rosenheck  R, Cramer  J, Xu  W,  et al; Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia.  A comparison of clozapine and haloperidol in hospitalized patients with refractory schizophrenia.  N Engl J Med. 1997;337(12):809-815.PubMedGoogle ScholarCrossref
    9.
    Chakos  M, Lieberman  J, Hoffman  E, Bradford  D, Sheitman  B.  Effectiveness of second-generation antipsychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of randomized trials.  Am J Psychiatry. 2001;158(4):518-526.PubMedGoogle ScholarCrossref
    10.
    Wahlbeck  K, Cheine  M, Essali  A, Adams  C.  Evidence of clozapine’s effectiveness in schizophrenia: a systematic review and meta-analysis of randomized trials.  Am J Psychiatry. 1999;156(7):990-999.PubMedGoogle Scholar
    11.
    Essali  A, Al-Haj Haasan  N, Li  C, Rathbone  J.  Clozapine versus typical neuroleptic medication for schizophrenia.  Cochrane Database Syst Rev. 2009;(1):CD000059.PubMedGoogle Scholar
    12.
    Leucht  S, Cipriani  A, Spineli  L,  et al.  Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis.  Lancet. 2013;382(9896):951-962.PubMedGoogle ScholarCrossref
    13.
    Asenjo Lobos  C, Komossa  K, Rummel-Kluge  C,  et al.  Clozapine versus other atypical antipsychotics for schizophrenia.  Cochrane Database Syst Rev. 2010;(11):CD006633.PubMedGoogle Scholar
    14.
    Leucht  S, Corves  C, Arbter  D, Engel  RR, Li  C, Davis  JM.  Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis.  Lancet. 2009;373(9657):31-41.PubMedGoogle ScholarCrossref
    15.
    Davis  JM, Chen  N, Glick  ID.  A meta-analysis of the efficacy of second-generation antipsychotics.  Arch Gen Psychiatry. 2003;60(6):553-564.PubMedGoogle ScholarCrossref
    16.
    McEvoy  JP, Lieberman  JA, Stroup  TS,  et al; CATIE Investigators.  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(4):600-610.PubMedGoogle ScholarCrossref
    17.
    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: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUTLASS 1).  Arch Gen Psychiatry. 2006;63(10):1079-1087.PubMedGoogle ScholarCrossref
    18.
    Higgins  JP, Welton  NJ.  Network meta-analysis: a norm for comparative effectiveness?  Lancet. 2015;386(9994):628-630.PubMedGoogle ScholarCrossref
    19.
    Cipriani  A, Higgins  JP, Geddes  JR, Salanti  G.  Conceptual and technical challenges in network meta-analysis.  Ann Intern Med. 2013;159(2):130-137.PubMedGoogle ScholarCrossref
    20.
    Leucht  S, Komossa  K, Rummel-Kluge  C,  et al.  A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia.  Am J Psychiatry. 2009;166(2):152-163.PubMedGoogle ScholarCrossref
    21.
    Elbourne  DR, Altman  DG, Higgins  JP, Curtin  F, Worthington  HV, Vail  A.  Meta-analyses involving cross-over trials: methodological issues.  Int J Epidemiol. 2002;31(1):140-149.PubMedGoogle ScholarCrossref
    22.
    Divine  GW, Brown  JT, Frazier  LM.  The unit of analysis error in studies about physicians’ patient care behavior.  J Gen Intern Med. 1992;7(6):623-629.PubMedGoogle ScholarCrossref
    23.
    Higgins  JPT, Green  S.  Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0. Chichester, England: Wiley & Sons; 2011.
    24.
    Bian  ZX, Li  YP, Moher  D,  et al.  Improving the quality of randomized controlled trials in Chinese herbal medicine, part I: clinical trial design and methodology.  Zhong Xi Yi Jie He Xue Bao. 2006;4(2):120-129.PubMedGoogle ScholarCrossref
    25.
    Wu  T, Li  Y, Bian  Z, Liu  G, Moher  D.  Randomized trials published in some Chinese journals: how many are randomized?  Trials. 2009;10:46.PubMedGoogle ScholarCrossref
    26.
    Kay  SR, Fiszbein  A, Opler  LA.  The Positive and Negative Syndrome Scale (PANSS) for schizophrenia.  Schizophr Bull. 1987;13(2):261-276.PubMedGoogle ScholarCrossref
    27.
    Overall  JE, Gorham  DR.  The Brief Psychiatric Rating Scale.  Psychol Rep. 1962;10:799-812.Google ScholarCrossref
    28.
    Guy  W.  ECDEU Assessment Manual for Psychopharmacology–Revised. Rockville, MD: US Dept of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute of Mental Health, Psychopharmacology Research Branch, Division of Extramural Research Programs; 1976:218-222. DHEW Publication ADM 76-338.
    29.
    Levine  SZ, Rabinowitz  J, Engel  R, Etschel  E, Leucht  S.  Extrapolation between measures of symptom severity and change: an examination of the PANSS and CGI.  Schizophr Res. 2008;98(1-3):318-322.PubMedGoogle ScholarCrossref
    30.
    Leucht  S, Kane  JM, Etschel  E, Kissling  W, Hamann  J, Engel  RR.  Linking the PANSS, BPRS, and CGI: clinical implications.  Neuropsychopharmacology. 2006;31(10):2318-2325.PubMedGoogle Scholar
    31.
    Leucht  S, Davis  JM, Engel  RR, Kane  JM, Wagenpfeil  S.  Defining ‘response’ in antipsychotic drug trials: recommendations for the use of scale-derived cutoffs.  Neuropsychopharmacology. 2007;32(9):1903-1910.PubMedGoogle ScholarCrossref
    32.
    DerSimonian  R, Laird  N.  Meta-analysis in clinical trials.  Control Clin Trials. 1986;7(3):177-188.PubMedGoogle ScholarCrossref
    33.
    Caldwell  DM, Ades  AE, Higgins  JP.  Simultaneous comparison of multiple treatments: combining direct and indirect evidence.  BMJ. 2005;331(7521):897-900.PubMedGoogle ScholarCrossref
    34.
    Dias  S, Sutton  AJ, Ades  AE, Welton  NJ.  Evidence synthesis for decision making 2: a generalized linear modeling framework for pairwise and network meta-analysis of randomized controlled trials.  Med Decis Making. 2013;33(5):607-617.PubMedGoogle ScholarCrossref
    35.
    Lunn  DJ, Thomas  A, Best  N, Spiegelhalter  D.  WinBUGS—a Bayesian modelling framework: concepts, structure, and extensibility.  Stat Comput. 2000;10:325-337.Google ScholarCrossref
    36.
    Higgins  JP, Green  S, Scholten  RJ. Maintaining reviews: updates, amendments and feedback. In: Higgins  JP, Green  S, eds.  Cochrane Handbook for Systematic Reviews of Interventions. Chichester, England: John Wiley & Sons Ltd; 2008:31-49.
    37.
    Salanti  G, Ades  AE, Ioannidis  JP.  Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial.  J Clin Epidemiol. 2011;64(2):163-171.PubMedGoogle ScholarCrossref
    38.
    Salanti  G.  Indirect and mixed-treatment comparison, network, or multiple-treatments meta-analysis: many names, many benefits, many concerns for the next generation evidence synthesis tool.  Res Synth Methods. 2012;3(2):80-97.PubMedGoogle ScholarCrossref
    39.
    Jansen  JP, Naci  H.  Is network meta-analysis as valid as standard pairwise meta-analysis? it all depends on the distribution of effect modifiers.  BMC Med. 2013;11:159.PubMedGoogle ScholarCrossref
    40.
    Chaimani  A, Higgins  JP, Mavridis  D, Spyridonos  P, Salanti  G.  Graphical tools for network meta-analysis in STATA.  PLoS One. 2013;8(10):e76654.PubMedGoogle ScholarCrossref
    41.
    Dias  S, Welton  NJ, Sutton  AJ, Caldwell  DM, Lu  G, Ades  AE.  Evidence synthesis for decision making 4: inconsistency in networks of evidence based on randomized controlled trials.  Med Decis Making. 2013;33(5):641-656.PubMedGoogle ScholarCrossref
    42.
    Song  F, Altman  DG, Glenny  AM, Deeks  JJ.  Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses.  BMJ. 2003;326(7387):472.PubMedGoogle ScholarCrossref
    43.
    Veroniki  AA, Vasiliadis  HS, Higgins  JP, Salanti  G.  Evaluation of inconsistency in networks of interventions.  Int J Epidemiol. 2013;42(1):332-345.PubMedGoogle ScholarCrossref
    44.
    Higgins  JPT, Jackson  D, Barrett  JK, Lu  G, Ades  AE, White  IR.  Consistency and inconsistency in network meta-analysis: concepts and models for multi-arm studies.  Res Synth Methods. 2012;3(2):98-110.PubMedGoogle ScholarCrossref
    45.
    Jackson  D, Barrett  JK, Rice  S, White  IR, Higgins  JP.  A design-by-treatment interaction model for network meta-analysis with random inconsistency effects.  Stat Med. 2014;33(21):3639-3654.PubMedGoogle ScholarCrossref
    46.
    White  IR, Barrett  JK, Jackson  D, Higgins  JPT.  Consistency and inconsistency in network meta-analysis: model estimation using multivariate meta-regression.  Res Synth Methods. 2012;3(2):111-125.PubMedGoogle ScholarCrossref
    47.
    Gardner  DM, Murphy  AL, O’Donnell  H, Centorrino  F, Baldessarini  RJ.  International consensus study of antipsychotic dosing.  Am J Psychiatry. 2010;167(6):686-693.PubMedGoogle ScholarCrossref
    48.
    Leucht  S, Samara  M, Heres  S,  et al.  Dose equivalents for second-generation antipsychotic drugs: the classical mean dose method.  Schizophr Bull. 2015;41(6):1397-1402.PubMedGoogle ScholarCrossref
    49.
    Leucht  S, Samara  M, Heres  S, Patel  MX, Woods  SW, Davis  JM.  Dose equivalents for second-generation antipsychotics: the minimum effective dose method.  Schizophr Bull. 2014;40(2):314-326.PubMedGoogle ScholarCrossref
    50.
    Chaimani  A, Salanti  G.  Using network meta-analysis to evaluate the existence of small-study effects in a network of interventions.  Res Synth Methods. 2012;3(2):161-176.PubMedGoogle ScholarCrossref
    51.
    Kane  JM, Meltzer  HY, Carson  WH  Jr, McQuade  RD, Marcus  RN, Sanchez  R; Aripiprazole Study Group.  Aripiprazole for treatment-resistant schizophrenia: results of a multicenter, randomized, double-blind, comparison study versus perphenazine.  J Clin Psychiatry. 2007;68(2):213-223.PubMedGoogle ScholarCrossref
    52.
    Howard  JS  III.  Haloperidol for chronically hospitalized psychotics: a double-blind comparison with thiothixene and placebo: a follow-up open evaluation.  Dis Nerv Syst. 1974;35(10):458-463.PubMedGoogle Scholar
    53.
    Honigfeld  G, Patin  J, Singer  J.  Clozapine: antipsychotic activity in treatment-resistant schizophrenics.  Adv Ther. 1984;1(2):77-97.Google Scholar
    54.
    Hall  WB, Vestre  ND, Schiele  BC, Zimmermann  R.  A controlled comparison of haloperidol and fluphenazine in chronic treatment-resistant schizophrenics.  Dis Nerv Syst. 1968;29(6):405-408.PubMedGoogle Scholar
    55.
    Browne  FWA, Cooper  SJ, Wilson  R, King  DJ.  Serum haloperidol levels and clinical response in chronic, treatment-resistant schizophrenic patients.  J Psychopharmacol. 1988;2(2):94-103.PubMedGoogle ScholarCrossref
    56.
    Azorin  JM, Spiegel  R, Remington  G,  et al.  A double-blind comparative study of clozapine and risperidone in the management of severe chronic schizophrenia.  Am J Psychiatry. 2001;158(8):1305-1313.PubMedGoogle ScholarCrossref
    57.
    Hong  CJ, Chen  JY, Chiu  HJ, Sim  CB.  A double-blind comparative study of clozapine versus chlorpromazine on Chinese patients with treatment-refractory schizophrenia.  Int Clin Psychopharmacol. 1997;12(3):123-130.PubMedGoogle ScholarCrossref
    58.
    Kane  JM, Marder  SR, Schooler  NR,  et al.  Clozapine and haloperidol in moderately refractory schizophrenia: a 6-month randomized and double-blind comparison.  Arch Gen Psychiatry. 2001;58(10):965-972.PubMedGoogle ScholarCrossref
    59.
    Volavka  J, Czobor  P, Sheitman  B,  et al.  Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder.  Am J Psychiatry. 2002;159(2):255-262.PubMedGoogle ScholarCrossref
    60.
    Bitter  I, Dossenbach  MR, Brook  S,  et al; Olanzapine HGCK Study Group.  Olanzapine versus clozapine in treatment-resistant or treatment-intolerant schizophrenia.  Prog Neuropsychopharmacol Biol Psychiatry. 2004;28(1):173-180.PubMedGoogle ScholarCrossref
    61.
    Conley  RR, Kelly  DL, Richardson  CM, Tamminga  CA, Carpenter  WT  Jr.  The efficacy of high-dose olanzapine versus clozapine in treatment-resistant schizophrenia: a double-blind crossover study.  J Clin Psychopharmacol. 2003;23(6):668-671.PubMedGoogle ScholarCrossref
    62.
    Meltzer  HY, Bobo  WV, Roy  A,  et al.  A randomized, double-blind comparison of clozapine and high-dose olanzapine in treatment-resistant patients with schizophrenia.  J Clin Psychiatry. 2008;69(2):274-285.PubMedGoogle ScholarCrossref
    63.
    Moresco  RM, Cavallaro  R, Messa  C,  et al.  Cerebral D2 and 5-HT2 receptor occupancy in schizophrenic patients treated with olanzapine or clozapine.  J Psychopharmacol. 2004;18(3):355-365.PubMedGoogle ScholarCrossref
    64.
    Naber  D, Riedel  M, Klimke  A,  et al.  Randomized double blind comparison of olanzapine vs. clozapine on subjective well-being and clinical outcome in patients with schizophrenia.  Acta Psychiatr Scand. 2005;111(2):106-115.PubMedGoogle ScholarCrossref
    65.
    Tollefson  GD, Birkett  MA, Kiesler  GM, Wood  AJ; Lilly Resistant Schizophrenia Study Group.  Double-blind comparison of olanzapine versus clozapine in schizophrenic patients clinically eligible for treatment with clozapine.  Biol Psychiatry. 2001;49(1):52-63.PubMedGoogle ScholarCrossref
    66.
    Bondolfi  G, Dufour  H, Patris  M,  et al; Risperidone Study Group.  Risperidone versus clozapine in treatment-resistant chronic schizophrenia: a randomized double-blind study.  Am J Psychiatry. 1998;155(4):499-504.PubMedGoogle ScholarCrossref
    67.
    Breier  AF, Malhotra  AK, Su  TP,  et al.  Clozapine and risperidone in chronic schizophrenia: effects on symptoms, parkinsonian side effects, and neuroendocrine response.  Am J Psychiatry. 1999;156(2):294-298.PubMedGoogle Scholar
    68.
    McGurk  SR, Carter  C, Goldman  R,  et al.  The effects of clozapine and risperidone on spatial working memory in schizophrenia.  Am J Psychiatry. 2005;162(5):1013-1016.PubMedGoogle ScholarCrossref
    69.
    Wahlbeck  K, Cheine  M, Tuisku  K, Ahokas  A, Joffe  G, Rimón  R.  Risperidone versus clozapine in treatment-resistant schizophrenia: a randomized pilot study.  Prog Neuropsychopharmacol Biol Psychiatry. 2000;24(6):911-922.PubMedGoogle ScholarCrossref
    70.
    Sacchetti  E, Galluzzo  A, Valsecchi  P, Romeo  F, Gorini  B, Warrington  L; MOZART Study Group.  Ziprasidone vs clozapine in schizophrenia patients refractory to multiple antipsychotic treatments: the MOZART study [published correction appears in Schizophr Res. 2010;121(1-3)281].  Schizophr Res. 2009;113(1):112-121.PubMedGoogle ScholarCrossref
    71.
    Altamura  AC, Velonà  I, Curreli  R, Mundo  E, Bravi  D.  Is olanzapine better than haloperidol in resistant schizophrenia? a double-blind study in partial responders.  Int J Psychiatry Clin Pract. 2002;6(2):107-111.PubMedGoogle ScholarCrossref
    72.
    AstraZeneca Clinical Trials. A multicentre, double-blind, randomised comparison of quetiapine (Seroquel) and chlorpromazine in the treatment of subjects with treatment-resistant schizophrenia. 5077IL/0031. http://www.astrazenecaclinicaltrials.com/Submission/View?id=988. Verified November 2013. Accessed March 14, 2014.
    73.
    AstraZeneca Clinical Trials. A multicentre, double-blind, randomised trial to compare the effects of seroquel and chlorpromazine in patients with treatment resistant schizophrenia [TRESS]. 5077IL/0054. http://www.astrazenecaclinicaltrials.com/Submission/View?id=994. Verified November 2013. Accessed March 14, 0214.
    74.
    Breier  A, Hamilton  SH.  Comparative efficacy of olanzapine and haloperidol for patients with treatment-resistant schizophrenia.  Biol Psychiatry. 1999;45(4):403-411.PubMedGoogle ScholarCrossref
    75.
    Buchanan  RW, Ball  MP, Weiner  E,  et al.  Olanzapine treatment of residual positive and negative symptoms.  Am J Psychiatry. 2005;162(1):124-129.PubMedGoogle ScholarCrossref
    76.
    Chen  JJ, Chan  HY, Chen  CH, Gau  SS, Hwu  HG.  Risperidone and olanzapine versus another first generation antipsychotic in patients with schizophrenia inadequately responsive to first generation antipsychotics.  Pharmacopsychiatry. 2012;45(2):64-71.PubMedGoogle ScholarCrossref
    77.
    Conley  RR, Tamminga  CA, Bartko  JJ,  et al.  Olanzapine compared with chlorpromazine in treatment-resistant schizophrenia.  Am J Psychiatry. 1998;155(7):914-920.PubMedGoogle ScholarCrossref
    78.
    Daniel  DG, Goldberg  TE, Weinberger  DR,  et al.  Different side effect profiles of risperidone and clozapine in 20 outpatients with schizophrenia or schizoaffective disorder: a pilot study.  Am J Psychiatry. 1996;153(3):417-419.PubMedGoogle ScholarCrossref
    79.
    Emsley  RA, Raniwalla  J, Bailey  PJ, Jones  AM; PRIZE Study Group.  A comparison of the effects of quetiapine (‘seroquel’) and haloperidol in schizophrenic patients with a history of and a demonstrated, partial response to conventional antipsychotic treatment.  Int Clin Psychopharmacol. 2000;15(3):121-131.PubMedGoogle ScholarCrossref
    80.
    Kane  JM, Khanna  S, Rajadhyaksha  S, Giller  E.  Efficacy and tolerability of ziprasidone in patients with treatment-resistant schizophrenia.  Int Clin Psychopharmacol. 2006;21(1):21-28.PubMedGoogle ScholarCrossref
    81.
    Kane  JM, Potkin  SG, Daniel  DG, Buckley  PF.  A double-blind, randomized study comparing the efficacy and safety of sertindole and risperidone in patients with treatment-resistant schizophrenia.  J Clin Psychiatry. 2011;72(2):194-204.PubMedGoogle ScholarCrossref
    82.
    Kinon  BJ, Kane  JM, Johns  C,  et al.  Treatment of neuroleptic-resistant schizophrenic relapse.  Psychopharmacol Bull. 1993;29(2):309-314.PubMedGoogle Scholar
    83.
    See  RE, Fido  AA, Maurice  M, Ibrahim  MM, Salama  GM.  Risperidone-induced increase of plasma norepinephrine is not correlated with symptom improvement in chronic schizophrenia.  Biol Psychiatry. 1999;45(12):1653-1656.PubMedGoogle ScholarCrossref
    84.
    Sirota  P, Pannet  I, Koren  A, Tchernichovsky  E.  Quetiapine versus olanzapine for the treatment of negative symptoms in patients with schizophrenia.  Hum Psychopharmacol. 2006;21(4):227-234.PubMedGoogle ScholarCrossref
    85.
    Smith  RC, Infante  M, Singh  A, Khandat  A.  The effects of olanzapine on neurocognitive functioning in medication-refractory schizophrenia.  Int J Neuropsychopharmacol. 2001;4(3):239-250.PubMedGoogle ScholarCrossref
    86.
    Wirshing  DA, Marshall  BD  Jr, Green  MF, Mintz  J, Marder  SR, Wirshing  WC.  Risperidone in treatment-refractory schizophrenia.  Am J Psychiatry. 1999;156(9):1374-1379.PubMedGoogle Scholar
    87.
    Conley  RR, Kelly  DL, Nelson  MW,  et al.  Risperidone, quetiapine, and fluphenazine in the treatment of patients with therapy-refractory schizophrenia.  Clin Neuropharmacol. 2005;28(4):163-168.PubMedGoogle ScholarCrossref
    88.
    US Department of Health and Human Services Food and Drug Administration Office of Regulatory Affairs. Guidance for industry: guideline for the monitoring of clinical investigations. http://www.ahc.umn.edu/img/assets/19826/Clinical%20monitoring.pdf. Published January 1988. Accessed October 24, 2014.
    89.
    Brunoni  AR, Tadini  L, Fregni  F.  Changes in clinical trials methodology over time: a systematic review of six decades of research in psychopharmacology.  PLoS One. 2010;5(3):e9479.PubMedGoogle ScholarCrossref
    90.
    Kane  JM, Correll  CU.  Past and present progress in the pharmacologic treatment of schizophrenia.  J Clin Psychiatry. 2010;71(9):1115-1124.PubMedGoogle ScholarCrossref
    91.
    Cohen  J.  Statistical Power Analysis for the Behavioral Sciences. 2nd ed. Hillsdale, NJ: Erlbaum; 1988.
    92.
    Essock  SM, Frisman  LK, Covell  NH, Hargreaves  WA.  Cost-effectiveness of clozapine compared with conventional antipsychotic medication for patients in state hospitals.  Arch Gen Psychiatry. 2000;57(10):987-994.PubMedGoogle ScholarCrossref
    93.
    Agid  O, Siu  CO, Potkin  SG,  et al.  Meta-regression analysis of placebo response in antipsychotic trials, 1970-2010.  Am J Psychiatry. 2013;170(11):1335-1344.PubMedGoogle ScholarCrossref
    94.
    Leucht  S, Arbter  D, Engel  RR, Kissling  W, Davis  JM.  How effective are second-generation antipsychotic drugs? a meta-analysis of placebo-controlled trials.  Mol Psychiatry. 2009;14(4):429-447.PubMedGoogle ScholarCrossref
    95.
    Rutherford  BR, Pott  E, Tandler  JM, Wall  MM, Roose  SP, Lieberman  JA.  Placebo response in antipsychotic clinical trials: a meta-analysis.  JAMA Psychiatry. 2014;71(12):1409-1421.PubMedGoogle ScholarCrossref
    96.
    Lewis  SW, Barnes  TR, 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(4):715-723.PubMedGoogle ScholarCrossref
    97.
    Nyakyoma  K, Morriss  R.  Effectiveness of clozapine use in delaying hospitalization in routine clinical practice: a 2 year observational study.  Psychopharmacol Bull. 2010;43(2):67-81.PubMedGoogle Scholar
    98.
    Ciudad  A, Haro  JM, Alonso  J,  et al.  The Schizophrenia Outpatient Health Outcomes (SOHO) study: 3-year results of antipsychotic treatment discontinuation and related clinical factors in Spain.  Eur Psychiatry. 2008;23(1):1-7.PubMedGoogle ScholarCrossref
    99.
    Schneider  C, Papachristou  E, Wimberley  T,  et al.  Clozapine use in childhood and adolescent schizophrenia: a nationwide population-based study.  Eur Neuropsychopharmacol. 2015;25(6):857-863.PubMedGoogle ScholarCrossref
    100.
    Tiihonen  J, Lönnqvist  J, Wahlbeck  K,  et al.  11-Year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study).  Lancet. 2009;374(9690):620-627.PubMedGoogle ScholarCrossref
    101.
    Ringbäck Weitoft  G, Berglund  M, Lindström  EA, Nilsson  M, Salmi  P, Rosén  M.  Mortality, attempted suicide, re-hospitalisation and prescription refill for clozapine and other antipsychotics in Sweden: a register-based study.  Pharmacoepidemiol Drug Saf. 2014;23(3):290-298.PubMedGoogle ScholarCrossref
    102.
    Davis  JM, Chen  N.  Dose response and dose equivalence of antipsychotics.  J Clin Psychopharmacol. 2004;24(2):192-208.PubMedGoogle ScholarCrossref
    103.
    Kinon  BJ, Ahl  J, Stauffer  VL, Hill  AL, Buckley  PF.  Dose response and atypical antipsychotics in schizophrenia.  CNS Drugs. 2004;18(9):597-616.PubMedGoogle ScholarCrossref
    104.
    Simpson  GM, Josiassen  RC, Stanilla  JK,  et al.  Double-blind study of clozapine dose response in chronic schizophrenia.  Am J Psychiatry. 1999;156(11):1744-1750.PubMedGoogle Scholar
    105.
    Thompson  SG, Higgins  JP.  How should meta-regression analyses be undertaken and interpreted?  Stat Med. 2002;21(11):1559-1573.PubMedGoogle ScholarCrossref
    106.
    Zhang  JP, Gallego  JA, Robinson  DG, Malhotra  AK, Kane  JM, Correll  CU.  Efficacy and safety of individual second-generation vs first-generation antipsychotics in first-episode psychosis: a systematic review and meta-analysis.  Int J Neuropsychopharmacol. 2013;16(6):1205-1218.PubMedGoogle ScholarCrossref
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