Real-World Effectiveness of Antipsychotic Treatments in a Nationwide Cohort of 29 823 Patients With Schizophrenia | Psychiatry and Behavioral Health | JAMA Psychiatry | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 35.153.100.128. Please contact the publisher to request reinstatement.
1.
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
2.
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
3.
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
4.
Hofer  A, Hummer  M, Huber  R, Kurz  M, Walch  T, Fleischhacker  WW.  Selection bias in clinical trials with antipsychotics.  J Clin Psychopharmacol. 2000;20(6):699-702.PubMedGoogle ScholarCrossref
5.
Baandrup  L, Gasse  C, Jensen  VD,  et al.  Antipsychotic polypharmacy and risk of death from natural causes in patients with schizophrenia: a population-based nested case-control study.  J Clin Psychiatry. 2010;71(2):103-108.PubMedGoogle ScholarCrossref
6.
Tiihonen  J, Wahlbeck  K, Lönnqvist  J,  et al.  Effectiveness of antipsychotic treatments in a nationwide cohort of patients in community care after first hospitalisation due to schizophrenia and schizoaffective disorder: observational follow-up study.  BMJ. 2006;333(7561):224.PubMedGoogle ScholarCrossref
7.
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
8.
Tiihonen  J, Haukka  J, Taylor  M, Haddad  PM, Patel  MX, Korhonen  P.  A nationwide cohort study of oral and depot antipsychotics after first hospitalization for schizophrenia.  Am J Psychiatry. 2011;168(6):603-609.PubMedGoogle ScholarCrossref
9.
Tiihonen  J, Suokas  JT, Suvisaari  JM, Haukka  J, Korhonen  P.  Polypharmacy with antipsychotics, antidepressants, or benzodiazepines and mortality in schizophrenia.  Arch Gen Psychiatry. 2012;69(5):476-483.PubMedGoogle ScholarCrossref
10.
Tiihonen  J, Mittendorfer-Rutz  E, Torniainen  M, Alexanderson  K, Tanskanen  A.  Mortality and cumulative exposure to antipsychotics, antidepressants, and benzodiazepines in patients with schizophrenia: an observational follow-up study.  Am J Psychiatry. 2016;173(6):600-606.PubMedGoogle ScholarCrossref
11.
Crump  C, Winkleby  MA, Sundquist  K, Sundquist  J.  Comorbidities and mortality in persons with schizophrenia: a Swedish national cohort study.  Am J Psychiatry. 2013;170(3):324-333.PubMedGoogle ScholarCrossref
12.
Kiviniemi  M, Suvisaari  J, Koivumaa-Honkanen  H, Häkkinen  U, Isohanni  M, Hakko  H.  Antipsychotics and mortality in first-onset schizophrenia: prospective Finnish register study with 5-year follow-up.  Schizophr Res. 2013;150(1):274-280.PubMedGoogle ScholarCrossref
13.
Hayes  RD, Downs  J, Chang  CK,  et al.  The effect of clozapine on premature mortality: an assessment of clinical monitoring and other potential confounders.  Schizophr Bull. 2015;41(3):644-655.PubMedGoogle ScholarCrossref
14.
Vanasse  A, Blais  L, Courteau  J,  et al.  Comparative effectiveness and safety of antipsychotic drugs in schizophrenia treatment: a real-world observational study.  Acta Psychiatr Scand. 2016;134(5):374-384.PubMedGoogle ScholarCrossref
15.
Torniainen  M, Mittendorfer-Rutz  E, Tanskanen  A,  et al.  Antipsychotic treatment and mortality in schizophrenia.  Schizophr Bull. 2015;41(3):656-663.PubMedGoogle ScholarCrossref
16.
WHO Collaborating Centre for Drug Statistics Methodology. The Anatomical Therapeutic Chemical Classification System: structure and principles. https://www.whocc.no/atc/structure_and_principles/. Updated March 25, 2011. Accessed February 1, 2017.
17.
Lichtenstein  P, Halldner  L, Zetterqvist  J,  et al.  Medication for attention deficit-hyperactivity disorder and criminality.  N Engl J Med. 2012;367(21):2006-2014.PubMedGoogle ScholarCrossref
18.
Chang  Z, Lichtenstein  P, Långström  N, Larsson  H, Fazel  S.  Association between prescription of major psychotropic medications and violent reoffending after prison release.  JAMA. 2016;316(17):1798-1807.PubMedGoogle ScholarCrossref
19.
Tiihonen  J.  Real-world effectiveness of antipsychotics.  Acta Psychiatr Scand. 2016;134(5):371-373.PubMedGoogle ScholarCrossref
20.
Alphs  L, Nasrallah  HA, Bossie  CA,  et al.  Factors associated with relapse in schizophrenia despite adherence to long-acting injectable antipsychotic therapy.  Int Clin Psychopharmacol. 2016;31(4):202-209.PubMedGoogle ScholarCrossref
21.
Kishimoto  T, Robenzadeh  A, Leucht  C,  et al.  Long-acting injectable vs oral antipsychotics for relapse prevention in schizophrenia: a meta-analysis of randomized trials.  Schizophr Bull. 2014;40(1):192-213.PubMedGoogle ScholarCrossref
22.
Ostuzzi  G, Bighelli  I, So  R, Furukawa  TA, Barbui  C.  Does formulation matter? a systematic review and meta-analysis of oral versus long-acting antipsychotic studies  [published online November 17, 2016].  Schizophr Res. 2016;S0920-9964(16)30503-5. doi:10.1016/j.schres.2016.11.010PubMedGoogle Scholar
23.
Subotnik  KL, Casaus  LR, Ventura  J,  et al.  Long-acting injectable risperidone for relapse prevention and control of breakthrough symptoms after a recent first episode of schizophrenia: a randomized clinical trial.  JAMA Psychiatry. 2015;72(8):822-829.PubMedGoogle ScholarCrossref
24.
Rabinowitz  J, Levine  SZ, Barkai  O, Davidov  O.  Dropout rates in randomized clinical trials of antipsychotics: a meta-analysis comparing first- and second-generation drugs and an examination of the role of trial design features.  Schizophr Bull. 2009;35(4):775-788.PubMedGoogle ScholarCrossref
25.
Taipale  H, Tanskanen  A, Koponen  M, Tolppanen  AM, Tiihonen  J, Hartikainen  S.  Agreement between PRE2DUP register data modeling method and comprehensive drug use interview among older persons.  Clin Epidemiol. 2016;8:363-371.PubMedGoogle ScholarCrossref
Original Investigation
July 2017

Real-World Effectiveness of Antipsychotic Treatments in a Nationwide Cohort of 29 823 Patients With Schizophrenia

Author Affiliations
  • 1Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
  • 2Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital, Kuopio, Finland
  • 3EPID Research Oy, Espoo, Finland
  • 4Janssen-Cilag, Solna, Sweden
  • 5Janssen-Cilag, Beerse, Belgium
  • 6National Institute for Health and Welfare, The Impact Assessment Unit, Helsinki, Finland
  • 7School of Pharmacy, University of Eastern Finland, Kuopio, Finland
JAMA Psychiatry. 2017;74(7):686-693. doi:10.1001/jamapsychiatry.2017.1322
Key Points

Question  Are there any clinically meaningful differences between specific antipsychotic medications or routes of administration regarding the risk of psychiatric rehospitalization or other treatment failure?

Findings  This database study of a nationwide cohort of patients using within-individual analysis to eliminate selection bias found that clozapine and long-acting injections of antipsychotic medications are associated with the lowest risk of rehospitalization and treatment failure.

Meaning  Clozapine and long-acting injections of antipsychotic medications were the pharmacologic treatments with the highest rates of prevention of relapse in schizophrenia.

Abstract

Importance  It has remained unclear whether there are clinically meaningful differences between antipsychotic treatments with regard to preventing relapse of schizophrenia, owing to the impossibility of including large unselected patient populations in randomized clinical trials, as well as residual confounding from selection biases in observational studies.

Objective  To study the comparative real-world effectiveness of antipsychotic treatments for patients with schizophrenia.

Design, Setting, and Participants  Prospectively gathered nationwide databases were linked to study the risk of rehospitalization and treatment failure from July 1, 2006, to December 31, 2013, among all patients in Sweden with a schizophrenia diagnosis who were 16 to 64 years of age in 2006 (29 823 patients in the total prevalent cohort; 4603 in the incident cohort of newly diagnosed patients). Within-individual analyses were used for primary analyses, in which each individual was used as his or her own control to eliminate selection bias. Traditional Cox proportional hazards multivariate regression was used for secondary analyses.

Main Outcomes and Measures  Risk of rehospitalization and treatment failure (defined as psychiatric rehospitalization, suicide attempt, discontinuation or switch to other medication, or death).

Results  There were 29 823 patients (12 822 women and 17 001 men; mean [SD] age, 44.9 [12.0] years). During follow-up, 13 042 of 29 823 patients (43.7%) were rehospitalized, and 20 225 of 28 189 patients (71.7%) experienced treatment failure. The risk of psychiatric rehospitalization was the lowest during monotherapy with once-monthly long-acting injectable paliperidone (hazard ratio [HR], 0.51; 95% CI, 0.41-0.64), long-acting injectable zuclopenthixol (HR, 0.53; 95% CI, 0.48-0.57), clozapine (HR, 0.53; 95% CI, 0.48-0.58), long-acting injectable perphenazine (HR, 0.58; 95% CI, 0.52-0.65), and long-acting injectable olanzapine (HR, 0.58; 95% CI, 0.44-0.77) compared with no use of antipsychotic medication. Oral flupentixol (HR, 0.92; 95% CI, 0.74-1.14), quetiapine (HR, 0.91; 95% CI, 0.83-1.00), and oral perphenazine (HR, 0.86; 95% CI, 0.77-0.97) were associated with the highest risk of rehospitalization. Long-acting injectable antipsychotic medications were associated with substantially lower risk of rehospitalization compared with equivalent oral formulations (HR, 0.78; 95% CI, 0.72-0.84 in the total cohort; HR, 0.68; 95% CI, 0.53-0.86 in the incident cohort). Clozapine (HR, 0.58; 95% CI, 0.53-0.63) and all long-acting injectable antipsychotic medications (HRs 0.65-0.80) were associated with the lowest rates of treatment failure compared with the most widely used medication, oral olanzapine. The results of several sensitivity analyses were consistent with those of the primary analyses.

Conclusions and Relevance  Clozapine and long-acting injectable antipsychotic medications were the pharmacologic treatments with the highest rates of prevention of relapse in schizophrenia. The risk of rehospitalization is about 20% to 30% lower during long-acting injectable treatments compared with equivalent oral formulations.

×