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      Comparative Effectiveness of Antipsychotic Drugs for Rehospitalization in Schizophrenia—A Nationwide Study With 20-Year Follow-up

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          Abstract

          Very little is known about the comparative long-term effectiveness of novel antipsychotics in relapse prevention, especially in first-episode schizophrenia. Nationwide data from Finnish health care registers were gathered prospectively for all persons with periods of inpatient care due to schizophrenia in Finland during 1972–2014. Altogether 62250 persons were included in the prevalent cohort, and 8719 in the incident (first-episode schizophrenia) cohort. The follow-up for antipsychotic use started at 1996 for the prevalent cohort, and at the first discharge from inpatient care for the incident cases. Within-individual Cox regression models for risk of psychiatric and all-cause hospitalization were constructed to compare risk during antipsychotic use and no use using individual as his/her own control to eliminate selection bias. With follow-up time up to 20 years (median = 14.1, interquartile range = 6.9–20.0), 59% of the prevalent cohort were readmitted to psychiatric inpatient care. Olanzapine long-acting injection (LAI; adjusted hazard ratio = 0.46, 95% confidence interval = 0.36–0.61), clozapine (0.51, 0.49–0.53), and paliperidone LAI (0.51, 0.40–0.66) were associated with the lowest risk of psychiatric rehospitalization in the prevalent cohort. Among first-episode patients, the lowest risks were observed for flupentixol LAI (0.24, 0.12–0.49), olanzapine LAI (0.26, 0.16–0.44), and perphenazine LAI (0.39, 0.31–0.50). Clozapine and LAIs were associated with the lowest risk of all-cause hospitalization in both cohorts. Clozapine and LAIs are the most effective treatments in preventing psychiatric and all-cause hospitalization among chronic and first-episode patients with schizophrenia.

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

          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. This database study uses a nationwide cohort to examine the comparative real-world effectiveness of antipsychotic treatments for patients with schizophrenia. 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.
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            A nationwide cohort study of oral and depot antipsychotics after first hospitalization for schizophrenia.

            Data on the effectiveness of antipsychotics in the early phase of schizophrenia are limited. The authors examined the risk of rehospitalization and drug discontinuation in a nationwide cohort of 2,588 consecutive patients hospitalized for the first time with a diagnosis of schizophrenia between 2000 and 2007 in Finland. The authors linked national databases of hospitalization, mortality, and antipsychotic prescriptions and computed hazard ratios, adjusting for the effects of sociodemographic and clinical variables, the temporal sequence of the antipsychotics used, and the choice of the initial antipsychotic for each patient. Of 2,588 patients, 1,507 (58.2%) collected a prescription for an antipsychotic during the first 30 days after hospital discharge, and 1,182 (45.7%, 95% confidence interval [CI]=43.7-47.6) continued their initial treatment for 30 days or longer. In a pairwise comparison between depot injections and their equivalent oral formulations, the risk of rehospitalization for patients receiving depot medications was about one-third of that for patients receiving oral medications (adjusted hazard ratio=0.36, 95% CI=0.17-0.75). Compared with oral risperidone, clozapine (adjusted hazard ratio=0.48, 95% CI=0.31-0.76) and olanzapine (adjusted hazard ratio=0.54, 95% CI=0.40-0.73) were each associated with a significantly lower rehospitalization risk. Use of any antipsychotic compared with no antipsychotic was associated with lower mortality (adjusted hazard ratio=0.45, 95% CI=0.31-0.67). In Finland, only a minority of patients adhere to their initial antipsychotic during the first 60 days after discharge from their first hospitalization for schizophrenia. Use of depot antipsychotics was associated with a significantly lower risk of rehospitalization than use of oral formulations of the same compounds. Among oral antipsychotics, clozapine and olanzapine were associated with more favorable outcomes. Use of any antipsychotic was associated with lower mortality.
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              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.

              To study the association between prescribed antipsychotic drugs and outcome in schizophrenia or schizoaffective disorder in the community. Prospective cohort study using national central registers. Community care in Finland. Nationwide cohort of 2230 consecutive adults hospitalised in Finland for the first time because of schizophrenia or schizoaffective disorder, January 1995 to December 2001. Rates of discontinuation of drugs (all causes), rates of rehospitalisation, and mortality associated with monotherapy with the 10 most commonly used antipsychotic drugs. Multivariate models and propensity score methods were used to adjust estimates of effectiveness. Initial use of clozapine (adjusted relative risk 0.17, 95% confidence interval 0.10 to 0.29), perphenazine depot (0.24, 0.13 to 0.47), and olanzapine (0.35, 0.18 to 0.71) were associated with the lowest rates of discontinuation for any reason when compared with oral haloperidol. During an average follow-up of 3.6 years, 4640 cases of rehospitalisation were recorded. Current use of perphenazine depot (0.32, 0.22 to 0.49), olanzapine (0.54, 0.41 to 0.71), and clozapine (0.64, 0.48 to 0.85) were associated with the lowest risk of rehospitalisation. Use of haloperidol was associated with a poor outcome among women. Mortality was markedly raised in patients not taking antipsychotics (12.3, 6.0 to 24.1) and the risk of suicide was high (37.4, 5.1 to 276). The effectiveness of first and second generation antipsychotics varies greatly in the community. Patients treated with perphenazine depot, clozapine, or olanzapine have a substantially lower risk of rehospitalisation or discontinuation (for any reason) of their initial treatment than do patients treated with haloperidol. Excess mortality is seen mostly in patients not using antipsychotic drugs.
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                Author and article information

                Journal
                Schizophr Bull
                Schizophr Bull
                schbul
                Schizophrenia Bulletin
                Oxford University Press (US )
                0586-7614
                1745-1701
                October 2018
                20 December 2017
                20 December 2017
                : 44
                : 6
                : 1381-1387
                Affiliations
                [1 ]Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
                [2 ]School of Pharmacy, University of Eastern Finland, Kuopio, Finland
                [3 ]EPID Research Oy, Espoo, Finland
                [4 ]The Impact Assessment Unit, National Institute for Health and Welfare, Helsinki, Finland
                [5 ]Department of Forensic Psychiatry, Niuvanniemi Hospital, University of Eastern Finland, Kuopio, Finland
                Author notes
                To whom correspondence should be addressed; Department of Clinical Neuroscience, Karolinska Institutet, Byggnad R5, S-17176 Stockholm, Sweden; tel: +358 50 3418363, fax: +358 17 3682419, e-mail: jari.tiihonen@ 123456ki.se .
                Article
                sbx176
                10.1093/schbul/sbx176
                6192491
                29272458
                e80a1380-d8fb-4912-90ae-211eae9c8839
                © The Author(s) 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                Page count
                Pages: 7
                Funding
                Funded by: Finnish Ministry of Social Affairs
                Funded by: Niuvanniemi Hospital
                Funded by: Eli Lilly
                Award ID: F1D-HL-0341
                Categories
                Regular Articles

                Neurology
                treatment,hospitalization,nationwide cohort
                Neurology
                treatment, hospitalization, nationwide cohort

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