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      Definitions and drivers of relapse in patients with schizophrenia: a systematic literature review

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          Abstract

          Relapse in patients with schizophrenia has devastating repercussions, including worsening symptoms, impaired functioning, cognitive deterioration and reduced quality of life. This progressive decline exacerbates the burden of illness on patients and their families. Relapse prevention is identified as a key therapeutic aim; however, the absence of widely accepted relapse definition criteria considerably hampers achieving this goal. We conducted a literature review in order to investigate the reporting of relapses and the validity of hospitalization as a proxy for relapse in patients with schizophrenia. The primary aim was to assess the range and validity of methods used to define relapse in observational or naturalistic settings. The secondary aim was to capture information on factors that predicted or influenced the risk of relapse. A structured search of the PubMed database identified articles that discussed relapse, and hospitalization as a proxy of relapse, in patients with schizophrenia. National and international guidelines were also reviewed. Of the 150 publications and guidelines identified, 87 defined relapse and 62% of these discussed hospitalization. Where hospitalization was discussed, this was as a proxy for, or a component of, relapse in the majority of cases. However, hospitalization duration and type varied and were not always well defined. Scales were used to define relapse in 53 instances; 10 different scales were used and multiple scales often appeared within the same definition. There were 95 references to factors that may drive relapse, including non-adherence to antipsychotic medication (21/95), stress/depression (11/95) and substance abuse (9/95). Twenty-five publications discussed the potential of antipsychotic therapy to reduce relapse rates—continuous antipsychotic therapy was associated with reduced frequency and duration of hospitalization. Non-pharmacological interventions, such as psychoeducation and cognitive behavioural therapy, were also commonly reported as factors that may reduce relapse. In conclusion, this review identified numerous factors used to define relapse. Hospitalization was the factor most frequently used and represents a useful proxy for relapse when reporting in a naturalistic setting. Several factors were reported to increase the risk of relapse, and observation of these may aid the identification of at-risk patients.

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          Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis.

          Relapse prevention with antipsychotic drugs compared with placebo in patients with schizophrenia has not been sufficiently addressed by previous systematic reviews. We aimed to assess the association between such drugs and various outcomes in patients with schizophrenia to resolve controversial issues. We searched the Cochrane Schizophrenia Group's specialised register for reports published before Nov 11, 2008; and PubMed, Embase, and ClinicalTrials.gov for those before June 8, 2011. We also contacted pharmaceutical companies and searched the reference lists of included studies and previous reviews. Randomised trials of patients with schizophrenia continued on or withdrawn from any antipsychotic drug regimen after stabilisation were eligible. Our primary outcome was relapse between 7 and 12 months. We also examined safety and various functional outcomes. We used the random effects model and verified results for the primary outcome with a fixed effects model. Heterogeneity was investigated with subgroup and meta-regression analyses. We identified 116 suitable reports from 65 trials, with data for 6493 patients. Antipsychotic drugs significantly reduced relapse rates at 1 year (drugs 27%vs placebo 64%; risk ratio [RR] 0·40, 95% CI 0·33-0·49; number needed to treat to benefit [NNTB] 3, 95% CI 2-3). Fewer patients given antipsychotic drugs than placebo were readmitted (10%vs 26%; RR 0·38, 95% CI 0·27-0·55; NNTB 5, 4-9), but less than a third of relapsed patients had to be admitted. Limited evidence suggested better quality of life (standardised mean difference -0·62, 95% CI -1·15 to -0·09) and fewer aggressive acts (2%vs 12%; RR 0·27, 95% CI 0·15-0·52; NNTB 11, 6-100) with antipsychotic drugs than with placebo. Employment data were scarce and too few deaths were reported to allow significant differences to be identified. More patients given antipsychotic drugs than placebo gained weight (10%vs 6%; RR 2·07, 95% CI 2·31-3·25), had movement disorders (16%vs 9%; 1·55, 1·25-1·93), and experienced sedation (13%vs 9%; 1·50, 1·22-1·84). Substantial heterogeneity in size of effect was recorded. In subgroup analyses, number of episodes, whether patients were in remission, abrupt or gradual withdrawal of treatment, length of stability before trial entry, first-generation or second-generation drugs, and allocation concealment method did not significantly affect relapse risk. Depot preparations reduced relapse (RR 0·31, 95% CI 0·21-0·41) more than did oral drugs (0·46, 0·37-0·57; p=0·03); depot haloperidol (RR 0·14, 95% CI 0·04-0·55) and fluphenazine (0·23, 0·14-0·39) had the greatest effects. The effects of antipsychotic drugs were greater in two unblinded trials (0·26, 0·17-0·39) than in most blinded studies (0·42, 0·35-0·51; p= 0·03). In a meta-regression, the difference between drug and placebo decreased with study length. Maintenance treatment with antipsychotic drugs benefits patients with schizophrenia. The advantages of these drugs must be weighed against their side-effects. Future studies should focus on outcomes of social participation and clarify the long-term morbidity and mortality of these drugs. German Ministry of Education and Research. Copyright © 2012 Elsevier Ltd. All rights reserved.
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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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              Adherence to treatment with antipsychotic medication and health care costs among Medicaid beneficiaries with schizophrenia.

              The authors' goal was to evaluate the relationship between adherence to treatment with antipsychotic medication and health expenditures. A secondary objective was to identify risk factors predictive of nonadherence. Data included Medicaid eligibility and claims data from 1998 to 2000 for San Diego County, Calif. Pharmacy records were used to assess adherence to treatment with antipsychotic medication according to the cumulative possession ratio (the number of days medications were available for consumption divided by the number of days subjects were eligible for Medi-Cal). Regression models were used to examine risk factors, hospitalizations, and costs associated with nonadherence, partial adherence, adherence, and excess fills of antipsychotic medication. Forty-one percent of Medicaid beneficiaries with schizophrenia were found to be adherent to treatment with their antipsychotic medications: 24% were nonadherent, 16% were partially adherent, and 19% were excess fillers. Rates of psychiatric hospitalization were lower for those who were adherent (14%) than for those who were nonadherent (35%), partially adherent (24%), or had excess fills (25%). Rates of medical hospitalization were lower for those who were adherent (7%) than for those who were nonadherent (13%) or had excess fills (12%). Those who were adherent had significantly lower hospital costs than the other groups; pharmacy costs were higher among those who were adherent than among those who were nonadherent or partially adherent and were highest for excess fillers. Total costs for excess fillers (14,044 US dollars) were substantially higher than total costs for any other group. Despite the widespread use of atypical antipsychotic medications, alarmingly high rates of both underuse and excessive filling of antipsychotic prescriptions were found in Medicaid beneficiaries with schizophrenia. The high rates of antipsychotic nonadherence and associated negative consequences suggest interventions on multiple levels.
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                Author and article information

                Contributors
                Journal
                Ann Gen Psychiatry
                Ann Gen Psychiatry
                Annals of General Psychiatry
                BioMed Central
                1744-859X
                2013
                23 October 2013
                : 12
                : 32
                Affiliations
                [1 ]Department of Psychiatry, Hospital Meixoeiro, Complejo Hospitalario Universitario de Vigo, Vigo 36200, Spain
                [2 ]Janssen-Cilag NV/SA, Antwerpseweg 15-17, Beerse 2340, Belgium
                [3 ]Janssen Health Economics Market Access and Reimbursement, Europe, Middle East and Africa, Hammerbakken 19, Birkerød 3460, Denmark
                [4 ]Medical and Scientific Affairs, Janssen-Cilag Europe, Middle East and Africa, Johnson & Johnson Platz 5a, Neuss 41470, Germany
                Article
                1744-859X-12-32
                10.1186/1744-859X-12-32
                4015712
                24148707
                66dc8c79-df4a-48b0-bb78-fca7f12760a1
                Copyright © 2013 Olivares et al.; licensee BioMed Central Ltd.

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 20 November 2012
                : 7 October 2013
                Categories
                Review

                Clinical Psychology & Psychiatry
                relapse,hospitalization,schizophrenia,definition,adherence,drivers
                Clinical Psychology & Psychiatry
                relapse, hospitalization, schizophrenia, definition, adherence, drivers

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