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      What is the risk-benefit ratio of long-term antipsychotic treatment in people with schizophrenia? : FORUM - IS THE RISK-BENEFIT RATIO OF LONG-TERM ANTIPSYCHOTIC TREATMENT FAVORABLE FOR MOST PEOPLE WITH SCHIZOPHRENIA, AND WHAT CAN WE DO TO IMPROVE IT?

      1 , 2 , 3 , 4 , 1 , 2 , 3 , 1 , 2 , 3
      World Psychiatry
      Wiley

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          Abstract

          <p class="first" id="d10401761e218">The long‐term benefit‐to‐risk ratio of sustained antipsychotic treatment for schizophrenia has recently been questioned. In this paper, we critically examine the literature on the long‐term efficacy and effectiveness of this treatment. We also review the evidence on the undesired effects, the impact on physical morbidity and mortality, as well as the neurobiological correlates of chronic exposure to antipsychotics. Finally, we summarize factors that affect the risk‐benefit ratio. There is consistent evidence supporting the efficacy of antipsychotics in the short term and mid term following stabilization of acute psychotic symptoms. There is insufficient evidence supporting the notion that this effect changes in the long term. Most, but not all, of the long‐term cohort studies find a decrease in efficacy during chronic treatment with antipsychotics. However, these results are inconclusive, given the extensive risk of bias, including increasing non‐adherence. On the other hand, long‐term studies based on national registries, which have lower risk of bias, find an advantage in terms of effectiveness during sustained antipsychotic treatment. Sustained antipsychotic treatment has been also consistently associated with lower mortality in people with schizophrenia compared to no antipsychotic treatment. Nevertheless, chronic antipsychotic use is associated with metabolic disturbance and tardive dyskinesia. The latter is the clearest undesired clinical consequence of brain functioning as a potential result of chronic antipsychotic exposure, likely from dopaminergic hypersensitivity, without otherwise clear evidence of other irreversible neurobiological changes. Adjunctive psychosocial interventions seem critical for achieving recovery. However, overall, the current literature does not support the safe reduction of antipsychotic dosages by 50% or more in stabilized individuals receiving adjunctive psychosocial interventions. In conclusion, the critical appraisal of the literature indicates that, although chronic antipsychotic use can be associated with undesirable neurologic and metabolic side effects, the evidence supporting its long‐term efficacy and effectiveness, including impact on life expectancy, outweighs the evidence against this practice, overall indicating a favorable benefit‐to‐risk ratio. However, the finding that a minority of individuals diagnosed initially with schizophrenia appear to be relapse free for long periods, despite absence of sustained antipsychotic treatment, calls for further research on patient‐level predictors of positive outcomes in people with an initial psychotic presentation. </p>

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          A systematic review and meta-analysis of recovery in schizophrenia.

          Our primary aims were (a) to identify the proportion of individuals with schizophrenia and related psychoses who met recovery criteria based on both clinical and social domains and (b) to examine if recovery was associated with factors such as gender, economic index of sites, and selected design features of the study. We also examined if the proportions who met our definition of recovery had changed over time. A comprehensive search strategy was used to identify potential studies, and data were extracted for those that met inclusion criteria. The proportion who met our recovery criteria (improvements in both clinical and social domains and evidence that improvements in at least 1 of these 2 domains had persisted for at least 2 years) was extracted from each study. Meta-regression techniques were used to explore the association between the recovery proportions and the selected variables. We identified 50 studies with data suitable for inclusion. The median proportion (25%-75% quantiles) who met our recovery criteria was 13.5% (8.1%-20.0%). Studies from sites in countries with poorer economic status had higher recovery proportions. However, there were no statistically significant differences when the estimates were stratified according to sex, midpoint of intake period, strictness of the diagnostic criteria, duration of follow-up, or other design features. Based on the best available data, approximately, 1 in 7 individuals with schizophrenia met our criteria for recovery. Despite major changes in treatment options in recent decades, the proportion of recovered cases has not increased.
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            Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia.

            Progressive brain volume changes in schizophrenia are thought to be due principally to the disease. However, recent animal studies indicate that antipsychotics, the mainstay of treatment for schizophrenia patients, may also contribute to brain tissue volume decrement. Because antipsychotics are prescribed for long periods for schizophrenia patients and have increasingly widespread use in other psychiatric disorders, it is imperative to determine their long-term effects on the human brain. To evaluate relative contributions of 4 potential predictors (illness duration, antipsychotic treatment, illness severity, and substance abuse) of brain volume change. Predictors of brain volume changes were assessed prospectively based on multiple informants. Data from the Iowa Longitudinal Study. Two hundred eleven patients with schizophrenia who underwent repeated neuroimaging beginning soon after illness onset, yielding a total of 674 high-resolution magnetic resonance scans. On average, each patient had 3 scans (≥2 and as many as 5) over 7.2 years (up to 14 years). Brain volumes. During longitudinal follow-up, antipsychotic treatment reflected national prescribing practices in 1991 through 2009. Longer follow-up correlated with smaller brain tissue volumes and larger cerebrospinal fluid volumes. Greater intensity of antipsychotic treatment was associated with indicators of generalized and specific brain tissue reduction after controlling for effects of the other 3 predictors. More antipsychotic treatment was associated with smaller gray matter volumes. Progressive decrement in white matter volume was most evident among patients who received more antipsychotic treatment. Illness severity had relatively modest correlations with tissue volume reduction, and alcohol/illicit drug misuse had no significant associations when effects of the other variables were adjusted. Viewed together with data from animal studies, our study suggests that antipsychotics have a subtle but measurable influence on brain tissue loss over time, suggesting the importance of careful risk-benefit review of dosage and duration of treatment as well as their off-label use.
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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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                Author and article information

                Journal
                World Psychiatry
                World Psychiatry
                Wiley
                17238617
                June 2018
                June 2018
                May 24 2018
                : 17
                : 2
                : 149-160
                Affiliations
                [1 ]Zucker Hillside Hospital, Psychiatry Research, Northwell Health; Glen Oaks NY USA
                [2 ]Hofstra Northwell School of Medicine; Hempstead NY USA
                [3 ]Feinstein Institute for Medical Research; Manhasset NY USA
                [4 ]Department of Child and Adolescent Psychiatry; Charité Universitätsmedizin; Berlin Germany
                Article
                10.1002/wps.20516
                5980517
                29856543
                d7b1955a-0a11-471b-8466-634c3bee4bfc
                © 2018

                http://doi.wiley.com/10.1002/tdm_license_1.1

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