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      EPA guidance on treatment of negative symptoms in schizophrenia

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          Abstract

          Negative symptoms of schizophrenia remain a major therapeutic challenge. The progress in the conceptualization and assessment is not yet fully reflected by treatment research. Nevertheless, there is a growing evidence base regarding the effects of biological and psychosocial interventions on negative symptoms. The importance of the distinction between primary and secondary negative symptoms for treatment selection might seem evident, but the currently available evidence remains limited. Good clinical practice is recommended for the treatment of secondary negative symptoms. Antipsychotic treatment should be optimized to avoid secondary negative symptoms due to side effects and due to positive symptoms. For most available interventions, further evidence is needed to formulate sound recommendations for primary, persistent, or predominant negative symptoms.

          However, based on currently available evidence recommendations for the treatment of undifferentiated negative symptoms (including both primary and secondary negative symptoms) are provided. Although it has proven difficult to formulate an evidence-based recommendation for the choice of an antipsychotic, a switch to a second-generation antipsychotic should be considered for patients who are treated with a first-generation antipsychotic. Antidepressant add-on to antipsychotic treatment is an option. Social skills training is recommended as well as cognitive remediation for patients who also show cognitive impairment. Exercise interventions also have shown promise. Finally, access to treatment and to psychosocial rehabilitation should be ensured for patients with negative symptoms. Overall, there is definitive progress in the field, but further research is clearly needed to develop specific treatments for negative symptoms.

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          The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.

          Systematic reviews and meta-analyses are essential to summarize evidence relating to efficacy and safety of health care interventions accurately and reliably. The clarity and transparency of these reports, however, is not optimal. Poor reporting of systematic reviews diminishes their value to clinicians, policy makers, and other users. Since the development of the QUOROM (QUality Of Reporting Of Meta-analysis) Statement--a reporting guideline published in 1999--there have been several conceptual, methodological, and practical advances regarding the conduct and reporting of systematic reviews and meta-analyses. Also, reviews of published systematic reviews have found that key information about these studies is often poorly reported. Realizing these issues, an international group that included experienced authors and methodologists developed PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) as an evolution of the original QUOROM guideline for systematic reviews and meta-analyses of evaluations of health care interventions. The PRISMA Statement consists of a 27-item checklist and a four-phase flow diagram. The checklist includes items deemed essential for transparent reporting of a systematic review. In this Explanation and Elaboration document, we explain the meaning and rationale for each checklist item. For each item, we include an example of good reporting and, where possible, references to relevant empirical studies and methodological literature. The PRISMA Statement, this document, and the associated Web site (http://www.prisma-statement.org/) should be helpful resources to improve reporting of systematic reviews and meta-analyses.
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            Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis

            Summary Background Schizophrenia is one of the most common, burdensome, and costly psychiatric disorders in adults worldwide. Antipsychotic drugs are its treatment of choice, but there is controversy about which agent should be used. We aimed to compare and rank antipsychotics by quantifying information from randomised controlled trials. Methods We did a network meta-analysis of placebo-controlled and head-to-head randomised controlled trials and compared 32 antipsychotics. We searched Embase, MEDLINE, PsycINFO, PubMed, BIOSIS, Cochrane Central Register of Controlled Trials (CENTRAL), WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov from database inception to Jan 8, 2019. Two authors independently selected studies and extracted data. We included randomised controlled trials in adults with acute symptoms of schizophrenia or related disorders. We excluded studies in patients with treatment resistance, first episode, predominant negative or depressive symptoms, concomitant medical illnesses, and relapse-prevention studies. Our primary outcome was change in overall symptoms measured with standardised rating scales. We also extracted data for eight efficacy and eight safety outcomes. Differences in the findings of the studies were explored in metaregressions and sensitivity analyses. Effect size measures were standardised mean differences, mean differences, or risk ratios with 95% credible intervals (CrIs). Confidence in the evidence was assessed using CINeMA (Confidence in Network Meta-Analysis). The study protocol is registered with PROSPERO, number CRD42014014919. Findings We identified 54 417 citations and included 402 studies with data for 53 463 participants. Effect size estimates suggested all antipsychotics reduced overall symptoms more than placebo (although not statistically significant for six drugs), with standardised mean differences ranging from −0·89 (95% CrI −1·08 to −0·71) for clozapine to −0·03 (−0·59 to 0·52) for levomepromazine (40 815 participants). Standardised mean differences compared with placebo for reduction of positive symptoms (31 179 participants) varied from −0·69 (95% CrI −0·86 to −0·52) for amisulpride to −0·17 (−0·31 to −0·04) for brexpiprazole, for negative symptoms (32 015 participants) from −0·62 (−0·84 to −0·39; clozapine) to −0·10 (−0·45 to 0·25; flupentixol), for depressive symptoms (19 683 participants) from −0·90 (−1·36 to −0·44; sulpiride) to 0·04 (−0·39 to 0·47; flupentixol). Risk ratios compared with placebo for all-cause discontinuation (42 672 participants) ranged from 0·52 (0·12 to 0·95; clopenthixol) to 1·15 (0·36 to 1·47; pimozide), for sedation (30 770 participants) from 0·92 (0·17 to 2·03; pimozide) to 10·20 (4·72 to 29·41; zuclopenthixol), for use of antiparkinson medication (24 911 participants) from 0·46 (0·19 to 0·88; clozapine) to 6·14 (4·81 to 6·55; pimozide). Mean differences compared to placebo for weight gain (28 317 participants) ranged from −0·16 kg (−0·73 to 0·40; ziprasidone) to 3·21 kg (2·10 to 4·31; zotepine), for prolactin elevation (21 569 participants) from −77·05 ng/mL (−120·23 to −33·54; clozapine) to 48·51 ng/mL (43·52 to 53·51; paliperidone) and for QTc prolongation (15 467 participants) from −2·21 ms (−4·54 to 0·15; lurasidone) to 23·90 ms (20·56 to 27·33; sertindole). Conclusions for the primary outcome did not substantially change after adjusting for possible effect moderators or in sensitivity analyses (eg, when excluding placebo-controlled studies). The confidence in evidence was often low or very low. Interpretation There are some efficacy differences between antipsychotics, but most of them are gradual rather than discrete. Differences in side-effects are more marked. These findings will aid clinicians in balancing risks versus benefits of those drugs available in their countries. They should consider the importance of each outcome, the patients' medical problems, and preferences. Funding German Ministry of Education and Research and National Institute for Health Research
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              A meta-analysis of cognitive remediation for schizophrenia: methodology and effect sizes.

              Cognitive remediation therapy for schizophrenia was developed to treat cognitive problems that affect functioning, but the treatment effects may depend on the type of trial methodology adopted. The present meta-analysis will determine the effects of treatment and whether study method or potential moderators influence the estimates. Electronic databases were searched up to June 2009 using variants of the key words "cognitive," "training," "remediation," "clinical trial," and "schizophrenia." Key researchers were contacted to ensure that all studies meeting the criteria were included. This produced 109 reports of 40 studies in which ≥70% of participants had a diagnosis of schizophrenia, all of whom received standard care. There was a comparison group and allocation procedure in these studies. Data were available to calculate effect sizes on cognition and/or functioning. Data were independently extracted by two reviewers with excellent reliability. Methodological moderators were extracted through the Clinical Trials Assessment Measure and verified by authors in 94% of cases. The meta-analysis (2,104 participants) yielded durable effects on global cognition and functioning. The symptom effect was small and disappeared at follow-up assessment. No treatment element (remediation approach, duration, computer use, etc.) was associated with cognitive outcome. Cognitive remediation therapy was more effective when patients were clinically stable. Significantly stronger effects on functioning were found when cognitive remediation therapy was provided together with other psychiatric rehabilitation, and a much larger effect was present when a strategic approach was adopted together with adjunctive rehabilitation. Despite variability in methodological rigor, this did not moderate any of the therapy effects, and even in the most rigorous studies there were similar small-to-moderate effects. Cognitive remediation benefits people with schizophrenia, and when combined with psychiatric rehabilitation, this benefit generalizes to functioning, relative to rehabilitation alone. These benefits cannot be attributed to poor study methods.
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                Author and article information

                Journal
                Eur Psychiatry
                Eur Psychiatry
                EPA
                European Psychiatry
                Cambridge University Press (Cambridge, UK )
                0924-9338
                1778-3585
                2021
                17 March 2021
                : 64
                : 1
                : e21
                Affiliations
                [1 ]Department of Psychiatry, University of Campania Luigi Vanvitelli , Naples, Italy
                [2 ]Division of Adult Psychiatry, Department of Psychiatry, Geneva University Hospitals , Geneva, Switzerland
                [3 ]Department of Psychiatry and Psychotherapy, Semmelweis University , Budapest, Hungary
                [4 ]Copenhagen Research Centre for Mental Health (CORE), Copenhagen University Hospital , Copenhagen, Denmark
                [5 ]Department of Clinical Medicine, Faculty of Health and Medical Science, University of Copenhagen , Copenhagen, Denmark
                [6 ]Centre for Clinical Intervention and Neuropsychiatric Schizophrenia Research, CINS, Glostrup, Denmark
                [7 ]Center for Neuropsychiatric Schizophrenia Research, CNSR , Glostrup, Denmark
                [8 ]Department of Psychiatry, University of Munich , Munich, Germany
                [9 ]Service de Psychiatrie, CHU de Caen , 14000 Caen, France
                [10 ]Normandie Univ , UNICAEN, ISTS EA 7466, GIP Cyceron, 14000 Caen, France
                [11 ]Normandie Univ, UNICAEN , UFR de Médecine, 14000 Caen, France
                [12 ]Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine University , Düsseldorf, Germany
                Author notes
                [* ]Stefan Kaiser, E-mail: Stefan.Kaiser@ 123456hcuge.ch
                Author information
                https://orcid.org/0000-0002-1592-7656
                https://orcid.org/0000-0002-3013-2034
                https://orcid.org/0000-0002-6195-9456
                https://orcid.org/0000-0002-8530-5596
                Article
                S0924933821000134
                10.1192/j.eurpsy.2021.13
                8057437
                33726883
                3e051795-dd63-47a5-8f4b-dc71c4c4a157
                © The Author(s), 2021. Published by Cambridge University Press on behalf of the European Psychiatric Association 2021

                This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 21 December 2020
                : 14 February 2021
                : 15 February 2021
                Page count
                Figures: 1, Tables: 21, References: 93, Pages: 15
                Categories
                EPA Guidance

                Clinical Psychology & Psychiatry
                negative symptoms,schizophrenia,treatment
                Clinical Psychology & Psychiatry
                negative symptoms, schizophrenia, treatment

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