Treatments of Negative Symptoms in Schizophrenia: Meta-Analysis of 168 Randomized Placebo-Controlled Trials

Fusar‐Poli, Paolo; Papanastasiou, Evangelos; Ståhl, Daniel; Rocchetti, Matteo; Carpenter, William T.; Shergill, Sukhwinder S.; McGuire, Philip

doi:10.1093/schbul/sbu170

Cited by 550 publications

(382 citation statements)

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“…These investigators concluded that antidepressants prescribed along with antipsychotics were more effective in treating the negative symptoms of schizophrenia than antipsychotics alone. They reported a small-to-medium effect size (−0.48; p < 0.05), comparable with a later meta-analysis of 26 relevant RCTs by Fusar-Poli et al 57 which yielded similar, respective figures (−0.349; p = 0.001). Nevertheless, a Cochrane review, 58 although agreeing that a combination of antipsychotics and antidepressants may be effective in treating negative symptoms of schizophrenia, considered that the research information available was currently too limited to allow any firm conclusions to be drawn, and that large, pragmatic, well-designed and well-reported long-term trials were justified.…”

Section: Efficacy Of Antidepressant Augmentation For Negative Symptomssupporting

confidence: 79%

Antidepressant Controlled Trial For Negative Symptoms In Schizophrenia (ACTIONS): a double-blind, placebo-controlled, randomised clinical trial

Barnes

Leeson

Paton

et al. 2016

Health Technol Assess

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BackgroundNegative symptoms of schizophrenia represent deficiencies in emotional responsiveness, motivation, socialisation, speech and movement. When persistent, they are held to account for much of the poor functional outcomes associated with schizophrenia. There are currently no approved pharmacological treatments. While the available evidence suggests that a combination of antipsychotic and antidepressant medication may be effective in treating negative symptoms, it is too limited to allow any firm conclusions.ObjectiveTo establish the clinical effectiveness and cost-effectiveness of augmentation of antipsychotic medication with the antidepressant citalopram for the management of negative symptoms in schizophrenia.DesignA multicentre, double-blind, individually randomised, placebo-controlled trial with 12-month follow-up.SettingAdult psychiatric services, treating people with schizophrenia.ParticipantsInpatients or outpatients with schizophrenia, on continuing, stable antipsychotic medication, with persistent negative symptoms at a criterion level of severity.InterventionsEligible participants were randomised 1 : 1 to treatment with either placebo (one capsule) or 20 mg of citalopram per day for 48 weeks, with the clinical option at 4 weeks to increase the daily dosage to 40 mg of citalopram or two placebo capsules for the remainder of the study.Main outcome measuresThe primary outcomes were quality of life measured at 12 and 48 weeks assessed using the Heinrich’s Quality of Life Scale, and negative symptoms at 12 weeks measured on the negative symptom subscale of the Positive and Negative Syndrome Scale.ResultsNo therapeutic benefit in terms of improvement in quality of life or negative symptoms was detected for citalopram over 12 weeks or at 48 weeks, but secondary analysis suggested modest improvement in the negative symptom domain, avolition/amotivation, at 12 weeks (mean difference –1.3, 95% confidence interval –2.5 to –0.09). There were no statistically significant differences between the two treatment arms over 48-week follow-up in either the health economics outcomes or costs, and no differences in the frequency or severity of adverse effects, including corrected QT interval prolongation.LimitationsThe trial under-recruited, partly because cardiac safety concerns about citalopram were raised, with the 62 participants recruited falling well short of the target recruitment of 358. Although this was the largest sample randomised to citalopram in a randomised controlled trial of antidepressant augmentation for negative symptoms of schizophrenia and had the longest follow-up, the power of statistical analysis to detect significant differences between the active and placebo groups was limited.ConclusionAlthough adjunctive citalopram did not improve negative symptoms overall, there was evidence of some positive effect on avolition/amotivation, recognised as a critical barrier to psychosocial rehabilitation and achieving better social and community functional outcomes. Comprehensive assessment of side-effect burden did not identify any serious safety or tolerability issues. The addition of citalopram as a long-term prescribing strategy for the treatment of negative symptoms may merit further investigation in larger studies.Future workFurther studies of the viability of adjunctive antidepressant treatment for negative symptoms in schizophrenia should include appropriate safety monitoring and use rating scales that allow for evaluation of avolition/amotivation as a discrete negative symptom domain. Overcoming the barriers to recruiting an adequate sample size will remain a challenge.Trial registrationEuropean Union Drug Regulating Authorities Clinical Trials (EudraCT) number 2009-009235-30 and Current Controlled Trials ISRCTN42305247.FundingThis project was funded by the NIHR Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 20, No. 29. See the NIHR Journals Library website for further project information.

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Section: Efficacy Of Antidepressant Augmentation For Negative Symptomssupporting

confidence: 79%

Antidepressant Controlled Trial For Negative Symptoms In Schizophrenia (ACTIONS): a double-blind, placebo-controlled, randomised clinical trial

Barnes

Leeson

Paton

et al. 2016

Health Technol Assess

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“…1,9 In spite of the strong negative impact of apathy related symptoms in schizophrenia, 7 treatment studies for this frequent behavioral condition have provided limited evidence of efficiency. 10 One reason for this could be the simplistic conception of apathy, frequently considered as a unitary syndrome. However, there is now evidence that apathy can no longer be considered as a unique construct but rather as a multidimensional and multifaceted psychopathological state comprising cognitive, emotional, behavioral and self-initiation components, with different underlying psychological, biological or environmental processes.…”

Section: Introductionmentioning

confidence: 99%

Working Memory Deficit as a Risk Factor for Severe Apathy in Schizophrenia: A 1-Year Longitudinal Study

Raffard

Gutierrez

Yazbek

et al. 2016

SCHBUL

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Apathy, described as impaired motivation and goal-directed behavior, is a common yet often overlooked multidimensional psychopathological state in schizophrenia. Its underlying cognitive processes remain largely unexplored. Data was drawn from a longitudinal hospital study of patients with a DSM-IV diagnosis of schizophrenia; 137 (82.5%) participated at the 1-month follow-up and 81 (59.1%) at the 1-year follow-up. Apathy was assessed with the Lille Apathy Rating Scale, validated in French and in schizophrenia. Severe apathy, overall (total score > −13) and on 4 previously identified distinct dimensions, was considered. Episodic verbal learning was assessed with the California Verbal Learning Test, executive functioning with the Trail Making Test, the Six Element Test and the Stop Signal Paradigm and working memory with the Letter-Number Sequencing Test. After controlling for confounding variables, only episodic verbal learning was associated with severe overall apathy in the cross-sectional study. At 1 year, working memory was associated with an increased risk of severe overall apathy, adjusting for baseline apathy. Using a dimensional approach to apathy, specific types of cognition were found to be associated with specific dimensions of apathy. Our findings confirm the need for a multidimensional approach of negative symptoms in schizophrenia. Moreover, cognitive functioning could be a risk factor for developing severe apathy. Cognitive remediation may thus be a useful non-pharmacological intervention for treating apathy in schizophrenia patients.

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“…For example, a recent meta-analyses of negative symptom clinical trials revealed most did not even deal with the primary/secondary distinction in discussion and almost none used a study design that would permit an efficacy interpretation. 11 Even as an editor I have little success in bringing strong inference methods into common use. The vast majority of research in our field is not based on an important hypothesis in a theoretical context where negative results force a new conceptualization or where competing hypotheses are separated into valid and nonvalid.…”

Section: W T Carpentermentioning

confidence: 99%

Fifty Years: Do Over or Move Forward

Carpenter

2017

Schizophrenia Bulletin

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The following text reflects remarks presented at the 2016 SIRS meeting where four of us from the durable goods department were asked to comment on what we would do if starting our careers today. For reasons best understood in the framework of ego psychology I opted to indicate how I would change what I have done before speculating on beginning a career now envisioning the next 50 years.My best contributions to knowledge and understanding regarding schizophrenia have been in the context of bright and fun colleagues who think deeply and critically. My most regrettable self-identified flaw is the failure to be bold in pressing the field to change rapidly in areas that related to our data and my understanding of collective knowledge. Several examples will illustrate before commenting on the future I would like to have.1. Stop DSM-III from moving schizophrenia to a reality distortion disorder. In the late 1960s it was clear that the diagnosis of schizophrenia needed to be harmonized internationally and a (the) critical problem was perceived as a broad definition applied in the United States that ignore the central features of true or nuclear schizophrenia. These features were not the weakening of the well-springs of volition that Kraepelin defined, together with the dissociative pathology described by Bleuler, as the two central clinical features. Rather, psychopathology proposed by Schneider as indicating the presence of schizophrenia and by Langsfeldt to distinguish true from pseudo schizophrenia was viewed as critical. DSM-III gave unique status to first rank symptoms (FRS) with the presence of a single FRS being sufficient to meet the criteria for a diagnosis of schizophrenia.In the early 1970's, together with John Strauss and John Bartko, we conducted the only empirical test of the central hypotheses related to Langfeldt and Schneider criteria. 1,2 We found them in psychotic conditions other than schizophrenia and within schizophrenia these symptoms lacked prognostic significance. Schneider and Langfeldt positive schizophrenia did not differ from schizophrenia without these reality distortion symptoms. Heterogeneity of the syndrome was not reduced. My mistake was to only make these data known to the DSM-III leaders and publish results, trusting the normal processes to be effective. The result was a unique role in DSM for FRSs that was not changed until DSM-5 in 2013. Negative symptoms were omitted from the criteria DSM-III and the concept shifted to a reality distortion syndrome (ego boundary disturbances if you prefer the concepts of 50 years ago) contributing to the greatly diminished current attention to thought disorder. We also provided data on the clinical features most discriminating in differential diagnosis of schizophrenia and published in Science without any effect on the DSM-III criteria. 3At the SIRS conference I noted the effectiveness of a forceful personality and believe that if I had been more like Fuller Torrey I would have found a way for science rather than pre-conceptions to define core path...

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Treatments of Negative Symptoms in Schizophrenia: Meta-Analysis of 168 Randomized Placebo-Controlled Trials

Abstract: Although some statistically significant effects on negative symptoms were evident, none reached the threshold for clinically significant improvement.

Cited by 550 publications

References 49 publications

Antidepressant Controlled Trial For Negative Symptoms In Schizophrenia (ACTIONS): a double-blind, placebo-controlled, randomised clinical trial

Antidepressant Controlled Trial For Negative Symptoms In Schizophrenia (ACTIONS): a double-blind, placebo-controlled, randomised clinical trial

Working Memory Deficit as a Risk Factor for Severe Apathy in Schizophrenia: A 1-Year Longitudinal Study

Fifty Years: Do Over or Move Forward

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