Antipsychotic drugs for patients with schizophrenia and predominant or prominent negative symptoms: a systematic review and meta-analysis
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Negative symptoms are the core of schizophrenia, but whether antipsychotics are efficacious for their treatment is unclear. Moreover, there is debate whether patients in relevant trials should have predominant negative symptoms or whether prominent negative symptoms are also acceptable.
We systematically reviewed randomised, blinded antipsychotic drug trials in patients with schizophrenia and either predominant or prominent negative symptoms (last search Dec 12, 2017). Separate pairwise meta-analyses were conducted in these two populations. The primary outcome was negative symptoms. Depressive, symptoms, positive symptoms, and extrapyramidal side-effects were analysed as causes of secondary negative symptoms.
We included 21 randomized-controlled trials with 3451 participants which revealed the following significant differences in the primary outcome: in patients with predominant negative symptoms amisulpride was superior to placebo (N = 4; n = 590, SMD 0.47, CI 0.23, 0.71), olanzapine was superior to haloperidol in a small trial (n = 35) and cariprazine outperformed risperidone (N = 1, n = 456, SMD − 0.29, CI − 0.48, − 0.11). In patients with prominent negative symptoms, olanzapine and quetiapine were superior to risperidone in single trials. Overall, studies in prominent negative symptoms were potentially more confounded by improvements of secondary negative symptoms.
Amisulpride is the only antipsychotic that outperformed placebo in the treatment of predominant negative symptoms, but there was a parallel reduction of depression. Cariprazine was better than risperidone in a large trial that was well-controlled for secondary negative symptoms, but the trial was sponsored by its manufacturer. Future trials should apply scientifically developed definitions such as the deficit syndrome and the persistent negative symptoms concept.
KeywordsDeficit syndrome Deficit schizophrenia Persistent negative symptoms Depressive symptoms Positive symptoms Study design
This work was supported by a grant from the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, BMBF, Grant Number FKZ 01KG1508). The authors thank Georgia Salanti for the work on the original proposal, Samantha Roberts for help in the literature search and Leonie Reichelt, Hannah Röder, Susanne Bächer and Lio Bäckers for help in data extraction. Special thanks to Rolf Engel, who participated in the development of the project and supervised Marc Krause for his doctoral thesis of which this publication will be part. For full text acquisition and proofreading of the final manuscript, we thank Patricia Kratchowill. We thank all authors of the included studies, particularly those who sent us additional information about their trials.
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Conflict of interest
In the last 3 years, Stefan Leucht has received honoraria for consulting from LB Pharma, Lundbeck, Otsuka, Teva Pharmaceutical Industries Ltd, LTS Lohmann, Geodon Richter, Recordati, Boehringer Ingelheim, and for lectures from Janssen, Lilly, Lundbeck, Otsuka, SanofiAventis and Servier.
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