A systematic review and synthesis of 489 studies investigating treatments for negative symptoms in the schizophrenia spectrum: Trial designs, demographics and clinical characteristics.

Negative symptoms in schizophrenia spectrum are associated with minimal treatment responses. The search for effective treatments is potentially hampered by heterogenous study-designs and sample characteristics depending on the intervention category. This PRISMA-compliant systematic review/synthesis aims to describe the literature on negative symptoms interventions for schizophrenia spectrum disorders by comparing 12 study design, demographical and clinical variables in different intervention categories: antipsychotics (AP), other pharmacological agents (OPA), brain stimulation (BS), psychological/psychosocial (PSI), lifestyle (LS), mixed interventions. Kruskal-Wallis and Chi-square tests measured differences between intervention-groups. Out of 19,935 articles, 489 (AP=149/OPA=187/BS=49/PSI=79/LS=19/mixed=6) were selected for data extraction. Concerning study designs, AP had the largest average arm size (mean ± SD=91.1 ± 122.8participants), OPA the highest double/triple-blinding (97.9 %) rates, PSI the longest follow-up (26.7 ± 21.8weeks). Age/gender demographical differences were significant but of negligible magnitude. OPA illness duration (14.8 ± 9.0years) was longer compared to AP (11.4 ± 6.7years). Positive and Negative Syndrome Scale (PANSS) negative scores were milder in PSI (18.6 ± 6.9) compared to AP/OPA/BS (23.8 ± 6.4/23.4 ± 4.9/24.2 ± 9.2). PANSS total scores were worse in AP (83.6 ± 18.2) than in OPA/BS/PSI (77.1 ± 20.5/75.5 ± 14.7/67.0 ± 23.3). The same was true for dropout rates (AP=25.5 %, OPA/BS/PSI=14.3/9.7/14.5 %). Prevalent treatment as usual was "none" for AP (36.7 %) and "antipsychotic" for other categories (42.3-82.8 %). Implementing cross-over, factorial or multi-arm designs may increase the comparability between studies investigating different intervention categories. Concerning clinical differences, reporting individual treatments at baseline and clinical severity, evaluating cognitive profiles and considering patients' perspectives will allow to better understand the efficacy of the available treatments and develop tailored interventions.