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

Abstract

Objectives: Existing treatments for schizophrenia can improve positive symptoms, but it is unclear if they have any impact on negative symptoms. This meta-analysis was conducted to assess the efficacy of available treatments for negative symptoms in schizophrenia.

Methods: All randomized-controlled trials of interventions for negative symptoms in schizophrenia until December 2013 were retrieved; 168 unique and independent placebo-controlled trials were used. Negative symptom scores at baseline and follow-up, duration of illness, doses of medication, type of interventions, and sample demographics were extracted. Heterogeneity was addressed with the I (2) and Q statistic. Standardized mean difference in values of the Negative Symptom Rating Scale used in each study was calculated as the main outcome measure.

Results: 6503 patients in the treatment arm and 5815 patients in the placebo arm were included. No evidence of publication biases found. Most treatments reduced negative symptoms at follow-up relative to placebo: second-generation antipsychotics: -0.579 (-0.755 to -0.404); antidepressants: -0.349 (-0.551 to -0.146); combinations of pharmacological agents: -0.518 (-0.757 to -0.279); glutamatergic medications: -0.289 (-0.478 to -0.1); psychological interventions: -0.396 (-0.563 to -0.229). No significant effect was found for first-generation antipsychotics: -0.531 (-1.104 to 0.041) and brain stimulation: -0.228 (-0.775 to 0.319). Effects of most treatments were not clinically meaningful as measured on Clinical Global Impression Severity Scale.

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

Keywords: antipsychotics; negative symptoms; psychosis; schizophrenia; treatment.

Fig. 1.

Prisma diagram.

Fig. 2.

Forest plot showing the pooled standardized mean difference (SMD) (and 95% CI) for the included placebo-controlled trials. The size of the box represents the weight given to the trials of the respective treatment group. A negative effect size corresponds to improvement in the treatment group relative to the placebo group over time. The red line indicates no statistical significant difference from placebo over time. The dashed line indicates minimally detectable clinical improvements over time. The latter line at y = −0.97 is the predicted SMDs of negative symptoms when mean net CGI-S reduction in treatment is 1 (metaregression of negative symptoms on CGI-S: constant = −0.23, β = .735 [95% CI: 0.423 to 1.047], t = 4.70, P < .0001, adjusted r ² = 42.5%). CGI-S, Clinical Global Impression Severity Scale. For color, see the figure online.

Fig. 3.

Correlation between negative symptoms and CGI-S (CGI-S: Clinical Global Impression Severity Scale); 68 trials included effect size estimates for CGI-S and negative symptoms. A Pearson’s correlation between the 2 measures demonstrated a medium to large correlation between the 2 variables (r = .46, 95% CI: 0.25 to 0.63, P = .0001). A metaregression showed that with CGI-S predicts negative symptoms (β = .735, 95% CI: 0.423 to 1.047, t = 4.7, P < .0001, adjusted r ² = 42.5%). Including treatment group as a covariate in the model slightly increased the effect to β = .744 (95% CI: 0.41 to 1.079, t = 4.45, P < .0001). There were no significant treatment group differences (F(5, 61) = 0.11, P = .99). On the basis of these results we estimated a threshold for minimally detectable clinical improvements over time (y = −0.97 is the predicted SMDs of negative symptoms when mean CGI-S reduction is 1 more in treatment group compared with control group). As a sensitivity analysis, the analysis was rerun without the potential influential case at the left bottom corner (de Lucena et al). The regression coefficient was reduced (β = .48, 95% CI: 0.189 to 0.776, t = 3.28, P = .002) and estimated thresholds for minimal detectable clinical improvement was estimated to be y = −0.78 (95% CI: −1.024 to −0.53). SMD, standardized mean difference.