The role of PANSS symptoms and adverse events in explaining the effects of paliperidone on social functioning: a causal mediation analysis approach.

To date, no study has evaluated the joint role of symptoms and adverse events as mediators of the effect of second-generation antipsychotics on patients' social functioning. We used recently developed methods for mediation analysis with multiple mediators to clarify the interplay of adverse events and symptoms in explaining the effects of paliperidone (R code for implementing the mediation analysis for multiple mediators is provided). We used data from 490 participants in a 6-week randomized dose-response trial that assigned three fixed dosages of ER OROS paliperidone (3, 9, and 15 mg/day). The primary outcome was an individual's score on the social performance scale assessed after 6 weeks. The sum of Positive and Negative Syndrome Scale (PANSS), weight gain, and extrapyramidal symptoms measured via the Simpson-Angus Scale after 5 weeks were investigated as potential mediators and effect modifiers of treatment effects. Results from mediation analyses showed that the improvements in social functioning are partly explained by reduction in PANSS symptoms. Suggestive evidence that adverse events could play a role as mediators was found. In particular, weight gain displayed a non-linear relationship with social functioning, whereby beneficial effects observed at small levels of weight gain were reduced in the presence of excessive weight gain. In conclusion, we found that the short-term effects of paliperidone on social functioning were dependent on the successful reduction in PANSS symptoms and possibly the occurrence of excessive weight gain, thus suggesting future directions for treatment and interventions.