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.

迄今为止，还没有研究评估症状和不良事件作为第二代抗精神病药对患者社会功能影响的中介作用的联合作用。我们使用最近开发的多介质中介分析方法来阐明不良事件和症状之间的相互作用，以解释帕潘立酮的作用（提供了用于实施多介质中介分析的 R 代码）。我们在一项为期 6 周的随机剂量反应试验中使用了 490 名参与者的数据，该试验分配了三种固定剂量的 ER OROS 帕潘立酮（3、9 和 15 毫克/天）。主要结果是 6 周后评估的个人社会表现量表得分。 5周后通过辛普森-安格斯量表测量的阳性和阴性症状量表（PANSS）、体重增加和锥体外系症状的总和被作为治疗效果的潜在调节因素和效果调节剂进行研究。中介分析结果表明，社会功能的改善部分可以通过 PANSS 症状的减少来解释。发现了不良事件可能发挥中介作用的暗示性证据。特别是，体重增加与社会功能呈现非线性关系，在体重增加过多的情况下，小体重增加所观察到的有益效果会减少。总之，我们发现帕潘立酮对社会功能的短期影响取决于 PANSS 症状的成功减少以及可能发生的体重过度增加，从而提出了未来的治疗和干预方向。