Abstract
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.
Highlights
The treatment goals for schizophrenia are to rapidly ameliorate or eliminate symptoms, prevent relapse, induce sustained recovery, and improve personal and social functioning
We aimed at investigating the interplay of psychiatric symptoms and adverse events, such as weight gain (WG) and extrapyramidal symptoms, in explaining the short-term effects of paliperidone treatment at different doses on patients’ social functioning
By using recent developments in the field of causal interaction and mediation, we could quantify the role of Positive and Negative Syndrome Scale (PANSS), WG, and extrapyramidal symptoms as mediators of the treatment effect.[14]
Summary
The treatment goals for schizophrenia are to rapidly ameliorate or eliminate symptoms, prevent relapse, induce sustained recovery, and improve personal and social functioning. Positive symptoms refer to an excess or distortion of normal functions (e.g., hallucinations and delusions), and negative symptoms represent a diminution or loss of normal functions.[1] Patient's personal and social functioning remains an area of deficit in patients with schizophrenia,[2] with only limited data available regarding the effects of either atypical or conventional antipsychotic agents on this domain. Among patients affected by psychotic disorders, schizophrenia patients display the highest deficit in social functioning.[3,4] Social functioning has been recognized as an important contributor to overall quality of life and a determinant of treatment success.[4] Cognitive impairments impact functioning skills in schizophrenia patients and it is known that positive and negative symptoms add to the influence of cognitive impairments for prediction of real-world outcomes.[5,6] A study assessing predictors of Social Skills Performance Assessment (SSPA)[7] suggests that specific negative symptoms, including passive-apathetic social withdrawal, blunted affect, and lack of spontaneity are important predictors of SSPA, and of the items capturing social outcomes. The occurrence of side-effects such as extrapyramidal symptoms (EPS) and excessive weight gain (WG)
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