Effects of Ziprasidone or Haloperidol on Theory of Mind in Patients With Schizophrenia: A 16-week Pilot Trial

Objectives: Schizophrenia is associated with impairment in theory of mind (ToM), which is defined as the ability to make judgments about mental states and is related to medial prefrontal cortical activity. Ziprasidone, but not haloperidol, is known to have a protective effect in the medial prefrontal cortex. Thus, we hypothesized that these 2 drugs would have different efficacy in improving ToM task performance in patients with schizophrenia. Methods: Patients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnosis of schizophrenia matched for sex, duration of illness, and education were randomized to receive ziprasidone (n=30) or haloperidol (n=30). All patients were assessed using the Positive and Negative Syndrome Scale and the Personal and Social Functioning Scale. ToM was assessed using a first-order false belief task, a second-order false belief task, the faux-pas task, and the Reading the Mind in the Eyes Task, in order of developmental complexity and difficulty. The primary outcome was change in ToM performance from baseline to 16 weeks of treatment. Results: For the first-order false belief task, there were no significant differences between the groups ( P >0.05). For the second-order false belief task, the interaction effect was significant ( P <0.05), and the simple effect of time showed a significant difference only in the ziprasidone group ( P <0.001). For the faux-pas task, the interaction effect was not significant ( P >0.05). For the Reading the Mind in the Eyes Task, the interaction effect was significant ( P <0.05), and the simple effect of time showed a significant difference only in the ziprasidone group ( P <0.001). The Positive and Negative Syndrome Scale results were similar between the groups. The ziprasidone group performed better than the haloperidol group on the Personal and Social Functioning Scale. There were no major safety concerns or adverse events. Conclusions: The findings of this study suggest that ziprasidone could improve ToM and might be superior to haloperidol for improving complex ToM as well as personal and social functioning in patients with schizophrenia. Trial Registration Chinese Clinical Trial Register: ChiCTR2200060542.