Neural mechanism underlying the beneficial effect of Theory of Mind psychotherapy on early-onset schizophrenia: a randomized controlled trial

BACKGROUND: Psychosocial interventions have emerged as an important component of a comprehensive therapeutic approach in early-onset schizophrenia, typically representing a more severe form of the disorder. Despite the feasibility and efficacy of Theory of Mind (ToM) psychotherapy for schizophrenia, relatively little is known regarding the neural mechanism underlying its effect on early-onset schizophrenia. METHODS: We performed a randomized, active controlled trial in patients with early-onset schizophrenia, who were randomly allocated into either an intervention (ToM psychotherapy) or an active control (health education) group. Diffusion tensor imaging data were collected to construct brain structural networks, with both global and regional topological properties measured using graph theory. RESULTS: We enrolled 28 patients with early-onset schizophrenia in our study. After 5 weeks of treatment, both the intervention and active control groups showed significant improvement in psychotic symptoms, yet the improvement was greater in the intervention group. Importantly, in contrast with no brain structural network change after treatment in the active control group, the intervention group showed increased nodal centrality of the left insula that was associated with psychotic symptom improvement. LIMITATIONS: We did not collect important information concerning the participants’ cognitive abilities, particularly ToM performance. CONCLUSION: These findings suggest a potential neural mechanism by which ToM psychotherapy exerts a beneficial effect on early-onset schizophrenia via strengthening the coordination capacity of the insula in brain structural networks, which may provide a clinically translatable biomarker for monitoring or predicting responses to ToM psychotherapy. Clinical trial registration: NCT05577338; ClinicalTrials.gov