293. Differential longitudinal changes in spontaneous neural activity in treatment-resistant schizophrenia patients undergoing clozapine treatment

Abstract

Abstract Background While abnormal spontaneous neural activity within cortico-striatal circuits is a hallmark feature of schizophrenia, a significant subset of patients presents with treatment-resistant schizophrenia (TRS), characterized by persistent severe symptoms despite multiple standard treatments. Clozapine remains the only effective pharmacological option for TRS, yet its unique mechanism of action on brain function is not fully understood. Although functional and structural abnormalities within these circuits have been frequently noted in TRS patients, longitudinal neurobiological studies assessing the impact of clozapine initiation on intrinsic brain activity and its correlation with clinical improvement are scarce. Aims & Objectives We aimed to investigate the divergent longitudinal trajectory of spontaneous brain activity by comparing TRS patients commencing clozapine with non-treatment-resistant schizophrenia (NTRS) patients maintained on standard medication over the same period, thereby seeking neural substrates specifically related to clozapine treatment efficacy and associated symptomatic changes. Method Both the TRS and NTRS groups (30 patients each) were included in this longitudinal investigation. Resting-state functional magnetic resonance imaging scans were acquired at baseline and after an 18-week follow-up. Changes in the fractional amplitude of low-frequency fluctuations (fALFF), a metric of spontaneous neural activity, were quantified. Clinical symptoms were evaluated concurrently using the positive and negative syndrome scale (PANSS). We assessed the group × time interaction on fALFF and examined correlations between fALFF alterations and PANSS score changes within the interacting region. Results No significant demographic differences (gender or age) were observed between the groups. A significant group × time interaction effect on fALFF was identified in the left inferior parietal cortex (IPC), indicating that the pattern of change in spontaneous brain activity over 18 weeks was significantly different between the two groups. Specifically, fALFF values in the IPC increased in the TRS group following clozapine commencement, whereas they decreased in the NTRS group over the follow-up period. Analysis of both groups combined revealed a negative trend between changes in IPC fALFF value and changes in total PANSS. Discussion & Conclusions The initiation of clozapine treatment in TRS is linked to a divergent longitudinal trajectory of spontaneous brain activity within the inferior parietal cortex (IPC). This differential fALFF change suggests that pharmacological factors unique to clozapine may critically influence IPC function, a region pivotal for attention and reality monitoring. Our findings provide novel neurobiological evidence specifically concerning the longitudinal effect of clozapine in TRS and highlight the IPC as a key region associated with therapeutic outcomes. Further studies are required to fully elucidate the mechanism by which clozapine modulates IPC activity and its long-term functional implications.