Longitudinal Changes in Functional Connectivity in Antipsychotic-treated and Antipsychotic-naive Patients with First Episode Psychosis

Abstract Background: Altered functional connectivity (FC) is a common finding in resting-state functional Magnetic Resonance Imaging (rs-fMRI) studies of people with psychosis, yet how FC disturbances evolve in the early stages of illness, and how antipsychotics may influence the temporal evolution of these disturbances, remains unclear. Here, we scanned first episode psychosis (FEP) patients who were and were not exposed to antipsychotic medication during the first six months of illness at baseline, three months, and 12 months, to characterize how FC changes over time and in relation to medication use. Methods: Sixty-two antipsychotic-naive patients with FEP received either an atypical antipsychotic or a placebo pill over a treatment period of 6 months. Both FEP groups received intensive psychosocial therapy. A healthy control group (n=27) was also recruited. A total of 202 rs-fMRI scans were obtained across three timepoints: baseline, 3-months and 12-months. Our primary aim was to differentiate patterns of FC in antipsychotic-treated and antipsychotic-naive patients within the first 3 months of treatment, and to examine associations with clinical and functional outcomes. A secondary aim was to investigate long-term effects at the 12-month timepoint. Results: At baseline, FEP patients showed widespread functional dysconnectivity in comparison to controls, with reductions predominantly affecting interactions between the default mode network (DMN), limbic systems, and the rest of the brain. From baseline to 3 months, patients receiving placebo showed increased FC principally within the same systems, and some of these changes correlated with improved clinical outcomes. Antipsychotic exposure was associated with increased FC primarily between the thalamus and the rest of the brain. At the 12-month follow-up, antipsychotic treatment was associated with a prolonged increase of FC primarily in the DMN and limbic systems. Conclusions and Relevance: Antipsychotic-naive FEP patients show widespread functional dysconnectivity at baseline, followed by an early normalization of DMN and paralimbic dysfunction in patients receiving a psychosocial intervention only. Antipsychotic exposure is associated with distinct FC changes, principally concentrated on thalamo-cortical and limbic networks.