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White matter integrity, duration of untreated psychosis, and antipsychotic treatment response in medication-naïve first-episode psychosis patients

Abstract

It is becoming increasingly clear that longer duration of untreated psychosis (DUP) is associated with adverse clinical outcomes in patients with psychosis spectrum disorders. Because this association is often cited when justifying early intervention efforts, it is imperative to better understand underlying biological mechanisms. We enrolled 66 antipsychotic-naïve first-episode psychosis (FEP) patients and 45 matched healthy controls in this trial. At baseline, we used a human connectome style diffusion-weighted imaging (DWI) sequence to quantify white matter integrity in both groups. Patients then received 16 weeks of treatment with risperidone, 51 FEP completed the trial. We compared whole-brain fractional anisotropy (FA), mean diffusivity, axial diffusivity (AD), and radial diffusivity between groups. To test if structural white matter integrity mediates the relationship between longer DUP and poorer treatment response, we fit a mediator model and estimated indirect effects. We found decreased whole-brain FA and AD in medication-naive FEP compared with controls. In patients, lower FA was correlated with longer DUP (r = −0.32; p = 0.03) and poorer subsequent response to antipsychotic treatment (r = 0.40; p = 0.01). Importantly, we found a significant mediation effect for FA (indirect effect: −2.70; p = 0.03), indicating that DUP exerts its effects on treatment response through affecting white matter integrity. Our data provide empirical support to the idea the DUP may have fundamental pathogenic effects on the natural history of psychosis, suggest a biological mechanism underlying this phenomenon, and underscore the importance of early intervention efforts in this disabling neuropsychiatric syndrome.

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Fig. 1: Progress thorugh phases of the trial.
Fig. 2: Diffusion-weighted imaging (DWI) data processing pipeline.
Fig. 3: White matter integrity, duration of untreated psychosis, and response to antipsychotic treatment.
Fig. 4: Regional patterns of associations between white matter integrity and duration of untreated psychosis (DUP) as well as to response to antipsychotic treatment (TR).

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Acknowledgements

This work was supported by the National Institute of Mental Health (R01MH112800 and R01MH102951, ACL; K23MH106683, NVK). We would like to thank UAB IT Research Computing for providing the HPC resources (compute, storage and networking) for this project. Cheaha is supported in part by the National Science Foundation under Grant No. OAC-1541310, the University of Alabama at Birmingham, and the Alabama Innovation Fund.

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Correspondence to Nina Vanessa Kraguljac.

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ACL has received an investigator initiated grant from Janssen Pharmaceuticals. The other authors declare that they have no conflict of interest.

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Kraguljac, N.V., Anthony, T., Morgan, C.J. et al. White matter integrity, duration of untreated psychosis, and antipsychotic treatment response in medication-naïve first-episode psychosis patients. Mol Psychiatry 26, 5347–5356 (2021). https://doi.org/10.1038/s41380-020-0765-x

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