Abstract
Background
It is becoming increasingly clear that longer duration of untreated psychosis (DUP) is associated with adverse clinical outcomes in patients with psychosis spectrum disorders. Especially because this association is often cited when justifying early intervention efforts, it is imperative to better understand underlying biological mechanisms.
Methods
We recruited 74 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. DWI scans were acquired with opposite phase encoding directions [TR/TE: 3230ms/ 89.20ms; multiband acceleration factor 4, Flip angle: 84°; slice thickness 1.5mm, 92 slices, voxel size 1.5mm3, 92 diffusion weighted images distributed equally over 2 shells with b-values of ̴ 1500s/mm2 and ̴ 3000s/mm2, as well as 7 interspersed b= ̴ 0s/mm2 images]). Preprocessing of DWI images was performed in TORTOISE (version 3.1.2). This included correction for thermal noise, Gibbs-ringing, high b-value based bulk motion and eddy-current distortions using a MAP-MRI model, resampling of images to 1mm3, and rotation of gradient tables independently for each DWI phase encoding direction. Then, DR-BUDDI was used to correct EPI distortions with input from the anatomical image and to combine the two datasets using geometric averaging to generate the final corrected dataset. Tensors were computed with DIFF_CALC using a linear fitting algorithm. To spatially normalize images to the Illinois Institute of Technology atlas (IIT4) space, we implemented an optimized non-linear image registration procedure using a modified version of 3dQwarp in AFNI. 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.
Results
Groups did not differ in age (FEP: 23.83+/-6.21 years; HC: 24.78+/-6.24 years), sex (FEP: 65.2% male; HC: 64.4% male), or parental socioeconomic status (FEP: 5.95+/-4.83; HC: 4.22+/-4.06). We found decreased whole brain FA and AD in medication-naive FEP compared to 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.
Discussion
To our knowledge, this is the first study to examine a putative role of white matter integrity in the observed association between DUP and clinical outcomes in first episode psychosis. 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.
The Role of Untreated Psychosis in Neurodegeneration: A Review of Hypothesized Mechanisms of Neurotoxicity in First-Episode Psychosis