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

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.

Neurite Orientation Dispersion and Density Imaging (NODDI) and Duration of Untreated Psychosis in Antipsychotic Medication-Naïve First Episode Psychosis Patients.

Background: Diffusion tensor imaging suggests that white matter alterations are already evident in first episode psychosis patients (FEP) and may become more prominent as the duration of untreated psychosis (DUP) increases. But because the tensor model lacks specificity, it remains unclear how to interpret findings on a biological level. Here, we used a biophysical diffusion model, Neurite Orientation Dispersion and Density Imaging (NODDI), to map microarchitecture in FEP, and to investigate associations between DUP and microarchitectural integrity. Methods: We scanned 78 antipsychotic medication-naïve FEP and 64 healthy controls using a multi-shell diffusion weighted sequence and used the NODDI toolbox to compute neurite density (ND), orientation dispersion index (ODI) and extracellular free water (FW) maps. AFNI's 3dttest++ was used to compare diffusion maps between groups and to perform regression analyses with DUP. Results: We found that ND was decreased in commissural and association fibers but increased in projection fibers in FEP. ODI was largely increased regardless of fiber type, and FW showed a mix of increase in decrease across fiber tracts. We also demonstrated associations between DUP and microarchitecture for all NODDI indices. Conclusions: We demonstrated that complex microarchitecture abnormalities are already evident in antipsychotic-naïve FEP. ND alterations are differentially expressed depending on fiber type, while decreased fiber complexity appears to be a uniform marker of white matter deficit in the illness. Importantly, we identified an empirical link between longer DUP and greater white matter pathology across NODDI indices, underscoring the critical importance of early intervention in this devastating illness.

Neurometabolic correlates of 6 and 16 weeks of treatment with risperidone in medication-naive first-episode psychosis patients.

Antipsychotic medications are the cornerstone of treatment in schizophrenia spectrum disorders. In first-episode psychosis, the recommended time for an antipsychotic medication trial is up to 16 weeks, but the biological correlates of shorter and longer antipsychotic treatment trials in these cohorts remain largely unknown. We enrolled 29 medication-naive first-episode patients (FEP) and 22 matched healthy controls (HC) in this magnetic resonance spectroscopy (MRS) study, examining the levels of combined glutamate and glutamine (commonly referred to as Glx) in the bilateral medial prefrontal cortex (MPFC) with a PRESS sequence (TR/TE = 2000/80 ms) before initiation of antipsychotic treatment, after 6 and 16 weeks of treatment with risperidone. Data were quantified in 18 HC and 20 FEP at baseline, for 19 HC and 15 FEP at week 6, and for 14 HC and 16 FEP at week 16. At baseline, none of the metabolites differed between groups. Metabolite levels did not change after 6 or 16 weeks of treatment in patients. Our data suggest that metabolite levels do not change after 6 or 16 weeks of treatment with risperidone in FEP. It is possible that our choice of sequence parameters and the limited sample size contributed to negative findings reported here. On the other hand, longer follow-up may be needed to detect treatment-related metabolic changes with MRS. In summary, our study adds to the efforts in better understanding glutamatergic neurometabolism in schizophrenia, especially as it relates to antipsychotic exposure.

Micro- and Macrostructural White Matter Integrity in Never-Treated and Currently Unmedicated Patients With Schizophrenia and Effects of Short-Term Antipsychotic Treatment.

BACKGROUND: Schizophrenia is associated with progressive white matter changes, but it is unclear whether antipsychotic medications contribute to these. Our objective was to characterize effects of short-term treatment with risperidone on white matter diffusion indices. METHODS: We recruited 42 patients with schizophrenia (30 never treated and 12 currently untreated) and 42 matched healthy control subjects in this prospective case-control neuroimaging study. Patients received a 6-week trial of risperidone. Using diffusion tensor imaging, we assessed microstructural (fractional anisotropy, mean diffusivity, and radial diffusivity) and macrostructural (radial fiber trophy) white matter integrity deficits in unmedicated patients compared with control subjects and change in white matter integrity in patients before and after antipsychotic treatment (mean risperidone dose at end point was 3.73 ± 1.72 mg). RESULTS: At baseline, fractional anisotropy was decreased in the left medial temporal white matter (cluster extent: 123 voxels; Montreal Neurological Institute peak coordinates: x = -51, y = -44, z = -7; α < .05), and mean diffusivity was increased in the fusiform/lingual gyrus white matter extending to the hippocampal part of the cingulum (cluster extent: 185 voxels; peak coordinates: x = -27, y = -49, z = 2; α < .04) in patients compared with control subjects. Radial diffusivity and macrostructure were not abnormal. None of the diffusion indices showed a significant change after 6 weeks of treatment with both voxelwise and whole-brain white matter analyses. CONCLUSIONS: We demonstrate microstructural white matter integrity abnormalities in the absence of macrostructural impairment in unmedicated patients with primarily early-stage schizophrenia. In our data, we found no significant white matter changes after short-term treatment with risperidone.