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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.

Since Emil Kraepelin’s conceptualization of endogenous psychoses as dementia praecox and manic depression, the separation between primary psychotic disorders and primary affective disorders has been much debated. We conducted a systematic review of case–control studies contrasting magnetic resonance imaging studies in schizophrenia and bipolar disorder. A literature search in PubMed of studies published between January 2005 and December 2016 was conducted, and 50 structural, 29 functional, 7 magnetic resonance spectroscopy, and 8 combined imaging and genetic studies were deemed eligible for systematic review. Structural neuroimaging studies suggest white matter integrity deficits that are consistent across the illnesses, while gray matter reductions appear more widespread in schizophrenia compared to bipolar disorder. Spectroscopy studies in cortical gray matter report evidence of decreased neuronal integrity in both disorders. Functional neuroimaging studies typically report similar functional architecture of brain networks in healthy controls and patients across the psychosis spectrum, but find differential extent of alterations in task related activation and resting state connectivity between illnesses. The very limited imaging-genetic literature suggests a relationship between psychosis risk genes and brain structure, and possible gene by diagnosis interaction effects on functional imaging markers. While the existing literature suggests some shared and some distinct neural markers in schizophrenia and bipolar disorder, it will be imperative to conduct large, well designed, multi-modal neuroimaging studies in medication-naïve first episode patients that will be followed longitudinally over the course of their illness in an effort to advance our understanding of disease mechanisms.

Background Heterogeneity in the etiology, pathophysiology, and clinical features of schizophrenia challenges clinicians and researchers. A helpful approach could be stratifying patients according to the presence or absence of clinical features of the deficit syndrome (DS). DS is characterized by enduring and primary negative symptoms, a clinically less heterogeneous subtype of the illness, and patients with features of DS are thought to present abnormal brain network characteristics, however, this idea has received limited attention. We investigated functional brain network topology in patients displaying deficit features and those who do not. Design We applied graph theory analytics to resting-state functional magnetic resonance imaging data of 61 antipsychotic medication-naïve first episode psychosis patients, 18 DS and 43 non-deficit schizophrenia (NDS), and 72 healthy controls (HC). We quantified small-worldness, global and nodal efficiency measures, shortest path length, nodal local efficiency, and synchronization and contrasted them among the 3 groups. Results DS presented decreased network integration and segregation compared to HC and NDS. DS showed lower global efficiency, longer global path lengths, and lower global local efficiency. Nodal efficiency was lower and the shortest path length was longer in DS in default mode, ventral attention, dorsal attention, frontoparietal, limbic, somatomotor, and visual networks compared to HC. Compared to NDS, DS showed lower efficiency and longer shortest path length in default mode, limbic, somatomotor, and visual networks. Conclusions Our data supports increasing evidence, based on topological perturbations of the functional connectome, that deficit syndrome may be a distinct form of the illness.

A number of neuroimaging studies have provided evidence in support of the hypothesis that faulty interactions between spatially disparate brain regions underlie the pathophysiology of schizophrenia, but it remains unclear to what degree antipsychotic medications affect these. We hypothesized that the balance between functional integration and segregation of brain networks is impaired in unmedicated patients with schizophrenia, but that it can be partially restored by antipsychotic medications. We included 32 unmedicated patients with schizophrenia (SZ) and 32 matched healthy controls (HC) in this study. We obtained resting-state scans while unmedicated, and again after 6 weeks of treatment with risperidone to assess functional integration and functional segregation of brain networks using graph theoretical measures. Compared with HC, unmedicated SZ showed reduced global efficiency and increased clustering coefficients. This pattern of aberrant functional network integration and segregation was modulated with antipsychotic medications, but only in those who responded to treatment. Our work lends support to the concept of schizophrenia as a dysconnectivity syndrome, and suggests that faulty brain network topology in schizophrenia is modulated by antipsychotic medication as a function of treatment response. Antipsychotic medication: Restoring brain connectivity A neuroimaging study suggests that antipsychotics restore connectivity between spatially distinct brain regions. Faulty structural and functional interactions between different brain regions contribute to schizophrenia, but whether current medications are able to influence this is unclear. Adrienne Lahti and colleagues at the University of Alabama at Birmingham scanned the brains of 32 unmedicated patients with schizophrenia and 32 matched healthy controls. They found differences in both the speed of information transfer and number of interactions between brain regions. Interestingly, in scans carried out six weeks later, the differences between controls and patients who responded favorably to treatment with risperidone were significantly reduced. No changes were observed in patients who did not show clinical improvement, indicating that the extent to which antipsychotics influence brain connectivity could be used to predict treatment response in schizophrenia.

Diffusion tensor imaging (DTI) studies show widespread white matter abnormalities in schizophrenia, but it is difficult to directly relate these parameters to biological processes. Neurite orientation dispersion and density imaging (NODDI) is geared toward biophysical characterization of white matter microstructure, but only few studies have leveraged this technique to study white matter alterations. We recruited 42 schizophrenia patients (30 antipsychotic-naïve and 12 currently untreated) and 42 matched controls in this prospective study. We assessed the orientation dispersion index (ODI) and extracellular free water (FW) using single-shell DTI data before and after a 6-week trial of risperidone. Longitudinal data were available for 27 patients. Voxelwise analyses showed significantly increased ODI in the posterior limb of the internal capsule in unmedicated patients (242 voxels; x = −24; y = 6; z = 6; p < 0.01; α < 0.04), but no alterations in FW. Whole brain measures did not reveal alterations in ODI but a 6.3% trend-level increase in FW in unmedicated SZ (t = −1.873; p = 0.07). Baseline ODI was negatively correlated with subsequent response to antipsychotic treatment (r = −0.38; p = 0.049). Here, we demonstrated altered fiber complexity in medication-naïve and unmedicated patients with a schizophrenia spectrum illness. Lesser whole brain fiber uniformity was predictive of poor response to treatment, suggesting this measure may be a clinically relevant biomarker. Interestingly, we found no significant changes in NODDI indices after short-term treatment with risperidone. Our data show that biophysical diffusion models have promise for the in vivo evaluation of brain microstructure in this devastating neuropsychiatric syndrome.

Abstract The deficit syndrome is thought to be a more homogenous clinical subgroup within the syndrome of schizophrenia that is characterized by enduring negative symptoms. It is hypothesized that distinct pathophysiological processes underlie the subtypes, where the deficit syndrome reflects an early onset nonprogressive developmental process, and the nondeficit form of the illness is characterized by attenuated neuroplasticity secondary to elevated glutamate levels. We used single-voxel magnetic resonance spectroscopy (PRESS; TE: 30 ms) to measure left frontal white matter neurometabolite levels in 61 antipsychotic-naïve first-episode psychosis patients (39 who did not display deficit features, 22 who did display deficit features, assessed with the Schedule for the Deficit Syndrome) and 59 healthy controls. Metabolite levels were quantified with the LCModel. We used a MANCOVA to determine neurometabolite differences between healthy controls, deficit syndrome patients, and nondeficit patients. We report a significant group difference when all metabolites were considered jointly (F[10,208] = 2.16; P = .02). Post hoc analyses showed that patients presenting without deficit features had higher glutamate levels than patients with deficit features and controls. Patients presenting without deficit features also had significantly higher myoinositol levels than controls; myoinositol levels were trend-level higher in patients presenting with deficit features compared to controls. Our data support the idea that the pathophysiology of patients presenting without deficit features may differ from those presenting with deficit features.

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.