Smooth pursuit eye movement, prepulse inhibition, and auditory paired stimuli processing endophenotypes across the schizophrenia-bipolar disorder psychosis dimension.

BACKGROUND: This study examined smooth pursuit eye movement (SPEM), prepulse inhibition (PPI), and auditory event-related potentials (ERP) to paired stimuli as putative endophenotypes of psychosis across the schizophrenia-bipolar disorder dimension. METHODS: Sixty-four schizophrenia probands (SZP), 40 psychotic bipolar I disorder probands (BDP), 31 relatives of SZP (SZR), 26 relatives of BDP (BDR), and 53 healthy controls (HC) were tested. Standard clinical characterization, SPEM, PPI, and ERP measures were administered. RESULTS: There were no differences between either SZP and BDP or SZR and BDR on any of the SPEM, PPI, or ERP measure. Compared with HC, SZP and BDP had lower SPEM maintenance and predictive pursuit gain and ERP theta/alpha and beta magnitudes to the initial stimulus. PPI did not differ between the psychosis probands and HC. Compared with HC, SZR and BDR had lower predictive pursuit gain and ERP theta/alpha and beta magnitudes to the first stimulus with differences ranging from a significant to a trend level. Neither active symptoms severity nor concomitant medications were associated with neurophysiological outcomes. SPEM, PPI, and ERP scores had low intercorrelations. CONCLUSION: These findings support SPEM predictive pursuit and lower frequency auditory ERP activity in a paired stimuli paradigm as putative endophenotypes of psychosis common to SZ and BD probands and relatives. PPI did not differ between the psychosis probands and HC. Future studies in larger scale psychosis family samples targeting putative psychosis endophenotypes and underlying molecular and genetic mediators may aid in the development of biology-based diagnostic definitions.

Gray matter volume as an intermediate phenotype for psychosis: Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP).

OBJECTIVE: The study examined gray matter volume across psychosis diagnoses organized by dimensional and DSM-IV categories from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) sample. METHOD: In total, 351 probands with psychosis (146 with schizophrenia, 90 with schizoaffective disorder, and 115 with psychotic bipolar I disorder), 369 of their first-degree relatives (134 were relatives of individuals with schizophrenia, 106 of individuals with schizoaffective disorder, and 129 of individuals with psychotic bipolar I disorder), and 200 healthy comparison subjects were assessed. Gray matter volumes from 3-T T1-weighted images were analyzed using the VBM8 toolbox for SPM8, and outcomes were determined at a false discovery rate-corrected threshold of p<0.005. RESULTS: Across the psychosis dimension, probands (N=351) and relatives with psychosis spectrum disorders (N=34) showed substantial overlapping gray matter reductions throughout the neocortex, whereas relatives without psychosis spectrum (N=332) had normal gray matter volumes relative to comparison subjects. Across DSM-IV diagnoses, schizophrenia and schizoaffective probands showed overlapping gray matter reductions in numerous cortical and subcortical regions, whereas psychotic bipolar probands showed limited gray matter reductions localized to the frontotemporal cortex relative to comparison subjects. All relative groups had gray matter volumes that did not differ from comparison subjects. CONCLUSIONS: Across the dimensional psychosis categories, these findings indicate extensive neocortical gray matter reductions in psychosis probands and relatives with psychosis spectrum disorders, possibly reflecting lifetime psychosis burden, but normal gray matter in nonpsychotic relatives. Traditional DSM-IV psychosis grouping revealed partially divergent gray matter phenotypes for probands with schizophrenia or schizoaffective disorder (extensive neocortical or subcortical gray matter reductions) relative to those with psychotic bipolar disorder (smaller reductions were limited to frontotemporal regions). The dimensional conceptualization of psychosis appears useful in defining more homogenous disease categories that may help identify underlying psychosis biomarkers and develop a biologically driven diagnostic system and targeted treatments.

Brain gray matter phenotypes across the psychosis dimension.

This study sought to examine whole brain and regional gray matter (GM) phenotypes across the schizophrenia (SZ)-bipolar disorder psychosis dimension using voxel-based morphometry (VBM 8.0 with DARTEL segmentation/normalization) and semi-automated regional parcellation, FreeSurfer (FS 4.3.1/64 bit). 3T T1 MPRAGE images were acquired from 19 volunteers with schizophrenia (SZ), 16 with schizoaffective disorder (SAD), 17 with psychotic bipolar I disorder (BD-P) and 10 healthy controls (HC). Contrasted with HC, SZ showed extensive cortical GM reductions, most pronounced in fronto-temporal regions; SAD had GM reductions overlapping with SZ, albeit less extensive; and BD-P demonstrated no GM differences from HC. Within the psychosis dimension, BD-P showed larger volumes in fronto-temporal and other cortical/subcortical regions compared with SZ, whereas SAD showed intermediate GM volumes. The two volumetric methodologies, VBM and FS, revealed highly overlapping results for cortical GM, but partially divergent results for subcortical volumes (basal ganglia, amygdala). Overall, these findings suggest that individuals across the psychosis dimension show both overlapping and unique GM phenotypes: decreased GM, predominantly in fronto-temporal regions, is characteristic of SZ but not of psychotic BD-P, whereas SAD display GM deficits overlapping with SZ, albeit less extensive.

Predictive pursuit association with deficits in working memory in psychosis.

BACKGROUND: Deficits in smooth pursuit eye movements are an established phenotype for schizophrenia (SZ) and are being investigated as a potential liability marker for bipolar disorder. Although the molecular determinants of this deficit are still unclear, research has verified deficits in predictive pursuit mechanisms in SZ. Because predictive pursuit might depend on the working memory system, we have hypothesized a relationship between the two in healthy control subjects (HC) and SZ and here examine whether it extends to psychotic bipolar disorder (BDP). METHODS: Volunteers with SZ (n = 38), BDP (n = 31), and HC (n = 32) performed a novel eye movement task to assess predictive pursuit as well as a standard visuospatial measure of working memory. RESULTS: Individuals with SZ and BDP both showed reduced predictive pursuit gain compared with HC (p < .05). Moreover, each patient group showed worse performance in visuospatial working memory compared with control subjects (p < .05). A strong correlation (r = .53, p = .007) was found between predictive pursuit gain and working memory in HC, a relationship that showed a trend correlation within the BDP group but not among SZ. CONCLUSIONS: Individuals with SZ and BDP showed similar deficits in predictive pursuit, suggesting that this alteration could be a characteristic trait of the psychosis domain. The correlation between predictive pursuit and working memory in HC supports the assumption that working memory is related to predictive pursuit eye movements; however, the degradation of working memory in people with psychosis disrupts its association with eye-tracking behavior.

Cognitive endophenotypes of psychosis within dimension and diagnosis.

This study sought to characterize the psychosis phenotype, contrasting cognitive features within traditional diagnosis and psychosis dimension in a family sample containing both schizophrenia and psychotic bipolar I disorder. Seventy-six probands with psychosis [44 probands with schizophrenia, 32 probands with psychotic bipolar I disorder] and 55 first-degree relatives [30 relatives of schizophrenia probands, 25 relatives of bipolar probands] were recruited. Standardized clinical and neuropsychological measures were administered. No differences in cognitive performance emerged between probands with schizophrenia and probands with psychotic bipolar disorder, or between relatives of probands with schizophrenia and relatives of probands with bipolar disorder in the domains of working and declarative memory, executive function and attention. Relatives overall showed higher cognitive performance compared to probands, as expected. However, when we segmented the probands and relatives along a psychosis dimension, independent of diagnostic groups, results revealed lower cognitive performance in probands compared to relatives without psychosis spectrum disorders, whereas relatives with psychosis spectrum disorders showed an intermediate level of performance across all cognitive domains. In this study, cognitive performance did not distinguish either probands or their first-degree relatives within traditional diagnostic groups (schizophrenia and psychotic bipolar disorder), but distinguished probands and relatives with and without lifetime psychosis manifestations independent of diagnostic categories. These data support the notion that schizophrenia and psychotic bipolar disorder present a clinical continuum with overlapping cognitive features defining the psychosis phenotype.

Genetics and intermediate phenotypes of the schizophrenia--bipolar disorder boundary.

Categorization of psychotic illnesses into schizophrenic and affective psychoses remains an ongoing controversy. Although Kraepelinian subtyping of psychosis was historically beneficial, modern genetic and neurophysiological studies do not support dichotomous conceptualization of psychosis. Evidence suggests that schizophrenia and bipolar disorder rather present a clinical continuum with partially overlapping symptom dimensions, neurophysiology, genetics and treatment responses. Recent large scale genetic studies have produced inconsistent findings and exposed an urgent need for re-thinking phenomenology-based approach in psychiatric research. Epidemiological, linkage and molecular genetic studies, as well as studies in intermediate phenotypes (neurocognitive, neurophysiological and anatomical imaging) in schizophrenia and bipolar disorders are reviewed in order to support a dimensional conceptualization of psychosis. Overlapping and unique genetic and intermediate phenotypic signatures of the two psychoses are comprehensively recapitulated. Alternative strategies which may be implicated into genetic research are discussed.