Trajectory of neurological examination abnormalities in antipsychotic-naïve first-episode psychosis population: a 1 year follow-up study.

BACKGROUND: Neurological Examination Abnormalities (NES) are quantified by measuring subtle, partially localizable (cerebello-thalamo-prefrontal cortical circuit) and heritable neurological signs comprising sensory integration, motor coordination and complex motor sequencing that are associated with first-episode psychosis (FEP). A few studies have evaluated NES longitudinally and as a predictor for diagnostic and response classification, but these studies have been confounded, underpowered and divergent. We examined (1) baseline and longitudinal NES differences between diagnostic and year 1 response groups; (2) if NES predicts diagnostic and response groups and (3) relationships between clinical variables and NES measures in antipsychotic-naïve FEP. METHODS: NES and clinical measures were obtained for FEP-schizophrenia (FEP-SZ, n = 232), FEP non-schizophrenia (FEP-NSZ, n = 117) and healthy controls (HC, n = 204). Response groups with >25% improvement in average year 1 positive and negative symptomatology scores were classified as responsive (n = 97) and <25% improvement as non-responsive (n = 95). Analysis of covariance, NES trajectory analysis and logistic regression models assessed diagnostic and response group differences. Baseline and longitudinal NES relationships with clinical variables were performed with Spearman correlations. Data were adjusted for age, sex, race, socioeconomic status and handedness. RESULTS: Cognitive perceptual (COGPER) score was better than repetitive motor (REPMOT) at differentiating FEP-SZ from FEP-NSZ and distinguishing responders from non-responders. We identified significant group-specific associations between COGPER and worse GAF, positive and negative symptomatology and some of these findings persisted at 1-year assessment. CONCLUSION: NES are an easy to administer, bedside-elicited, endophenotypic measure and could be a cost-effective clinical tool in antipsychotic-naïve FEP.

Over 30 years of STEP: The Pittsburgh experience with first-episode psychosis.

AIMS: For over 30 years, combined research and treatment settings in the US have been critical to conceptualizing care for first-episode psychosis (FEP). Here we describe an early example of such a context, the Services for the Treatment of Early Psychosis (STEP) clinic, which is affiliated with the University of Pittsburgh. METHODS: We describe STEP's historical roots and establishment in the early 1990s; STEP's research and treatment contributions, alongside its growth and ongoing leadership. RESULTS: Research-based clinics, like STEP, preceded and helped pave the way for the Recovery After an Initial Schizophrenia Episode project in the US and the ensuing Coordinated Specialty Care (CSC) approach, now widely adopted in the US. Early clinic-based research at STEP helped establish protocols for psychopharmacology, the relevance of effective early treatment, including psychosocial approaches, and highlighted disparities in treatment outcomes across race/ethnicity. Multidisciplinary collaboration and dialogue with consumers contributed to early treatment, combining psychosocial and pharmacological approaches. STEP adopted CSC and is situated within a bi-state Learning Health System. STEP has retained a relatively unique 5-year treatment model and exists within continuum of care ideally suited to studying psychotic illness and treatment outcomes. CONCLUSIONS: STEP remains the largest academic FEP clinic in Pennsylvania. Academic FEP clinics like STEP will have a critical role within Learning Health Systems nationally to model participatory approaches, sustain early intervention treatment quality and ongoing treatment developments.

Grey matter and cognitive deficits in young relatives of schizophrenia patients.

Grey-matter volumetric and cognitive deficits in young, high-risk relatives of schizophrenia patients may be vulnerability markers of the illness. Although these markers may be correlated, it is unclear if their distributions in relatives overlap. We examined convergence of these markers in 94 young first and second-degree relatives (HR) and 81 healthy controls. Subjects were assessed using WCST, CPT-IP and Benton-Hamscher tests and on grey-matter volumes of brain regions related to language, attention and executive function using FreeSurfer to process T1-MR-images. K-means clustering using cognitive performance scores split relatives into sub-samples with better (HR+C, n=35) and worse (HR-C, n=59) cognition after controlling for age and gender. All regional volumes and language related regional laterality-indices were compared between HR-C, HR+C and control subjects, controlling for age, gender and intra-cranial volume. Volumes of caudate nuclei, thalami, hippocampi, inferior frontal gyri, Heschl's gyri, superior parietal cortices, supramarginal gyri, right angular gyrus, right middle frontal gyrus and right superior frontal gyrus, leftward laterality of supramarginal and inferior frontal gyri and rightward laterality of the angular gyrus were reduced in HR-C compared to controls. Volumes of Heschl's gyri, left supramarginal gyrus, inferior frontal gyri, hippocampi and caudate nuclei HR-C were smaller in HR-C compared to HR+C. HR+C showed deficits compared to controls only for the superior parietal and right angular volumes. Premorbid neuroanatomical and laterality alterations in schizophrenia may selectively manifest in cognitively compromised relatives. Overlapping structural and cognitive deficits may define a hyper vulnerable sub-sample among individuals at familial predisposition to schizophrenia.

Gray matter loss in young relatives at risk for schizophrenia: relation with prodromal psychopathology.

The maturation of neocortical regions mediating social cognition during adolescence and young adulthood in relatives of schizophrenia patients may be vulnerable to heritable alterations of neurodevelopment. Prodromal psychotic symptoms, commonly emerging during this period in relatives, have been hypothesized to result from alterations in brain regions mediating social cognition. We hypothesized these regions to show longitudinal alterations and these alterations to predict prodromal symptoms in adolescent and young adult relatives of schizophrenia patients. 27 Healthy controls and 23 relatives were assessed at baseline and one-year follow-up using scale of prodromal symptoms and gray matter volumes of hypothesized regions from T1-MRI images. Regional volumes showing deficits on ANCOVA and repeated-measures ANCOVAs (controlling intra cranial volume, age and gender) were correlated with prodromal symptoms. At baseline, bilateral amygdalae, bilateral pars triangulares, left lateral orbitofrontal, right frontal pole, angular and supramarginal gyrii were smaller in relatives compared to controls. Relatives declined but controls increased or remained stable on bilateral lateral orbitofrontal, left rostral anterior cingulate, left medial prefrontal, right inferior frontal gyrus and left temporal pole volumes at follow-up relative to baseline. Smaller volumes predicted greater severity of prodromal symptoms at both cross-sectional assessments. Longitudinally, smaller baseline volumes predicted greater prodromal symptoms at follow-up; greater longitudinal decreases in volumes predicted worsening (increase) of prodromal symptoms over time. These preliminary findings suggest that abnormal longitudinal gray matter loss may occur in regions mediating social cognition and may convey risk for prodromal symptoms during adolescence and early adulthood in individuals with a familial diathesis for schizophrenia.

3-Hydroxykynurenine and clinical symptoms in first-episode neuroleptic-naive patients with schizophrenia.

One branch of the tryptophan catabolic cascade is the kynurenine pathway, which produces neurotoxic [3-hydroxykynurenine (3-OHKY), quinolinic acid] and neuroinhibitory (kynurenic acid) compounds. Kynurenic acid acts as a competitive antagonist at the glycine site of N-methyl-d-asparate receptors at high concentrations and as a non-competitive antagonist on the α7-nicotinic acetylcholine receptor at low concentrations. Kynurenine compounds also influence cognitive functions known to be disrupted in schizophrenia. Alterations in tryptophan metabolism are therefore of potential significance for the pathophysiology of this disorder. In this paper, tryptophan metabolites were measured from plasma using high-pressure liquid chromatography coupled with electrochemical coulometric array detection, and relationships were tested between these metabolic signatures and clinical symptoms for 25 first-episode neuroleptic-naive schizophrenia patients. Blood samples were collected and clinical and neurological symptoms were rated at baseline and again at 4 wk following initiation of treatment. Level of 3-OHKY and total clinical symptom scores were correlated when patients were unmedicated and neuroleptic-naive, and this relationship differed significantly from the correlation observed for patients 4 wk after beginning treatment. Baseline psychosis symptoms were predicted only by neurological symptoms. Moreover, baseline 3-OHKY predicted clinical change at 4 wk, with the lowest concentrations of 3-OHKY being associated with the greatest improvement in symptoms. Taken together, our findings suggest a neurotoxic product of tryptophan metabolism, 3-OHKY, predicts severity of clinical symptoms during the early phase of illness and before exposure to antipsychotic drugs. Baseline level of 3-OHKY may also predict the degree of clinical improvement following brief treatment with antipsychotics.

Abnormalities of the corpus callosum in non-psychotic high-risk offspring of schizophrenia patients.

Alterations in the structure of the corpus callosum (CC) have been observed in schizophrenia. Offspring of schizophrenia parents have 10-15 times higher risk for developing schizophrenia. We examined CC volume in offspring at genetic high-risk (HR) subjects. Since the sub-regions of the CC are topographically mapped to cortical brain regions, we hypothesized that HR subjects may show a decrement in total volume and differential volume decreases in sub-regions of the CC. The offspring of schizophrenia parents (HR; n=70; 36 males) and healthy volunteers with no family or personal history of psychotic disorders (healthy controls (HC); n=73; 37 males) matched for age, gender and education were selected for the study. Magnetic resonance images were collected using a GE 1.5 T scanner and processed using FreeSurfer image analysis software. The CC was divided into five neuroanatomically based partitions. The volume of total CC and the five sub-regions were measured blind to clinical information. With covariation for intracranial volume, HR subjects had significantly reduced total CC, more prominently observed in the anterior splenium. An age-related increase in CC volume was found in the anterior and posterior splenium of healthy controls but not in HR subjects. The volume reduction was greater in male than female HR subjects. The volume reduction in the CC may reflect a reduction in axonal fibers crossing the hemispheres and/or myelination between the left and right temporo-parietal cortices. The absence of an age-related volume increase suggests an abnormal developmental trajectory that may underlie susceptibility to schizophrenia.

Visual Cortical Alterations and their Association with Negative Symptoms in Antipsychotic-Naïve First Episode Psychosis.

Visual perceptual and processing deficits are common in schizophrenia and possibly point towards visual pathway alterations. However, no studies have examined visual cortical morphology in first-episode psychosis (FEP). In an antipsychotic-naïve FEP population, we investigated primary visual (V1), association area (V2), and motion perception (V5/MT) morphology compared to controls. We found reductions in the V1 and V2 areas, greater MT area and lower MT thickness in the FEP-schizophrenia group when compared to controls. Also, lower MT thickness was associated with worse negative symptoms. Our results shed light on this poorly studied area of visual cortex morphology in FEP.

Neurological abnormalities among offspring of persons with schizophrenia: relation to premorbid psychopathology.

BACKGROUND: Neurological Examination Abnormalities (NEA, often called "neurological soft signs") have been observed in early schizophrenia and may be heritable. We investigated the prevalence, and neurocognitive and psychopathological correlates of NEA among offspring of schizophrenia patients who are at increased genetic risk for this illness. METHODS: Neurological examinations were conducted on high risk (HR, n=74) and healthy comparison subjects (HS, n=86), using the Heinrichs-Buchanan scale. Cognitive-perceptual (CogPer) and repetitive motor (RepMot) subscores, and total NEA scores were computed. All HR and HS were assessed using K-SADS/SCID for diagnoses. Schizotypy was measured using the Magical Ideation and the Perceptual Aberration subscales (Chapman scale), attention using Continuous Performance Test (CPT-IP) and executive functions using the Wisconsin Card Sorting Test (WCST). RESULTS: CogPer (F(1,160)=7.14, p=0.008) but not RepMot NEA scores were higher in HR subjects compared to HS after controlling for age and sex. CogPer NEA scores were higher in HR subjects with axis I psychopathology compared to those without (F(2,170)-6.41, p=0.002). HR subjects had higher schizotypy scores (composite of the magical ideation and perceptual aberration scales) (F(1,141)=23.25, p=0.000004). Schizotypy scores were negatively correlated with sustained attention and executive functions. In addition, schizotypy was positively correlated with CogPer NEA scores. CONCLUSIONS: Young relatives at increased genetic risk for schizophrenia show more frequent NEA. CogPer but not RepMot NEA scores were elevated, consistent with our prior observation of CogPer NEA being relatively specific for schizophrenia. The observed relationships between NEA, cognitive impairments, schizotypy and axis I disorders suggest that NEA may characterize a subgroup of HR offspring at an elevated risk for psychopathology.

Association study of 21 circadian genes with bipolar I disorder, schizoaffective disorder, and schizophrenia.

OBJECTIVE: Published studies suggest associations between circadian gene polymorphisms and bipolar I disorder (BPI), as well as schizoaffective disorder (SZA) and schizophrenia (SZ). The results are plausible, based on prior studies of circadian abnormalities. As replications have not been attempted uniformly, we evaluated representative, common polymorphisms in all three disorders. METHODS: We assayed 276 publicly available 'tag' single nucleotide polymorphisms (SNPs) at 21 circadian genes among 523 patients with BPI, 527 patients with SZ/SZA, and 477 screened adult controls. Detected associations were evaluated in relation to two published genome-wide association studies (GWAS). RESULTS: Using gene-based tests, suggestive associations were noted between EGR3 and BPI (p = 0.017), and between NPAS2 and SZ/SZA (p = 0.034). Three SNPs were associated with both sets of disorders (NPAS2: rs13025524 and rs11123857; RORB: rs10491929; p < 0.05). None of the associations remained significant following corrections for multiple comparisons. Approximately 15% of the analyzed SNPs overlapped with an independent study that conducted GWAS for BPI; suggestive overlap between the GWAS analyses and ours was noted at ARNTL. CONCLUSIONS: Several suggestive, novel associations were detected with circadian genes and BPI and SZ/SZA, but the present analyses do not support associations with common polymorphisms that confer risk with odds ratios greater than 1.5. Additional analyses using adequately powered samples are warranted to further evaluate these results.

Longitudinal trajectory of early functional recovery in patients with first episode psychosis.

BACKGROUND: There is a large variability in the recovery trajectory and outcome of first episode of psychosis [FEP] patients. To date, individuals' outcome trajectories at early stage of illness and potential risk factors associated with a poor outcome trajectory are largely unknown. This study aims to apply three separate predictors (positive symptoms, negative symptoms, and soft neurological signs) to identify homogeneous function outcome trajectories in patients with FEP using objective data-driven methods, and to explore the potential risk /protective factors associated with each trajectory. METHODS: A total of 369 first episode patients (93% antipsychotic naive) were included in the baseline assessments and followed-up at 4-8 weeks, 6 months, and 1 year. K means cluster modeling for longitudinal data (kml3d) was used to identify distinct, homogeneous clusters of functional outcome trajectories. Patients with at least 3 assessments were included in the trajectory analyses (N = 129). The Scale for the Assessment of Negative Symptoms (SANS), Scale for the Assessment of Positive Symptoms (SAPS), and Neurological examination abnormalities (NEA) were used as predictors against Global Assessment of Functioning Scale (GAF). RESULTS: In each of the three predictor models, four distinct functional outcome trajectories emerged: "Poor", "Intermediate", High" and "Catch-up". Individuals with male gender; ethnic minority status; low premorbid adjustment; low executive function/IQ, low SES, personality disorder, substance use history may be risk factors for poor recovery. CONCLUSIONS: Functioning recovery in individuals with FEP is heterogeneous, although distinct recovery profiles are apparent. Data-driven trajectory analysis can facilitate better characterization of individual longitudinal patterns of functioning recovery.

Clinical psychopathology in youth at familial high risk for psychosis.

AIM: While the course of psychopathology has been explored from an index mental health diagnosis onwards, there are few detailed, prospective studies of the occurrence of clinical psychopathology in youth with familial risk for severe mental illnesses such as psychosis. We sought to describe the appearance of Axis I psychopathology in a unique sample of adolescents with a family history of schizophrenia (FHR). METHODS: One hundred and sixty two first- and second-degree relatives (mean age 15.7 ± 3.6; range 8-25) of probands with schizophrenia or schizoaffective disorder were assessed at baseline and annual intervals for up to 3 years, focusing on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) Axis I psychopathology. RESULTS: Fourteen individuals (8.6%) developed a psychotic disorder. One hundred and five subjects (65%) met criteria for an Axis I disorder over the course of the study, the most common of which was a depressive episode (40 subjects; 25%). Of the 148 individuals who did not develop psychosis, 91 (61%) had one or more Axis I disorders compared with 10/14 converters who had a comorbid Axis I disorder (71%). Ordered by increasing age of onset, diagnoses included cognitive and externalizing disorders, anxiety disorders, affective disorders, substance use disorders and psychotic disorders. CONCLUSIONS: In addition to an elevated risk of psychosis, young FHR relatives manifest a broad range of non-psychotic Axis I psychopathology in childhood and adolescence. This breadth of diagnoses has implications for the structure and function of mental health services for young people.

Psychopathology among offspring of parents with schizophrenia: relationship to premorbid impairments.

INTRODUCTION: A broad range of psychopathology, including externalizing disorders is seen in offspring at genetic risk for schizophrenia. However, it is unclear whether such psychopathology may underlie a higher predisposition to the premorbid antecedents of schizophrenia. We examined the prevalence and correlates of psychopathology in an ongoing study of offspring genetically at risk for schizophrenia. METHODS: Seventy five consenting high risk offspring (HR: offspring, age 15.68+/-3.27 years; male/female 34/41) and 82 matched comparison subjects (40 males and 42 females; age 15.92+/-3.0 years) participated in this study. Diagnoses were ascertained using structured psychiatric interviews and consensus meetings, including all available clinical information. RESULTS: Sixty (60%) of the HR offspring had one or more lifetime diagnosis of axis I psychiatric disorder. HR subjects with axis I psychopathology had significantly more soft neurological signs, poorer premorbid adjustment, and higher schizotypy scores as measured by Chapman psychosis proneness scales. Among those with psychopathology, HR subjects with externalizing disorders showed the most abnormal scores in schizotypy. DISCUSSION: A substantial proportion of HR offspring of parents with schizophrenia manifest a broad range of childhood psychiatric disorders. Psychopathology, especially externalizing disorders such as attention deficit hyperactivity disorder (ADHD) may represent a subgroup with an increased risk for schizophrenia spectrum disorders. This possibility needs to be examined by prospective follow-up studies, and would be of considerable importance to early diagnosis and intervention efforts in schizophrenia.

Cannabis use and brain structural alterations in first episode schizophrenia--a region of interest, voxel based morphometric study.

Structural alterations of the brain in schizophrenia have been associated with genetic and environmental factors. Among the environmental factors, cannabis use has been associated with increased risk for patients with schizophrenia, but the effect of cannabis on their brain structure is unclear. We examined gray matter alterations in first episode schizophrenia patients (FES) with cannabis use (FES+C; n=15) compared to FES without cannabis use (FES-C; n=24) and 42 healthy controls who did not use cannabis. We conducted a voxel based morphometric analysis of a priori determined regions of interest consisting of the CB1 receptor rich brain regions. We observed a decrease in gray matter density in the right posterior cingulate cortex (PCC) in FES+C when compared with FES-C. The results suggest that cannabis use may be associated with altered brain structure, in particular regions rich in CB1 receptors. These findings need to be confirmed by larger, prospective studies.

An integrated psychobiological predictive model of emergent psychopathology among young relatives at risk for schizophrenia.

OBJECTIVE: Studies of young relatives at elevated risk for schizophrenia have pointed to the importance of a variety of neurobiological, cognitive, and clinical risk factors for the disorder; yet few have employed integrated models to estimate the joint contribution of these factors to heightened schizophrenic risk. We tested the predictive power of an integrated psychobiological model of schizophrenia risk to subsequent psychopathology development among young relatives at risk for the disorder. METHODS: Young first (n=66) and second (n=20) degree relatives of schizophrenia probands were followed for an average of 3 (SD=1.13) years to examine their trajectories toward psychopathology development. Neurobiologic, cognitive, and clinical measures were employed in an integrated structural equation model to estimate their contribution to the prospective emergence of psychopathology. RESULTS: Results indicated that neurobiological, neurocognitive, and psychosis proneness factors at baseline were all uniquely predictive of subsequent psychopathology development, and that an integrated model of psychopathology development that took into account these factors provided an excellent fit to the observed data. Subsequent classification analyses of model accuracy using likelihood ratios adjusting for the base-rate of psychopathology development in this sample revealed that individuals identified by this model had a 71% chance of developing psychopathology in the future. CONCLUSIONS: An integrated model of biobehavioral risk factors may provide a powerful method for predicting psychopathology and schizophrenia risk in at-risk samples. If validated, this model may be useful for early detection and intervention programs. Future research will need to focus particularly on predicting schizophrenia development and refining models to further enhance sensitivity.

Pregnenolone-progesterone-allopregnanolone pathway as a potential therapeutic target in first-episode antipsychotic-naïve patients with schizophrenia.

Neurosteroids are both endogenous and exogenous steroids that rapidly alter neuronal excitability through interactions with ligand-gated ion channels and other cell surface receptors. They are originated from cholesterol and have important implications for schizophrenia (SZ) pathophysiology and treatment strategies. Specifically, pregnenolone (PREG), progesterone (PROG) and allopregnanolone (ALLO) exhibit similar psychotropic properties. Using enzyme immunoassay, we compared the neurosteroids in PREG downstream pathways in plasma between healthy controls (HC, n = 43) and first-episode antipsychotic-naïve patients with SZ (FEAN-SZ, n = 53) before antipsychotic drug (APD) treatment. Comparisons were also made particularly along PREG-PROG-ALLO pathway in the same FEAN-SZ patients across multiple time points following initiation of treatment for 12 months (m). Firstly, at baseline, levels of PREG were significantly higher and those of ALLO were lower in FEAN-SZ than in HC, whereas PROG, cortisol, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) were not different. Consequently, the molar ratios of ALLO/PREG and ALLO/PROG in FEAN-SZ were significantly reduced. Secondly, in response to APD at 1 month, ALLO levels in FEAN-SZ were markedly elevated, whereas PREG and PROG levels decreased. Thirdly, among FEAN-SZ, lower levels of PROG (reflecting higher conversion to ALLO) at baseline may predict better therapeutic outcome after 1 month of APD treatment. These findings point to the perturbations of the PREG-PROG-ALLO pathway early in psychosis, and further study of this pathway may inform alternative and innovative therapeutic targets for SZ.

Reduced N-acetyl-aspartate levels in schizophrenia patients with a younger onset age: a single-voxel 1H spectroscopy study.

Schizophrenia is widely considered a neurodevelopmental disorder. The timing of psychosis onset may determine the degree of functional and biological deficits. In this study, the association between age of onset of psychosis and in vivo biochemical levels was assessed in first-episode, antipsychotic-naive (FEAN) schizophrenia subjects. We hypothesized greater biochemical deficits in the younger-onset FEAN subjects. In vivo, (1)H spectroscopy measurements of the left dorsolateral prefrontal cortex (DLPFC) were conducted on FEAN subjects (15 schizophrenia and 3 schizoaffective subjects) and healthy comparison subjects of comparable age and gender distribution (N=61). N-acetyl-aspartate was significantly lower in the left DLPFC of FEAN subjects as compared to healthy comparison subjects. However, there was a significant subject group-by-age interaction for N-acetyl-aspartate. Early-onset FEAN subjects showed lower N-acetyl-aspartate levels compared to the younger healthy comparison subjects, while adult-onset FEAN and older healthy comparison subjects did not differ. The lower N-acetyl-aspartate levels in the DLPFC of early-onset subjects suggest a reduction in functioning neurons or specifically a reduction in the proliferation of dendrites and synaptic connections, which is not apparent in the adult-onset schizophrenia subjects.

Association of sFlt-1 and worsening psychopathology in relatives at high risk for psychosis: A longitudinal study.

BACKGROUND: Angiogenic dysfunction and abnormalities in psychopathology and brain structure have been reported in schizophrenia, but their relationships are mostly unknown. We recently demonstrated that sFlt-1, anti-angiogenic factor, was significantly elevated in patients at familial high-risk for psychosis (FHR). We hypothesized that elevated sFlt-1 correlates with baseline and longitudinal changes in psychopathology, cognition, and brain structure. METHODS: Plasma sFlt-1 in FHR (n=35) and HC (n=39) was obtained at baseline. Schizotypal, cognitive, soft neurologic signs, and structural brain imaging (1.5T T1-weighted MRI, FreeSurfer software) measures were obtained in both groups. Longitudinal clinical and brain structural measures were obtained in a subgroup of FHR patients. Baseline data analysis used correlations between sFlt-1 and clinical/imaging measures and adjusted for multiple corrections. Linear mixed-effects models described differences in trajectories between high sFlt-1 and low sFlt-1. RESULTS: Baseline sFlt-1 was significantly correlated with soft neurologic signs (r=0.27, p=0.02) and right entorhinal volume (r=0.50, p=0.02), but not other baseline clinical/brain structural measures. Longitudinal examination of the FHR group (sFlt-1 high, n=14; sFlt-1 low, n=14) demonstrated that high sFlt-1 was significantly associated with worsening schizotypal symptoms (t=2.4, p=0.018). Reduced right hippocampal/parahippocampal volume/thickness trajectories were observed in high versus low sFlt-1 groups. CONCLUSIONS: The findings from this FHR study demonstrate that peripheral markers of angiogenic dysfunction can predict longitudinal clinical and brain structural changes. Also, these findings further support the hypothesis of altered microvascular circulation in schizophrenia and those at risk.

Genetically predisposed offspring with schizotypal features: an ultra high-risk group for schizophrenia?

Biomarkers proposed in the schizophrenia diathesis have included neurocognitive deficits in domains such as working memory that implicate prefrontal systems. However, the relationship between these biomarkers and psychopathological markers such as schizotypy has not been systematically assessed, particularly in adolescent offspring of schizophrenia patients. Convergence between these markers may identify individuals at especially high risk for schizophrenia. In the current study the authors assessed whether functional deficits in working memory assessed using the oculomotor delayed response task (ODR) and executive function assessed using the Wisconsin Card Sort task (WCST), and structural deficits in prefrontal cortex, in the adolescent offspring of patients were predictive of schizotypy. Schizotypal offspring made more perseverative errors on the WCST (p<.002) and showed age-related deficits on the ODR task (p<.02) compared to their non-schizotypal counterparts or healthy controls. Reduced gray matter concentration in prefrontal cortex (p<.001) was also associated with schizotypy. Schizotypy in offspring of schizophrenia patients appears to be highly associated with known biomarkers of the illness such as executive function impairment and reductions in cortical gray matter. Furthermore, schizotypy appears to interact with development leading to greater impairment in working memory in schizotypal offspring closer to the typical age of onset of schizophrenia than non-schizotypal offspring. Thus, clinical and neurocognitive biomarkers of the illness appear to be highly interrelated in this sample of at-risk offspring. We propose that schizotypy may define a hyper vulnerable sub-sample among individuals genetically predisposed to schizophrenia and that future studies that attempt to assess risk may benefit from such a convergent approach.

Angiogenic and immune signatures in plasma of young relatives at familial high-risk for psychosis and first-episode patients: A preliminary study.

Schizophrenia (SZ) is a heterogeneous disorder that presents in adolescence, persists into adulthood, and has many clinical features. Recent evidence suggests that abnormalities in inflammatory, neurotrophic, and angiogenic processes may play a role in the etiology of SZ. The identification of molecular biomarkers early in the course of disease is crucial to transforming diagnostic and therapeutic avenues. We investigated 14 molecular analytes focusing on inflammatory, neurotrophic and angiogenic pathways from the plasma of antipsychotic-naïve familial high risk for SZ (FHR; n=35) and first-episode psychosis (FEP; n=45) subjects, in comparison to healthy controls (HC, n=39). We identified distinct alterations in molecular signatures in young relatives at FHR for SZ prior to psychosis onset and FEP subjects. Firstly, the expression of soluble fms-like tyrosine kinase (sFlt-1), an anti-angiogenic factor that binds vascular endothelial growth factor (VEGF), was significantly increased in the FHR group compared to HC, but not in FEP. Secondly, interferon gamma (IFNγ) was significantly reduced in the FEP group compared to HC. Thirdly, network analysis revealed a positive correlation between sFlt-1 and VEGF, suggesting an activation of the angiogenic cascade in the FHR group, which persists in FEP. Our results indicate an angiogenesis and immunological dysfunction early in the course of disease, shifting the balance towards anti-angiogenesis and inflammation.

Personality dimensions in first-episode psychoses.

OBJECTIVE: The authors compared the patterns and specificity of premorbid personality dimensions in first-episode schizophrenia patients with those in patients with first-episode nonschizophrenia psychoses and healthy comparison subjects. METHOD: A series of 63 patients with first-episode schizophrenia and related psychotic disorders, 34 patients with first-episode nonschizophrenia psychoses, and 77 healthy comparison subjects were assessed with the Personality Disorder Evaluation, a semistructured interview schedule that measures personality dimensions. RESULTS: Cluster A as well as cluster C dimensional scores-in particular, the avoidant personality score-were higher for the schizophrenia patients, and cluster B dimensional scores were higher for the patients with nonschizophrenia psychoses. Cluster C dimensional scores, particularly the avoidant personality score, were highly intercorrelated with all cluster A dimensional scores. CONCLUSIONS: The observed association between avoidant personality and schizophrenia supports the recent literature on the comorbidity of nonspectrum personality disorders in schizophrenia. This association may be related to shared neurodevelopmentally mediated impairments in social cognition in schizophrenia and some cluster C personality dimensions.