Suraj Sarvode Mothi

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.

Callosal Abnormalities Across the Psychosis Dimension: Bipolar Schizophrenia Network on Intermediate Phenotypes

BACKGROUND The corpus callosum has been implicated in the pathogenesis of schizophrenia and bipolar disorder. However, it is unclear whether corpus callosum alterations are related to the underlying familial diathesis for psychotic disorders. We examined the corpus callosum and its subregion volumes and their relationship to cognition, psychotic symptoms, and age in probands with schizophrenia (SZ), psychotic bipolar disorder (PBD), and schizoaffective disorder; their first-degree relatives; and healthy control subjects. METHODS We present findings from morphometric and neurocognitive analyses of 1381 subjects (SZ probands, n = 224; PBD probands, n = 190; schizoaffective disorder probands, n = 142; unaffected relatives, n = 483 [SZ relatives, n = 195; PBD relatives, n = 175; schizoaffective disorder relatives, n = 113]; control subjects, n = 342). Magnetization prepared rapid acquisition gradient-echo T1 scans across five sites were obtained using 3-tesla magnets. Image processing was done using FreeSurfer Version 5.1. Neurocognitive function was measured using the Brief Assessment of Cognition in Schizophrenia scale. RESULTS Anterior and posterior splenial volumes were significantly reduced across the groups. The SZ and PBD probands showed robust and significant reductions, whereas relatives showed significant reductions of intermediate severity. The splenial volumes were positively but differentially correlated with aspects of cognition in the probands and their relatives. Proband groups showed a significant age-related decrease in the volume of the anterior splenium compared with control subjects. Among the psychosis groups, the anterior splenium in probands with PBD showed a stronger correlation with psychotic symptoms, as shown by the Positive and Negative Syndrome Scale. All five subregions showed significantly high familiality. CONCLUSIONS The splenial volumes were significantly reduced across the psychosis dimension. However, this volume reduction impacts cognition and clinical manifestation of the illnesses differentially.

Increased cardiometabolic dysfunction in first-degree relatives of patients with psychotic disorders

INTRODUCTION Elevated prevalence of comorbid cardio-vascular and metabolic dysfunction (CMD) is consistently reported in patients with severe psychotic disorders such as schizophrenia (SZ), schizoaffective (SZA) and bipolar disorder (BP-P). Since both psychosis and CMD are substantively heritable in nature, we attempted to investigate the occurrence of CMD disorders in first-degree relatives of probands with psychosis. METHODS Our sample included 861 probands with a diagnosis of SZ (n=354), SZA (n=212) and BP-P (n=295), 776 first-degree relatives of probands and 416 healthy controls. Logistic regression was used to compare prevalence of any CMD disorders (diabetes, hypertension, hyperlipidemia or coronary artery disease) across groups. Post hoc tests of independence checked for CMD prevalence across psychosis diagnosis (SZ, SZA and BP-P), both in relatives of probands and within probands themselves. RESULTS After controlling for potential confounders, first-degree relatives with (p<0.001) and without (p=0.03) Axis I non-psychotic or Axis- II cluster disorders were at a significant risk for CMD compared to controls. No significant difference (p=0.42) was observed in prevalence of CMD between relatives of SZ, SZA and BP-P, or between psychosis diagnoses for probands (p=0.25). DISCUSSION Prevalence of CMD was increased in the first-degree relatives of psychosis subjects. This finding suggests the possibility of overlapping genetic contributions to CMD and psychosis. Increased somatic disease burden in relatives of psychotic disorder probands points to need for early detection and preventive efforts in this population.

Cognitive-Behavioral Therapy for Adolescent Body Dysmorphic Disorder: A Pilot Study.

Body dysmorphic disorder (BDD) is a relatively common and severe disorder that typically onsets in adolescence, but often goes unrecognized. Despite BDDs severity and early onset, treatment outcome research on adolescent BDD is scarce. Cognitive-behavioral therapy is the gold-standard psychosocial treatment for BDD in adults and has shown promise in adolescents. The current study examined the development and testing of a new CBT for adolescents with BDD. We tested feasibility, acceptability, and treatment outcome in a sample of 13 adolescents (mean age 15.23years, range: 13-17) with primary BDD. Treatment was delivered in 12-22 weekly individual sessions. Standardized clinician ratings and self-report measures were used to assess BDD and related symptoms pre- and posttreatment and at 3- and 6-months follow-up. At posttreatment, BDD and related symptoms (e.g., insight, mood) were significantly improved. Scores on the Yale-Brown Obsessive Compulsive Scale for BDD indicated a 50% (intent-to-treat) and 68% (completer) improvement in BDD symptoms. Seventy-five percent of adolescents who started treatment and 100% of completers were considered treatment responders. Treatment gains were maintained at follow-up. High patient satisfaction ratings and patient feedback indicated that treatment was acceptable. This represents the largest study of a psychosocial treatment for adolescent BDD.

Polygenic risk for type 2 diabetes mellitus among individuals with psychosis and their relatives

BACKGROUND An elevated prevalence of Type 2 diabetes (T2D) has been observed in people with psychotic disorders and their relatives compared to the general population. It is not known whether this population also has increased genetic risk for T2D. METHODS Subjects included probands with schizophrenia, schizoaffective disorder, or psychotic bipolar I disorder, their first-degree relatives without psychotic disorders, and healthy controls, who participated in the Bipolar Schizophrenia Network for Intermediate Phenotypes study. We constructed sets of polygenic risk scores for T2D (PGRST2D) and schizophrenia (PGRSSCHIZ) using publicly available data from genome-wide association studies. We then explored the correlation of PGRST2D with psychiatric proband or relative status, and with self-reported diabetes. Caucasians and African-Americans were analyzed separately. We also evaluated correlations between PGRSSCHIZ and diabetes mellitus among Caucasian probands and their relatives. RESULTS In Caucasians, PGRST2D was correlated with self-reported diabetes mellitus within probands, but was not correlated with proband or relative status in the whole sample. In African-Americans, a PGRST2D based on selected risk alleles for T2D in this population did not correlate with proband or relative status. PGRSSCHIZ was not correlated with self-reported diabetes within Caucasian probands. CONCLUSION Differences in polygenic risk for T2D do not explain the increased prevalence of diabetes mellitus observed in psychosis probands and their relatives.

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.

Machine learning improved classification of psychoses using clinical and biological stratification: Update from the bipolar-schizophrenia network for intermediate phenotypes (B-SNIP)

a Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, 75 Fenwood Rd, Boston, MA 02115, USA b Department of Psychiatry, Massachusetts General Hospital Boston, MA 02114, USA c New York University, New York, NY 10012, USA d Baylor College of Medicine, Houston, TX, USA e Psychiatry, UT Southwestern, Dallas, TX, USA f Olin Neuropsychiatry Research Center, Hartford, CT, USA g Department of Psychiatry and Neurobiology, Yale University, New Haven, CT, USA h Department of Psychiatry, University of Cincinnati, Cincinnati, OH, USA i Department of Psychology, Bio-Imaging Research Center, University of Georgia, Athens, GA, USA

Treatment utilization and barriers to treatment among individuals with olfactory reference syndrome (ORS)

OBJECTIVE Olfactory reference syndrome (ORS) is characterized by a preoccupation that one is emitting a foul or offensive odor. Despite the profound psychosocial impact of ORS, many patients do not receive appropriate treatment, and there is no empirical research on treatment-seeking behavior in ORS. This study investigated treatment utilization patterns and barriers to treatment in individuals with ORS. METHOD 253 subjects completed an online survey between January-March 2010. Data were obtained from the Yale-Brown Obsessive Compulsive Scale Modified for ORS (ORS-YBOCS), Depression Anxiety Stress Scales (DASS), Work and Social Adjustment Scale (WSAS), and questionnaires specific to treatment utilization and barriers. RESULTS The sample was ethnically diverse, predominately male (67%), with an average age of 33.7years, and moderately severe ORS symptoms. Most participants first sought care from a medical specialist (44%), and mental health services were underutilized (14%). Higher functional impairment was significantly correlated with seeking care from a mental health provider, compared to a medical specialist. Nearly all participants endorsed multiple barriers to treatment, including (a) logistical/financial, (b) stigma/discrimination, and (c) treatment perception barriers. ORS symptom severity was significantly, positively correlated with number of logistical/financial and stigma/discrimination barriers. Treatment barriers were significantly influenced by ethnic group, ORS symptom severity, and source of odor. CONCLUSION Results highlight the importance of increasing awareness and enhancing access to care for individuals with ORS.