Tyler B. Grove

Risk factors associated with metabolic syndrome in bipolar and schizophrenia subjects treated with antipsychotics: the role of folate pharmacogenetics.

Abstract Folate has been implicated in cardiovascular disease with atypical antipsychotic (AAPs) use, and individuals with methylenetetrahydrofolate reductase (MTHFR) and catechol-O-methyl transferase (COMT) variants are at greater risk. This study examined the relationship between the MTHFR 677C/T, MTHFR 1298A/C, and COMT Val158Met variants; metabolic syndrome; and lifestyle measures in schizophrenia and bipolar subjects. A total of 237 subjects with bipolar or schizophrenia receiving an antipsychotic for at least 6 months were included in this cross-sectional analysis. Subjects were screened for the metabolic syndrome (National Cholesterol Education Program Adult Treatment Panel III criteria) and MTHFR 677C/T, MTHFR 1298A/C, and Val158Met genotypes. In addition, serum folate and homocysteine were measured along with lifestyle factors. The subject’s mean age was 44.7 (SD, 11.7) years; 72% were white, and 51% male; 61% were receiving an AAP; the mean body mass index was 32.6 (SD, 8.2) kg/m2, and 48% were current smokers. Overall, 41% met metabolic syndrome criteria (n = 98). There were no differences in age, sex, AAP exposure, or body mass index between genotype groups. Metabolic syndrome was related to age, smoking, and the MTHFR 677T and COMT 158Val alleles (&khgr;2 = 34.4, P < 0.0001). In addition, AAP use showed a trend association with metabolic syndrome (&khgr;2 = 3.21, P = 0.07). These data support our previous reports and add more data pointing to folate’s role in mediating a link between mental illness and cardiovascular disease. Use of this information clinically may help to reduce the risk for AAP metabolic complications in those whose clinical care necessitates the use of AAPs.

Seeing my world in a million little pieces: Narcissism, self-construal, and cognitive-perceptual style

In 4 studies we examine the association between narcissism, self-construal, and cognitive-perceptual style, hypothesizing that high self-focus in combination with low other-focus (i.e., social atomization) is related to an analytic cognitive-perceptual style. Participants completed the Narcissistic Personality Inventory, the Self-Construal Scale, and measures of cognitive-perceptual style such as the Analysis-Holism Scale, the Embedded Figures Test, a visual illusion test, and a measure of the representativeness heuristic. We found evidence for a decontextualized cognitive-perceptual style in socially atomized participants, which included those high in narcissism and also those who had a combination of high independent and low interdependent self-construal. A meta-analytic integration of our findings found that narcissism was positively related to independent and negatively related to interdependent self-construal, and mediation analyses found some evidence that the relationship between self-construal and cognitive-perceptual style is partially mediated by narcissism.

Metabolic syndrome in bipolar disorder and schizophrenia: dietary and lifestyle factors compared to the general population

Since a poor diet is often cited as a contributor to metabolic syndrome for subjects diagnosed with bipolar disorder and schizophrenia, we sought to examine dietary intake, cigarette smoking, and physical activity in these populations and compare them with those for the general population.

The influence of metabolic syndrome, physical activity and genotype on catechol-O-methyl transferase promoter-region methylation in schizophrenia

The catechol-O-methyl transferase (COMT) 158Val/Met variant has been suggested to play a role in COMT function. Epigenetic regulation of COMT may further influence the prevalence of metabolic syndrome in these patient populations. This study examined the correlation between COMT promoter methylation and metabolic syndrome in schizophrenia patients receiving atypical antipsychotic (AAP) therapy. DNA was extracted from peripheral blood samples of schizophrenia subjects screened for metabolic syndrome. Pyrosequencing was used to analyze two methylation sites of the soluble COMT (COMT-s) promoter region. Associations between AAP use, lifestyle variables, metabolic syndrome and COMT genotype with peak methylation values were analyzed. Data are reported in 85 subjects. Methylation on CpG site 1 had a mean of 79.08% (±4.71) and it was 12.43% (±1.19) on site 2. COMT genotype proved to be an indicator of COMT methylation status on site 1 (F(2, 84)=5.78, P=0.0044) and site 2 (F(2, 84),=3.79, P=0.027). A significant negative correlation between physical activity and COMT promoter region methylation was found in Val/Val homozygous patients (site 1: P=0.013 and site 2: P=0.019). Those homozygous for Met/Met showed a positive correlation between promoter site methylation and physical activity (site 1: P=0.027, site 2: P=0.005), and between CpG site methylation and metabolic syndrome (site 1: P=0.002; site 2: P=0.001). The results of this study suggest that COMT promoter region methylation is largely influenced by COMT genotype and that physical activity plays a significant role in epigenetic modulation of COMT.

Dietary, lifestyle and pharmacogenetic factors associated with arteriole endothelial-dependent vasodilatation in schizophrenia patients treated with atypical antipsychotics (AAPs).

PURPOSE Within schizophrenia cardiovascular disease (CVD) is highly prevalent secondary to atypical antipsychotic (AAP) use. Thorough assessments of diet, lifestyle, and endothelial functioning have not been done in this population. Omega 3 Fatty Acids (N-3 FAs) have garnered attention in relation to psychopathology as well as cardioprotection. This study examined the status of endothelial function within the schizophrenia population and determined pharmacogenetic, medication, dietary, and lifestyle factors associated with this functioning. METHODS Schizophrenia subjects were screened for the metabolic syndrome along with physical activity, smoking, and variants related to folate pharmacogenetics in this cross-sectional analysis. Arteriole endothelial-dependent vasodilatation was measured using non-invasive peripheral arterial tonometry (RH-PAT, EndoPAT2000). A 24h dietary food recall was used to construct intake profiles using the Nutrition Data Systems for Research software (NDSR). We examined associations between AAP use and RH-PAT values, and the influence of N-3 FA dietary intake on this measure. Preliminary data are reported in 83 subjects with a mean age (±s.d.) of 45.89 (±11.49), 64% were Caucasian (n=53), 64% were male (n=53), and 77% were receiving AAP treatment (n=63). RESULTS A significant positive relationship was found between RH-PAT values and N-3 FA intake (F=17.7(1,16), p=0.0007) in subjects not receiving AAPs. This relationship was lost in those treated with AAPs (F=0.25(1,43), p>0.6). Regression analysis confirmed the interaction effect of AAP treatment on the relationship between RH-PAT and N-3 FAs (p=0.0105). Endothelial dysfunction was also related to folate pharmacogenetic variants. CONCLUSIONS AAPs may counteract some vascular health benefits of a diet high in N-3 FAs. AAP use may necessitate a higher N-3 FA dose to regain these effects, but additional research is necessary to strengthen the preliminary findings. Pharmacogenetic variants related to folate and homocysteine metabolism may also increase endothelial dysfunction risk.

Emotional experience predicts social adjustment independent of neurocognition and social cognition in schizophrenia.

BACKGROUND Emotional abnormalities are prominent features of schizophrenia. While the capacity for emotions is essential to social adaptation, little is known about the role of emotional experience in the social dysfunction observed in schizophrenia. OBJECTIVE This study examined the contribution of emotional experience, neurocognition, and social cognition to functional outcome in schizophrenia. METHOD Self-reported emotional experience (anhedonia, affect intensity, and emotion frequency) was assessed in 33 stable schizophrenic/schizoaffective patients and 33 healthy controls. Symptoms, neurocognition, social cognition, and functional outcome were also assessed. RESULTS Patients and controls exhibited good internal reliability on all self-report scales, except for negative affect intensity. Patients reported equally intense but less frequent positive emotions, more intense and frequent negative emotions, and more anhedonia. Results of hierarchical regression analyses showed that emotional experience accounted for significant amounts of variance of social adjustment independent of neurocognition and social cognition. CONCLUSION These data show that emotional experience can be reliably assessed and is an important determinant of functional outcome in schizophrenia.

Endothelial nitric oxide synthetase genetic variants, metabolic syndrome and endothelial function in schizophrenia

Objective: The increasing rates of metabolic syndrome and cardiovascular disease in schizophrenia led to investigation into their causes, including atypical antipsychotics and pharmacogenetic variants. This study focused on the peripheral vasculature as a cardiovascular phenotype and the influence of atypical antipsychotics, the aberrant metabolism of nitric oxide caused by endothelial nitric oxide synthetase (eNOS) genetic variants and metabolic syndrome in a cross-sectional sample of schizophrenia subjects. Methods: Associations between eNOS genetic variants and endothelial function was assessed in a cohort of schizophrenia patients taking antipsychotic drugs, whom were undergoing a clinical assessment for endothelial function via the method of peripheral artery tonometry (RH-PAT), as well as metabolic syndrome criteria screening. Analyses were conducted on the entire cohort, then again after stratifying by metabolic syndrome, to investigate the effect of the eNOS variants and metabolic syndrome on endothelial functionality. Results: We included 203 subjects with a mean age of 46 years. The cohort was 36% female, 36% had metabolic syndrome and 85% were currently using atypical antipsychotics. We found associations between the eNOS T-786C and worse endothelial functioning (lower RH-PAT values) only in schizophrenia patients without metabolic syndrome. Conclusions: Our results suggested that when schizophrenia patients progress to meet metabolic syndrome criteria, the genetic protection of the eNOS T-786C variant on endothelial function is no longer seen: Other factors of this pro-inflammatory state may be overriding this effect. The results of this study need replication and the factors driving endothelial dysfunction in patients with metabolic syndrome warrant further investigation.

Differential hedonic experience and behavioral activation in schizophrenia and bipolar disorder

The Kraepelinian distinction between schizophrenia (SZ) and bipolar disorder (BP) emphasizes affective and volitional impairment in the former, but data directly comparing the two disorders for hedonic experience are scarce. This study examined whether hedonic experience and behavioral activation may be useful phenotypes distinguishing SZ and BP. Participants were 39 SZ and 24 BP patients without current mood episode matched for demographics and negative affect, along with 36 healthy controls (HC). They completed the Chapman Physical and Social Anhedonia Scales, Temporal Experience of Pleasure Scale (TEPS), and Behavioral Activation Scale (BAS). SZ and BP showed equally elevated levels of self-report negative affect and trait anhedonia compared to HC. However, SZ reported significantly lower pleasure experience (TEPS) and behavioral activation (BAS) than BP, who did not differ from HC. SZ and BP showed differential patterns of relationships between the hedonic experience and behavioral activation measures. Overall, the results suggest that reduced hedonic experience and behavioral activation may be effective phenotypes distinguishing SZ from BP even when affective symptoms are minimal. However, hedonic experience differences between SZ and BP are sensitive to measurement strategy, calling for further research on the nature of anhedonia and its relation to motivation in these disorders.

Self-assessment of psychological stress in schizophrenia: Preliminary evidence of reliability and validity

Heightened stress sensitivity is a common characteristic of schizophrenia and may be predictive of clinical and functional outcomes. However, systematic assessment is not part of routine clinical practice. This study investigated the reliability and predictive values of two versions of a new scale for the assessment of psychological stress in psychosis (Psychological Stress Index; PSI). Thirty-seven patients with schizophrenia/schizoaffective disorder and 30 healthy controls completed a battery of self-report measures at baseline and 4-8 weeks for test-retest. Thirty-four patients were followed up at 12 months. Both of the 18-item and 9-item PSI demonstrated good levels of reliability and could significantly discriminate patients from healthy controls. Both versions showed moderate convergence with self-report and clinician ratings of depression and anxiety, and superior predictive validity of 12-month follow-up clinical and functional outcomes compared to an existing measure of stress (Perceived Stress Scale). The clinical usefulness of the PSI is supported by its predictive power on cross-sectional and longitudinal outcome. The PSI-9 performed as well as, if not better than, the PSI-18 in this study, but further evaluation is warranted for more conclusive comparison.

Endothelial function, folate pharmacogenomics, and neurocognition in psychotic disorders

Cardiovascular disease (CVD) is a well-described complication of schizophrenia, however, mechanisms connecting CVD with other facets of psychotic disorders, such as neurocognition, are not understood. The current study examined folate metabolism as a potential mechanism of CVD and neurocognitive deficits by: 1) using endothelial dysfunction as a biomarker of CVD, and 2) comparing enzymes associated with neurocognition, CVD, and critical to folate metabolism, methylenetetrahydrofolate reductase (MTHFR) and catechol-o-methyl transferase (COMT). Endothelial function was assessed in 147 participants with schizophrenia, schizoaffective disorder, and psychotic disorder not otherwise specified grouped by MTHFR and COMT allele status. Regression models were used to compare neurocognitive performance based on the Brief Assessment of Cognition in Schizophrenia (BACS). Overall, endothelial function predicted BACS composite z-scores after controlling for age, race, level of education, serum folate levels, and MTHFR/COMT risk allele status. Participants with at least one or more MTHFR and/or COMT risk alleles had lower BACS Composite and BACS Symbol Coding adjusted mean z-scores than those with both MTHFR CC and COMT Met/Met genotypes. Thus, endothelial dysfunction may contribute to the neurocognitive deficits seen in psychotic disorders. CVD interventions may not only reduce CVD-related morbidity, but also lessen progressive neurocognitive deficits reported in psychotic disorders.