Faculty Bibliography

Background: Epigenetic dysregulation may be involved in the underlying molecular deficits in schizophrenia (SZ). Previous research by our group has show hypermethylation of GABAergic promoter gene in and increases in DNMT1 and DNMT3A in post mortem brain samples of patients with SZ. We have also shown that differences in DNMT1 and other epigenetically related enzymes are also found in the lymphocytes of living patients with chronic schizophrenia (CSZ). We now report preliminary results on epigenetic related mRNA's in lymphocytes on a larger sample of chronic schizophrenics and controls. Methods: CSZ (n =29) and non-psychotic controls (NPC) (n =31) subjects had a blood sample (50-60 cc) drawn, and lymphocyte pellet extracted by Ficoll gradient procedure. qPCR assays were used to measure epigenetically related mRNA's-DNMT1, DMNT3A, TET1, TET2, TET3, BDNF and NR3C (glucocorticoid receptor). We also assayed several immunological-related mRNA (which appeared as strong hits from RNA sequence analysis): T-Cell Surface Glycoprotein CD4, CCR1 (C-C motif chemokine receptor 1), FPRL3 (Formyl Peptide Receptor). Assays were performed using Taqman probes with B-Actin as housekeeping gene. Patients were also evaluated with psychopathology with PANSS, for cognitive function with MATRICS, and for odor identification and discrimination with Sniff and Sticks smell test. Results: In this sample CSZ showed significantly higher DMNT3A (P =.048) than NPC. Male CSZ showed significantly higher DNMT1 than NPC (P =.014), but in the total sample there was a trend, but no significant difference in DNMT1. Compared to NPC, CSZ subjects showed significantly higher levels of GABAergic enzymes measured by the GAD1 probe (which assayed GAD67 and GAD25 mRNA) (P =.030), higher levels of glucocorticoid receptor measured by the NRC3 probe (P =.006), and significantly lower levels of FRPRL3 (P =039). Higher levels of FPRL3 and CD4 were moderately correlated with PANSS positive symptoms in CSZ (FRPL3 r =+.43 P =.019, CD4 r =+.37 P =.054) and these correlations were slightly stronger in male CSZ. Higher DNMT1 and DNMT3A levels in lymphocytes of CSZ correlated negatively with scores on MATRICs battery (DNMT1-attention/vigilance-r =-.41, P =.031, working memory r =-.37, P =.048, composite score r =-.36, P =.063). Conclusions: CSZ demonstrate differences in epigenetically related mRNA's in their lymphocytes. In CSZ higher levels of DNMT were related to poorer cognitive performance and higher levels of immunological related mRNA to greater positive symptom scores. Some potential differences to our previously published results may be related to differences in mRNA's transcript variants detected by the Taqman probes and earlier research with specifically generated sequence probes

Schizophrenic patients have a high rate of smoking and cognitive deficits which may be related to a decreased number or responsiveness of nicotinic receptors in their brains. Varenicline is a partial nicotinic agonist which is effective as an antismoking drug in cigarette smokers, although concerns have been raised about potential psychiatric side-effects. We conducted a double-blind placebo controlled study in 87 schizophrenic smokers to evaluate the effects of varenicline (2 mg/day) on measures of smoking, cognition, psychiatric symptoms, and side-effects in schizophrenic patients who were cigarette smokers. Varenicline significantly decreased cotinine levels (P<0.001), and other objective and subjective measures of smoking (P < .01), and responses on a smoking urges scale (P = .02), more than placebo. Varenicline did not improve scores on a cognitive battery designed to test the effect of drugs on cognitive performance in schizophrenia (the MATRICS battery), either in overall MATRICS battery Composite or individual Domain scores, more than placebo. There were no significant differences between varenicline vs. placebo effects on total symptom scores on psychiatric rating scales, PANSS, SANS, or Calgary Depression scales, and there were no significant drug effects in any of these scales sub-scores when we used Benjamin-Hochberg corrected significance levels (alpha = .05). Varenicline patients did not show greater side-effects than placebo treated patients at any time point when controlled for baseline side-effect scores. Our study supports the use of varenicline as a safe drug for smoking reduction in schizophrenia but not as a cognitive enhancer. TRIAL REGISTRATION: ClinicalTrials.gov 00802919.

Background: Deficits in Odor identification and discrimination have been found in previous studies of patients with schizophrenia (SZ), and structural and functional abnormalities in the olfactory system of schizophrenia are well documented. Some studies have reported relationship between odor deficits in SZ and negative symptoms. We investigated these questions in a new sample of chronic SZ and controls who are also participating in a study of epigenetic markers in the lymphocytes of SZ. Sequencing of activation and silencing of gene methylation by methylating enzymes (DNMT1 3a) and change in histone acetylation may be involved in epigenetic modifications of the development of the olfactory system. Methods: In this initial group of sample we studied 34 patients with chronic SZ and 23 controls. Odor identification discrimination was assessed with Sniff n Sticks smell test battery for Odor Identification and Odor Discrimination. Current psychiatric symptoms were assessed with PANSS interview. Cognition was assessed by MATRCIS battery. A blood sample was drawn for measurement of mRNA of enzyme related to methylation of genes (DNMT, TETT 1)and genes products heavily regular by promoter methylation( BDNF, glucocorticoid receptor),although assays on these samples have not been completed at this time. Results: SZ had significantly (P <0.01)lower scores than controls on the small identification and discrimination tests of the Sniff n Sticks battery. However, on the odor identification, but not on discrimination, there was a significant sex effect, with identification being deficient in male SZ but not females. There were no differences between male vs. female controls on the odor tests. There was a moderate statistically significant association between scores on odor discrimination and scores on the MATRICS battery (composite r=0.39 P=0.02, and working memory r=0.44 P=0.01), but this association was stronger in females than males. In controls there was only a significant association with higher odor identification with the scores on the MCCB domain of attention vigilance and no sex difference. In SZ patients poorer performance on odor discrimination was associated with higher scores on Negative symptoms (r=0.51, P <0.01), and higher scores on PANSS Total (r=0.39, P=o0.03) and no strong differences in effects in males vs. female SZ. Relationships to biological markers are being investigated. Conclusions: This current research confirms the previously reported deficits in olfaction in schizophrenia, and the relationship of olfactory deficits to negative symptoms. It suggests that sex differences may be important in odor identification test, but not the odor discrimination test in SZ. This is the first study to show olfactory deficits related to performance on the MATRCIS battery and suggest that there may be a sex difference in the strength of this relationship

Schizophrenia is characterized by cognitive deficits which persist after acute symptoms have been treated or resolved. Transcranial direct current stimulation (tDCS) has been reported to improve cognition and reduce smoking craving in healthy subjects but has not been as carefully evaluated in a randomized controlled study for these effects in schizophrenia. We conducted a randomized double-blind, sham-controlled study of the effects of 5 sessions of tDCS (2 milliamps for 20minutes) on cognition, psychiatric symptoms, and smoking and cigarette craving in 37 outpatients with schizophrenia or schizoaffective disorder who were current smokers. Thirty subjects provided evaluable data on the MATRICS Consensus Cognitive Battery (MCCB), with the primary outcome measure, the MCCB Composite score. Active compared to sham tDCS subjects showed significant improvements after the fifth tDCS session in MCCB Composite score (p=0.008) and on the MCCB Working Memory (p=0.002) and Attention-Vigilance (p=0.027) domain scores, with large effect sizes. MCCB Composite and Working Memory domain scores remained significant at Benjamini-Hochberg corrected significance levels (alpha=0.05). There were no statistically significant effects on secondary outcome measures of psychiatric symptoms (PANSS scores), hallucinations, cigarette craving, or cigarettes smoked. The positive effects of tDCS on cognitive performance suggest a potential efficacious treatment for cognitive deficits in partially recovered chronic schizophrenia outpatients that should be further investigated.

The epigenetic dysregulation of the brain genome associated with the clinical manifestations of schizophrenia (SZ) includes altered DNA promoter methylation of several candidate genes. We and others have reported that two enzymes that belong to the DNA-methylation/demethylation network pathways-DNMT1 (DNA-methyltransferase) and ten-eleven translocator-1(TET1) methylcytosine deoxygenase are abnormally increased in corticolimbic structures of SZ postmortem brain. The objective of this study was to investigate whether the expression of these components of the DNA-methylation-demethylation pathways known to be altered in the brain of SZ patients are also altered in peripheral blood lymphocytes (PBL). The data show that increases in DNMT1 and TET1 and in glucocorticoid receptor (GCortR) and brain derived neurotrophic factor (BDNF) mRNAs in PBL of SZ patients are comparable to those reported in the brain of SZ patients. The finding that the expressions of DNMT1 and TET1 are increased and SZ candidate genes such as BDNF and GCortR are altered in the same direction in both the brain and PBL together with recent studies showing highly correlated patterns of DNA methylation across the brain and blood, support the hypothesis that a common epigenetic dysregulation may be operative in the brain and peripheral tissues of SZ patients.

Background: A few studies have suggested that Yoga may be effective in improving psychiatric symptoms, quality of life measures, and cognition in schizophrenic patients Studies in non-psychotic patients with type -2 diabetes show Yoga effects on weight reduction and improvement in glucose-lipid parameters. Studies in non-psychotic patients have also shown reduction in cortisol, TSH and alteration in ACTH response. Studies of response in glucocorticoid receptors in brain and blood cells have shown that behavioral treatments related to maternal care, maternal depression or stress and childhood abuse can alter glucorticoid receptors and their epigenetic control. We present results from a preliminary study of the effects of Yoga on these multiple aspects of clinical, cognitive, and biochemical response in schizophrenic patients. Methods: We conducted a study of Yoga in 21 chronic schizophrenic outpatients (schizophrenia or schizoaffective diagnosis) who participated in 12 weeks (1 h sessions 3x/week) of Hatha Yoga (group 1) or later a modified Yoga concentrating more on Qigong movements and procedures (group 2). Both groups practiced Coherent Breathing, gentle breathing at 5 breaths per minute with equal inhalation and exhalation. Patients entered had BMI >=27.5, and/or fasting glucose 4100 mg. Subjects were evaluated at baseline and end for a) Cognition (RBANS), b) Psychiatric Symptoms (PANSS), c) glucocorticoid receptor mRNA in lymphocytes, and d) appetite measures in response to a test meal. They were evaluated monthly for e) fasting glucose and lipid measures, f) cortisol, and ACTH, TSH, and g) weight and waist measures. Statistical analysis used paired sample t-test and repeated measures analyses of variance. Results: Three months of Yoga treatments produced significant increases in Cognitive Scores on RBANS Total Scores and Sum of Index Scores (P=.001) and increases in RBANS sub-scores of Attention, Delayed Memory, Figure Copy, Visual- Spatial Construction, Semantic Fluency and Language Index. There were no significant changes in PANSS scores, although there was a trend for decrease on the Depression factor (P=.08) and PANSS General Factor (P=.06), and other scores showed a slight trend for decrease. There were no significant changes in weight or glucose and lipid measures, but Waist and Hip circumference significantly decreased (P=.001). In the test meal volume of meal consumed was decreased after Yoga treatment. There was a trend (P=.2) for increase in serum ACTH and a tendency for increased cortisol in Yoga group 2. Serum cortisol and ACTH were highly correlated at baseline (r=.69, P=.001), but not correlated by 8 or 12 weeks of Yoga treatment (r's=0.07.-.0.13). In preliminary analysis from data form Yoga group 1, 9 patients showed approximately 50% decrease in lymphocyte glucocorticoid receptor mRNA (GR mRNA (baseline) 4.51 vs. (end) 2.08, P=.030). Conclusions: Our results suggest that Yoga improves cognitive function in schizophrenic patients and may modify glucocorticoid receptor function. Studies with appropriate controls, including exercise controls, are needed to further specify these effects. Longer periods of breathwork while walking may produce stronger effects