Faculty Bibliography

Background: Transcranial direct current stimulation (tDCS) has been reported to improve cognition and symptoms in schizophrenia. The brain mechanisms underlying these effects have not been systematically explored. We report a doubleblind study which measured effects of tDCS on cognition, symptoms, and brain activation in schizophrenia. Methods: 41 Chinese schizophrenics were randomized to receive 10 sessions of Active or Sham tDCS. Cognition was evaluated with the MATRICS(MCCB), Paced Auditory Serial Addition Task and CogState. Psychiatric symptoms were evaluated with PANSS. Brain function were evaluated with fMRI at baseline and after 10 tDCS sessions for resting state changes in brain activation. Results: There were no strong effects (P<.05) of Active vs Sham tDCS on cognition, but there were significant (P<.01) effects on differences in brain activation assessed by fMRI. On MCCB, there were trends (P=.06) for Active tDCS vs. Sham tDCS to improve Speed of Processing. There were no effects of active vs sham tDCS on psychiatric symptoms. There were significant differences between active vs sham tDCS on resting state activation in several brain areas including middle frontal gyrus, superior frontal gyrus and superior and inferior parietal gyrus; active tDCS increased and sham tDCS decreased activation. There were significant relationships between changes in several MCCB scores and changes in brain activation in specific areas. Conclusions: tDCS had significant effects on resting state brain activation which were significantly related to changes in MCCB. However, in this sample 10 sessions of active vs sham tDCS did not show marked effects on overall cognitive function

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.