Faculty Bibliography

RATIONALE: Nicotinic agonists may improve attention and memory in humans and may ameliorate some cognitive deficits associated with neuropsychiatric disorders such as schizophrenia. MATERIALS AND METHODS: We investigated the effects of a single dose of nicotine on episodic memory performance in 10 adults with schizophrenia and 12 healthy controls. Participants were nonsmokers in order to avoid confounding effects of nicotine withdrawal and reinstatement on memory. At each of two study visits, participants performed a test of episodic memory before and 4 h after application of a 14-mg transdermal nicotine (or identical placebo) patch in counterbalanced order. RESULTS: Compared with placebo, nicotine treatment was associated with more rapid and accurate recognition of novel items. There was a trend for a treatment by diagnosis interaction, such that the effect of nicotine to reduce false alarms was stronger in the schizophrenia than the control group. There was no effect of nicotine on accuracy or reaction time for identification of previously viewed items. CONCLUSIONS: These data suggest that nicotine improves novelty detection in non-smokers, an effect that may be more pronounced in non-smokers with schizophrenia. Because memory deficits are associated with functional impairment in schizophrenia and because impaired novelty detection has been linked to the positive symptoms of schizophrenia, study of the effects of chronic nicotinic agonist treatment on novelty detection may be warranted

BACKGROUND: Recent literature documents a stronger association between nonfasting triglycerides (TG) and cardiovascular risk compared to fasting TG. Given concerns over antipsychotic effects on serum TG, this analysis explored changes in nonfasting TG in phase 1 of the CATIE Schizophrenia Trial. METHODS: Change in nonfasting TG, adjusted for baseline value, was compared between antipsychotic treatment groups using subjects with nonfasting laboratory assessments at baseline and 3 months. RESULTS: Among the 246 subjects there were significant treatment differences in 3-month change from baseline (p=0.009). The greatest increases in median and adjusted mean nonfasting TG levels were seen among those randomized to quetiapine (mean+54.7 mg/dl, median+26 mg/dl) and olanzapine (mean+23.4 mg/dl, median+26.5 mg/dl), while ziprasidone was neutral (mean+0.0 mg/dl, median+8 mg/dl), and decreases were seen with risperidone (mean -18.4 mg/dl, median -6.5 mg/dl) and perphenazine (mean -1.3 mg/dl, median -22 mg/dl). Pairwise comparisons indicated a significant between-group difference for perphenazine vs. olanzapine (p=0.002) and a trend for perphenazine vs. quetiapine (p=0.006). CONCLUSIONS: This analysis provides further evidence for differential antipsychotic metabolic liabilities, and confirms signals for the effects of olanzapine and quetiapine on serum TG seen in earlier CATIE analyses. Future consensus recommendations will clarify the role of nonfasting TG monitoring in routine clinical practice

The purpose of the present study was to assess posttraumatic stress disorder (PTSD), cognitive function, and quality of life in patients with schizophrenia who had a self-reported history of trauma exposure. Outpatients diagnosed with schizophrenia or schizoaffective disorder were referred to the study. Each patient was assessed with the Positive and Negative Syndrome Scale (PANSS), the Harvard Trauma Questionnaire (HTQ), a cognitive assessment battery, Heinrich's Quality of Life Scale (QLS), and the Behavior and Symptom Identification Scale (BASIS). Eighty-seven subjects who reported experiencing at least one traumatic event were included in the study. Fifteen of 87 (17%) met the DSM-IV criteria for PTSD. The PTSD group had significantly worse overall cognitive performance than the non-PTSD group, especially in the domains of attention, working memory and executive function. In addition, the PTSD group showed significantly worse self-rated quality of life as measured by the BASIS total score. The development of PTSD is associated with poor cognitive function and subjectively, but not objectively, rated low quality of life in patients with schizophrenia. Evaluating PTSD in patients with schizophrenia could have important implications from both clinical and research perspectives

Dysfunction in the neuronal nicotinic acetylcholine receptor (nAChR) system has been implicated in the pathophysiology of schizophrenia, and it has been postulated that treatments that increase nAChR activity may improve symptoms of the disorder. We investigated the effects of the acetylcholinesterase inhibitor and allosteric nAChR modulator, galantamine, on cognitive performance and clinical symptoms when added to a stable antipsychotic medication regimen in nonsmoking outpatients with schizophrenia in a double-blind, placebo-controlled, parallel-group design. Participants were randomized to receive either galantamine (n=10) up to 32 mg/day or identical placebo (n=10) for 8 weeks and completed a cognitive battery at baseline and week 8 and clinical scales at baseline, week 4 and week 8. The primary outcome measure was attentional performance as measured by the d' measure in the Continuous Performance Test - Identical Pairs (CPT-IP) Version. Contrary to our hypothesis, galantamine treatment was associated with inferior performance on the CPT-IP, on the three-card Stroop task, and on the Letter-Number Span task without reordering. Galantamine had no effect on clinical symptoms. In summary, galantamine treatment, at a dose of 32 mg/day, was well tolerated but was not effective as an adjunctive treatment for cognitive deficits in stable nonsmokers with schizophrenia

BACKGROUND: The metabolic syndrome (MS) is associated with increased risk for diabetes mellitus and coronary heart disease, and is highly prevalent among schizophrenia patients. Given concerns over antipsychotic metabolic effects, this analysis explored MS status and outcomes in phase 1 of the CATIE Schizophrenia Trial. METHODS: The change in proportion of subjects with MS and individual criteria was compared between antipsychotic treatment groups, along with mean changes for individual criteria. Primary analyses examined subjects with fasting laboratory assessments at baseline and 3 months. Other analyses examined 3-month changes in MS status, waist circumference (WC), HDL cholesterol and blood pressure in all subjects, metabolic changes at the end of phase 1 participation (EOP), and repeated measures changes in HDL, blood pressure (BP) and WC over phase 1. RESULTS: At 3 months, there were no significant between-drug differences for the change in proportion of subjects meeting MS status or individual MS criteria in the smaller fasting cohort (n = 281) or for those meeting criteria for parameters not dependent on fasting status (BP, HDL, WC) among all subjects (n=660). Among all subjects whose MS status could be determined at 3 months (n=660), MS prevalence increased for olanzapine (from 34.8% to 43.9%), but decreased for ziprasidone (from 37.7% to 29.9%) (p=.001). Although effect sizes varied across subgroups, at 3 months olanzapine and quetiapine had the largest mean increase in waist circumference (0.7 in. for both) followed by risperidone (0.4 in.), compared to no change for ziprasidone (0.0 in.) and a decrease in waist circumference for perphenazine (-0.4 in.). Olanzapine also demonstrated significantly different changes in fasting triglycerides at 3 months (+21.5 mg/dl) compared to ziprasidone (-32.1 mg/dl). EOP exposure data was obtained, on average, nine months from baseline for all metabolic variables. Results from EOP and repeated measures analyses were consistent with those at 3 months for mean changes in WC and fasting triglycerides, but between group differences emerged for HDL and SBP. CONCLUSIONS: This large non-industry sponsored study confirms the differential metabolic effects between antipsychotics. Clinicians are advised to monitor all metabolic parameters, including WC, HDL and serum triglycerides, during antipsychotic treatment

Schizophrenia is characterized by heritable deficits in executive function. Two common, functional polymorphisms, catechol-O-methyltransferase (COMT) Val108/158Met and methylenetetrahydrofolate reductase (MTHFR) C677T, have separately been associated with executive function performance in schizophrenia. Given the closely related biochemistry of MTHFR and COMT, it is plausible that the T and Val alleles act synergistically to impair executive function. This investigation of 185 outpatients with schizophrenia examined the interactive effects of these two polymorphisms on Wisconsin Card Sorting Task (WCST) performance. Two WCST measures consistently associated with schizophrenia, perseverative errors and inability to generate categories, were contrasted among compound COMT-MTHFR genotype groups. Individuals homozygous for the COMT Val allele who also carried at least one copy of the MTHFR T allele exhibited a significantly higher percentage of perseverative errors than patients in the other genotype groups. While the T allele also exerted a negative effect on category generation, COMT genotype did not contribute to category performance. It is plausible that cumulative effects of the MTHFR T and COMT Val alleles on intracellular methylation profiles and prefrontal dopamine transmission underlie their interactive effect on perseverative errors

To perform well on any challenging task, it is necessary to evaluate your performance so that you can learn from errors. Recent theoretical and experimental work suggests that the neural sequellae of error commission in a dorsal anterior cingulate circuit index a type of contingency- or reinforcement-based learning, while activation in a rostral anterior cingulate circuit reflects appraisal of the affective or motivational significance of errors. Patients with schizophrenia show rigid, perseverative behaviour that is not optimally responsive to outcome. Findings of reduced anterior cingulate cortex (ACC) activity during error commission in schizophrenia suggest that difficulties in evaluating and modifying behaviour in response to errors may contribute to behavioural rigidity. Using event-related functional MRI and an antisaccade paradigm with concurrent monitoring of eye position, the present study examined error-related activation and its relation to task performance in the anatomic components of two ACC circuits that are theorized to make distinct contributions to error processing. Eighteen chronic-medicated schizophrenia patients and 15 healthy controls participated. Compared to controls, patients showed increased antisaccade error rates and decreased error-related activation in the reinforcement learning network--dorsal ACC, striatum and brainstem (possibly substantia nigra)--and also in the affective appraisal network--rostral ACC, insula and amygdala. These reductions remained when the effects of antipsychotic medication dose and error rate were statistically controlled. Activation in these networks was inversely related to error rate in both patient and control groups, but the slope of this relation was shallower in patients (i.e. across participants with schizophrenia, decrements in error rate were associated with smaller decrements in activation). This indicates that the blunted neural response to errors in schizophrenia was not simply a reflection of more frequent errors. Our findings demonstrate a blunted response to error commission that is associated with worse performance in two ACC circuits in schizophrenia. In the dACC circuit, the blunted response may reflect deficient modification of prepotent stimulus-response mappings in response to errors, and in the rACC network it may reflect diminished concern regarding behavioural outcomes. However, despite these deficits and in the absence of external feedback regarding errors, patients corrected their errors as frequently as controls suggesting intact error recognition and ability to institute corrective action. Impairments in evaluating and learning from errors in schizophrenia may contribute to behaviour that is rigid and perseverative rather than optimally guided by outcomes, and may compromise performance across a wide range of tasks

Whether antisaccade errors in schizophrenia are due to defects in implementing saccadic inhibition or difficulty in generating novel responses is uncertain. We investigated whether antisaccade errors were related to difficulty in inhibiting saccades when subjects were asked to maintain steady fixation, a situation that does not require a novel response. We examined the ocular motor data of 15 schizophrenia subjects and 16 healthy subjects. We assessed fixation in two situations: first, during the period before target onset during each saccadic trial, and second, during fixation trials that were interspersed with saccadic trials. We found that schizophrenia subjects had higher rates of fixation losses than control subjects in both situations. Second, both in healthy and schizophrenia subjects, antisaccade error rate was positively correlated with the frequency of fixation losses in the preparatory period of saccadic trials, but not with the frequency of fixation losses during fixation trials. Third, antisaccade errors were more likely to occur in trials with unstable fixation than in trials with stable fixation. Last, antisaccade error rate was also correlated with prosaccade error rate. We conclude that antisaccade errors are related to difficulties with implementing inhibitory control in the saccadic system. However, the finding of a correlation between the error rates for antisaccades and prosaccades suggests that this is not specifically concerned with inhibiting the automatic prosaccade, but a more general deficit in implementing goal-oriented behavior