Faculty Bibliography

The metabolic syndrome (MS) is highly prevalent among patients with schizophrenia (current estimates 35-40%), yet no data exist on the correlation of this diagnosis with illness severity, neurocognitive or quality of life measures in this population. METHODS: Using baseline data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial, assignment of MS status was performed using an updated definition derived from the National Cholesterol Education Program (NCEP) criteria. Those with and without MS were compared on the basis of primary and secondary variables of interest from baseline data encompassing psychiatric, neurocognitive and quality of life measures. RESULTS: Of 1460 subjects enrolled at baseline, MS status could be reliably assigned for 1231 subjects, with a prevalence of 35.8% using the NCEP derived criteria. After adjustment for age, gender, race, ethnicity and site variance, those with MS rated themselves significantly lower on physical health by SF-12 (p < .001), and scored higher on somatic preoccupation (PANSS item G1) (p = .03). There were no significant differences between the two cohorts on measures of symptom severity, depression, quality of life, neurocognition, or self-rated mental health. Neither years of antipsychotic exposure nor alcohol usage were significant predictors of MS status when adjusted for age, gender, race, and ethnicity. CONCLUSIONS: The metabolic syndrome is highly prevalent in this large cohort of schizophrenia patients and is strongly associated with a poor self-rating of physical health and increased somatic preoccupation. These results underscore the need for mental health practitioners to take an active role in the health monitoring of patients with schizophrenia to minimize the impact of medical comorbidity on long-term mortality and on daily functioning. Outcomes data from CATIE will provide important information on the metabolic and clinical impact of antipsychotic treatment for those subjects with MS and other medical comorbidities

The dopamine model of schizophrenia has been supplanted by several additional models in order to account for genetic findings, risk factors, course of illness, and the diversity of symptom domains. The increasing number and complexity of potential models for this heterogeneous disorder offer new targets for pharmacologic treatment that differ in their appropriate time points for intervention and in their potential effects on the course of illness. This article reviews relevant neurodevelopmental, biochemical, and neurodegenerative models with respect to potential pharmacologic opportunities

OBJECTIVE: Using functional MRI, we investigated whether, like healthy subjects, patients with schizophrenia show a relative hemispheric specialization in ventrolateral prefrontal cortex (PFC) for spatial and shape working memory (WM). We hypothesized that reduced specialization in schizophrenia would reflect a failure to adopt optimal domain-specific strategies and would contribute to WM deficits. METHODS: Twelve healthy subjects and 16 schizophrenia patients performed spatial and shape WM tasks and a non-WM control task. Direct comparisons of the spatial and shape WM tasks assessed specialization. RESULTS: Despite deficient WM performance, both patients and controls showed a relative hemispheric specialization in ventrolateral PFC for spatial (right) and shape (left) WM and did not differ in this regard. CONCLUSIONS: The finding of intact hemispheric specialization in ventrolateral PFC suggests that patients employ the same domain-specific strategies as healthy subjects during spatial and shape WM. Rather than reflecting a failure to adopt the optimal strategy, we hypothesize that WM deficits in schizophrenia reflect impairments of executive processes that are required for WM performance regardless of domain. These processes are associated with activity in the dorsolateral PFC, a region that has been repeatedly implicated in studies of WM

OBJECTIVE: The objective of this study was to examine the effects of tobacco abstinence and bupropion treatment on cognitive functioning in adult smokers with schizophrenia in the setting of a randomized, double-blind, placebo-controlled clinical trial of bupropion for smoking cessation. METHOD: Fifty-three adults with schizophrenia (DSM-IV) took part in a trial of bupropion for smoking cessation. Subjects were enrolled in the study from August 1999 to March 2003. Forty-five subjects remained in the trial at week 4; 41 subjects, 19 taking bupropion and 22 taking placebo, completed the baseline and week 4 cognitive assessments and were included in the analysis of adjusted effects of abstinence and bupropion treatment on cognitive function. RESULTS: Controlling for bupropion treatment and baseline performance, 7 days of tobacco abstinence was associated with slowed motor speed (finger tapping) but was not associated with worsening of performance on tests of attention (AX Continuous Performance Test [AX-CPT]), verbal learning and memory (California Verbal Learning Test [CVLT]), working memory (digit span), or executive function/inhibition (Stroop) and was not associated with worsening of any clinical measures. Controlling for abstinence status, bupropion was associated with reduction (improvement) in reaction time variability on the AX-CPT and with reduction in perseverative errors on the CVLT. CONCLUSION: We conclude that 1 week of tobacco abstinence is associated with slowed motor speed but is not associated with detectable worsening in performance on a range of neuropsychological tests or clinical symptoms in the subset of patients who were able to quit smoking. We also conclude that bupropion treatment may be associated with improvement in variability of attention

OBJECTIVE: The goal of this 10-year naturalistic study was to examine, in clozapine-treated patients, the change in cardiovascular risk factors following clozapine initiation and the mortality estimates from cardiovascular disease. METHOD: Data were collected from medical records from January 1992 to December 2003 and included age, gender, race, diagnosis, family history of diabetes, and age at clozapine initiation for clozapine-treated patients with schizophrenia or schizoaffective disorder (DSM-IV criteria). Clozapine dosage and laboratory results were recorded at 12-month intervals. RESULTS: At the time of clozapine initiation, the mean +/-?SD age of the 96 patients studied was 36.5 +/- 7.9 years; 28% (N = 27) were women. The Kaplan-Meier estimate for 10-year mortality from cardiovascular disease was 9%. African American and Hispanic American patients exhibited elevated risk of cardiovascular disease-related mortality (odds ratio [OR] = 7.2, p = .09; OR = 11.3, p = .04, respectively) compared to white patients. Body mass index (BMI) significantly increased the odds ratio of mortality (OR = 1.2, p < .01). The Kaplan-Meier estimate for new-onset diabetes mellitus was approximately 43%, and Hispanic American (OR = 4.3, p = .027) and African American (OR = 11.5, p = .0001) patients showed elevated risks of developing diabetes mellitus compared to white patients. Additionally, BMI (OR = 1.11, p = .0006), total cholesterol level (OR = 1.006, p = .04), and serum triglyceride level (OR = 1.002, p = .04) modestly increased the odds ratio for the development of diabetes mellitus. CONCLUSIONS: These results support the hypothesis that clozapine-treated patients appear to be at risk for death from cardiovascular disease secondary to clozapine-associated medical disorders such as obesity, diabetes, hypertension, and hyperlipidemia

RATIONALE: Atypical antipsychotic drugs are the drugs of choice for the treatment of schizophrenia. However, despite advances, no treatments have been established for patients who fail to improve with the most effective of these, clozapine. The inhibition of dopamine transmission through blockade of dopamine D2 receptors is considered to be essential for antipsychotic efficacy, but it is postulated that modulation of glutamate transmission may be equally important. In support of this, symptoms similar to schizophrenia can be induced in healthy volunteers using N-methyl-D-aspartate (NMDA) antagonist drugs that are also known to enhance glutamate transmission. Furthermore, lamotrigine, which can modulate glutamate release, may add to or synergise with atypical antipsychotic drugs, some of which may themselves modulate glutamate transmission. OBJECTIVES: We examine the evidence for the efficacy of lamotrigine. We consider how this fits with a glutamate neuron dysregulation hypothesis of the disorder. We discuss mechanisms by which lamotrigine might influence neuronal activity and glutamate transmission, and possible ways in which the drug might interact with antipsychotic medications. RESULTS: Data from four clinical studies support the efficacy of adjunctive lamotrigine in the treatment of schizophrenia. In addition, and consistent with a glutamate neuron dysregulation hypothesis of schizophrenia, lamotrigine can prevent the psychotic symptoms or behavioural disruption induced by NMDA receptor antagonists in healthy volunteers or rodents. CONCLUSIONS: The efficacy of lamotrigine is most likely explained within the framework of a glutamate neuron dysregulation hypothesis, and may arise primarily through the drugs ability to influence glutamate transmission and neural activity in the cortex. The drug is likely to act through inhibition of voltage-gated sodium channels, though other molecular interactions cannot be ruled out. Lamotrigine may add to or synergise with some atypical antipsychotic drugs acting on glutamate transmission; alternatively, they may act independently on glutamate and dopamine systems to bring about a combined therapeutic effect. We propose new strategies for the treatment of schizophrenia using a combination of anti-dopaminergic and anti-glutamatergic drugs

RATIONALE: Schizophrenia is a disorder with cognitive deficits that could stem from cholinergic dysfunction. OBJECTIVES: Our aim was to examine if donepezil administered to stable, medicated outpatients with schizophrenia improves cognition and psychopathology. METHODS: We conducted a double-blind placebo-controlled trial of donepezil up to 10 mg/day added for 8 weeks to ongoing antipsychotic treatment in 36 typical community-treated schizophrenia patients not selected for cognitive impairment. RESULTS: Donepezil did not improve measures of cognition or psychopathology. It was well tolerated. CONCLUSION: Consistent with other studies, addition of donepezil to stable patients with schizophrenia did not improve cognition or measures of psychopathology. This result does not support the hypothesis that residual symptoms and cognitive problems result from a cholinergic deficit that can be remedied by an acetylcholinesterase inhibitor. A donepezil add-on strategy might make sense in selected schizophrenia cases where a pathological process is known to affect cholinergic neurons (e.g., history of head injury or comorbid dementia)

OBJECTIVE: To determine the prevalence and clinical significance of obsessive-compulsive (OC) symptoms among a group of stable outpatients with schizophrenia. METHODS: We studied 118 patients with schizophrenia from an urban clinic, characterized using clinical symptoms scales, including the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), and neuropsychological testing. We categorized patients into three groups according to severity of OC symptoms and used multivariate linear regression and chi-square tests to compare groups on variables of interest. RESULTS: Only 10 patients (8.8%) had Y-BOCS scores greater than 16, a standard criterion for OCD studies. The patient group with the most OC symptoms (Y-BOCS scores >11) scored higher on the Hamilton Depression Scale, the positive symptoms subscale of the Positive and Negative Syndromes Scale (PANSS) and its delusions item, but not on any of the neuropsychological tests compared to the other two groups. Patients with most severe compulsive symptoms (but not OC symptoms together, or obsessions alone) were more likely to be treated with olanzapine or clozapine, atypical antipsychotic medications previously reported to induce or worsen OC symptoms. CONCLUSIONS: Our results confirm previous findings that patients with schizophrenia and comorbid OC symptoms have more positive symptoms but not the suggestion that such patients are more cognitively impaired than their counterparts without OC symptoms. We suggest possible explanations for discrepancies in the literature, including differences in patient sampling and definition of comorbid OC symptoms. Finally, our data suggest that olanzapine and clozapine may produce or worsen compulsions in some patients; prospective studies need to address this possibility

The objective of this study was to examine the efficacy of bupropion for smoking cessation in patients with schizophrenia. Adults with schizophrenia who smoked more than 10 cigarettes per day and wished to try to quit smoking were recruited from community mental health centers, enrolled in a 12-week group cognitive behavioral therapy intervention, and randomly assigned to receive either bupropion sustained-release 300 mg/d or identical placebo. Fifty-three adults, 25 on bupropion and 28 on placebo, were randomized, completed at least 1 postbaseline assessment and were included in the analysis. The primary outcome measures were 7-day point prevalence abstinence in the week after the quit date (week 4) and at the end of the intervention (week 12). Subjects in the bupropion group were significantly more likely to be abstinent for the week after the quit date (36% [9/25] vs. 7% [2/28], P = 0.016) and at end of the intervention (16% [4/25] vs. 0%, P = 0.043). Subjects in the bupropion group also had a higher rate of 4-week continuous abstinence (weeks 8-12) (16% [4/25] vs. 0%, P = 0.043) and a longer duration of abstinence (4.2 [3.2] weeks vs. 1.8 [0.96] weeks, t = 2.30, P = 0.037). The effect of bupropion did not persist after discontinuation of treatment. Subjects in the bupropion group had no worsening of clinical symptoms and had a trend toward improvement in depressive and negative symptoms. We conclude that bupropion does not worsen clinical symptoms of schizophrenia and is modestly effective for smoking cessation in patients with schizophrenia. The relapse rate is high after treatment discontinuation

BACKGROUND: In healthy individuals, the activity of the medial temporal lobe habituates rapidly with the repeated presentation of a stimulus. Using functional magnetic resonance imaging (fMRI), we tested the hypothesis that habituation of the medial temporal lobe is reduced in schizophrenia. METHODS: During fMRI scanning, fearful and happy faces were presented repeatedly to healthy control subjects (n =16) and patients with schizophrenia (n =18). Habituation of medial temporal lobe structures was measured by comparing the hemodynamic response occurring during the early and late portions of the presentation of each face. RESULTS: Control subjects demonstrated significant medial temporal lobe habituation to fearful but not to happy faces. In contrast, patients with schizophrenia did not demonstrate medial temporal lobe habituation in response to fearful or happy faces. In a direct, between-group comparison, right hippocampal habituation to fearful faces was significantly greater in control subjects than in the schizophrenia patients. Also, there were no significant differences between the patients and control subjects in the early medial temporal lobe response to fearful faces, suggesting that attenuated hippocampal habituation in schizophrenia is not associated with a reduction in initial activation. CONCLUSIONS: These findings suggest that there is abnormal modulation of hippocampal responses to fearful faces in schizophrenia