Faculty Bibliography

BACKGROUND: The feasibility and preliminary efficacy of a novel cognitive behavioral treatment for decreasing psychotic symptoms and improving social functioning was evaluated in a pilot study. This represents the first treatment outcome study of CBT for psychosis with a manualized, active comparison condition. METHODS: Thirty outpatients with schizophrenia or schizoaffective disorder, depressed type with residual psychotic symptoms were randomly assigned to either 16 weekly sessions of functional cognitive behavioral therapy (fCBT) or psychoeducation (PE) with assessments conducted at baseline and post-treatment by blind evaluators. RESULTS: Attrition was only 7% and did not differ between fCBT and PE, indicating good tolerability of both treatments. For this sample with persistent symptoms, between groups effects were not significantly different, but within group effect sizes indicated greater treatment benefit for fCBT on positive symptoms, particularly for the PSYRATS voices subscale. CONCLUSION: The results suggest that fCBT is well tolerated and holds promise for reducing persistent positive symptoms

OBJECTIVE: Weight gain is commonly observed with olanzapine treatment and can increase the risk for obesity, cardiovascular disease, hypertension, and diabetes mellitus. This study examined the effectiveness of sibutramine, an approved weight loss agent, in overweight and obese subjects taking olanzapine for schizophrenia or schizoaffective disorder. METHOD: Each subject had a DSM-IV diagnosis of schizophrenia or schizoaffective disorder, had been taking a stable dose of olanzapine for at least 4 months, and had a body mass index of >/=30 kg/m(2) or >/=27 kg/m(2) plus at least one cardiovascular risk factor. In a 12-week double-blind, randomized, placebo-controlled study, 37 subjects received placebo or sibutramine (up to 15 mg/day). For the first 8 weeks all subjects participated in weekly group sessions focused on nutrition and behavioral modification. RESULTS: The sibutramine and placebo groups had no significant baseline differences on age, gender, education, ethnicity, diagnosis, weight, body mass index, and blood pressure. At week 12 the sibutramine group had significantly greater losses than the placebo group in weight (mean=8.3 lb, SD=2.4, versus mean=1.8 lb, SD=1.6), waist circumference, body mass index, and hemoglobin A(1c). There were no significant differences on most side effects, although the sibutramine group exhibited a mean increase in systolic blood pressure of 2.1 mm Hg (SD=8.5), and anticholinergic side effects and sleep disturbances were at least twice as common in the sibutramine group. CONCLUSIONS: Sibutramine was an effective and well-tolerated adjunct to behavior modification for weight loss in patients with schizophrenia and schizoaffective disorder being treated with olanzapine

RATIONALE: D-Cycloserine, a partial agonist at the glycine site of the N-methyl-D-aspartate receptor, has demonstrated inconsistent efficacy for negative and cognitive symptoms of schizophrenia. The strongest evidence for efficacy has come from studies using D-cycloserine at a dose of 50 mg/day added to conventional antipsychotics in trials of 8 weeks duration or less. OBJECTIVE: To assess the efficacy for negative symptoms and cognitive impairment of D-cycloserine augmentation of conventional antipsychotics in a 6-month trial. METHODS: Fifty-five schizophrenia patients with prominent negative symptoms, treated with conventional antipsychotics, were randomly assigned to treatment with D-cycloserine 50 mg/day or placebo for 6 months in a double-blind, parallel group design. RESULTS: Twenty-six subjects completed the 6-month trial; drop-out rates did not differ between treatment groups. D-Cycloserine treatment did not differ from placebo treatment on any primary outcome measure at 8 or 24 weeks, including response of negative symptoms and performance on a cognitive battery. Serum D-cycloserine concentrations did not correlate with response of negative symptoms. CONCLUSION: D-Cycloserine did not exhibit therapeutic effects in this trial, possibly reflecting the high drop-out rate, a narrow range of therapeutic serum concentrations, a modest magnitude of therapeutic effect for the selected outcome measures, or loss of efficacy over time. Because D-cycloserine is a partial agonist with relatively low affinity for the glycine site, the magnitude of potential therapeutic effect may be smaller than that achieved by the higher-affinity full agonists, glycine and D-serine

BACKGROUND: While the evidence for hippocampal structural abnormalities in schizophrenia is now well accepted, whether there is differentially greater volume loss within specific subregions of the hippocampus remains a matter of some debate. Here we present volume estimates of anterior and posterior hippocampal volumes using a novel morphometric protocol. METHODS: We studied 25 male patients with schizophrenia and 25 age-matched male control subjects. Hippocampal volumes were estimated using a three-dimensional morphometric protocol for the analysis of high-resolution structural magnetic resonance images (MRI). Anterior hippocampal volumes were differentiated from posterior hippocampal volumes by the presence of the uncus in coronal slices. RESULTS: While the patients with schizophrenia had significantly smaller overall hippocampal volumes relative to the control group, there was no evidence for a topographically specific pattern of volume loss along the anterior-posterior hippocampal axis. CONCLUSIONS: These results confirm the presence of overall hippocampal volume decreases in patients with schizophrenia, but do not confirm a topographically specific localization of this effect. It appears that the hippocampal volume deficit in schizophrenia is diffuse, a finding that has important consequences for understanding the underlying pathophysiologic mechanisms in schizophrenia.

Although perseveration is sometimes attributed to defective set switching, the authors have recently shown that set-switching is normal in schizophrenia. In this article, the authors tested for persistent states of the saccadic response system, rather than set perseveration. Schizophrenic and healthy subjects performed antisaccades and prosaccades. The authors analyzed for 3 carry-over effects. First, whereas the latency of the current saccade correlated with that of the prior saccade in both groups, the correlations under mixed-task conditions declined in healthy but not in schizophrenic subjects. Second, antisaccades in penultimate trials delayed upcoming saccades in schizophrenic but not in healthy subjects. Third, schizophrenic subjects were more likely to erroneously perseverate the direction of a prior antisaccade but not a prior prosaccade. The authors concluded that, in schizophrenia, the effects of correct antisaccades are persistent not weak. Saccades in schizophrenia are characterized by perseveration of antisaccade-induced changes in the saccadic response system rather than failures to switch task set

BACKGROUND: Medical morbidity and mortality rates remain elevated in schizophrenia patients compared with the general population, in part due to potentially reversible medical risk factors. Psychiatrists should address this problem by adopting established strategies for prevention and intervention. METHOD: The literature on modifiable medical risk factors relevant to individuals with schizophrenia and corresponding guidelines for prevention and treatment established by expert consensus panels were reviewed. RESULTS: Schizophrenia patients are at elevated risk for cardiovascular disease due to high rates of cigarette smoking and, increasingly, due to obesity, diabetes, and hypertriglyceridemia. Rates of human immunodeficiency virus infection and infectious hepatitis are also higher in schizophrenia patients. Interventions that have reduced medical morbidity in the general population can be adopted to reduce premature mortality in individuals with schizophrenia. CONCLUSIONS: Patients with schizophrenia have high rates of potentially reversible medical morbidity. Implementation of practice guidelines for identifying and modifying risk factors could substantially improve the health of patients with schizophrenia

OBJECTIVE: To review the published literature on serious adverse cardiac events associated with the atypical antipsychotic agent, clozapine, and to make recommendations for cardiac assessment of candidates for clozapine treatment and for monitoring of cardiac status after treatment is initiated. DATA SOURCES: We searched the PubMed and MEDLINE databases for articles published from 1970 to 2004 that contain the keywords 'clozapine and myocarditis,' 'clozapine and cardiomyopathy,' 'clozapine and cardiotoxicity,' 'clozapine and sudden death' or 'clozapine and mortality.' We also manually searched the bibliographies of these articles for related sources. STUDY SELECTION: We reviewed the 30 case reports, case series, laboratory and clinical trials, data mining studies, and previous reviews identified by this search. DATA SYNTHESIS: Recent evidence suggests that clozapine is associated with a low (0.015% to 0.188%) risk of potentially fatal myocarditis or cardiomyopathy. The drug is not known to be independently associated with pathologic prolongation of the QTc interval, but it may contribute to pathologic QTc prolongation in patients with other risk factors for this condition. CONCLUSIONS: The low risk of a serious adverse cardiac event should be outweighed by a reduction in suicide risk for most patients taking clozapine. We provide recommendations for assessing and monitoring cardiac status in patients prior to and after initiation of treatment with clozapine

The objective of the present study was to examine patterns of cortical activation underlying D-cycloserine's therapeutic efficacy in schizophrenic patients using functional magnetic resonance imaging (fMRI). We measured frontal and temporal lobe activation following a word fluency task in 12 subjects meeting DSM-IV criteria for schizophrenia at baseline and after 8 weeks of supervised treatment, using a double-blind, placebo-controlled design. Half of the patients received D-cycloserine (n = 6) as a supplement to their conventional neuroleptic treatment while the other half (n = 6) was augmented with placebo. Patients receiving D-cycloserine, but not placebo, demonstrated a significant increase in temporal lobe activation. This increased activation was significantly associated with a reduction in negative symptoms. These results suggest that the addition of D-cycloserine to conventional neuroleptics may improve negative symptoms through enhanced temporal lobe function

BACKGROUND: While the incidence of new-onset diabetes mellitus may be increasing in patients with schizophrenia treated with certain atypical antipsychotic agents, it remains unclear whether atypical agents are directly affecting glucose metabolism or simply increasing known risk factors for diabetes. OBJECTIVE: To study the 2 drugs most clearly implicated (clozapine and olanzapine) and risperidone using a frequently sampled intravenous glucose tolerance test. DESIGN: A cross-sectional design in stable, treated patients with schizophrenia evaluated using a frequently sampled intravenous glucose tolerance test and the Bergman minimal model analysis. SETTING: Subjects were recruited from an urban community mental health clinic and were studied at a general clinical research center. Patients Fifty subjects signed informed consent and 41 underwent the frequently sampled intravenous glucose tolerance test. Thirty-six nonobese subjects with schizophrenia or schizoaffective disorder, matched by body mass index and treated with either clozapine, olanzapine, or risperidone, were included in the analysis. MAIN OUTCOME MEASURES: Fasting plasma glucose and fasting serum insulin levels, insulin sensitivity index, homeostasis model assessment of insulin resistance, and glucose effectiveness. RESULTS: The mean +/- SD duration of treatment with the identified atypical antipsychotic agent was 68.3 +/- 28.9 months (clozapine), 29.5 +/- 17.5 months (olanzapine), and 40.9 +/- 33.7 (risperidone). Fasting serum insulin concentrations differed among groups (F(33) = 3.35; P = .047) (clozapine>olanzapine>risperidone) with significant differences between clozapine and risperidone (t(33) = 2.32; P = .03) and olanzapine and risperidone (t(33) = 2.15; P = .04). There was a significant difference in insulin sensitivity index among groups (F(33) = 10.66; P<.001) (clozapine<olanzapine<risperidone), with subjects who received clozapine and olanzapine exhibiting significant insulin resistance compared with subjects who were treated with risperidone (clozapine vs risperidone, t(33) = -4.29; P<.001; olanzapine vs risperidone, t(33) = -3.62; P = .001 [P<.001]). The homeostasis model assessment of insulin resistance also differed significantly among groups (F(33) = 4.92; P = .01) (clozapine>olanzapine>risperidone) (clozapine vs risperidone, t(33) = 2.94; P = .006; olanzapine vs risperidone, t(33) = 2.42; P = .02). There was a significant difference among groups in glucose effectiveness (F(30) = 4.18; P = .02) (clozapine<olanzapine<risperidone) with significant differences between clozapine and risperidone (t(30) = -2.59; P = .02) and olanzapine and risperidone (t(30) = -2.34, P = .03). CONCLUSIONS: Both nonobese clozapine- and olanzapine-treated groups displayed significant insulin resistance and impairment of glucose effectiveness compared with risperidone-treated subjects. Patients taking clozapine and olanzapine must be examined for insulin resistance and its consequences

OBJECTIVE: On April 23, 2004, a joint meeting of the FDA, NIMH, MATRICS investigators, and experts from academia and the pharmaceutical industry was convened to develop guidelines for the design of clinical trials of cognitive-enhancing drugs for neurocognitive impairments in patients with schizophrenia. METHOD: Experts were asked to address specific questions relating to clinical trial design of adjunctive/co-treatment and broad spectrum agents. At the workshop, experts reviewed relevant evidence before offering the discussion panel proposed guidelines for a given subset of questions. The discussion panel, which consisted of presenters and representatives from FDA, NIMH, academia, and industry, deliberated to reach consensus on suggested guidelines. When evidence was insufficient, suggested guidelines represent the opinion of a cross-section of the presenters and discussion panel. RESULTS: Guidelines were developed for inclusion criteria, the use of co-primary outcome measures, and statistical approaches for study design. Consensus was achieved regarding diagnostic and concomitant medication inclusion criteria and on the use of cognitive screening measures. A key guideline was to limit the trial to patients in the residual phase of their illness, who have a predefined level of positive, negative, and affective symptoms. The most difficult issues were the feasibility of including a co-primary measure of functional improvement and the choice of comparator agent for a trial of a broad spectrum agent (with antipsychotic and cognitive-enhancing effects). CONCLUSIONS: The suggested guidelines represent reasonable starting points for trial design of cognitive-enhancing drugs, with the understanding that new data, subsequent findings, or other methodological considerations may lead to future modifications.