Faculty Bibliography

OBJECTIVE: We conducted this 6-week open-label trial to examine the effects of adjunctive aripiprazole in clozapine-treated subjects on weight, lipid and glucose metabolism, as well as positive and negative symptoms of schizophrenia. METHOD: Ten clozapine-treated subjects received aripiprazole augmentation; eight completed the 6-week trial and two ended at week 4. Eighty percent were male, the mean age was 38.7 +/- 8.9 years and the mean clozapine dose was 455 +/- 83 mg daily. RESULTS: There was a significant decrease in weight (P = 0.003), body mass index (P = 0.004), fasting total serum cholesterol (P = 0.002) and total triglycerides (P = 0.04) comparing baseline to study endpoint. There was no significant change in total Positive and Negative Syndrome Scale scores. CONCLUSION: This combination may be useful for clozapine-associated medical morbidity and must be studied in placebo-controlled double-blind randomized trials to determine efficacy and safety.

BACKGROUND: Patients with schizophrenia have difficulty using contextual information to recall the source of information. Given the importance of the hippocampus and prefrontal cortex (PFC) in this type of memory, we hypothesized that this cognitive deficit stemmed from aberrant fronto-hippocampal activation during memory retrieval. METHODS: Patients with schizophrenia (n = 16) and age-matched comparison subjects (n = 16) underwent functional magnetic resonance imaging while performing a verbal memory task that requires intact use of temporal context. Blood oxygen-level dependent (BOLD) signal during correct memory decisions was compared between the two groups with statistical parametric mapping. RESULTS: Contrary to our hypotheses, patients with schizophrenia demonstrated nearly identical memory performance to that of the comparison subjects. Despite this, there were significant between-group BOLD signal differences, including a pattern of task-dependent hypofrontality or hyperfrontality. In addition, whereas the highest-performing subset of the comparison group demonstrated robust modulation of hippocampal activity, this pattern was not seen in the highest-performing patients with schizophrenia. CONCLUSIONS: Despite memory performance similar to that of comparison subjects, patients with schizophrenia activated different neural pathways to achieve this success. This might reflect underlying neuropathology in fronto-hippocampal circuitry, the use of an alternate cognitive strategy to accomplish task performance, or both.

An impairment in the build-up and use of context has been proposed as a core feature of schizophrenia. The current study tested the hypothesis that schizophrenia patients show impairments in building up context within sentences because of abnormalities in combining semantic with syntactic information. Schizophrenia patients and healthy controls read and made acceptability judgments about sentences containing verbs that were semantically associated with individual preceding words but that violated either the meaning (animacy/semantic constraints) or the syntactic structure (morphosyntactic constraints) of their preceding contexts. To override these semantic associations and determine that such sentences are unacceptable, participants must integrate semantic with syntactic information. These sentences were compared with congruous and pragmatically/semantically violated sentences that imposed fewer semantic-syntactic integration demands. At sentence-final words and decisions, patients showed smaller reaction time differences than controls to animacy/semantically violated or morphosyntactically violated sentences relative to pragmatically/semantically violated or nonviolated sentences. The relative insensitivity to these violations in patients with schizophrenia may arise from impairments in combining semantic and syntactic information to build up sentence context.

Event-related potentials to critical verbs were measured as patients with schizophrenia and healthy controls read sentences word by word. Relative to their preceding context, critical verbs were (a) congruous, (b) incongruous and semantically unrelated to individual preceding words (pragmatic-semantic violations), (c) incongruous but semantically related to individual preceding words (animacy-semantic violations), or (d) syntactically anomalous. The N400 was modulated normally in patients, suggesting that semantic integration between individual words within sentences was normal in schizophrenia. The amplitude of the P600 to both syntactic and animacy-semantic violations was reduced in patients relative to controls. The authors suggest that, in schizophrenia, an abnormality in combining semantic and syntactic information online to build up propositional meaning leaves sentence processing to be primarily driven by semantic relationships between individual words.

This study examined clinical predictors of client and therapist alliance ratings early in therapy, the relationship between client and therapist alliance ratings, and the psychometric properties of the Working Alliance Inventory in individuals with schizophrenia receiving manual-based treatment. Assessment of clinical symptoms and social functioning were conducted at baseline, and alliance ratings were obtained at 5 weeks. The Working Alliance Inventory had high internal consistency, but there were low correlations between client and therapist ratings. Results also indicated that social functioning and the activation and autistic preoccupation factors on the Positive and Negative Syndrome Scale were significant predictors of therapists' alliance ratings. There were no significant relationships between clinical predictors and clients' therapeutic alliance ratings. The findings indicate that client interpersonal factors are significant predictors of the therapist-rated alliance in the treatment of schizophrenia. Low correlations between clients' and therapists' ratings of the alliance should be examined in future research.

Smaller medial temporal lobe volume is a frequent finding in studies of patients with schizophrenia, but the relative contributions of the hippocampus and three surrounding cortical regions (entorhinal cortex, perirhinal cortex, and parahippocampal cortex) are poorly understood. We tested the hypothesis that the volumes of medial temporal lobe regions are selectively changed in schizophrenia. We studied 19 male patients with schizophrenia and 19 age-matched male control subjects. Hippocampal and cortical volumes were estimated using a three-dimensional morphometric protocol for the analysis of high-resolution structural magnetic resonance images, and repeated measures ANOVA was used to test for region-specific differences. Patients had smaller overall medial temporal lobe volumes compared to controls. The volume difference was not specific for either region or hemisphere. The finding of smaller medial temporal lobe volumes in the absence of regional specificity has important implications for studying the functional role of the hippocampus and surrounding cortical regions in schizophrenia.

BACKGROUND: Insulin has emerged as an important determinant of food intake, energy expenditure, and weight control. This study examined the relationship between fasting serum insulin level and resting energy expenditure (REE) in a cross-sectional sample of nondiabetic schizophrenia patients. METHODS: Subjects were recruited from an urban community mental health clinic. Each subject underwent a series of anthropometric measures and an indirect calorimetry measure. A fasting blood sample was taken for plasma glucose, serum insulin, and lipid profile. RESULTS: Seventy-one subjects (54 male, 17 female) were included in the study. There was a significant positive relationship between REE and fasting serum insulin level (r = .39, p = .001). Stepwise multiple regression analysis was performed with various characteristics such as age, race, antipsychotic agent used, fat-free mass, BMI, waist circumference, waist-hip ratio, physical activity level, and fasting serum insulin as candidate predictors for REE. Only fat-free mass and insulin were able to enter into the regression model, which indicates that higher fat-free mass and higher fasting serum insulin level predict increased REE. CONCLUSIONS: A higher fasting serum insulin level is associated with an increased REE, which may prevent further weight gain in nondiabetic patients with schizophrenia

Persons diagnosed with schizophrenia have higher morbidity and mortality rates from cardiovascular disease, yet often have limited access to appropriate primary care screening or treatment. Metabolic disorders such as diabetes, hyperlipidemia and hypertension are highly prevalent in populations with schizophrenia, exceeding 50% in some studies; however, there have been few published studies on treatment rates among schizophrenia patients screened for these disorders. METHODS: Using the baseline data from subjects (N=1460) recruited into the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study, we examined the point prevalence of diabetes, hyperlipidemia and hypertension treatment at the time of enrollment for the entire cohort and those with fasting laboratory values obtained 8 or more hours since last meal. RESULTS: Rates of non-treatment ranged from 30.2% for diabetes, to 62.4% for hypertension, and 88.0% for dyslipidemia. Nonwhite men were more likely to be treated for DM and dyslipidemia than nonwhite women. CONCLUSIONS: These data indicate the high likelihood that metabolic disorders are untreated in patients with schizophrenia, with particularly high rates of non-treatment for hypertension and dyslipidemia. Nonwhite women may be especially vulnerable to undertreatment of dyslipidemia and diabetes compared to nonwhite men. The findings here support the need for increased attention to basic monitoring and treatment of cardiovascular risk factors in this vulnerable and often underserved psychiatric population

OBJECTIVE: The appropriateness and effectiveness of the outpatient medical management of cardiac risk factors for patients with diabetes who had a diagnosis of schizophrenia or a related psychotic syndrome were examined. METHODS: In a cross-sectional analysis of 4,236 patients with diabetes, ICD-9 billing codes were used to identify 214 patients with schizophrenia or a schizophrenia-related syndrome. Measures of treatment appropriateness and effectiveness for the management of cardiac risk factors (control of blood sugar, blood pressure, and lipids) were assessed for this group and compared with measures from patients with diabetes but no severe mental illness (N = 3,594). Odds ratios were adjusted for between-group differences in gender, race, age, and clinic setting. RESULTS: There were no statistically significant between-group differences on any of the five measures of treatment appropriateness, indicating that patients with schizophrenia received a similar regimen of medical treatment for cardiac factors. However, two of the seven measures of treatment effectiveness indicated significant deficiencies, with fewer patients with schizophrenia meeting the clinical quality benchmarks for cholesterol and low-density lipoprotein control. This disparity may have been caused by factors other than the measured treatment appropriateness variables, including the prescription of older lipid-lowering agents and a higher rate of missed appointments in the group with schizophrenia. CONCLUSIONS: Effective lipid control may be more difficult to attain for at least some patients with schizophrenia. Given that population's high rates of cardiovascular mortality, additional research to clarify the barriers to effective lipid management is essential