Faculty Bibliography

BACKGROUND: A unique group of individuals termed metabolically obese but normal weight (MONW) has been identified in the general population. The present study examined phenotypic characteristics of MONW individuals in a sample of normal weight, non-diabetic patients with schizophrenia. METHODS: Outpatients 19 to 75 years old diagnosed with schizophrenia or schizoaffective disorder participated in a multi-center, cross-sectional study. Those with normal weight (body-mass-index (BMI)<25 kg/m(2)) were included in the present analysis. Patients were further defined as MONW or metabolically nonobese based on a cut-off value of the homeostasis model assessment of insulin resistance (HOMA-IR = 1.86). Fasting blood samples were collected to determine levels of various metabolic parameters. In addition, lipoprotein subclass concentrations and sizes were analyzed using nuclear magnetic resonance (NMR) spectroscopy. RESULTS: Seventeen MONW individuals and 17 metabolically nonobese individuals matched by BMI and gender were identified from a study sample of 206 patients with schizophrenia. There were no significant differences between the two groups on anthropometric measures (waist circumference and waist/hip ratio, ps>0.3). However, the MONW group had significantly higher levels of intermediate VLDL particle and Apolipoprotein B, and significantly lower levels of large HDL particle compared with the metabolically nonobese group (p = 0.012, p = 0.036 and p = 0.041 respectively). CONCLUSION: The MONW individuals in non-diabetic schizophrenia patients seem to have an unfavorable metabolic profile and significant atherogenecity. Clinicians should be vigilant about the risk of cardiometabolic comorbidity even when the patient' body weight is normal.

BACKGROUND: Unequivocal evidence has emerged linking inflammation to the risk of metabolic problems. Previous research also has suggested a relationship between inflammation and schizophrenia. The present study examined whether white blood cell count (WBC), a marker of systemic inflammation, is associated with metabolic syndrome and psychiatric symptoms in non-diabetic patients with schizophrenia. METHODS: Outpatients 19 to 75 years old diagnosed with schizophrenia or schizoaffective disorder participated in a multi-center, cross-sectional study. Vital signs and anthropometric measures were obtained. Fasting blood samples were collected to determine levels of glucose, lipids and WBC. Psychiatric symptoms were assessed using the Brief Psychiatric Rating Scale (BPRS). RESULTS: In the sample of 199 patients, multiple logistic regression showed that WBC (log transformed) strongly predicted the condition of metabolic syndrome after potential confounding variables including age, gender, race, age of illness onset, family history of diabetes, smoking status and antipsychotic agent used were taken into consideration (odds ratio 47.2, 95% CI 3.4-658.7, p=0.004). On the other hand, significant correlations were found between WBC (log transformed) and BPRS-total score (r=0.18, p=0.014), negative symptom score (r=0.15, p=0.039) as well as anxious depression factor score (r=0.21, p=0.004) after potential confounding variables were taken into consideration. CONCLUSION: This study suggested that WBC, a simple, readily available and inexpensive measure, may potentially be a useful marker to predict an increased risk for metabolic syndrome and more severe psychiatric symptoms in non-diabetic patients with schizophrenia.

Immune system abnormalities in schizophrenia include a shift from a Type 1 (cellular) to a Type 2 (humoral) immune response. To characterize the activation status of the immune system in schizophrenia, we examined the pattern of gene expression in peripheral blood cells for three Th1 cytokines (interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2)), and one Th2 cytokine (interleukin-10 (IL-10)). In a cross-sectional study, we used quantitative reverse-transcription polymerase chain reaction (RT-PCR) to compare the mRNA levels of IFN-gamma, TNF-alpha, IL-2, and IL-10 in peripheral blood mononuclear cells (PBMCs) between 15 schizophrenia patients and 15 matched healthy controls. Expression of IFN-gamma and TNF-alpha was significantly reduced in patients with schizophrenia compared with normal controls. No differences in IL-2 and IL-10 gene expression were observed. These results are consistent with impaired Type 1 cellular immunity in schizophrenia. While the data illustrate the potential utility of mRNA-based approaches for the identification and analysis of immune biomarkers for neuropsychiatric disorders, correlation of gene expression with direct measures of cytokine concentrations is required

BACKGROUND: High dietary saturated fat (SF) intake is strongly linked to metabolic disturbances. The goal of this study was to understand the relationship between clozapine and risperidone with glucose and lipid metabolism and dietary fat intake in patients with schizophrenia. METHODS: Thirty-one clozapine-treated patients and 15 risperidone-treated patients were assessed using a 4-day dietary record, an IV glucose tolerance test, and lipid profiles. RESULTS: Clozapine-treated patients consumed a significantly higher percentage of SF than did risperidone-treated patients (13.7% +/- 3.4% vs 10.6% +/- 3.0 % of total energy; P = .007). Compared with the risperidone group, the clozapine group also had a significantly higher percentage of total fat in their diet (36% +/- 6.7% vs 30.9% +/- 5.7% of total energy; P = .007). Similarly, the clozapine group had a significant impairment in insulin sensitivity index (SI), glucose effectiveness (SG), and disposition index (DI) compared with the risperidone group (P < .05). Pearson correlation analysis of both groups showed that dietary SF was significantly correlated with impairment in glucose homeostasis (SG: r = -0.43; P = .004; DI: r = -0.35; P = .02). CONCLUSION: Abnormal glucose homeostasis in atypical clozapine-treated patients with schizophrenia may be associated with or aggravated by high dietary SF consumption

Patients with schizophrenia consistently show deficient performance on tasks requiring volitional saccades. We previously reported reduced fractional anisotropy in the white matter underlying right dorsal anterior cingulate cortex in schizophrenia, which, along with lower fractional anisotropy in the right frontal eye field and posterior parietal cortex, predicted longer latencies of volitional saccades. This suggests that reduced microstructural integrity of dorsal anterior cingulate cortex white matter disrupts connectivity in the right hemisphere-dominant network for spatial attention and volitional ocular motor control. To test this hypothesis, we examined functional connectivity of the cingulate eye field component of this network, which is located in dorsal anterior cingulate cortex, during a task comprising volitional prosaccades and antisaccades. In patients with schizophrenia, we expected to find reduced functional connectivity, specifically in the right hemisphere, which predicted prolonged saccadic latency. Twenty-seven medicated schizophrenia outpatients and 21 demographically matched healthy controls performed volitional saccades during functional magnetic resonance imaging. Based on task-related activation, seed regions in the right and left cingulate eye field were defined. In both groups, the right and left cingulate eye field showed positive correlations with the ocular motor network and negative correlations with the default network. Patients showed reduced positive functional connectivity of the cingulate eye field, specifically in the right hemisphere. Negative functional connectivity of the right cingulate eye field predicted faster saccades, but these relations differed by group, and were only present in controls. This pattern of relations suggests that the coordination of activity between ocular motor and default networks is important for efficient task performance and is disrupted in schizophrenia. Along with prior observations of reduced white matter microstructural integrity (fractional anisotropy) in schizophrenia, the present finding of reduced functional connectivity suggests that functional and structural abnormalities of the right cingulate eye field disrupt connectivity in the network for spatial attention and volitional ocular motor control. These abnormalities may contribute to deficits in overcoming prepotency in the service of directing eye gaze and attention to the parts of the environment that are the most behaviourally relevant

This overview outlines findings of cognitive and neurocognitive studies on comprehension of verbal, pictorial, and video stimuli in healthy participants and patients with schizophrenia. We present evidence for a distinction between two complementary neurocognitive streams of conceptual analysis during comprehension. In familiar situations, adequate understanding of events may be achieved by mapping the perceived information on the associative and similarity-based connections between concepts in semantic memory - a process reflected by an N400 waveform of event-related electrophysiological potentials (ERPs). However, in less conventional contexts, a more flexible mechanism may be needed. We suggest that this alternative processing stream, reflected by a P600 ERP waveform, may use discrete, rule-like goal-related requirements of real-world actions to comprehend relationships between perceived people, objects, and actions. This neurocognitive model of comprehension is used as a basis in discussing studies in schizophrenia. These studies suggest an imbalanced engagement of the two conceptual streams in schizophrenia, whereby patients may rely on the associative and similarity-based networks in semantic memory even when it would be more adaptive to recruit mechanisms that draw upon goal-related requirements. Finally, we consider the roles that these conceptual mechanisms may play in real-life behavior, and the consequences that their dysfunction may have for disorganized behavior and inability to plan actions to achieve behavioral goals in schizophrenia.

We previously reported that patients with schizophrenia failed to demonstrate normal sleep-dependent improvement in motor procedural learning. Here, we tested whether this failure was associated with the duration of Stage 2 sleep in the last quartile of the night (S2q4) and with spindle activity during this epoch. Fourteen patients with schizophrenia and 15 demographically matched controls performed a motor sequence task (MST) before and after a night of polysomnographically monitored sleep. Patients showed no significant overnight task improvement and significantly less than controls, who did show significant improvement. While there were no group differences in overall sleep architecture, patients showed significant reductions in fast sigma frequency power (45%) and in spindle density (43%) during S2q4 sleep at the electrode proximal to the motor cortex controlling the hand that performed the MST. Although spindle activity did not correlate with overnight improvement in either group, S2q4 sleep duration in patients significantly correlated with the plateau level of overnight improvement seen at the end of the morning testing session, and slow wave sleep (SWS) duration correlated with the delay in reaching this plateau. SWS and S2q4 sleep each predicted the initial level of overnight improvement in schizophrenia, and their product explained 77% of the variance, suggesting that both sleep stages are necessary for consolidation. These findings replicate our prior observation of reduced sleep-dependent consolidation of motor procedural learning in schizophrenia and link this deficit to specific sleep stages. They provide further evidence that sleep is an important contributor to cognitive deficits in schizophrenia

Nonadherence with medication treatment is common but difficult to detect in patients with schizoaffective disorder and schizophrenia, almost half of whom take less than 70% of prescribed doses. Like patients in all areas of medicine, patients with schizoaffective disorder weigh the perceived benefits of medications against perceived disadvantages, but this process is complicated by their impaired insight, the stigma of the diagnosis, and the often troubling side effects of antipsychotic medication. Interventions to improve adherence include encouraging acceptance of the illness, drawing analogies with treatment for chronic medical disease, and involving the patient in decision making. Clinicians must remain nonjudgmental, encouraging patients to disclose problems with adherence and anticipating that improvement in adherence may require a prolonged effort. Selection of antipsychotic medication is critical to avoid adverse side effects, and some medications may provide a sense of well-being, such as improvement in insomnia, anxiety, or depression. Depot (rather than oral) antipsychotics can improve adherence and provide the clinician with reliable information about the dosage of medication received, which can be used for purposes of dose adjustments or to guide response to relapse