Peter F. Buckley

Meta-Analysis of Cytokine Alterations in Schizophrenia: Clinical Status and Antipsychotic Effects

BACKGROUND Schizophrenia is associated with immune system dysfunction, including aberrant cytokine levels. We performed a meta-analysis of these associations, considering effects of clinical status and antipsychotic treatment following an acute illness exacerbation. METHODS We identified articles by searching PubMed, PsychInfo, and Institute for Scientific Information and the reference lists of identified studies. RESULTS Forty studies met the inclusion criteria. Effect sizes were similar for studies of acutely relapsed inpatients (AR) and first-episode psychosis (FEP). Interleukin (IL)-1β, IL-6, and transforming growth factor-β (TGF-β) appeared to be state markers, as they were increased in AR and FEP (p < .001 for each) and normalized with antipsychotic treatment (p < .001, p = .008, and p = .005, respectively). In contrast, IL-12, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and soluble IL-2 receptor (sIL-2R) appeared to be trait markers, as levels remained elevated in acute exacerbations and following antipsychotic treatment. There was no difference in IL-6 levels between stable medicated outpatients and control subjects (p = .69). In the cerebrospinal fluid, IL-1β was significantly decreased in schizophrenia versus controls (p = .01). CONCLUSIONS Similar effect sizes in AR and FEP suggest that the association between cytokine abnormalities and acute exacerbations of schizophrenia is independent of antipsychotic medications. While some cytokines (IL-1β, IL-6, and TGF-β) may be state markers for acute exacerbations, others (IL-12, IFN-γ, TNF-α, and sIL-2R) may be trait markers. Although these results could provide the basis for future hypothesis testing, most studies did not control for potential confounding factors such as body mass index and smoking.

Improvement in cognitive functions and psychiatric symptoms in treatment-refractory schizophrenic patients receiving clozapine.

Cognitive functions and psychopathology were assessed in 36 treatment-refractory schizophrenic patients before initiation of clozapine, and at 6 weeks and 6 months, thereafter. Before treatment, cognitive impairment was found in each measure of memory, attention, and executive function as compared with 26 normal controls. After both 6 weeks and 6 months of treatment, significant improvement occurred in the Controlled Oral Word Association Test, a measure of retrieval from reference memory. Improvement was also noted at 6 months in the Category Instance Generation Test, another measure of retrieval from reference memory, and in some, but not all, tests of executive function, attention, and recall memory. Clozapine treatment also resulted in significant improvement in Brief Psychiatric Rating Scale (BPRS) Total and Positive symptom scores at both 6-week and 6-month assessment points. There was some evidence for a relationship between improvement in psychopathology and cognitive function. The improvement in cognitive function during clozapine treatment could have consequences for capacity to work and social function.

Meta-Analysis of Oxidative Stress in Schizophrenia

BACKGROUND Schizophrenia is associated with impaired antioxidant defense, including abnormal serum, plasma, and red blood cell (RBC) oxidative stress parameters. We performed a meta-analysis of these associations, considering the effect of clinical status and antipsychotic treatment after an acute exacerbation of psychosis. METHODS We identified articles by searching PubMed, PsychInfo, and Institute for Scientific Information, and the reference lists of identified studies. RESULTS Forty-four studies met the inclusion criteria. Total antioxidant status seemed to be a state marker, because levels were significantly decreased in cross-sectional studies of serum and plasma in first-episode psychosis (FEP) and significantly increased in longitudinal studies of antipsychotic treatment for acute exacerbations of psychosis (p < .01 for each). The RBC catalase and plasma nitrite seemed to be state-related markers, because levels in cross-sectional studies were significantly decreased in FEP (p < .01) and significantly increased in stable outpatients (p = .01). In contrast, RBC superoxide dismutase seemed to be a trait marker for schizophrenia, because levels in cross-sectional studies were significantly decreased in acutely relapsed inpatients, FEP, and stable outpatients (p < .01 for each). CONCLUSIONS Oxidative stress abnormalities in FEP suggest an effect that might be independent of antipsychotic medications. Although some parameters (total antioxidant status, RBC catalase, and plasma nitrite) might be state markers for acute exacerbations of psychosis, others (RBC superoxide dismutase) might be trait markers; however, more longitudinal studies are needed. Our findings suggest that oxidative stress might serve as a potential biomarker in the etiopathophysiology and clinical course of schizophrenia.

1H-magnetic resonance spectroscopy of the left temporal and frontal lobes in schizophrenia: Clinical, neurodevelopmental, and cognitive correlates ☆

Twenty eight schizophrenic patients and 20 normal volunteers underwent proton magnetic resonance spectroscopy (MRS) on the left temporal and frontal lobe regions. Male patients showed a significant reduction in frontal but not temporal n-acetylaspartate (an intraneuronally distributed metabolite) in comparison with either male controls or female patients; frontal choline was raised in male patients relative to these groups. Putative neurodevelopmental indices, including obstetric complications, family history of schizophrenia, and minor physical anomalies, proved unrelated to MRS resonances. However, multiple aspects of memory function in patients were related to temporal but not frontal creatine, a pattern that was not apparent among controls. These MRS findings complement some previous structural MRI studies and much clinical and epidemiological evidence of important gender differences in schizophrenia. The findings also suggest that memory dysfunction in patients with schizophrenia may be associated with a particular pattern of temporal lobe metabolism on MRS.

Treatment-Resistant Schizophrenia

Although treatment-resistant schizophrenia (TRS) was described 50 years ago and has a gold standard treatment with clozapine based on well-defined criteria, there is still a matter of great interest and controversy. In terms of the underlying mechanisms of the development of TRS, progress has been made for the elucidation of the neurochemical mechanisms. Structural neuroimaging studies have shown that patients with TRS have significant reduction of the prefrontal cortex volume when compared with non- TRS. This article updates and enhances our previous review with new evidence mainly derived from new studies, clinical trials, systematic reviews, and meta-analyses.

Neurotrophins and schizophrenia

Neurotrophins have established roles in neuronal development, synaptogenesis, and response to stress/anxious stimuli. Moreover, these agents are neuromodulators of monoaminergic, GABAergic, and cholinergic systems. Amidst a growing appreciation of the developmental neurobiology of schizophrenia--as well as the propensity for progressive brain changes--there is emergent information on abnormalities in the expression of neurotrophins in schizophrenia. This article reviews the literature on neurotrophins and schizophrenia. A schema for understanding the neurobiology of relapse in schizophrenia is offered.

Clozapine-induced weight gain associated with the 5HT2C receptor −759C/T polymorphism

Weight gain has been documented as a significant adverse effect associated with many of the atypical antipsychotic medications. Several recent reports have linked a −759C/T polymorphism of the 5HT2C receptor gene and obesity as well as chlorpromazine, risperidone, and clozapine induced to weight gain. This aim was to determine the association between changes in body mass index (BMI) during clozapine treatment and the −759C/T polymorphism of the 5HT2C receptor gene. This study included 41 patients with treatment‐refractory schizophrenia (DSM‐IV) who were followed prospectively during treatment with clozapine. Weight and height measurements were obtained prior to starting clozapine and after 6‐months of treatment. Genomic DNA was isolated from a whole blood sample and analyzed for the −759C/T polymorphism of the 5HT2C receptor gene. A χ2 analysis comparing whether or not the subjects carried a −759T allele in subjects grouped as having an increase of more or less than 7% of their baseline BMI during treatment with clozapine found that the presence of the −759T allele was significantly higher in subjects with less than or equal to a 7% increase in baseline BMI compared to those with a greater than 7% increase in BMI. A multiple linear regression analysis showed that both baseline BMI and the presence or absence of the −759T allele had significant effects on 6‐month BMI. The T allele may have a protective function in preventing significant weight gain from clozapine. Subjects without the −759T variant allele were at a greater risk for weight gain from clozapine over 6‐months compared to those with the −759T allele.

Cortical localization of human sustained attention: Detection with functional MR using a visual vigilance paradigm

PURPOSE Our goal was to determine whether functional MRI on a standard 1.5 T system can localize activation during a visual vigilance sustained attention task and whether this corresponds to results described in a PET investigation of a similar task. METHOD Sixteen volunteers were studied on a 1.5 T system using a gradient echo technique. A single axial section was oriented within a stereotaxic coordinate space, 40 mm superior to the anterior-posterior commissure line. Images with eyes closed were followed by images during subject concentration on a small dim spot. Motion correction and pixel-by-pixel statistical analysis were performed. Talairach grids were applied for summary statistical analysis and comparison to PET data, with analysis using a series of planned contrasts within a repeated measures analysis of variance. RESULTS Predominantly right-sided frontal and parietal activation was observed, with statistical significance across subjects in the right frontal lobe (F > or = 5.9, p < or = 0.041). Comparison with previously reported PET data yielded a very similar pattern of activation (F = 13.2; df = 1,8; p = 0.007). CONCLUSION Activation of the right middle frontal gyrus and right parietal lobe during visual vigilance is detectable across functional imaging modalities.

Lack of insight in schizophrenia: impact on treatment adherence.

People with schizophrenia commonly lack insight, that is, they are unaware of their illness and the consequences thereof. One of the most important consequences of lack of insight is a failure to recognise the need for treatment, leading to treatment nonadherence. With several scales that now enable objective measurement of insight, it is possible to examine correlates of insight change, including course of illness and treatment adherence. Specific interventions, both pharmacological and psychotherapeutic, have been developed to enhance illness insight and treatment adherence. The extent to which second-generation antipsychotic medications, including a recently released long-acting formulation, improve insight and/or enhance treatment adherence remains to be determined.

Metabolic profiles of second-generation antipsychotics in early psychosis: Findings from the CAFE study

OBJECTIVE To further define the metabolic profiles of second-generation antipsychotics during the treatment of young patients with early psychosis, with a view to better inform prescribing clinicians. METHOD Weight, body mass index (BMI), glucose, and serum lipids were measured in the 52-week Comparison of Atypicals for First Episode (CAFE) study, in which olanzapine, quetiapine, and risperidone were evaluated, and whose primary outcomes have been reported elsewhere. These metabolic data were analyzed using a mixed random coefficients model for continuous longitudinal measures and a logistic regression model for categorical responses. RESULTS Of the 400 patients recruited, 31% were overweight and 18% were obese at baseline, and 17 (4.3%) patients met criteria for metabolic syndrome. After 12 and 52 weeks of treatment, weight gain >or=7% from baseline was reported in 29.2% and 50.0% of quetiapine-treated patients, 59.8% and 80.0% of olanzapine-treated patients, and 32.5% and 57.6% of risperidone-treated patients, respectively. Weight gain after 12 and 52 weeks of treatment was estimated as [Least Squares Mean (SE)] 15.6 (+/-1.1) and 24.2 (+/-1.9) lb for olanzapine, 8.6 (+/-1.1) and 14.0 (+/-1.9) lb with risperidone and 7.9 (+/-1.1) and 12.1 (+/-1.8) lb for quetiapine respectively. In women, greater weight gain occurred during risperidone treatment compared with quetiapine treatment. By week 52, increases in BMI >or=1 unit occurred with significantly higher frequency in olanzapine-treated patients compared with quetiapine- or risperidone-treated patients. By 52 weeks, treatment-emergent metabolic syndrome was reported in 51 individuals (13.4% of the total population), of whom 22 were receiving olanzapine, 18 quetiapine, and 11 risperidone. Risperidone was associated with the smallest elevations in triglyceride and total cholesterol levels. CONCLUSION Weight gain and metabolic syndrome occur commonly even in young patients receiving antipsychotic treatment for early psychosis. Targeted interventions are therefore warranted from the onset of antipsychotic therapy.