Herbert Y. Meltzer

Prevalence of the metabolic syndrome in patients with schizophrenia: baseline results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial and comparison with national estimates from NHANES III.

UNLABELLEDnOne important risk factor for cardiovascular disease is the metabolic syndrome (MS), yet limited data exist on its prevalence in US patients with schizophrenia.nnnMETHODSnUsing baseline data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial, assessment of MS prevalence was performed based on National Cholesterol Education Program (NCEP) criteria, and also using a fasting glucose threshold of 100 mg/dl (AHA). Subjects with sufficient anthropometric data, data on use of antihypertensives, hypoglycemic medications or insulin, and fasting glucose and lipid values >8 h from last meal were included in the analysis. Comparative analyses were performed using a randomly selected sample from NHANES III matched 1:1 on the basis of age, gender and race/ethnicity.nnnRESULTSnOf 1460 CATIE baseline subjects, 689 met analysis criteria. MS prevalence was 40.9% and 42.7%, respectively using the NCEP and AHA derived criteria. In females it was 51.6% and 54.2% using the NCEP and AHA criteria, compared to 36.0% (p = .0002) and 36.6% (p = .0003), respectively for males. 73.4% of all females (including nonfasting subjects) met the waist circumference criterion compared to 36.6% of males. In a logistic regression model with age, race and ethnicity as covariates, CATIE males were 138% more likely to have MS than the NHANES matched sample, and CATIE females 251% more likely than their NHANES counterparts. Even when controlling for differences in body mass index, CATIE males were still 85% more likely to have MS than the NHANES male sample, and CATIE females 137% more likely to have MS than females in NHANES.nnnCONCLUSIONSnThe metabolic syndrome is highly prevalent in US schizophrenia patients and represents an enormous source of cardiovascular risk, especially for women. Clinical attention must be given to monitoring for this syndrome, and minimizing metabolic risks associated with antipsychotic treatment.

Cellular changes in the postmortem hippocampus in major depression

BACKGROUNDnImaging studies report that hippocampal volume is decreased in major depressive disorder (MDD). A cellular basis for reduced hippocampal volume in MDD has not been identified.nnnMETHODSnSections of right hippocampus were collected in 19 subjects with MDD and 21 normal control subjects. The density of pyramidal neurons, dentate granule cell neurons, glia, and the size of the neuronal somal area were measured in systematic, randomly placed three-dimensional optical disector counting boxes.nnnRESULTSnIn MDD, cryostat-cut hippocampal sections shrink in depth a significant 18% greater amount than in control subjects. The density of granule cells and glia in the dentate gyrus and pyramidal neurons and glia in all cornv ammonis (CA)/hippocampal subfields is significantly increased by 30%-35% in MDD. The average soma size of pyramidal neurons is significantly decreased in MDD.nnnCONCLUSIONnIn MDD, the packing density of glia, pyramidal neurons, and granule cell neurons is significantly increased in all hippocampal subfields and the dentate gyrus, and pyramidal neuron soma size is significantly decreased as well. It is suggested that a significant reduction in neuropil in MDD may account for decreased hippocampal volume detected by neuroimaging. In addition, differential shrinkage of frozen sections of the hippocampus suggests differential water content in hippocampus in MDD.

A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia

Cognitive impairment is a core feature of schizophrenia and a major impediment to social and vocational rehabilitation. A number of studies have claimed cognitive benefits from treatment with various atypical antipsychotic drugs (APDs). The currently available evidence supporting cognitive improvement with atypical APDs was evaluated in two meta-analyses. Studies that (1) prospectively examined cognitive change to the atypical APDs clozapine, olanzapine, quetiapine, and risperidone, (2) included a commonly used neuropsychological test, and (3) provided data from which relevant effect sizes could be calculated, were included. Forty-one studies met these criteria. Neuropsychological test data from each study were combined into a Global Cognitive Index and nine cognitive domain scores. Two meta-analyses were carried out. The first included 14 controlled, random assignment trials that assigned subjects to an atypical APD and a typical APD control arm. The second analysis included all prospective investigations of atypical treatment and the within-group change score divided by its standard deviation served as an estimate of effect size (ES). The first analysis revealed that atypicals are superior to typicals at improving overall cognitive function (ES=0.24). Specific improvements were observed in the learning and processing speed domains. The second analysis extended the improvements to a broader range of cognitive domains (ES range=0.17-0.46) and identified significant differences between treatments in attention and verbal fluency. Moderator variables such as study blind and random assignment influence results of cognitive change to atypical APDs. Atypical antipsychotics produce a mild remediation of cognitive deficits in schizophrenia, and specific atypicals have differential effects within certain cognitive domains.

The role of M1 muscarinic receptor agonism of N-desmethylclozapine in the unique clinical effects of clozapine

RationaleClozapine is a unique antipsychotic, with efficacy against positive symptoms in treatment-resistant schizophrenic patients, and the ability to improve cognition and treat the negative symptoms characteristic of this disease. Despite its unique clinical actions, no specific molecular mechanism responsible for these actions has yet been described.Objectives and methodsTo comprehensively profile a large library of neuropsychiatric drugs, including most antipsychotics, at human monoamine receptors using R-SAT, an in vitro functional assay.ResultsProfiling revealed that N-desmethylclozapine (NDMC), the principal metabolite of clozapine, but not clozapine itself, is a potent and efficacious muscarinic receptor agonist, a molecular property not shared by any other antipsychotic. To further explore the role of NDMC muscarinic receptor agonist properties in mediating the physiological actions of clozapine, systemically administered NDMC was found to stimulate the phosphorylation of mitogen-activated protein kinase (MAP kinase) in mouse CA1 hippocampal neurons, an effect that was blocked by scopolamine, confirming central M1 muscarinic receptor agonist activity in vivo. Lastly, an analysis of clozapine and NDMC serum levels in schizophrenic patients indicated that high NDMC/clozapine ratios better predicted improvement in cognitive functioning and quality of life than the levels of either compound alone.ConclusionsThe muscarinic receptor agonist activities of NDMC are unique among antipsychotics, and provide a possible molecular basis for the superior clinical effects of clozapine pharmacotherapy.

Plasma glycine and serine levels in schizophrenia compared to normal controls and major depression: relation to negative symptoms

Previous studies have suggested decreased N-methyl-D-aspartate (NMDA)-type glutamate receptor function may contribute to increased negative symptoms in patients with schizophrenia. Consistent with this hypothesis, glycine, a co-agonist at NMDA receptors, has been reported to improve negative symptoms associated with the illness. This study was performed to determine if plasma levels of glycine or its ratio to serine, a precursor of glycine, are decreased in patients with schizophrenia compared to normal control subjects or patients with major depression. We also tested the hypothesis that these amino acids were correlated with negative symptoms in subjects with schizophrenia. Plasma levels of glycine, serine, and their ratio, were compared in 144 patients with schizophrenia, 44 patients with major depression, and 49 normal control subjects. All subjects were medication-free. Psychopathology was evaluated using the Brief Psychiatric Rating Scale (BPRS). Plasma glycine levels and glycine/serine ratios were decreased in patients with schizophrenia relative to control subjects and patients with major depression. By contrast, serine levels were increased in patients with schizophrenia compared to normal subjects but not compared to major depression. Patients with major depression also had increased plasma serine levels and decreased glycine/serine ratios compared to normal controls, but glycine levels were not different from those of normal controls. In subjects with schizophrenia, glycine levels predicted the Withdrawal-Retardation score (BPRS), whereas no such correlation was found in subjects with major depression. These results provide additional evidence that decreased availability of glycine may be related to the pathophysiology of negative symptoms. The decreases in plasma glycine levels support the evidence for an abnormality in the glutamatergic system in schizophrenia, and provide additional support for efforts to improve negative symptoms by augmentation of antipsychotic drugs with agonists at the glycine site of the NMDA receptor.

Combined analysis of 635 patients confirms an age-related association of the serotonin 2A receptor gene with tardive dyskinesia and specificity for the non-orofacial subtype

Tardive dyskinesia (TD) is an important limiting factor in the use of typical antipsychotic drugs. Genetic variability in the serotonin 2A (5-HT(2A)) receptor may influence risk for TD but the results of prior studies are not confirmatory. The objective of this study was to determine association of T102C and His452Tyr polymorphisms in the 5-HT(2A) receptor gene (HTR(2A)) with TD in a large, multicentre patient sample. The design employed case-control analysis controlling for possible confounders using pooled, original data from published and available unpublished samples and employing logistic regression, analysis of variance and meta-analysis. The study sample consisted of 635 patients with schizophrenia or schizoaffective disorder (256 with TD and 379 without TD) drawn from five research centres, divided into six groups based on population origin. The main outcome measure was association of a categorical diagnosis of TD based on the Research Diagnostic Criteria for TD with HTR(2A) T102C and His452Tyr genotypes and haplotypes. The findings indicate significant association of TD with HTR(2A) T102C genotype (p=0.002) over and above the effect of population group, also when controlling for age and gender (p=0.0008), but not with His452Tyr genotype. The T102C genotype was significantly associated with TD in older (>median age 47 yr, p=0.002) but not younger patients and in patients with non-orofacial (limb-truncal) (p=0.001) but not orofacial TD. By meta-analysis the Mantel-Haenszel (M-H) pooled odds ratio (OR) across all the available data was 1.64. A T102C-His452Tyr haplotype was significantly associated with TD (p=0.0008). These findings confirm that genetic variability in HTR(2A) contributes a small but significant degree of risk for the expression of TD, particularly in older patients and specifically for the non-orofacial (limb-truncal) type. Together with other genetic variants associated with TD the findings could be used to assess risk in patients who are candidates for treatment with typical antipsychotic medications.

Improvement in cognitive function following a switch to ziprasidone from conventional antipsychotics, olanzapine, or risperidone in outpatients with schizophrenia

OBJECTIVEnTo assess changes in cognitive function in stable outpatients with schizophrenia switched to ziprasidone from conventional antipsychotics (n = 108), olanzapine (n = 104), or risperidone (n = 58) because of suboptimal efficacy or poor tolerability.nnnMETHODSnIn three separate 6-week trials, patients received ziprasidone 40 mg b.i.d. for 2 days, followed by 20-80 mg b.i.d. for the next 40 days. Before switching, and at endpoint, patients were evaluated with tests of working and secondary verbal memory, vigilance, visuomotor speed, verbal fluency, and executive functioning. Principal components factor analysis was performed to test for clustering of cognitive variables.nnnRESULTSnSignificant improvements were seen at endpoint in secondary verbal memory (in all three groups), vigilance (in patients switched from conventional antipsychotics or risperidone), executive function (in patients switched from conventional antipsychotics or risperidone), and verbal fluency. Factor analysis on baseline scores suggested reduction of the cognitive variables to three factors: verbal skills, attention and short-term memory, and executive functioning. Analysis of z-transformed mean change in factor scores showed significant improvement in verbal skills and global score following the switch from conventional antipsychotics, olanzapine, or risperidone.nnnCONCLUSIONSnPatients requiring a change in antipsychotic therapy may exhibit cognitive improvement following a switch to ziprasidone.

Suggestive association between the C825T polymorphism of the G-protein β3 subunit gene (GNB3) and clinical improvement with antipsychotics in schizophrenia

G-proteins are composed of alpha, beta and gamma subunits. Once activated, these subunits play a major role in the conversion of external receptor activation into intracellular signals. The functional C825T polymorphism of the beta3 subunit gene (GNB3) has recently been shown to modulate antidepressant response, with the T-allele conferring an increased signaling and being associated with favorable antidepressant response. We hypothesized that this polymorphism may be associated with response to antipsychotics in a population of 145 chronic schizophrenic patients deriving from two study-samples and being mainly treated with clozapine for up to 6 months. Overall, the C/C genotype was significantly associated with relative clinical improvement as measured by Brief Psychiatric Rating Scale (BPRS) change scores after 6 and 12 weeks (p<0.01 and p=0.03, respectively), with estimated effect sizes ranging from 4.8 to 7%. Our results further suggest that this effect is only attributable to Caucasians when compared to African-Americans. Moreover, our findings point to the role of intracellular mechanisms in antipsychotic response.

Cognitive Factors in Schizophrenia: Causes, Impact, and Treatment

Greater attention has been given to the cognitive dimension in schizophrenia in recent years. This has resulted from increased recognition that cognitive impairment and negative symptoms of the disease have a greater impact on quality of life (QOL) compared to positive symptoms. Successful treatment of positive symptoms in patients with schizophrenia has not been shown to robustly translate into improvements in employment status or social relationships, while cognitive improvements are strongly associated with these important aspects of QOL and independence. These findings are based on extensive testing with standard cognitive tests for measuring executive function, verbal learning and memory, word recall, verbal working memory, spatial working memory, attention, and vigilance. Verbal learning and executive function, in particular, have been found to be valid predictors of employment success independent of the degree of severity of positive symptoms.

Prediction of the ability of clozapine to treat negative symptoms from plasma glycine and serine levels in schizophrenia

We previously reported that plasma levels of glycine, a co-agonist at N-methyl-D-asparate (NMDA)-type glutamate receptors, are decreased in patients with schizophrenia, and that glycine levels are negatively correlated with negative symptoms. The aim of the present study was to determine if glycine, or its ratio to serine, a precursor of glycine, predicts change in negative symptoms in subjects with schizophrenia during treatment with clozapine, an atypical antipsychotic drug with multiple effects on glutamatergic activity. Plasma levels of glycine, serine, and their ratio, were measured in 44 patients with schizophrenia who were subsequently treated with clozapine. Baseline glycine levels or glycine/serine ratios predicted the Scale for the Assessment of Negative Symptoms - Sum of the Global Scales and Avolition-Apathy after 6 wk of clozapine treatment. These results indicate the association of these amino acid measures with response to clozapine in terms of negative symptoms in patients with schizophrenia.