Clozapine augments delta, theta, and right frontal EEG alpha power in schizophrenic patients.

Objective. To explore the Quantitative EEG (QEEG) effects of established clozapine therapy regimes compared to those of previous ineffective antipsychotic regimes among 64 chronic (DSM-IV) schizophrenic patients. Methods. Data from 20 EEG channels referenced to linked ears were collected before and during maintenance clozapine therapy (mean duration 1.4 years). Absolute power was calculated in six frequency bands: delta (0.4-3.6 Hz), theta (4.2-7.8 Hz), alpha (8.2-11.8 Hz), beta1 (12.2-15.8 Hz), beta2 (16.2-19.8 Hz), and beta3 (20.2-23.8 Hz). Results. Clozapine augments power globally in the delta and theta bands, but this effect is more pronounced over frontal areas. Beta3 power was reduced. Alpha showed a frontal increase, more pronounced in the right, coupled with a posterior decrease with no net change in overall power. Conclusion. The demonstration of a significant clozapine-induced alpha topographic shift frontally and to the right is a novel discovery that may serve to encourage further investigations of subcortical structures in attempts to better understand the diverse aetiologies and optimal treatments of the schizophrenias.

Dysglycemia in a community sample of people treated for schizophrenia: the Diabetes in Schizophrenia in Central-South Ontario (DiSCO) study.

OBJECTIVE: Despite increasing recognition of schizophrenia as a risk factor for diabetes, the prevalence and correlates of dysglycemia in people with schizophrenia have not been adequately studied. Discerning the modifiable risk factors is crucial for developing diabetes prevention strategies in schizophrenia. METHODS: Socio-demographic, clinical and recent laboratory data were compiled from the case records and supplemental sources of 1123 people treated for schizophrenia who were living across five different communities in the region. RESULTS: Screening rates for fasting plasma glucose (FPG) varied between 63-100% across the five communities, while other metabolic indices were monitored less frequently. 39 subjects (3.5%) in the sample had an existing diagnosis of type 2 diabetes. Among the others, 845 (78%) had FPG measured in the preceding 6 months, with the following results: FPG < or = 5.6 mmol/l in 474 (56%), 5.6-6.9 mmol/l in 268 (31%), and > or = 7 mmol/l in 103 (12.2%) subjects. Dysglycemia (FPG > or = 5.6 mmol/l) was significantly associated with older age (odds ratio [OR] 1.031), longer duration of schizophrenia (OR 1.062), self reported family history of diabetes (OR 8.87), body mass index (OR 1.081), excess weight (OR 1.014) and independent living status (OR 1.779), while European ethnicity (OR 0.706) and regular physical activity (OR 0.958) lowered the risk. No statistically significant correlations were noted with gender, level of education or functioning, or the type of antipsychotic drug prescribed. CONCLUSIONS: There was a two-fold increase in the prevalence of dysglycemia, while there was a substantial under-recognition of and intervention for, diabetes and pre-diabetes in this sample of people treated for schizophrenia.

Schizophrenia in an adult with 6p25 deletion syndrome.

Chromosomal deletions at 6p25-p24 are rare findings in patients with developmental delay. There is limited information about the adult phenotype. We present a 36-year-old patient with schizophrenia, mild mental retardation, progressive hearing deficits, and characteristic facial features. Ocular (Axenfeld-Rieger anomaly) abnormalities were diagnosed in infancy; vision, however, has remained unimpaired. There were no other major congenital anomalies. Brain imaging showed only minor changes. There was no family history of intellectual deficits or psychosis. Karyotyping revealed a 6p25 deletion, and detailed fluorescence in situ hybridization (FISH) analyses using 23 probes confirmed a 6.7 Mb 6p25-pter deletion. The breakpoint is near a possible 6p25-p24 locus for schizophrenia. Psychotic illness may be part of the neurodevelopmental abnormalities and long-term outcome of patients with 6p terminal deletions. Other similarly affected patients likely remain to be diagnosed in adult populations of schizophrenia and/or mental retardation.

cDNA array reveals increased expression of glucose-dependent insulinotropic polypeptide following chronic clozapine treatment: role in atypical antipsychotic drug-induced adverse metabolic effects.

Clozapine is an atypical antipsychotic drug with unique pharmacological and therapeutic properties. Unlike the typical antipsychotic drug, haloperidol, clozapine does not cause extrapyramidal side effects; however, weight gain, dyslipidemia, and type II diabetes are commonly associated with the use of this drug in subjects with schizophrenia. The aim of this study was to profile gene expression in the rat striatum following clozapine treatment. Chronic treatment with clozapine revealed upregulation of several genes including the glucose-dependent insulinotropic polypeptide (GIP) gene by over 200% in the rat striatum. The cDNA array results for the GIP gene were confirmed by real-time RT-PCR as well as by radioimmunoassay. Expression of the GIP gene in the central nervous system is consistent with the results of retinal GIP gene expression as reported by other investigators. Taken together, these findings implicate the possible role of GIP as a neuromodulator in the central nervous system. GIP is an insulinotropic agent with stimulatory effects on insulin synthesis and release from the pancreas. However, changes in brain GIP levels are most likely unrelated to the metabolic adverse effects (dyslipidemia, type II diabetes, weight gain) associated with clozapine treatment. Therefore, we also measured GIP gene expression in the K-cell-rich regions, duodenum and jejunum (small intestine), and plasma GIP levels using radioimmunoassay following chronic treatment with clozapine. GIP mRNA levels in the small intestine and the plasma GIP at the protein level were significantly elevated in clozapine-treated subjects. Furthermore, as observed in humans, chronic clozapine treatment also caused weight gain, and increased levels of insulin, triglycerides and leptin in the plasma. These results suggest that adverse metabolic effects associated with clozapine treatment may be related to its ability to increase intestinal gene expression for GIP.

Differential display polymerase chain reaction reveals increased expression of striatal rat glia-derived nexin following chronic clozapine treatment.

Clozapine is considered a prototype of the 'so-called' atypical antipsychotic drug class. It has affinity for a broad range of receptors and, in comparison to typical antipsychotic drugs, produces less extrapyramidal side effects. However, its mechanism of action remains unclear. Differential display polymerase chain reaction (ddPCR) was implemented in this study to contribute to the current understanding of this mechanism at the genetic level and to identify novel genes regulated by clozapine. This technique generated approximately 2400 gene sequences that were analyzed for differential gene expression following protracted clozapine treatment. One of these sequences, originally termed Clozapine Regulated Gene (CRG), was shown to be significantly upregulated following the treatment. Northern hybridization confirmation of this finding revealed that chronic clozapine administration caused a five-fold increase in CRG mRNA. Elongation of the 5'- and 3'-ends of CRG indicated that the fragment was in fact rat glia-derived nexin mRNA. Western blotting demonstrated that levels of the mRNA's associated protein also increased comparably (three-fold) following chronic treatment with the antipsychotic drug. This study presents a possible neuroprotective role of nexin in clozapine treatment, particularly in the prevention of neuronal proteolytic degradation, since nexin has been shown to be a protease inhibitor.

A comparison of the oxidation of clozapine and olanzapine to reactive metabolites and the toxicity of these metabolites to human leukocytes.

Olanzapine was shown to be oxidized to a reactive intermediate by HOCl, which is the major oxidant produced by activated neutrophils. A mass spectrum obtained using a flow system in which the reactants were fed into a mixing chamber and the products flowed directly into a mass spectrometer revealed a reactive intermediate at m/z 311. This is 2 mass units less than the protonated molecular ion of parent olanzapine and suggests that the reactive intermediate is a nitrenium ion. The reactive intermediate could be trapped with glutathione or N-acetylcysteine to produce two conjugates. These data are analogous to results we reported previously with the structurally related atypical antipsychotic agent clozapine. However, the clozapine and olanzapine reactive metabolites showed differences in their ability to cause toxicity to human neutrophils. Toxicity to neutrophils was observed only at high concentrations of clozapine (>50 microM) when HOCl was used to generate reactive metabolite. In contrast, concentration-dependent toxicity (p < 0.05) was observed when neutrophils were incubated with clozapine (0-20 microM) and H2O2 to generate clozapine reactive metabolite. No toxicity was observed with clozapine alone (at concentrations of > 50 microM). Similar results were observed in monocytes and HL-60 cells. Olanzapine reactive metabolite only seemed to cause slight toxicity at the highest concentrations tested (20 microM), even when the reactive metabolite was generated using H2O2. Neutrophils from two patients with a history of clozapine-induced agranulocytosis seemed to be more sensitive to the toxic effects of the clozapine reactive metabolite; however, the numbers are too small to draw any definite conclusions.

Do QEEG topographic map data have a multivariate normal distribution? Implications for tests of individual maps.

The study was designed to test whether topographic map data expressed in log power units have a multivariate normal (MVN) distribution in a healthy population, and to determine if any deviation from normality poses serious difficulties for the use of standard multivariate statistical tests in assessing the significance of deformations of the map in individual cases. Data on 361 healthy adults using 20 electrodes in the classic 10/20 configuration were recorded in six frequency bands. The log-transformed power data were shown to deviate markedly from MVN. The actual distributions of multivariate tests were computed for the sample using the 'jackknife' method, and shown to deviate markedly from the F-distributions that would be expected for MVN data. These 'jackknife' sampling distributions were then used to demonstrate significant deformations in the topographic maps of a patient who had sustained traumatic head injury.

Clozapine: current status and role in the pharmacotherapy of schizophrenia.

OBJECTIVE: This study evaluates clozapine and its present role in the pharmacotherapy of schizophrenia. METHOD: Clozapine's current clinical status is reviewed, as is its position with respect to other treatment options. RESULTS: Clozapine represents the prototype of "atypical" neuroleptics, with evidence of clinical efficacy in both positive and negative symptoms, as well as a diminished risk of extrapyramidal side effects. It is the only neuroleptic to date that has established itself as having little, if any, risk of tardive dyskinesia. More recent research has focused on its potential for overall savings in health care costs, as well as possible benefits in the area of neuropsychological functioning. CONCLUSION: Evidence suggesting that the course of schizophrenia can be altered by effective treatment favours a systematic approach that optimizes treatment options. While clozapine does not represent a 1st-line agent because of its risk of agranulocytosis, it has an integral role to play in treatment-resistant schizophrenia or in individuals experiencing intolerable side effects with conventional neuroleptics.

The effect of laterality of stimulus presentation on auditory P300 topography in schizophrenia.

Reduced P300 amplitude in schizophrenia has been a consistent finding. Recent studies have raised the question of characteristic topographic distribution. This study reports the effects of binaural and unilateral stimuli on the P300 topography in schizophrenia. An auditory "oddball" paradigm was repeated 3 times with left, right and binaural stimulation. Data were recorded using a 19-electrode montage with linked ear reference. Subjects were 18 untreated, hallucinating, paranoid patients with schizophrenia and 24 healthy matched volunteers. For the control subjects, stimulus conditions had no effect on P300 topography. For the sample with schizophrenia, topography under unilateral left stimulation resembled that of control subjects. Binaural and right-sided stimulation shifted peak amplitudes to the right and frontally. In addition to the usually observed parietal peak, a second P300 maximum having a different time course appeared over right frontal areas. The data provide further support for lateralized dysfunction in schizophrenia.

Computerized pattern recognition of EEG artifact.

Automated artifact classification of quantified EEG (QEEG) epochs from 9 males using linear discriminant analysis showed greater than 85% agreement with judges' opinions. These results were replicated (n = 600 epochs for each sample). Testing the entire sample (n = 5800) illustrated reliable eye artifact (94%) but reduced muscle artifact classification (70%) accuracy. Agreement was lowest in the case of more subtle forms of muscle artifact (i.e., low amplitude muscle), however, less than 4% of these were wrongly classified as non-artifact. Improved data collection techniques retaining high frequency energies are anticipated to improve muscle artifact recognition. Results indicate that low levels of artifact contamination would result when only those epochs classified as non-artifact were accepted for inclusion in further analysis.

Clozapine in the treatment of refractory schizophrenia: Canadian policies and clinical guidelines.

Clozapine is an atypical neuroleptic agent that has recently become available in Canada with potential clinical efficacy in the treatment of refractory schizophrenia, and in patients with schizophrenia neurologically intolerant to conventional neuroleptics. Although it causes few extra-pyramidal symptoms, the drug has a number of other adverse effects including a risk of agranulocytosis in one to two percent of all patients. Because of this, the use of the drug is permitted only if the white blood count is monitored weekly. The monitoring system, outlined in this article, requires a coordinated effort between clinical staff, pharmacy, laboratory and the Clozaril Support and Assistance Network. Clinical guidelines are proposed, detailing the indications and contraindications for treatment and the pharmacokinetics, dosing, adverse effects, and drug interactions with clozapine. In addition, the economics, government policies and implications for future research are considered. Although there are administrative and clinical difficulties associated with its use, clozapine represents an advance in therapeutic research. Patients and family members will be inquiring about the drug and may deserve a trial. This article aims to inform Canadian mental health professionals about the safe and beneficial use of clozapine.

Developmental and neurologic correlates of treatment response in schizophrenia.

Reliable predictors of outcome in schizophrenia remain elusive, and assessment of unidimensional variables is unlikely to provide new information. We examined developmental, neurologic and psychosocial variables together to assess their correlation with several separate aspects of outcome in male schizophrenic patients (N = 31) treated with neuroleptics for a minimum of six months. Outcome measures evaluating social performance were significantly inter-correlated, but these measures did not correlate significantly with "positive" symptom measures. Persistent positive symptoms were predicted by post-natal neurologic impairment. Persistent negative symptoms and social dysfunction were predicted by psychosocial dysfunction during the developmental years. Poor early treatment response significantly correlated with persistent positive symptoms and psychosocial dysfunction. Impairment on neurobehavioral testing correlated significantly with post-natal neurologic impairment and with persistent positive symptoms.

Serotonergic interhemispheric asymmetry: gender difference in the orbital cortex.

The asymmetry of tritiated imipramine (IMI) binding sites (which are associated with serotonergic mechanisms) were investigated in the orbital frontal cortex in 6 women and men who died of natural causes, and who did not have a history of mental disorders. There was significant interhemispheric asymmetry in both sexes, higher Bmax on the right side compared with the left. The Bmax values of IMI binding in the right orbital cortex in women were significantly higher than in men. Our preliminary findings--gender difference of serotonergic mechanisms in some area of the human brain--are in accordance with the observed gender differences in a variety of serotonin-regulated behaviors (sexual behavior, aggression and impulse control), and serotonergic mental disorders (eating disorders, suicidal behavior, anxiety disorders and depression).

Serotonergic interhemispheric asymmetry: neurochemical and pharmaco-EEG evidence.

1. Postmortem neurochemical investigations revealed interhemispheric asymmetry in the mediofrontal region of human brain. Significantly higher right hemisphere serotonin metabolite (5HIAA) content as well as increased maximal imipramine binding (IB) were found in the right hemisphere than in the left side. 2. IB did not show a gender difference in the mediofrontal area. However, women had higher IB in the right orbital frontal cortex than did men. 3. In vivo pharmaco-EEG results tend to support the postmortem neurochemical data. Intravenous chlorimipramine resulted in an asymmetric topographic distribution of the P300 auditory evoked potential, peak amplitudes were shifted to the right hemisphere.

Limbic system dysfunction as a factor in some schizophreniform psychoses: case report and overview.

A case is presented of a young woman whose schizophreniform psychosis was unresponsive to neuroleptic treatment, but who subsequently responded well to Carbamazepine. Several converging lines of investigation, suggesting an underlying Limbic System dysfunction, are discussed. Background to the Limbic System concept is provided.

Prepreparatory interval effects on redundancy deficit reaction time patterns in schizophrenic and normal subjects using the embedded-set procedure.

The relative influence of genuine "redundancy deficit" and the artifactual effects of prepreparatory interval on measures of the redundancy deficit reaction time pattern (faster reaction time on trials with long preparatory intervals when the interval is of predictable vs. unpredictable length) was investigated in a study using the "embedded-set" procedure. Twenty normal and 20 schizophrenic subjects received two series of reaction time trials containing embedded sets (blocks) of four isotemporal 1-, 3-, and 7-second trials. The 7-second blocks (the blocks of interest for the calculation of redundancy deficit) were preceded by long prepreparatory intervals in one condition and by short intervals for the second. Each subject received both conditions, with the orders counterbalanced. The results indicated redundancy deficit for both schizophrenics and normals with short prepreparatory intervals, but in neither group with long prepreparatory intervals. This suggests that redundancy deficit in the embedded-set procedure (which is normally heavily biased with short prepreparatory intervals) may be more related to the enhancing effect of short prepreparatory intervals on the first (unpredictable) trial of the set than to impaired performance on the fourth (predictable) trial. The finding of similar effects in both schizophrenic and normal subjects raises questions about the specificity of redundancy deficit to schizophrenic reaction time performance. The results were discussed with reference to the original "long run" reaction time procedure for studying the same phenomenon, and theoretical issues related to the interpretation of results from the two procedures were considered.

Growth hormone responses to apomorphine HCl in schizophrenic patients on drug holidays and at relapse.

In nine schizophrenic patients on drug holiday, growth hormone (GH) response to apomorphine HCl 0.75 mg (APO) was compared with normal control data. Patients were tested at two month intervals for up to 14 months. Seven patients relapsed, and of these, five had exaggerated GH responses to APO at that time. Of these five, three had exaggerated GH responses to APO prior to clinical deterioration. Further work is required to determine whether this test can be a useful predictor of relapse.

Attention/information processing, neuropsychological functioning, and thought disorder during the acute and partial recovery phases of schizophrenia: a longitudinal study.

Schizophrenic subjects were administered the span of apprehension task, which is a measure of visual information processing; two neuropsychological tests; and measures of specific aspects of thought disorder and general clinical state. The measures were administered both when patients were acutely disturbed and when they were partially recovered. Normal control subjects were tested over a comparable 12-week interval. Improvements in both overall clinical condition and specific aspects of thought disorder occurred in the schizophrenic patients during this time. The patients, however, continued to show impaired information processing, indicating that the span of apprehension task is sensitive to schizophrenic dysfunction across wide variations in clinical state and, therefore, may be a marker of vulnerability to schizophrenia. The span of apprehension task was found to be significantly correlated with a measure of thought disorder that assesses resistance to associative distractors and two neuropsychological tests--the Trail-Making Test from the Halstead-Reitan battery and the Digit Symbol Substitution Test--during the testing session conducted while the subjects were partially recovered.