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Biomedical subjects

J P McEvoy

Publications and source records attributed to J P McEvoy.

At least 19 recordsLinked to original sources
PubMed2006

Olanzapine and haloperidol in first episode psychosis: two-year data.

Few studies have assessed the comparative efficacy and safety of atypical and typical antipsychotic medications in patients within their first episode of psychosis. This study examined the effectiveness of the atypical antipsychotic olanzapine and the typical antipsychotic haloperidol in patients experiencing their first episode of a schizophrenia-related psychotic disorder over a 2-year treatment period. Two hundred and sixty-three patients were randomized to olanzapine or haloperidol in a doubleblind, multisite, international 2-year study. Clinical symptoms and side effects were assessed at baseline and longitudinally following randomization for the duration of the study. Olanzapine and haloperidol treatment were both associated with substantial and comparable reductions in symptom severity (the primary outcome measure) over the course of the study. However, the treatment groups differed on two secondary efficacy measures. Patients were less likely to discontinue treatment with olanzapine than with haloperidol: mean time (in days) in the study was significantly greater for those treated with olanzapine compared to haloperidol (322.09 vs. 230.38, p<0.0085). Moreover, remission rates were greater in patients treated with olanzapine as compared to those treated with haloperidol (57.25% vs. 43.94%, p<0.036). While extrapyramidal side effects were greater in those treated with haloperidol, weight gain, cholesterol level and liver function values were greater in patients treated with olanzapine. The data from this study suggest some clinical benefits for olanzapine as compared to haloperidol in first episode patients, which must be weighed against those adverse effects that are more likely with olanzapine.

Adult↗
PubMed2000

Fast voltammetric studies of the kinetics and energetics of coupled electron-transfer reactions in proteins.

A wealth of information on the reactions of redox-active sites in proteins can be obtained by voltammetric studies in which the protein sample is arranged as a layer on an electrode surface. By carrying out cyclic voltammetry over a wide range of scan rates and exploiting the ability to poise or pulse the electrode potential between cycles, data are obtained that are conveniently (albeit simplistically) analysed in terms of plots of peak potentials against scan rate. A simple reversible electron-transfer process gives rise to a 'trumpet'-shaped plot because the oxidation and reduction peaks separate increasingly at high scan rate; the electrochemical kinetics are then determined by fitting to Butler-Volmer or Marcus models. Much more interesting though are the ways in which this 'trumpet plot' is altered, often dramatically, when electron transfer is coupled to biologically important processes such as proton transfer, ligand exchange, or a change in conformation. It is then possible to derive particularly detailed information on the kinetics, energetics and mechanism of reactions that may not revealed clearly or even at all by other methods. In order to interpret the voltammetry of coupled systems, it is important to be able to define 'ideal behaviour' for systems that are expected to show simple and uncoupled electron transfer. Accordingly, this paper describes results we have obtained for several proteins that are expected to show such behaviour, and compares these results with theoretical predictions.

Electrochemistry↗
PubMed1999

Smoking and therapeutic response to clozapine in patients with schizophrenia.

BACKGROUND: Of patients with schizophrenia, 70 to 80% smoke. Nicotine corrects certain information processing and cognitive psychomotor deficits seen in many patients with schizophrenia. Clozapine, but not conventional antipsychotics, has been shown to correct some of these deficits. METHODS: We assessed psychopathology and smoking in 70 patients with treatment refractory schizophrenia (55 smokers and 15 nonsmokers) at baseline when they were receiving conventional antipsychotics and again after they were switched to clozapine. RESULTS: Smokers showed significantly greater therapeutic response to clozapine than nonsmokers. Smokers smoked less when treated with clozapine than when treated with conventional antipsychotics. CONCLUSIONS: Certain patients with schizophrenia have contributing pathophysiologic mechanisms that respond favorably to either nicotine or clozapine.

Adult↗
PubMed1999

Safety and tolerability of oral loading divalproex sodium in acutely manic bipolar patients.

BACKGROUND: Achieving therapeutic blood levels of a mood stabilizer as quickly as possible is desirable in patients with acute mania. We examined the feasibility and safety of an accelerated oral loading strategy (divalproex, 30 mg/kg/day, on days 1 and 2, followed by 20 mg/kg/day on days 3-10) designed to bring serum valproate concentrations to therapeutic levels (i.e., above 50 microg/mL). METHOD: Fifty-nine patients who met DSM-IV diagnostic criteria for current manic episode and who had a Mania Rating Scale score > or = 14 were randomly assigned on a double-blind basis to receive divalproex oral loading (N = 20); divalproex nonloading (N = 20) at a starting dose of 250 mg t.i.d. on days 1 and 2, followed by standard dose titration for days 3 to 10; or lithium carbonate (N = 19) at a starting dose of 300 mg t.i.d., followed by standard dose titration for days 3 to 10. RESULTS: Eighty-four percent of the divalproex-loading patients, but only 30% of the divalproex-nonloading patients, had valproate serum levels above 50 microg/mL at day 3 of the study. None of the lithium-treated patients had serum lithium levels above 0.8 mEq/L at study day 3. No patient was removed from the study because of an adverse event. There were no significant differences between the groups in the frequencies or types of adverse events. CONCLUSION: Accelerated oral loading with divalproex sodium is a feasible and safe method to bring serum valproate concentrations to effective levels rapidly.

Acute Disease↗
PubMed1997

Neurotrophin-3 levels in the cerebrospinal fluid of patients with schizophrenia or medical illness.

Neurotrophin-3 (NT-3) may have a potential role in the pathogenesis of schizophrenia, given evidence of abnormal neurodevelopment in schizophrenia, as well as a potential association of an NT-3 gene polymorphism with schizophrenia. Cerebrospinal fluid NT-3 protein was assayed using an enzyme-linked immunosorbent assay in five patients with schizophrenia and 49 patients with medical illness. None of the patients with schizophrenia had detectable levels of NT-3 (above 4.7 pg/ml). Eleven samples from 10 different patients with medical or neurological illness had detectable levels of NT-3, associated with surgery for hydrocephalus or central nervous system infection.

Adolescent↗
PubMed1997

Clozapine-induced electroencephalogram changes as a function of clozapine serum levels.

Specific electroencephalogram (EEG) changes during clozapine therapy were prospectively studied in a cohort of 50 chronic state hospital patients with schizophrenia who were randomly assigned to one of three nonoverlapping clozapine serum level ranges (50-150 ng/mL, 200-300 ng/mL, and 350-450 ng/mL). EEGs were obtained before clozapine was instituted, and after 10 weeks of treatment. Fifty-three percent of patients showed EEG changes during the 10-week study period. We observed three seizures (6%), one in a patient on 900 mg (serum level 320 ng/mL) clozapine, and two in patients with lower clozapine serum levels (200-300 ng/mL) who had prior histories of seizures and inadequate valproate coverage. Thirteen percent of patients developed spikes with no relationship to dose or serum level of clozapine. Fifty-three percent of patients developed slowing on EEG. Compared to plasma levels below 300 ng/mL, a clozapine serum level between 350 and 450 ng/mL led to more frequent and more severe slowing. The EEG slowing correlated with observed sleepiness, although this factor was not sufficient to explain the severity of high-dose effects.

Adult↗
PubMed1997

A double-blind comparison of abecarnil and diazepam in the treatment of uncomplicated alcohol withdrawal.

Treatment of the alcohol withdrawal syndrome is best accomplished using pharmacologic agents that have minimal interaction with alcohol, have limited adverse effects, and are without abuse potential. The partial benzodiazepine receptor agonist beta-carboline compound, abecarnil, has been shown in animal and human studies to possess a number of these characteristics and to be useful in the reduction of alcohol withdrawal convulsions in mice. In this study, 49 alcohol-dependent inpatients who exhibited at least moderate symptoms of uncomplicated alcohol withdrawal were treated over a 5-day detoxification period with abecarnil or diazepam and rated daily for alcohol withdrawal symptoms and adverse events. Both the abecarnil and diazepam treatment groups exhibited a similar marked reduction in withdrawal symptoms over time. In addition, similar rates of successful treatment and improvement were observed after 1 day of treatment and at termination in alcoholics treated with either medication. Overall, rates of adverse events and changes in liver enzymes were similar in both treatment groups and were generally benign. Because of the unique pharmacologic profile of abecarnil in animal and in non-clinical human studies, including anticonvulsant action, low abuse liability, and a favorable side effect profile, further study of compounds of the partial benzodiazepine receptor agonist type in the treatment of alcohol withdrawal syndromes seems warranted.

Adult↗
PubMed1996

A study of the potential confounding effects of diet, caffeine, nicotine and lorazepam on the stability of plasma and urinary homovanillic acid levels in patients with schizophrenia.

Ten men inpatients who met DSM-III-R criteria for schizophrenia participated. On five occasions at least one week apart, each subject had an intravenous line placed at 0730 after an overnight fast. On each occasion blood samples were drawn at 0800 and hourly thereafter through 1200 noon for measurement of plasma homovanillic acid (HVA). Total four-hour urine collections were obtained for measurement of urinary HVA. Subjects received five experimental conditions, in randomized sequence: no intervention, smoking one cigarette per hour, drinking one caffeinated cola per hour, lorazepam 2 mg IV push, or a high monoamine meal. Baseline (0800) plasma HVA measures showed only minor intrinsic variability. The average standard deviation in baseline plasma HVA over five occasions of measurement was low relative to the changes in HVA produced during treatment with antipsychotic medications. The high monoamine meal significantly elevated plasma HVA, with a similar trend for urinary HVA. Neither caffeine, nicotine, nor lorazepam significantly affected plasma or urinary HVA.

Adult↗
PubMed1996

A randomized, controlled, dose-ranging trial of sertindole in patients with schizophrenia.

Sertindole is a novel antipsychotic agent with high selectivity for the mesolimbic dopaminergic pathway and nanomolar affinities for dopamine D2, serotonin 5-HT2, and norepinephrine NE alpha 1 receptors. This 40-day randomized, placebo-controlled, dose-ranging multicenter study was designed to assess the effect of sertindole on previously neuroleptic-responsive, hospitalized schizophrenic patients (n = 205). Sertindole doses began at 4 mg/day and were increased to 8, 12, or 20 mg/day, depending on randomization. Efficacy measures included the Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), and Clinical Global Impression (CGI). Extrapyramidal symptoms (EPS) were assessed by movement rating scales, EPS-related adverse events, and use of anti-EPS medications. A dose-related improvement was observed for PANSS, BPRS, and CGI, with statistically significant mean differences (P < 0.05) between placebo and 20-mg/day sertindole (decreases from baseline of -5.8 versus -16.9 for PANSS, -4.8 versus -10.4 for BPRS, respectively). The differences in CGI final improvement score between placebo and 20-mg/day sertindole were 3.8 versus 2.9, respectively. EPS-related events were comparable in the placebo and sertindole groups. In conclusion, sertindole 20 mg/day was effective, well tolerated, and not associated with significant motor system abnormalities.

Adult↗
PubMed1996

Cognitive effects of neonatal hippocampal lesions in a rat model of schizophrenia.

Lesioning the ventral hippocampus of neonatal rats has been proposed as an experimental model of schizophrenia. This lesion causes a syndrome of hyperresponsivity to the stimulant effects of amphetamine, impaired grooming and disrupted social interactions, effects that emerge during adolescence, much like schizophrenia. Persisting cognitive effects of neonatal ventral hippocampal lesions were assessed in the current study, because the hippocampus is critically important for a variety of cognitive functions and cognitive impairment and because it is an important feature of schizophrenia. Spatial learning and working memory were assessed in the radial-arm maze, which is sensitive to the adverse effects of hippocampal lesions made in adults. Lesioned rats showed pronounced deficits in radial-arm maze choice accuracy that persisted throughout training. Deficits were seen during the prepubertal period as well as in adulthood. Even though the lesioned rats performed more poorly, they were significantly less sensitive to the amnestic effects of the nicotinic antagonist mecamylamine and the muscarinic antagonist scopolamine. No significant effects of nicotine or amphetamine were seen in either the lesioned or control groups. The long-lasting deficits in spatial learning and working memory resulting from neonatal ventral hippocampal lesions show that, unlike frontal cortical lesions during the same age, the effects of hippocampal lesions are not overcome during development. The resistance to the amnestic effects of nicotinic and muscarinic acetylcholine (ACh) antagonists suggests that the hippocampus is a critical site for the action of these drugs. Neonatal hippocampal lesions may provide a good model of the cognitive impairments of schizophrenia and may be useful to assess novel drug effects to counteract the cognitive deficits in schizophrenia.

Amphetamine↗
PubMed1996

Common sense, insight, and neuropsychological test performance in schizophrenia patients.

We report an exploratory study examining the interrelationships among common sense, insight into psychosis, and performance on a battery of neuropsychological tests in 32 patients with schizophrenia evaluated at the time of discharge from involuntary hospitalization at a State psychiatric hospital. Common sense, as measured by the Social Knowledge Questionnaire, was associated with better performance across tests measuring parietal lobe functioning and vocabulary. In addition, patients with more common sense were more likely to say that they were ill and needed treatment. A global measure of insight, the Insight and Treatment Attitudes Questionnaire (ITAQ), was related to performance on a test of left parietal lobe function. However, the responses to the ITAQ item that may best reflect current awareness of mental illness in patients at the time of discharge ("After you are discharged, is it possible you may have mental problems again?") were related to performance on tests of the functioning of the prefrontal lobes and the right and left parietal lobes. These results add to the growing evidence that some of the deficits in awareness of illness among patients with schizophrenia are related to the neuropsychological dysfunction commonly seen in patients with this disorder.

Adult↗
PubMed1996

Response of patients with treatment-refractory schizophrenia to clozapine within three serum level ranges.

OBJECTIVE: This study sought to determine the relationships between serum clozapine levels and therapeutic response. METHOD: Fifty-six inpatients who met the DSM-III-R criteria for chronic schizophrenia and who had not responded to extended treatment with classical antipsychotics were randomly assigned to 12 weeks of double-blind treatment with clozapine at one of three serum level ranges: low (50-150 ng/ml), medium (200-300 ng/ml), or high (350-450 ng/ml). Baseline clinical assessments were completed before the patients' regular antipsychotic and anticholinergic drugs were discontinued. During clozapine treatment, serum levels were ascertained weekly to allow adjustment of clozapine doses so as to maintain each patient near the midpoint of his or her assigned serum level range. Clinical assessments were completed after 6 and 12 weeks of treatment. RESULTS: The analyses of the results of treatment supported the superior efficacy of the 200-300 ng/ml and 350-450 ng/ml serum clozapine level ranges over the 50-150 ng/ml range, with no advantage for 350-450 ng/ml over 200-300 ng/ml. Sleepiness increased with increasing serum levels. CONCLUSIONS: Serum clozapine levels per unit of daily dose were at the lower end of the range noted in previous reports, possibly reflecting the current study's dosing schedules of twice or three times a day, the 11- to 13-hour postdose sampling time, and the moderate doses given. Serum clozapine levels, if interpreted in relation to daily clozapine dosing schedules, postdose sampling time, and total daily dose, may help to guide dosing to provide adequate opportunities for therapeutic response and to limit certain side effects of clozapine treatment.

Clozapine↗
PubMed1995

Pharmacotherapy of impaired affect in recovering schizophrenic patients.

BACKGROUND: Prominent and persistent anxiety, depression, and/or negative features characterize a substantial minority of recovered or residually psychotic schizophrenic outpatients and contribute to poor outcome. Because extrapyramidal side effects of typical neuroleptic medications often resemble such features, we first systematically studied the contribution of extrapyramidal side effects to these problems and their treatment. For patients who remained distressed, controlled trials of supplemental thymoleptics were undertaken. METHODS: In trial 1, 92 distressed (depressed and/or anxious) patients and 36 patients in a defect state (patients with negative symptoms) participated in a double-blind, intramuscular challenge that compared centrally acting benztropine mesylate with peripherally acting glycopyrrolate. In trial 2, 57 distressed patients and 22 patients in a defect state were randomly assigned to a double-blind, neuroleptic medication dose-reduction group. In trial 3, 57 chronically distressed patients who were maintained on a low dose of fluphenazine decanoate were randomly assigned to a supplemental desipramine hydrochloride, lithium carbonate, or placebo group under double-blind conditions for 12 weeks. RESULTS: For patients who were already maintained on antiparkinsonian medication, impaired affect was not resolved by additional benztropine. Only distressed patients with a family history of severe mental disorder (often affective) showed improvement with neuroleptic medication dose reduction. Patients in the defect-state group reported less dysphoria on a reduced neuroleptic medication dose, but negative symptoms persisted. Desipramine improved diverse aspects of mood and residual psychoticism, possibly as a prophylaxis against minor affective exacerbations. Depression improved in women only. Lithium positively affected multiple indexes of anxiety and anxious depression. CONCLUSION: Most often, persistent affective impairments are neither resistant extrapyramidal side effects nor characterological traits. Thymoleptics improve the nonphasic, chronic types of anxiety and depression in contrast to the acute, episodic forms, for which little support can be found in the literature.

Adolescent↗