Clozapine conflict.
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Antipsychotic Agents↗
Biomedical subjects
A Breier
Publications and source records attributed to A Breier.
Individual variation in D2 dopamine receptor occupancy in clozapine-treated patients.
OBJECTIVE: The objectives of this study were 1) to pursue the question of clozapine's striatal D2 occupancy in relation to its clinical effectiveness; 2) to investigate the relation between schizophrenic symptoms, clozapine blood levels, and estimated D2 occupancy during clinically stable and unstable conditions; and 3) to examine long-term stability in D2 occupancy. METHOD: Specific binding of the D2 radioligand [123I]benzamide ([123I]IBZM) was studied with single photon emission computed tomography in 13 patients with schizophrenia when they were clinically stable during chronic clozapine treatment, after clozapine dose reduction of > or = 50%, and in a subgroup (N = 7) after restabilization on clozapine regimens. Clozapine's estimated D2 occupancy was based on comparison with values from drug-free normal subjects. RESULTS: A wide range of estimated D2 occupancies (18% to > or = 80%) were associated with sustained, favorable response to clozapine without correlation with residual symptoms. Clozapine blood levels were negatively related to [123I]IBZM specific binding. Acute dose reduction was associated with predicted worsening in positive and negative symptoms and increases in [123I]IBZM specific binding. Independent of clozapine blood level, patients with more symptoms showed lower [123I]IBZM specific binding, consistent with competition of endogenous dopamine for D2 binding sites in patients with greater symptoms. Restabilization on clozapine regimens produced D2 occupancies closely correlated with baseline values. CONCLUSIONS: There was no evidence for a critical degree of D2 occupancy required to sustain clozapine's therapeutic effects across subjects. Simple linear regression was the best-fit model for clozapine's D2 occupancy. Longitudinal follow-up suggests stability over time of D2 occupancy in relation to dose and clinical response within individual patients.
Adult↗
Fluoxetine augmentation of clozapine treatment in patients with schizophrenia.
OBJECTIVE: The authors examined the efficacy of fluoxetine augmentation of clozapine treatment response in schizophrenic outpatients who, despite adequate treatment with clozapine, continued to exhibit persistent positive or negative symptoms. METHOD: Thirty-three patients completed on 8-week, double-blind, parallel-groups comparison of adjunctive fluoxetine and placebo. RESULTS: There were no significant differences in positive, negative, depressive, or obsessive-compulsive symptoms between patients given adjunctive fluoxetine or placebo. CONCLUSIONS: These results suggest that fluoxetine is not effective in augmenting clozapine treatment response.
Adult↗
Childhood-onset schizophrenia: brain MRI rescan after 2 years of clozapine maintenance treatment.
OBJECTIVE: The effect of clozapine on striatal morphology was examined in adolescents with childhood-onset schizophrenia. METHOD: Eight adolescent patients with onset of psychosis before age 12 and eight matched comparison subjects had initial and 2-year follow-up brain magnetic resonance imaging scans. Basal ganglia and lateral ventricle volumes were measured. The patients were on a clozapine regimen during the 2-year interim. RESULTS: Caudate volume was larger in the patients at the initial scanning, decreased in the patients between scans, and did not differ significantly between the patients and the comparison subjects at the second scanning. CONCLUSIONS: Caudate enlargement in patients with childhood-onset schizophrenia who are taking typical neuroleptics appears to be secondary to medication exposure. Rescanning to examine basal ganglia morphology is indicated for these patients when they are taking an atypical neuroleptic.
Adolescent↗
Differential effect of clozapine on weight: a controlled study.
OBJECTIVE: This study examined whether clozapine induces more weight gain than haloperidol and whether weight gain is related to clinical improvement. METHOD: The weight and symptoms of 39 outpatients with schizophrenia who were randomly assigned to double-blind treatment with either clozapine or haloperidol were assessed. The weight and symptoms of 33 of the patients who chose to take clozapine during a 1-year follow-up after the study ended were also assessed. RESULTS: The patients treated with clozapine gained significantly more weight over baseline (7%) than the haloperidol-treated patients (1%). Weight gain was not significantly correlated with improvements in either positive or negative symptoms. Fifty-eight percent of the patients followed for 1 year gained at least 10% over their baseline weight. CONCLUSIONS: Weight gain is an important side effect of clozapine and is unrelated to the drug's differential antipsychotic efficacy.
Ambulatory Care↗
Lack of association between polymorphisms in the 5-HT2A receptor gene and the antipsychotic response to clozapine.
OBJECTIVE: The authors' goal was to determine whether either of two 5-HT2A receptor polymorphisms, 102-T/C and 452-His/Tyr, are associated with clozapine response. METHOD: Brief Psychiatric Rating Scale (BPRS) ratings were obtained in 70 patients with schizophrenia or schizoaffective disorder to determine their response to clozapine compared with a typical neuroleptic. Patients were genotyped with the polymerase chain reaction and restriction fragment length polymorphism analysis. RESULTS: Neither 102-T/C nor 452-His/Tyr was associated with clozapine response. There were no significant differences in BPRS scores among patients with different 5-HT2A genotypes at week 10 of clozapine administration. CONCLUSIONS: Allelic variation in the 5-HT2A gene is not associated with individual differences in clozapine response.
Adult↗
Overcoming of P-glycoprotein mediated vincristine resistance of L1210/VCR mouse leukemic cells could be induced by pentoxifyline but not by theophylline and caffeine.
Effects of xanthine derivatives (pentoxifylline, caffeine, theophylline, 1-methyl-3-isobutylxanthine) on P-glycoprotein mediated vincristine resistance of L1210/VCR mouse leukemic cell subline were studied. From the applied xanthines only PTX was found to reverse the vincristine resistance of the above cells. Moreover, only PTX, but not other xanthine, increased the accumulation of [3H]vincristine by L1210/VCR cells. Thus it may be concluded that PTX-induced reversal of vincristine resistance could not be explained from the point of known pharmacological effects of PTX that are common for other xanthines such as inhibition of phosphodiesterase activity, calcium mobilizing effect, inhibition of tumor necrosis factor alpha (TNF), etc.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
The membrane effect of benfluron: modulation of the heart sarcolemmal (Na+, K+)-ATPase and Mg(2+)-ATPase activities.
The effect of Benfluron on the heart sarcolemmal (Na+, K+)-ATPase and Mg(2+)-ATPase activities was studied in crude membrane fraction as well as in purified sarcolemmal membranes isolated from rat heart. Benfluron in concentration range 10(-7) -5 x 10(-5) mol.l-1 did not exert any effect on ATPase activities studied. 10(-4) mol.l-1 Benfluron was stimulatory towards (Na+, K+)-ATPase, while Mg(2+)-ATPase activity was depressed. Kinetic analysis of interaction of Benfluron with (Na+, K+)-ATPase revealed an increase in the Vmax and decrease in the K(m) values for ATP. The possible mechanism of interaction of the drug with (Na+, K+)-ATPase is discussed.
Animals↗
Competitive inhibition of (Na/K)-ATPase by furylethylenes with respect to potassium ions.
The effects of newly synthetized derivatives of furylethylene: i) 1-(5-nitro-2-furyl)-2-phenylsulfonyl-2-furylcarbonyl ethylene (FE1), ii) 1-(5-phenylsulfonyl-2-furyl)-2-phenylsulfonyl-2-furylcarb onyl ethylene (FE2), iii) 1-(5-phenylsulfonyl-2-furyl)-2-phenylsulfonyl-2-tienocarb onyl ethylene (FE3), on the reaction kinetics of the dog kidney (Na/K)-ATPase were tested. Besides the conjugated triene moiety of the furylethylene skeleton, the groups responsible for the reaction with nucleophilic groups, the formyl group that connects the second furyl ring in FE1 and FE2 and the formyl group that connects the thienyl ring to the furylethylene moiety in FE3. Among the furylethylenes tested, only FE1 was found to react effectively with beta-mercaptoethanol (beta ME) and glycine (GLY) as model substances containing nucleophilic groups, and also exhibit an inhibitory interaction with the (Na/K)-ATPase. A suppression of the reactivity of the formyl group due to the replacement of the furyl ring with the more aromatic thienyl ring in FE3 did not induce any significant change in the reactivity of the compound with the model substances or with (Na/K)-ATPase. On the other hand, replacement of the NO2 group on the furylethylene moiety (in FE1) by the less electron-attracting phenylsulfonyl group (in FE2 and FE3) yielded a considerable suppression of the inhibitory effect on (Na/K)-ATPase. Moreover, in comparison to FE1, FE2 and FE3 were found to react less potently with the model nucleophilic substances. The results indicated that the conjugated triene moiety on the furylethylene part of the molecule of FE1 may be made responsible for the inhibitory interaction with the nucleophilic aminoacid residue on the (Na/K)-ATPase molecule. FE1 interfered competitively with the (Na/K)-ATPase activation by increasing amounts of potassium. This was manifested by a significant increase in the apparent K0.5App value and a decrease in the apparent cooperativity constant, nApp, for potassium ions, but had no influence on the apparent VmaxApp value for potassium. With respect to the activation of the enzyme with sodium ions and ATP, only FE1 decreased the VmaxApp values while having no considerable influence on the other kinetic variables. It was concluded that FE1 inhibits the (Na/K)-ATPase by selective interaction with some essential nucleophilic (probably SH and/or NH2) aminoacid residues located in, or closed to the potassium binding site of the enzyme molecule.
Animals↗
Borna disease virus and schizophrenia.
The development of a new serological assay method to detect antibodies in human sera recognizing Borna disease virus (BDV) proteins and a clinical pilot study are presented. Psychiatric patients from a schizophrenia research clinic in Baltimore, Maryland, were examined for antibodies to BDV antigen with traditional indirect immunofluorescence assays (IFA) that used both single and double labeling techniques and also with a Western blot assay capable of detecting antibodies to the three BDV proteins from a human neuroblastoma cell line. Thirteen of 90 (14.4%) patients and 0/20 control subjects had antibodies that recognized more than one BDV protein on the Western blot. Three patients had antibodies that recognized all three BDV proteins. Magnetic resonance imaging assessments of the volume of the putamen (with controls for total cranial volume) differentiated BDV+ from BDV- patients, and there were trend differences for bilateral amygdalae and the left amygdala-hippocampal process. We conclude that: (1) the Western blot assay is superior to IFA assays in BDV serology studies, (2) detection of antibodies to more than one BDV protein is a useful working criterion for seropositivity, (3) the 14.5 kDa BDV protein is 10 times more predictive of seropositivity than either the 38/40 kDa or the 24 kDa protein, (4) there is tentative evidence for a schizophrenia-control difference in the prevalence of anti-BDV antibodies, and (5) it is likely that there are neuroanatomical/behavioral features that differentiate seropositive from seronegative schizophrenic patients.
Adult↗
The effects of calcium and calcium channel blockers on sodium pump.
The effects of 10 mM Ca2+ and Ca2+ channel blockers verapamil, diltiazem and flunarizine on the ouabain-sensitive electrogenic Na+, K+ pump activity of mouse diaphragm muscle fibres enriched with Na+ were compared with the changes in cytosolic [Ca2+]. The electrogenic Na+ pump activity produced by adding K+ to muscles previously bathed for 4 h in a K(+)-free, 2-mM [Ca2+] solution increased the resting membrane potential by about 18 mV. This hyperpolarization was completely inhibited after 10 min incubation in 10 mM Ca2+. Verapamil 10(-5) M, 10(-5) M diltiazem and 10(-7) M flunarizine effectively prevented the effect of elevated [Ca2+]. At these concentrations, these drugs did not affect the K(+)-induced hyperpolarization. In mouse diaphragm, the basal cytosolic [Ca2+] measured by the fluorescent indicator 1-[2-(5-carboxyoxazol-2-yl)-6- aminobenzofuran-5-oxy]2-(2'-amino-5'-methylphenoxy)ethane-N,N,N',N '- tetraacetic acid acetoxymethyl ester (fura-2/AM) was 261 +/- 6 nM. After 4 h in a Liley K(+)-free, 2 mM [Ca2+] solution, the cytosolic [Ca2+] increased to 314 +/- 28 nM. Increase in [Ca2+] from 2 to 10 mM caused a twofold increase of cytosolic [Ca2+] to 637 +/- 26 nM. This rise was, like the Ca(2+)-induced inhibition of electrogenic pump, prevented by 10(-5) M verapamil, 10(-5) M diltiazem and 10(-7) M flunarizine. The results suggest that substances which block Ca2+ entry into the cell prevent the Ca(2+)-induced inhibition of the Na+ pump.
Animals↗
Serotonin, schizophrenia and antipsychotic drug action.
A rapidly growing body of data suggests that dysfunction in serotonergic (5-HT) function may be involved in the pathophysiology of schizophrenia, and that pharmacologic agents for this illness have their therapeutic effects mediated through serotonergic mechanisms. The purpose of this paper is to critically review data relevant to 5-HT's role in the pathophysiology and drug treatment of schizophrenia. Pathophysiologic evidence includes the psychotomimetic effects of lysergic acid (LSD), postmortem studies, single-dose 'challenge' studies and investigations of CSF and peripheral levels of 5-HT and its metabolites. The current nomenclature, potential therapeutic effects and importance of 5-HT receptor subtype antagonism will be examined. In addition, relatively novel strategies of 5-HT uptake blockade and direct acting 5-HT agonists will be assessed. A hypothesis of cortical-subcortical imbalance with an increase in subcortical 5-HT function responsible for positive symptoms and a decrease in prefrontal 5-HT function responsible for negative symptoms is proposed. Future implications of these data are discussed.
Antipsychotic Agents↗
Patient response and resource management: another view of clozapine treatment of schizophrenia.
OBJECTIVE: Issues in clozapine treatment were considered in terms of implications for resource management. METHOD: A critical review of the literature on time course and pattern of response to clozapine was used to address treatment of negative symptoms, late responders, and extent of clinical benefit in ordinary settings. RESULTS: Superior efficacy of clozapine for partial and poor neuroleptic responders is observed in about one-half of the cases. Response is rapid once a therapeutic dose is reached, and the data do not support the proposition that some patients first respond only after 3-12 months of therapy. The cumulative benefit over several months of treatment and the broad range of symptoms involved in response are similar to those for typical neuroleptic drugs, suggesting that clozapine's superiority is based on greater effectiveness rather than a unique profile of treatment effects. Clozapine appears to be effective for secondary, but not primary, negative symptoms. Modal response is moderate, and extensive rehabilitation and clinical services are required to substantially enhance functional outcome. CONCLUSIONS: Many more patients merit trials with clozapine. Economic costs and adverse drug effects can be minimized by selecting patients most likely to benefit and discontinuing clozapine treatment when benefit is not observed within 2-4 months. Appropriate patients include 1) those with good responses to typical neuroleptics who experience substantial adverse effects and 2) those whose disorders respond poorly to standard neuroleptics and are defined by psychotic symptoms, thought disorder, and hostility. Treatment of primary negative symptoms is not supported by the current experimental data.
Antipsychotic Agents↗
Expressed emotion. Trait or state?
BACKGROUND: This exploratory study addresses the question of whether expressed emotion (EE) is a response characteristic of the parent (trait) or a parental response to specific circumstances or persons (state). METHOD: Seventeen parents participated in two audiotaped interviews, using modified versions of the Camberwell Family Interview. One interview concerned the child with chronic schizophrenia and the other a well sibling. Subsequent ratings of the EE variables of critical comments (CC), emotional overinvolvement (EOI) and warmth were completed and compared. RESULTS: EE response patterns directed towards patients, as compared with towards siblings, were significantly different on two measures: EOI (P = 0.01) and warmth (P = 0.02). The parents showed significantly more emotional overinvolvement with the child with schizophrenia and significantly more warmth towards the well child. CONCLUSIONS: These data suggest that the EE variables of EOI and warmth are related to the state of child, and the lack of a significant difference in CC suggests that this is a parental trait.
Adolescent↗
Distribution of proteins in aqueous two-phase systems formed by dextran and polyethylene glycol. Influence of protein hydrophobicity.
Aqueous two-phase systems formed by mixing polyethylene glycol (PEG) and dextran (DXT) were studied. The composition of DXT and PEG phase was established by the size exclusion HPLC method. The concentrations of DXT and PEG in both phases as a function of total concentration of both polymers was fitted by nonlinear regression. This procedure yielded an empirical numerical model (with two independent variables: bulk concentration of DXT and PEG) characterizing the composition of either phase at any applied concentration of the polymers. The distributions of bovine serum albumin (BSA) and immunoglobulin G (IgG) were studied in this system in relation to the composition of both phases. Both proteins were predominantly distributed in the dextran phase. The protein affinity to the respective phase was found to increase with: i) the increasing phase dextran concentration; and ii) the decreasing phase PEG concentration. Chemical modification of primary amino groups of BSA by 2,4,6-trinitrobenzene sulfonic acid (TNBS) raised the affinity of the conjugate to the less polar PEG phase.
Animals↗
Effect of phorbol myristate acetate (PMA) on P-glycoprotein mediated vincristine resistance of L1210 cells.
Effect of phorbol myristate acetate (PMA) on P-glycoprotein (P-GP)-mediated vincristine resistance of the multidrug resistant mouse leukemic cell line L1210/VCR was studied by one hour lasting incubation of cells in the presence of PMA, and after three days of cultivation in the presence of the same substance. After the incubation with 100 micrograms.1-1 PMA the accumulation of [3H]-vincristine by the above cells was significantly depressed. Moreover, full reverse of verapamil-induced stimulation of [3H]-vincristine accumulation was observed in the presence of PMA. In contrary, when cells were cultivated three days in the presence of PMA, only slight but non-significant increase of [3H]-vincristine accumulation was observed. Slight increase of vincristine accumulation by cells cultivated in the presence of PMA was also supported by higher sensitivity of these cells to vincristine.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
The comparative efficacy and long-term effect of clozapine treatment on neuropsychological test performance.
Previous studies have suggested that clozapine may improve neuropsychological test performance. The current study was designed to examine the comparative efficacy and the long-term effect of clozapine (versus haloperidol), on neuropsychological test performance. Neuropsychological measures of executive/attention, visuospatial, and memory function were administered to schizophrenic patients at baseline, at the end of a 10-week double-blind study, and after 1 year of open clozapine treatment. Symptoms and function ratings were obtained at the same time points. The 10-week double-blind study revealed significant group-by-time interactions for two measures: Categorical Fluency and WAIS-R Block Design. At the end of 1 year of open treatment there were significant improvements in Verbal Fluency, Mooney Faces Closure, and WAIS-R Block Design performance, and trend improvements in Stroop Color-Word Interference, Category Fluency, and WMS-R Logical Memory performance. Improvements in neuropsychological performance were unrelated to symptom changes. Change in selected neuropsychological measures were significantly correlated with improvement in quality of life. The results suggest that long-term clozapine treatment may have beneficial effects on a broad range of cognitive functions.
Adult↗
Stability of neurological signs with clozapine treatment.
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Adult↗