Analysis of the B7 costimulatory pathway in allograft rejection

Stimulus control induced by (-)-2,5-dimethoxy-4-methylamphetamine (DOM) is believed to be mediated by agonism at 5-HT2A receptors. We hypothesized that blockade of (-) DOM-induced stimulus control may thus prove useful in the pre-clinical characterization of novel antipsychotic agents by providing an in vivo index of antagonism at that receptor. A previous study (Fiorella et al., 1995a) observed no antagonism by typical agents such as haloperidol and thioridazine, partial antagonism by the atypical agent, clozapine, and full antagonism by risperidone, a second atypical antipsychotic. The present investigation extends these observations to include seven additional drugs: SCH 23390, sulpiride, amperozide, melperone, octoclothepin, tiospirone and ritanserin. Of the drugs tested in rats in which (-) DOM-induced stimulus control had reliably been established, only tiospirone and ritanserin produced complete antagonism of the (-) DOM stimulus. Intermediate levels of antagonism were observed following treatment with amperozide, melperone, and octoclothepin. Finally, SCH 23390 and sulpiride yielded no evidence of antagonistic activity in (-) DOM-trained animals. Because clozapine and risperidone are both classified as atypical antipsychotics yet yield different degrees of antagonism of (-) DOM-induced stimulus control, we tested the substitution of risperidone for clozapine in rats trained with clozapine as a discriminative stimulus. No significant substitution was observed. In conclusion it appears that complete or partial antagonism of the (-) DOM stimulus serves as an effective pre-clinical means of identifying antipsychotics with significant 5-HT2A antagonist properties. However, the failure of risperidone to substitute for clozapine in pigeons (Hoenicke et al., 1992) and in rats (present study) suggests that despite their shared 5-HT2A antagonist properties, clozapine and risperidone differ with respect to their stimulus effects.     

Different effects of subchronic clozapine and haloperidol on dye-coupling between neurons in the rat striatal complex

Atypical antipsychotic drugs, such as clozapine, are distinguished from classical antipsychotics (e.g. haloperidol) by their lower liability for producing motor side-effects. Although initial studies suggested that the clinical efficacy of antipsychotic drugs is related to their affinity for the D2 dopamine receptor, the delayed onset of both the therapeutic effects and the extrapyramidal symptoms associated with these drugs implicates a more complex mechanism of action. In this study, we found that continuous (but not acute) treatment of rats with either drug caused an increase in dye coupling between neurons in the limbic component of the rat striatal complex (i.e. the shell region of the nucleus accumbens) after withdrawal of the drugs. Furthermore, continuous treatment with haloperidol, but not clozapine, also increased dye coupling in the motor-related part of the striatal complex (i.e. the dorsal striatum). Thus, both therapeutically effective drugs show a delayed effect on dye coupling between neurons in the accumbens shell, whereas only the drug associated with motor side effects altered coupling between cells in the dorsal striatum. Antipsychotic drugs may therefore alleviate the profound disturbances in cognitive function of schizophrenics by producing sustained alterations in the way signals from the cortex are integrated within these brain regions.     

The microcirculation and survival of experimental flow-through venous flaps

We assessed the effects of chronic (21 day) administration of antipsychotic drugs on the density of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor in rat brain. We used two typical antipsychotic drugs, haloperidol and pimozide, and two atypical antipsychotic drugs, risperidone and clozapine. Antipsychotic drugs as a group significantly elevated the density of the AMPA receptor measured with an AMPA receptor agonist ([3H]AMPA), but not with an AMPA receptor antagonist, 6-cyano-7-nitro-quinoxaline-2,3-dione ([3H]CNQX). In all regions studied, the magnitude of the increase seen with chronic typical antipsychotic drugs was significantly greater than that seen with chronic atypical antipsychotic drugs. In frontal cortex and striatum, typical antipsychotics but not atypical antipsychotics elevated AMPA receptor binding over control. These findings suggest that antipsychotic drugs alter the agonist affinity of the AMPA receptor without altering the number of AMPA receptors. Typical antipsychotic drugs may be more potent in this effect than atypical antipsychotic drugs, especially in critical corticostriatal circuits.     

Relative predispositional effects and mode of inheritance of HLA-DRB1 alleles among community-based Caucasian females with rheumatoid arthritis

This review addresses two questions. First, why does clozapine apparently occupy low levels of dopamine D2 receptors in patients, in contrast to all other antipsychotic drugs which occupy 70-80% of brain dopamine D2 receptors? Second, what is the receptor basis of action of antipsychotic drugs which elicit low levels of Parkinsonism? Antipsychotic doses of clozapine occupy between 0% and 50% of D2 receptors, as measured in patients by a variety of radioligands. It has recently been found, however, that the percent occupancy of a receptor by a drug depends on the radioligand used to measure that receptor. Based on this new finding, this review concludes that clozapine clinically occupies high levels of D2 receptors in the absence of any radioligand. This occupancy is estimated to be of the order of 70-80% in the dopamine-rich region of the human striatum, and even higher in the limbic D2-containing regions which are low in endogenous synaptic dopamine. This conclusion arises from two different approaches. One approach is to relate the reported clozapine occupancies in the human striatum with the dissociation constants of the various radioligands at the D2 receptor. This relation extrapolates to approximately 70-80% occupancy by clozapine when clozapine competes with endogenous dopamine at the D2 receptor. The second approach is to calculate the D2 occupancy of each antipsychotic drug, using the average spinal fluid concentration and the correct dissociation constant of the antipsychotic, thereby revealing that all antipsychotic drugs, including clozapine, occupy approximately 70-80% of dopamine D2 receptors in the human striatum, and possibly higher in the limbic regions. As determined by the new dissociation constants, antipsychotic drugs which elicit Parkinsonism (trifluperazine, chlorpromazine, raclopride, haloperidol, fluphenazine, risperidone) bind more tightly than dopamine to D2, while those antipsychotic drugs which elicit little or no Parkinsonism (melperone, seroquel, perlapine, clozapine, remoxipride, molindone, sulpiride, olanzapine, sertindole) bind more loosely than dopamine to D2 receptors. Compared to the tightly bound antipsychotic drugs, the more loosely bound antipsychotics generally require higher clinical doses, require fewer days for clinical adjustment, but may dissociate from the D2 receptor more rapidly and could lead to clinical relapse somewhat earlier than that found with the traditional tightly bound antipsychotic drugs.     

Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia

OBJECTIVE: Dopamine D2 receptor occupancy measurements provide a valid predictor of antipsychotic response, extrapyramidal side effects, and elevation of prolactin levels. The new antipsychotics clozapine, risperidone, and olanzapine obtain antipsychotic response with few extrapyramidal side effects and little prolactin elevation. The purpose of this study was to compare the D2 and serotonin 5-HT2 receptor occupancies of these drugs in patients receiving multiple-dose, steady-state regimens. METHOD: Forty-four patients with schizophrenia (16 taking risperidone, 2-12 mg/day; 17 taking olanzapine, 5-60 mg/day; and 11 taking clozapine, 75-900 mg/day) had their D2 and 5-HT2 occupancies determined with the use of [11C]raclopride and [18F]setoperone, respectively, and positron emission tomography imaging. RESULTS: Clozapine showed a much lower D2 occupancy (16%-68%) than risperidone (63%-89%) and olanzapine (43%-89%). Risperidone and olanzapine gave equal D2 occupancies at doses of 5 and 20 mg/day, respectively. All three drugs showed greater 5-HT2 than D2 occupancy at all doses, although the difference was greatest for clozapine. CONCLUSIONS: Clozapine, at doses known to be effective in routine clinical settings, showed a D2 occupancy clearly lower than that of typical antipsychotics, while risperidone and olanzapine at their usual clinical doses gave the same level of D2 occupancy as low-dose typical antipsychotics. The results also suggest that some previous clinical comparisons of antipsychotics may have been confounded by different levels of D2 occupancy. Clinical comparisons of these drugs, matching for D2 occupancy, may provide a better measure of their true "atypicality" and will help in understanding the contribution of non-D2 receptors to antipsychotic effects.     

Clozapine occupies high levels of dopamine D2 receptors

An important discrepancy has been noted concerning the number of dopamine D2 receptors which must be occupied in patients by clozapine, in contrast to other antipsychotic drugs, in order to achieve an antipsychotic effect. For example, when D2 receptors are labelled by radioactive raclopride or spiperone congeners in patients, psychosis-controlling doses of all antipsychotic drugs occupy about 70% or more of the D2 receptors in patients. However, equi-effective psychosis-controlling doses of clozapine (approximately 400 mg/day; approximately 70-130 nM in spinal fluid) only occupy between 20% and 50% of the D2 receptors in patients. This discrepancy of a consistently lower occupancy of D2 by psychosis-controlling doses of clozapine may be resolved when one considers that the neuroleptic concentration for half-occupancy of D2 receptors in vitro (i.e. the inhibition constant) depends on the radioligand used to label the receptor. Radioligands with higher tissue/buffer partition coefficients are less displaced by clozapine. This principle applies both in vitro and in vivo. Thus, allowing for this principle, psychosis-controlling doses of clozapine can be shown to occupy over 70% of the brain dopamine D2 receptors in patients, as found with other neuroleptics.     

Clozapine and risperidone in chronic schizophrenia: effects on symptoms, parkinsonian side effects, and neuroendocrine response

OBJECTIVE: Clozapine and risperidone were the first two "second-generation" antipsychotic drugs approved for schizophrenia. There is currently little information about their comparative efficacy from head-to-head clinical trials. The purpose of this study was to examine the comparative efficacy of clozapine and risperidone for positive and negative symptoms, depression, parkinsonian side effects, and indexes of neuroendocrine function in schizophrenic patients who met a priori criteria for partial response to traditional neuroleptic agents. METHOD: After a baseline fluphenazine treatment period, 29 patients participated in a 6-week, double-blind, parallel-group comparison of the effects of these agents. RESULTS: Clozapine was superior to risperidone for positive symptoms and parkinsonian side effects, but there were no significant differences between the drugs on two measures of negative symptoms, Brief Psychiatric Rating Scale total scores, and depression scores. The clozapine patients, but not the risperidone patients, demonstrated significant reductions from the fluphenazine baseline in positive symptoms, total symptoms, and depression. In addition, clozapine produced fewer effects on plasma prolactin than risperidone or fluphenazine. The mean daily doses during week 6 of the trial were 403.6 mg of clozapine and 5.9 mg of risperidone. CONCLUSIONS: The findings from this study indicate that these drugs have both important differences and similarities in their comparative efficacy in chronically ill, partially responsive patients with schizophrenia. Further research on second-generation antipsychotic drugs in this patient population that addresses key methodological issues, such as optimal dose and treatment duration, are needed.     

Simulation exercises, a problem oriented method of learning public health in medical education]

Spontaneous and amphetamine-elicited locomotor activity in rats is reduced by most clinically effective antipsychotic drugs. We have recently demonstrated that intracerebroventricular infusion of kainic acid (KA), which produces cell loss in the hippocampus and other limbic-cortical brain regions, increases spontaneous and amphetamine-elicited locomotion. The present study determined if KA lesions alter the suppressive effects of the antipsychotic drugs, haloperidol and clozapine, on spontaneous and amphetamine-elicited locomotor behavior. Young adult male rats (70 days of age) received intracerebroventricular infusions of vehicle or KA, which produced hippocampal pyramidal cell loss in each rat and more variable cell loss or gliosis in the amygdala, piriform cortex, and laterodorsal thalamus. Thirty days post-surgery, lesioned and control rats were tested once a week for locomotor responses to drug treatments. As observed previously, spontaneous locomotor activity and hyperactivity elicited by amphetamine (1.50 mg/kg s.c.) were greater in lesioned animals than controls. In addition, the level of spontaneous activity and/or amphetamine-elicited hyperlocomotion observed in lesioned rats after haloperidol treatment (0.13, 0.35, or 1.50 mg/kg s.c.) was greater than that found in controls. Locomotor responses to low (6.30 mg/kg) and moderate doses of clozapine (20 mg/kg) were similar in lesioned and control rats, although lesioned rats were more active than controls following the administration of a high dose of clozapine (30 mg/kg). These data indicate that the hyperactivity associated with limbic-cortical lesions may be insensitive to reversal by haloperidol, yet uniquely sensitive to suppression by clozapine.     

Atypical antipsychotic drugs selectively increase neurotensin efflux in dopamine terminal regions

Typical antipsychotic drugs, such as haloperidol and chlorpromazine, increase synthesis of the neuropeptide neurotensin (NT) in both the striatum and the nucleus accumbens, whereas atypical antipsychotic drugs, such as clozapine and olanzapine, do so only in the nucleus accumbens. By using in vivo microdialysis, we now report that acute administration of haloperidol, clozapine, or olanzapine failed to alter the release of NT in either the striatum or nucleus accumbens. In contrast, chronic administration of haloperidol for 21 days increased NT release in both the striatum and nucleus accumbens, whereas treatment for 21 days with the atypical antipsychotic drugs, clozapine or olanzapine, increased NT release selectively in the nucleus accumbens. These findings suggest that (i) increased NT mRNA expression and NT tissue concentrations are associated with increases in the extracellular fluid concentrations of the peptide and (ii) atypical antipsychotic drugs may exert their therapeutic effects and produce fewer side effects by virtue of their selectivity in limbic compared with striatal, target neurons.     

Anticipation in multiplex schizophrenia pedigrees

The dopamine D4 receptor, recently identified by molecular biological techniques, is expressed in areas of the brain implicated in the pathophysiology of schizophrenia. Although it has a lower affinity than the D2 receptor for most antipsychotic drugs, the D4 receptor has a higher affinity for clozapine, which may explain the unique efficacy of clozapine in the treatment of schizophrenia. However, there is no association between genetic alterations of the D4 gene and either the development of schizophrenia or response to clozapine administration, nor is the absence of the receptor related to major neuropsychiatric deficits. The report of an increase in D4 receptor density in the striatum in schizophrenia has not been consistently confirmed. Thus, it appears that there is little to support the development of D4 antagonists as potential antipsychotic agents.     

Medial prefrontal cortical D2 and striatolimbic D4 dopamine receptors: common targets for typical and atypical antipsychotic drugs

1. In vitro receptor autoradiography was used to examine the long-term effects of a typical (fluphenazine), atypical (clozapine), or potential atypical antipsychotic (S[+]-N-n-propylnorapomorphine; [+]-NPA) on different dopamine (DA) receptor subtypes. 2. D1-Like and D3 receptor levels were not changed with any treatment in any brain region examined. 3. D2 Receptors in caudate-putamen (CPu), nucleus accumbens (NAc) and olfactory tubercle (OT) were significantly increased by long-term treatment with fluphenazine, but not with clozapine or S[+]-NPA. 4. D2 Receptor levels in medial prefrontal cortex (MPC), but not dorsolateral frontal cortex (DFC), were elevated after repeated daily administration of fluphenazine, clozapine, and S[+]-NPA. 5. D4-Like receptors, assayed under D4-selective conditions, were increased by fluphenazine, clozapine and S(+)-NPA in both NAc and CPu, but by none of these treatments in OT, DFC or MPC. 6. These results support a common role for medial prefrontal cortical D2 and striatolimbic D4 receptors in mediating the clinical actions of typical and atypical antipsychotic drugs.     

Differential effects of clozapine and haloperidol on dopamine receptor mRNA expression in rat striatum and cortex

The regulation of the dopamine (DA) receptors is of considerable interest, in part because treatment with antipsychotic drugs is known to upregulate striatal D2-like receptors. While previous studies have focused on the regulation of striatal DA receptors, less is known about the pharmacological regulation of cortical DA receptors. The purpose of this study was to examine the regulation of DA mRNA receptor expression in the cortex compared to the striatum following treatment with antipsychotic agents. Adult male Sprague-Dawley rats were injected daily with haloperidol (2 mg/kg/day), clozapine (20 mg/kg/day) or a control vehicle for a period of 14 days. Following treatment, brains were subjected to in situ hybridization for the mRNAs encoding the five dopamine receptors; only D1, D2, and D3 receptor mRNAs were detected in these regions. Haloperidol tended to either modestly upregulate or have no effect on dopamine receptor mRNAs detected in striatal structures, while clozapine generally downregulated these mRNAs. On the other hand, in the cortex, both drugs had striking effects on D1 and D2 mRNA levels. Cortical D1 mRNA was upregulated by haloperidol, but this effect was primarily restricted to cingulate cortex; clozapine also upregulated D1 mRNA, but primarily in parietal regions. Haloperidol downregulated D2 mRNA in the majority of cortical regions, but most dramatically in frontal and cingulate regions; clozapine typically upregulated this mRNA, but primarily in regions other than frontal and cingulate cortex. These results indicate that clozapine and haloperidol each have regionally-specific effects, and differentially regulate dopamine receptor mRNA expression in striatal and cortical regions of the rat brain.     

Discriminative stimulus properties in rats of the novel antipsychotic quetiapine.

Rats discriminated the novel antipsychotic quetiapine (Seroquel). Full generalization was seen with the novel ("atypical") antipsychotics, clozapine, olanzapine, and risperidone. Generalization was not seen with the older "typical" antipsychotics, haloperidol, chlorpromazine, and loxapine, or with the novel atypical antipsychotic, amisulpride. The pattern of generalization resembled that seen in rats trained to discriminate a low dose (1.25 mg/kg) of clozapine, which dissociates most novel antipsychotics from typical antipsychotics. However, the failure of the novel antipsychotic amisulpride to generalize demonstrates that this bioassay does not detect all novel antipsychotics. These data suggest that the discrimination of antipsychotics such as quetiapine may be of value in the development of novel antipsychotics, although the relationship between the discriminative properties of such drugs and their clinical actions is unclear. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Semi-automatic computer construction of three-dimensional shapes for the finite element method

Seven patients with idiopathic Parkinson's disease, aged 62 to 76 years, average duration of the disease approximately eleven years, suffering from severe hallucinosis and paranoid delusions of different degree, in whom conventional therapeutic strategies (administration of benzodiazepines and mild neuroleptics) had no antipsychotic effect, received clozapine, a non-classical highly potent neuroleptic, while blood count was strictly monitored. Paranoid ideas disappeared in all seven patients after a maximum of four days administration of 25-125 mg/day. No deterioration of parkinsonian symptoms, quantified according to UPDRS was seen. Given the protection of clozapine, we could increase the L-dopa dose in two cases, thereby improving the patients' motor function. Blood count showed no abnormalities in any of the patients during an average observation period of seventeen months. Our results support the assumption that clozapine has a potent antipsychotic effect in the treatment of psychotic decompensation in advanced Parkinson's disease in carefully selected patients. We saw no negative influence of the neuroleptic on extrapyramidal symptoms.     

Clozapine blunts N-methyl-D-aspartate antagonist-induced psychosis: a study with ketamine

Several lines of evidence suggest that the glutamatergic N-methyl-D-aspartate (NMDA) receptor is involved in the antipsychotic efficacy of the atypical antipsychotic agent clozapine. Clinical data on the interaction between clozapine's mechanism of action and NMDA receptor function have been lacking secondary to a paucity of pharmacologic probes of the NMDA system. We have utilized a double-blind, placebo-controlled infusion paradigm with subanesthetic doses of the NMDA antagonist ketamine to test the hypothesis that clozapine would blunt ketamine-induced psychotic symptoms in schizophrenic patients. Ten schizophrenic patients underwent ketamine infusions while antipsychotic drug free and also during treatment with clozapine. Antipsychotic drug-free patients experienced increases in ratings of positive and negative symptoms. Clozapine treatment significantly blunted the ketamine-induced increase in positive symptoms. These data suggest that NMDA receptor function may be involved in the unique antipsychotic efficacy of clozapine.     

Licking behavior in the rat: measurement and situational control of licking frequency

OBJECTIVE: In a preliminary report, the authors observed that clozapine was superior to haloperidol in the treatment of positive and negative symptoms in stable outpatients with schizophrenia. In this final report, they examine the effects of clozapine on positive and negative symptoms in patients with and without the deficit syndrome to determine which patients receive the positive symptom advantage of clozapine and the extent of clozapine's therapeutic effects on negative symptoms. In addition, they examine the long-term effects of clozapine on positive, negative, and affective symptoms, social and occupational functioning, and quality of life. METHOD: Seventy-five outpatients with schizophrenia, who met retrospective and prospective criteria for residual positive or negative symptoms, were entered into a 10-week double-blind, parallel-groups comparison of clozapine and haloperidol. Patients who completed the double-blind study were then entered into a 1-year open-label clozapine study. RESULTS: For patients who completed the 10-week double-blind study, clozapine was superior to haloperidol in treating positive symptoms. This effect was not observed in the intent-to-treat analyses. There was no evidence of any superior efficacy or long-term effect of clozapine on primary or secondary negative symptoms. Long-term clozapine treatment was associated with significant improvements in social and occupational functioning but not in overall quality of life. CONCLUSIONS: For schizophrenic patients who are able to tolerate clozapine therapy, clozapine has superior efficacy for positive symptoms but not negative symptoms and is associated with long-term improvements in social and occupational functioning for patients with and without the deficit syndrome.     

Artificial neural networks and logistic regression as tools for prediction of survival in patients with Stages I and II non-small cell lung cancer

BACKGROUND: This study examines the role of participation in psychosocial treatment as a mediator of the clinical effectiveness of clozapine. METHODS: Subjects participated in a 12-month double-blind random-assignment trial comparing clozapine and haloperidol in patients hospitalized 30 to 364 days for refractory schizophrenia at 15 Department of Veterans Affairs medical centers. A broker-advocate case management intervention was used to facilitate participation in psychosocial treatments and to document such participation. RESULTS: Between those who continued receiving clozapine (n=122) or a conventional antipsychotic drug (n=169) for 12 months, those receiving clozapine were more likely to participate in psychosocial rehabilitation treatment. Although they were no more likely to receive clinical recommendations for such treatments, they were more likely to both verbally accept recommendations and to act on them. Structural equation modeling shows that participation in psychosocial treatment did not play a mediating role in clozapine's effect on outcomes at 6 months, but was associated with both reduced symptoms and improved quality of life at 12 months. CONCLUSIONS: Clozapine facilitates participation in psychosocial treatment, and such enhanced participation is associated with improved quality-of-life and symptom outcomes. Psychosocial rehabilitation should be offered concomitantly with clozapine.     

Olanzapine: a serotonin-dopamine-receptor antagonist for antipsychotic therapy

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, dosage and administration, and cost of olanzapine are reviewed. Olanzapine is a serotonin-dopamine-receptor antagonist indicated for use in the treatment of schizophrenia and other psychotic disorders. The affinity of olanzapine for neuroreceptors is similar to that of clozapine. The drug is well absorbed from the GI tract; food has no effect. Olanzapine is more effective than placebo and equal to haloperidol in reducing psychotic symptoms on two rating scales. However, unlike typical dopamine-receptor antagonists used for antipsychotic therapy, olanzapine is more effective in reducing the negative symptoms of schizophrenia. The most frequent adverse drug reactions (ADRs) associated with olanzapine are somnolence, agitation, insomnia, and headache. Constipation and dry mouth occur as dose-dependent ADRs. Unlike clozapine, olanzapine does not cause agranulocytosis. No cases of tardive dyskinesia or neuroleptic malignant syndrome have been reported. Olanzapine has been associated with slight increases in hepatic transaminases. More study is needed to determine whether olanzapine interacts significantly with other drugs. The recommended starting dosage is 5-10 mg orally once daily. Efficacy beyond six weeks has not been evaluated; patients treated for longer than six weeks should be periodically reassessed. Olanzapine costs about 10 times more than typical antipsychotics because a generic version is not available; however, olanzapine costs less than clozapine therapy and may cost less than haloperidol in terms of total health care costs. Olanzapine offers an effective alternative for treating schizophrenia and has a favorable adverse-effect profile.     

Differential effects of unique profile antipsychotic drugs on extracellular amino acids in the ventral pallidum and globus pallidus of rats

The effects of antipsychotic drugs (APDs) on brain dopamine receptors in the striatum are ultimately expressed through efferent projections which primarily use amino acid transmitters, including gamma-aminobutyric acid and glutamate. The present study examined the effects of APDs on extracellular amino acid levels in the rat ventral pallidum (VP) and globus pallidus (GP), areas that receive projections from distinct striatal subregions. Clozapine, an APD with low motor side effect liability, and metoclopramide, a low-potency APD with high motor side effect liability, were compared with haloperidol, a widely used APD with high motor side effect liability. Drugs were administered subcutaneously and amino acid levels were monitored concurrently in the VP and GP by intracranial microdialysis. High doses of haloperidol and metoclopramide increased and clozapine decreased extracellular gamma-aminobutyric acid levels in the GP but not the VP. Low, but not high, doses of the three drugs tended to increase extracellular glutamate levels in both pallidal regions. Clozapine, but not the other two drugs, decreased extracellular threonine in the GP and glycine and threonine in the VP. Results indicate a correlation between increased gamma-aminobutyric acid levels in the GP and the propensity of the APDs tested to induce motor side effects. The novel effects of clozapine on extracellular glycine and threonine further distinguish this drug as a unique antipsychotic compound.     

Symptomatic colonic polyps in childhood: not so benign

We investigated the degree of striatal dopamine-2 (D2) receptor occupancy in six schizophrenic patients receiving clinically effective antipsychotic treatment with olanzapine 10-25 mg/day in comparison to patients treated with clozapine 300-600 mg/day (n = 6) or haloperidol 5-20 mg/day (n = 10). 123I Iodobenzamide (IBZM) and single photon emission computerized tomography (SPECT) were used for the visualization of striatal D2 receptors. For the quantification of striatal D2 receptor occupancy, striatal IBZM binding in patients treated with antipsychotics was compared to that in untreated healthy controls (n = 8) reported earlier. Olanzapine led to a mean striatal D2 receptor occupancy rate of 75% (range 63-85). Haloperidol-treated patients showed dose-dependently (Pearson r = 0.64; P < 0.05) a significantly higher (P < 0.05) mean occupancy rate of 84% (range 67-94). During clozapine treatment, the mean D2 receptor occupancy of 33% (range < 20-49) was significantly lower than with olanzapine (P < 0.005). The higher striatal D2 receptor occupancy of haloperidol was correlated with the incidence and severity of extrapyramidal motor side-effects (EPS). No clinical relevant EPS occurred during treatment with olanzapine or clozapine. There was no correlation between the degree of striatal D2 receptor occupancy and clinical improvement.