Antipsychotic-Induced Side Effects Related to Receptor Affinity

Peacock, Linda; Gerlach, Jes

doi:10.1007/978-3-642-61007-3_13

Cited by 5 publications

(5 citation statements)

References 71 publications

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“…They also interact in vivo with other receptors, including D 1 (risperidone, olanzapine, and clozapine), muscarinic cholinergic (olanzapine and clozapine), and α 1 (clozapine) sites. In order to determine if broad occupancy of receptors was sufficient by itself to confer an atypical APD‐like SMR, we also examined the effects of chlorpromazine, which has high affinities for several receptors (including D 2 , D 1 , 5‐HT 2A , α 1 , and muscarinic cholinergic sites) but is a typical APD (Peacock & Gerlach, 1996).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, in order to determine if low D 2 receptor occupancy contributes to the pattern of compartmental activation, we examined the effects of administration of 0.1 mg/kg haloperidol, which results in < 50% in vivo occupancy of D 2 receptors (Schotte et al ., 1996). Finally, we examined the effects of another typical APD, chlorpromazine, which differs from haloperidol and racopride by displaying high affinities for several receptors in addition to the D 2 site (Peacock & Gerlach, 1996).…”

Section: Methodsmentioning

confidence: 99%

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Differential effects of typical and atypical antipsychotic drugs on striosome and matrix compartments of the striatum

Bubser

Deutch

2002

Eur J of Neuroscience

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Administration of typical antipsychotic drugs (APDs) is often accompanied by extrapyramidal side-effects (EPS). Treatment with atypical APDs has a lower incidence of motor side-effects and atypical APDs are superior to typical APDs in treating the negative symptoms of schizophrenia. Although typical APDs strongly induce the immediate-early gene c-fos in the striatum while atypical APDs do so only weakly, it is possible that the effects of atypical APDs are more pronounced within certain regions of the striatum. The striatum contains two histochemically defined compartments, the striosome (patch) and the matrix. These compartments have been well characterized anatomically but their functional attributes are unclear. We therefore examined the effects of typical and atypical APDs on Fos expression in the striosome and matrix of the rat. Typical and atypical APDs were distinguished by the pattern of striatal compartmental activation they induced: the striosome : matrix ratio of Fos-li neurons was greater in rats treated with atypical APDs. Pretreating animals with selective antagonists of receptors that atypical APDs target with high affinity did not increase the striosome : matrix Fos ratio of typical APD-treated rats and thus did not mimic the ratio seen in response to atypical APDs. However, pretreatment with the atypical APD clozapine did recapitulate the characteristic compartmental Fos pattern seen in response to typical APDs. These data suggest that some characteristics of atypical APDs, such as the lower EPS liability and greater reduction of negative symptoms, may be linked to the coordinate regulation of the striatal striosome and matrix.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Differential effects of typical and atypical antipsychotic drugs on striosome and matrix compartments of the striatum

Bubser

Deutch

2002

Eur J of Neuroscience

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“…The frequency of such antipsychotic-induced agranulocytosis is approximately 1% per annum, varying from one drug to another and being considered highest with clozapine (Atkin et al, 1996). As has been pointed out (Peacock and Gerlach, 1996), currently, there is no way of reliably identifying patients who are at risk of agranulocytosis. Previously, we have investigated several phenomena of potential relevance to the development of agranulocytosis.…”

Section: Introductionmentioning

confidence: 99%

Antipsychotic drugs result in the formation of immature neutrophil leucocytes in schizophrenic patients

Delieu

Badawoud²,

Williams

et al. 2001

J Psychopharmacol

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Subclinical abnormality of neutrophil populations of patients suffering from schizophrenia and medicated with antipsychotic drugs was evaluated using cellular immaturity as a criterion. Neutrophil maturity of patients and controls was compared by determining mean nuclear lobularity in peripheral blood smears. White blood cell and neutrophil counts were made. Subjects were patients medicated with chlorpromazine (n = 17) or clozapine (n = 48). Controls (n = 58) were healthy, non-medicated clinical and academic staff. Determination of mean lobe number involved assessment of 300 neutrophils per individual. For subject and control groups, means and medians of mean lobe numbers and mean white cell and neutrophil counts were determined. Means for each group were compared using the Mann-Whitney U-test; variances using F ratios. Means of lobe numbers of both patient populations were significantly different (p < 0.0001) compared to controls. Two-thirds of patients had mean lobe numbers outside the control range. Dose-response (mean lobe number) plots were significant for patients medicated with both chlorpromazine and clozapine. White cell and neutrophil counts in patients and controls did not differ significantly. For six patients, mean lobe numbers were obtained before and after medication commenced and all showed lowering of mean lobe number. The mean lobe number of the one patient who subsequently suffered from agranulocytosis was at the low end of the patient range. Thus, patients medicated with antipsychotic drugs typically have immature neutrophils, but normal white cell and neutrophil numbers. This effect is probably drug-induced. Mean lobe number may predict patients at risk from agranulocytosis.

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“…Despite the demonstrable effectiveness of dopamine D 2 receptor antagonists, however, a substantial number (up to 20%) of patients are considered unresponsive to these typical antipsychotics (Kane et al 1988). Furthermore, the typical antipsychotics have significant and serious side effects that make them less than optimal therapeutic agents (see Peacock and Gerlach 1996). For example, they cause acute drug-induced parkinsonian symptoms (Arana and Hyman 1991), they may worsen the negative symptoms associated with schizophrenia (Lader 1993), and they increase the risk of the disabling neurological condition known as tardive dyskinesia (Jeste and Caligiuri 1993).…”

mentioning

confidence: 99%

Interactions of the Novel Antipsychotic Aripiprazole (OPC-14597) with Dopamine and Serotonin Receptor Subtypes

Lawler

Prioleau

Lewis

et al. 1999

Neuropsychopharmacology

378

298

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cells; C-6 cells; SchizophreniaSchizophrenia is a chronic psychiatric illness with two major types of symptoms-positive or psychotic symptoms, such as hallucinations and delusions, and negative or deficit symptoms, such as amotivation, apathy, and asociality. Approximately 1% of the population suffers from schizophrenia (Kaplan and Sadock 1988). The serendipitous discovery of chlorpromazine four decades ago not only provided the first efficacious therapeutic intervention, but also opened horizons into research about the etiology and therapy of this disease. It was soon hypothesized that chlorpromazine and similar drugs worked by being pharmacological antagonists of the neurotransmitter dopamine (Seeman et al. 1976;Creese et al. 1976), a hypothesis that ultimately provided the foundation for the commonly accepted division of dopamine receptors into two classes (Garau et al. 1978), now often called D 1 and D 2 (Kebabian and Calne 1979).During the past decade, molecular cloning studies have resulted in the identification of several genes coding for dopamine receptors. There now are at least two From the Departments of Pharmacology (CP, RBM) and Psychiatry (CPL, RBM), and Medicinal Chemistry (RBM), Curricula in Toxicology (CPL, RBM), and Neurobiology (MML, RBM), UNC Neuroscience Center (CPL, CP, MML, RBM), University of North Carolina School of Medicine, Chapel Hill, North Carolina; and Molecular Neuropharmacology Section (CM, DJ, JAS, AMG, DRS), National Institutes of Neurological Disorders and Stroke, Bethesda, Maryland.Address correspondence to: Dr. Cindy Lawler, CB #7250; UNC Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7250. Received April 17, 1998; revised August 27, 1998; accepted September 21, 1998. (Zhou et al. 1990;Monsma et al. 1990;Sunahara et al. 1990;Dearry et al. 1990) and D 1B (Tiberi et al. 1991) or D 5 (Sunahara et al. 1991], both of these linked functionally to stimulation of cAMP synthesis, and preferentially recognizing 1-phenyl-tetrahydrobenzazepines (e.g., SCH23390). The D 2 -like receptors come from at least three genes and include multiple splice variants. The D 2 -like receptors [D 2S (Bunzow et al. 1988), D 2L (Giros et al. 1989;Monsma et al. 1989), D 3 (Sokoloff et al. 1990, and D 4 ] sometimes are linked to inhibition of cAMP synthesis and have a different pharmacological specificity from the D 1 -like receptors (i.e., having much higher affinity for spiperone or sulpiride).The traditional view of antipsychotic drug efficacy posits a primary role for pharmacological antagonism of D 2 -like receptors. Despite the demonstrable effectiveness of dopamine D 2 receptor antagonists, however, a substantial number (up to 20%) of patients are considered unresponsive to these typical antipsychotics (Kane et al. 1988). Furthermore, the typical antipsychotics have significant and serious side effects that make them less than optimal therapeutic agents (see Peacock and Gerlach 1996). For example, they cause acute drug-induced parkinsonian symptoms (...

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Antipsychotic-Induced Side Effects Related to Receptor Affinity

Cited by 5 publications

References 71 publications

Differential effects of typical and atypical antipsychotic drugs on striosome and matrix compartments of the striatum

Differential effects of typical and atypical antipsychotic drugs on striosome and matrix compartments of the striatum

Antipsychotic drugs result in the formation of immature neutrophil leucocytes in schizophrenic patients

Interactions of the Novel Antipsychotic Aripiprazole (OPC-14597) with Dopamine and Serotonin Receptor Subtypes

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