Two Cases of De Novo Pathological Gambling Associated With Aripiprazole
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Objectives Pathological gambling can be potentiated by treatment with dopamine agonists. Aripiprazole, bearing a partial agonist activity at dopamine D2 and D3 receptors, has also been linked to such a behavioral aberration, usually on subjects predisposed with tendency of impulsive or addictive behaviors. Methods Review of patient's medical records and literature review. Results Two young patients' pathological gambling emerged simply due to exposure to aripiprazole, neither related to manic or psychotic symptoms nor with history of addictive or impulsive behaviors. Their pathological gambling disappeared soon after switching aripiprazole to other antipsychotics. One patient has tested such a relationship by reexposure to aripiprazole while his compulsion to gamble recurred. Conclusions In addition to previously recognized risk factors, pathological gambling might occur in young patients whose history did not reveal an addictive tendency while they were sensitive to the pharmacological effect, as well as adverse effects, of psychotropic agents.Keywords:
Aripiprazole
Article AbstractBecause this piece does not have an abstract, we have provided for your benefit the first 3 sentences of the full text.Sir: Aripiprazole is a new atypical antipsychotic with a partial agonist activity at D2 and 5-HT1A receptors and with potent 5-HT2A receptor antagonism. Dose titration is considered necessary by some authors,1 but not by others.2,3 Recently, multiple cases of worsening of psychotic symptoms after add-on treatment with aripiprazole have been reported.4-8
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Hyperprolactinemia is an important but often a neglected side effect of antipsychotic treatment. Aripiprazole is one of the new atypical antipsychotics that has partial agonist effects on dopamine D2 receptors and has a low possibility of hyperprolactinemia. In the present case report, we discuss a female patient who was diagnosed as suffering from depression with psychotic symptoms. Her prolactin levels were elevated while on treatment with aripiprazole. Clinicians should consider that aripiprazole may result in moderate elevation of prolactin levels although it is reported that it has a lower risk of elevation of prolactin levels.
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Aripiprazole, due to its partial agonist activity at the D2 receptors, is often recommended as the drug of choice in patients who develop antipsychotic-induced hyperprolactinemia. We report a case of a female patient who developed hyperprolactinemia while on treatment with aripiprazole. This partial D2 agonistic activity of aripiprazole could be dose related, and hence, at higher doses, aripiprazole by itself can have dopamine antagonistic properties and hence cause prolactin system abnormalities.
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In this study, we determined the crystal structure of an engineered human adenosine A2A receptor bound to a partial agonist and compared it to structures cocrystallized with either a full agonist or an antagonist/inverse agonist. The interaction between the partial agonist, belonging to a class of dicyanopyridines, and amino acids in the ligand binding pocket inspired us to develop a small library of derivatives and assess their affinity in radioligand binding studies and potency and intrinsic activity in a functional, label-free, intact cell assay. It appeared that some of the derivatives retained the partial agonist profile, whereas other ligands turned into inverse agonists. We rationalized this remarkable behavior with additional computational docking studies.
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Abstract Concentration/dose addition is widely used for compounds that act by similar mechanisms. But it cannot make predictions for mixtures of full and partial agonists for effect levels above that of the least efficacious component. As partial agonists are common, we developed generalized concentration addition, which has been successfully applied to systems in which ligands compete for a single binding site. Here, we applied a pharmacodynamic model for a homodimer receptor system with 2 binding sites, the androgen receptor, that acts according to the classic homodimer activation model: Each cytoplasmic monomer protein binds ligand, undergoes a conformational change that relieves inhibition of dimerization, and binds to DNA response elements as a dimer. We generated individual dose-response data for full (dihydroxytestosterone, BMS564929) and partial (TFM-4AS-1) agonists and a competitive antagonist (MDV3100) using reporter data generated in the MDA-kb2 cell line. We used the Schild method to estimate the binding affinity of MDV3100. Data for individual compounds fit the homodimer pharmacodynamic model well. In the presence of a full agonist, the partial agonist had agonistic effects at low effect levels and antagonistic effects at high levels, as predicted by pharmacological theory. The generalized concentration addition model fits the empirical mixtures data—full/full agonist, full/partial agonist, and full agonist/antagonist—as well or better than relative potency factors or effect summation. The ability of generalized concentration addition to predict the activity of mixtures of different types of androgen receptor ligands is important as a number of environmental compounds act as partial androgen receptor agonists or antagonists.
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Binding studies were carried out on human fat cell membranes with the major radioligands available for alpha-2 adrenergic receptor identification: the antagonist [3H]yohimbine, the partial agonist [3H]clonidine ([3H]CLO) and the full agonist radioligand [3H]UK-14,304 ([3H]UK). Binding approaches performed with [3H]UK and [3H]CLO; two imidazoline derivatives exhibiting full and partial agonist properties, respectively, in biological assays clearly indicate that: 1) partial and full agonists label an equivalent number of binding sites corresponding to the high affinity form of the alpha-2 receptor; 2) there is some correlation between the KiH/KiL ratio defined in competition of [3H]yohimbine binding and the intrinsic activity defined in biological assays; 3) differences exist between the dissociation of the full-agonist ([3H]UK) and the partial-agonist ([3H]CLO); 4) the interaction of the full agonist with the alpha-2 receptor promotes the formation of an agonist-alpha-2 receptor-Gi protein complex (HRGi) complex which is more stable than that obtained with the partial agonist as objectivated by the sensitivity to the effects of guanosine 5'-(imido)triphosphate and N-ethylmaleimide; 5) the full-agonist is characterized by a "tight agonist binding" which is not observed with the partial agonist. From a functional point of view, the lower biological activity of the partial alpha-2 agonist could be explained by the formation of more labile HRGi complexes having weaker stability by comparison with the full agonist agents which promote stronger HRGi complexes and sustained activity.
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The operational model of agonism (Black & Leff, 1983) has been extended to describe the interaction between a partial agonist and a full agonist at the same receptor. The derived equation explicitly describes the interaction and allows the affinity (and efficacy) of the partial agonist to be estimated by direct fitting of raw experimental agonist concentration‐effect (E/[A]) curve data. The model was used to analyse experimental E/[A] curve data generated for the interaction between pilocarpine (partial agonist) and carbachol (full agonist) at the M 3 ‐muscarinic receptor mediating contraction of the guinea‐pig isolated trachea. Pilocarpine affinity estimates obtained by operational model‐fitting were compared with those obtained by use of the null method (Stephenson, 1956). These analyses demonstrated that the two methods gave comparable results (mean pK B estimates were 5.79 and 5.86 for the operational model and null method respectively). When multiple concentrations of partial agonist are used, simultaneous operational model‐fitting of all the E/[A] curve data allows the competitive nature of the interaction to be studied. We conclude that operational model‐fitting is a valid and analytically simple alternative to the conventional null method of analysing full/partial agonist interactions.
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Abstract Responses to partial agonist TCR signals include positive selection of thymocytes, survival of naive T cells, and homeostatic proliferation. As part of an effort to understand the molecular basis of these processes, we have determined how agonist and partial agonist ligands act differently to induce a change in gene expression. We have found that the early growth response gene 1 (Egr1) promoter is activated by agonist and partial agonist ligands, but the partial agonist induces 10-fold lower promoter activity. Both agonist and partial agonist ligands require all six serum response elements in the Egr1 promoter to reach maximum induction. Although slightly fewer cells respond to the partial agonist, all of the responding cells have reduced activity compared with the cells responding to agonist. The factors binding to the serum response elements of the Egr1 promoter form a ternary complex (TC) consisting of serum response factor and either Elk-1 or serum response factor accessory protein-1a. Formation of a stable TC and inducible promoter activity are both dependent on extracellular signal-related kinase activation. Examination of TC formation over time reveals that this complex is induced well by partial agonist ligands, but it is not sustained, whereas agonist stimulation induces longer lived TCs. Therefore, the data suggest that both agonist and partial agonist ligands can induce formation of multiple TC on the Egr1 promoter, but the ability of the agonist ligand to maintain these complexes for an extended time results in the increased potency of the agonist.
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Aripiprazole is a novel atypical antipsychotic drug chemically characterized as a quinolinone derivative [5]. Aripiprazole is a partial agonist at dopamine D2 and serotonin 5-HT1A-receptors and has antagonist activity at the 5-HT2A-receptor. It has a low-to-moderate affinity for the 5-HT2C-receptor and H1-receptor. Clinical studies have shown a clinically significant smaller weight gain for patients treated with aripiprazole than with other antipsychotics [1] [3]. Switching from other antipsychotics to aripiprazole has been reported to result in a slight reduction of body weight [2]. We present a case of significant weight loss in a patient switching from olanzapine to aripiprazole. To our knowledge, no similar case has been reported yet.
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