S Kapur

..The implications of these findings for clinical care, animal models, future target discovery and drug development are discussed...

..e. positive, negative, cognitive, and affective) with more selective drugs that can be combined and individually titrated to the needs of each patient...

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..While these methods are often used interchangeably, there has been no systematic comparison of their sensitivities and consistency...

..The objective of this study was to determine the relationship between kon, koff and the affinity (Ki) of antipsychotic agents for the D2 receptors, with particular reference to typical and atypical antipsychotic agents...

..The study provides a rationale as well as clinically comparable dosing regimens for animal studies and raises questions about the inferences drawn from previous studies that have used doses unrepresentative of the clinical situation...

..1 = 6), olanzapine (0.30/0.43 = 0.7). These results indicate that dissociation between central and peripheral D2 receptor occupancy is a major determinant of the degree of prolactin elevation observed at therapeutic doses...

..This article provides a new hypothesis about the mechanism of action of atypical antipsychotics...

..g., positive, negative, cognitive, and affective) that can be flexibly used and titrated in the service of patients' presenting psychopathology...

..The objective of this overview is to link the neurobiology (brain), the phenomenological experience (mind), and pharmacological aspects of psychosis-in-schizophrenia into a unitary framework...

..These findings confound the inferences one can draw from the ketamine/PCP models of schizophrenia...

..The purpose of this study was to investigate olanzapine's binding to the serotonin 5-HT2 and dopamine D2 receptors in schizophrenic patients being treated with clinically relevant doses...

..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...

..The purpose of this study was to document loxapine's 5-HT2 and D2 receptor occupancy in vivo in patients with psychoses...

..This dose range is much lower than that used in most clinical settings and points to the potential efficacy of loxapine at lower doses...

..The following study was undertaken to explore these effects across the clinical dose range and relate this information to its clinical profile...

..Thus, in agreement with the previous ROI studies, voxel-by-voxel analysis confirmed the lack of substantial 5-HT(2A)R BP differences between schizophrenic patients and control subjects...

..The purpose of this study was to determine the dopamine D2 receptor occupancy induced by low-dose haloperidol treatment in a prospective trial...

..The justification, limitations and the value of this framework in understanding and investigating newer antipsychotics is discussed...

..Combined serotonin-2/dopamine-2 (5-HT2/D2) antagonism represents one such model, and we now have PET evidence available that can be extrapolated to our understanding and clinical use of both conventional and novel antipsychotics...

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..The objective of this study was to evaluate 5-HT2 receptors in depressed patients who were medication-free and who had not made recent suicide attempts...

..Our results question the current reliance on plasma kinetics as the main basis for dosing regimens of antipsychotics. Studies of brain kinetics may provide a sounder basis for determining dosing schedules of psychotropic medications...

..Hence, careful age matching may be recommended for future studies using PET and [11C]WAY-100635 to examine 5-HT1A receptors...

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..We exemplify how this dosing confounder could lead to inappropriate conclusions. Data from the bedside translated to the bench--using D2 occupancy as a mediating variable--will lead to more valid animal models...

..A similar deficit can be produced by dopamine (DA) and by 5-HT(2A/C) receptor agonists in rats. Antipsychotic compounds reverse this effect...

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..However, the quantitative relationship between striatal D2 occupancy and effects in these models is not known...

..A review of pharmacologic and behavioral data suggested that amoxapine should also conform to this profile; therefore, we undertook a positron-emission tomography (PET) study of its 5-HT2 and D2 occupancy...

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..Thus, while DA depletion "uncovers" D(2)receptors, it does not do so for D(1) receptors. The implications of this finding for measuring endogenous DA and its effects on in vivo receptor binding in humans are discussed...

..The implications of these findings for the next generation of combined 5-HT2/D2 antagonists are discussed...

..A growing interest in first-episode schizophrenia reflects the belief that this line of investigation will lead to further developments regarding schizophrenia's aetiology, course and outcome...

..The precise pharmacologic mechanisms underlying "atypicality" remain unclear, but several conceptual frameworks are highlighted that characterize, and perhaps differentiate, these newer agents...

..The objective of this study was to evaluate the effect of 6 weeks of paroxetine treatment on 5-HT(2A) receptors in depressed patients...

..It is concluded that amphetamine sensitization likely impacts behaviour by altering the functioning of mesolimbic dopamine systems and prefrontal cortical function and can serve as a model of certain domains of schizophrenia...

..These results support further investigation with intravenous d-fenfluramine to study the net functional effects of serotonergic stimulation in health and illness...

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..This seems to be particularly important in individuals experiencing a first episode of schizophrenia, as they appear to be especially responsive to pharmacotherapy and quite sensitive to adverse effects...

..The implications of this finding for understanding antipsychotic action as well as the continued use of these models in drug discovery is discussed...

..We hypothesized that deficits in gray matter volume would be present in patients presenting with a first episode of nonaffective psychosis...

..The results of the present study provide qualified support for the hypothesis that stuttering adults show atypical lateralization of language processes...

..Therefore, although we found some support for amoxapine having antipsychotic properties, this drug seems to carry a risk of worsening motor function in patients with PD...

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..These results substantiate the use of [11C]-(+)-PHNO as an agonist radiotracer for D2-imaging. The sensitivity of its binding to competition with endogenous DA suggests an association with the subset of high affinity state D2-receptors...

..Partial agonism of aripiprazole offers a good explanation for this dissociation and provides a framework for understanding occupancy-functional relationships of partial D2 agonist antipsychotics...

..The model's primary contribution is to link dopamine neuron firing, receptor manipulation, and behavior within a common formal framework that may offer insights into clinical observations...

..The results suggest that dopamine stabilizers exhibit locomotor stabilizing as well as antipsychotic-like effects, with low motor side effect liability, in a dose range that corresponds to high D2 in vivo occupancy...

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..The present study used positron emission tomography (PET) to evaluate its dopamine D(2) binding profile at doses of 25, 50, or 75 mg administered every 2 weeks...

..We undertook this study to determine whether response to the atypical antipsychotic olanzapine occurs at lower levels of D2 receptor occupancy...

..2-3.5-fold increase of DA D2(High) receptors may explain why amphetamine-sensitized animals are much more sensitive to DA agonists, even though the total density of D2 receptors may apparently be unchanged or even decreased...

..The objective of this positron emission tomography (PET) study was to examine the striatal dopamine D(2) binding of long-acting risperidone administered intramuscularly once a month...

..An extended-release (XR) formulation of quetiapine is currently being developed to achieve similar efficacy using a once-daily dosing regimen. We compared the central D(2) receptor binding between the IR and XR formulations...

..Based on prior data, we predicted that variations in the within-day kinetics of antipsychotic drug delivery would produce different outcomes, even if we held achieved dose, route, and total duration of treatment constant...

..The findings suggest that JTC might moderate the effects of treatment on symptomatology, but it does not mediate the treatment induced reduction in delusional intensity...

..The authors conducted a positron emission tomography (PET) study to characterize the simultaneous effects of aripiprazole at the D(2), 5-HT(2), and 5-HT(1A) receptors in patients with schizophrenia or schizoaffective disorder...

..This differential binding of agonist vs. antagonist radioligand, especially in the critically important region of the limbic striatum/pallidum, offers new avenues to investigate the role of the dopamine system in health and disease...

..However, supplemental oral olanzapine or another dosing strategy may be necessary to maintain adequate therapeutic response during the first few injection cycles...

..The authors present the first double-blind controlled study to examine the relationship between striatal and extrastriatal dopamine D(2) receptor binding potential and occupancy values and adverse subjective experience...

..These findings provide a model and a mechanism for antipsychotic treatment failure and suggest new directions for the development of more effective antipsychotics...

..The article discusses the caveats, limitations as well as the clinical implications of the salience framework...

..Recent research has shown that antipsychotic action begins within the first week. The authors tested the hypothesis that psychosis improves within the first 24 hours of antipsychotic treatment...

..Future studies aimed at evaluating the relative merits of "transiently high" versus "continuously high" D(2) occupancy are warranted...

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..A dose-response relationship between dopamine D(2) occupancy and acute extrapyramidal symptoms (EPS) has been well established. However, the link with the induction of tardive dyskinesia (TD) is less clear...

..Our results suggest that 6-[18F]-L-m-tyrosine PET may not be a useful tool in the study of the effect of antipsychotics on dopamine synthesis in human subjects...

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..Early intervention, instituted once the prodromal state was already developed, prevented further progression into the full phenotype analogous to schizophrenia...

..The purpose of this study was to systematically compare the two drugs in in vitro and in vivo animal models, and to understand mechanisms underlying their differential typical/atypical profiles...

..The implications for the design of future antipsychotics is discussed...

..Atypical antipsychotics are thought not to elevate prolactin levels. The authors examined data suggesting that atypical antipsychotics do elevate prolactin levels but more transiently than typical antipsychotics...

..Furthermore, even at maximum occupancy, 70% is not exceeded. Several mechanisms have been proposed as explanations for this low D(2) receptor occupancy, but clear evidence is limited...

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..The aberrant activations and response are consistent with the idea that patients aberrantly assign motivational salience to neutral stimuli, and this process may be one of the aberrations that predisposes them to psychosis...

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..To examine if this leads to an atypical antipsychotic effect in the clinical context, the authors examined the antipsychotic and side-effect profile of amoxapine in acutely psychotic patients with schizophrenia...

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..However, it did not prove to have fewer extrapyramidal side effects than haloperidol, possibly because the baseline scores were very low...

..Since amoxapine is off-patent, it may be a valuable low-cost alternative to new atypical antipsychotics, particularly in low-income countries where the majority of the patients are still treated with typical antipsychotics...

..11)C]-(+)-PHNO PET might be a superior measure for release of endogenous dopamine than PET employing conventional D(2/3) antagonist radioligands...

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..These results further add to a growing literature showing that activating D(1) receptors in the mPFC improves aspects of cognition...

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..The model distinguishes itself from existing accounts by offering novel predictions pertaining to the firing of dopamine neurons in various untested behavioral scenarios...

..The implications of this framework for relapse and other clinical phenomena, animal models and future studies are discussed...

..CONCLUSIONS: Therapeutic doses of clozapine, olanzapine, and, to a lesser extent, quetiapine are associated with clinically relevant AA...

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..These results support the notion that MAM treatment may simulate some aspects of schizophrenic cognition...

..The reversal of these deficits by a D1 receptor agonist provides further evidence that prefrontal D1 dopamine receptors are involved in cognition, and may be a potential target for treatment of impaired cognition in schizophrenia...

..However, it remains unclear whether TOM deficits constitute a trait- or a state-related deficit and whether they respond to antipsychotic treatment, and also whether the change in TOM and change in psychosis are associated...

..The APD action in this model is most consistent with an effect on 'expected future reward'--an idea closely linked to motivational drives and consistent with several leading theories of dopamine action...