Shitij Kapur

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

..Our data suggest that the ventral striatum, a crucial element of the brain "reward" system, is directly activated in anticipation of aversive stimuli...

..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...

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

..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...

..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...

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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...

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..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...

..This study demonstrates that [11C]-(+)-PHNO can be used for the quantitative measurement of D2/3 densities and should enable further studies of potential D2/3 dysregulation in several important psychiatric and neurologic illnesses...

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

..The objective of this study was to examine whether this sensitivity is due to a central pharmacokinetic (i.e., higher occupancy for a given plasma level) or pharmacodynamic (i.e., greater functional effects for a given occupancy) effect...

..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...

..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...

..These data provide insight into the distinct effects of DA agents on the functional connectivity between striatal, limbic, and prefrontal areas...

..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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..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...

..It is possible that receptors with high affinity are not accessible by [(11)C]-(+)-PHNO because they are occupied by endogenous dopamine, a possibility that can be ruled out in future experiments...

..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...

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..The cortical midline structures (CMS) and subcortical regions, including the amygdala and striatum, are linked with self-reference in healthy adults. Less is known about the neural substrates of altered self-reference in schizophrenia...

..90 (S.D.=15.33), an effect that was sustained for 6 months. This sustained improvement was observed despite very high levels of DA D2 occupancy (82-99%), in contrast to the effects of antagonist antipsychotics on subjective well-being...

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..This suggests that as far as antipsychotics are concerned, not only dose but disbursment throughout the day have an impact on eventual pharmacodynamic and behavioral outcomes...

..Based on a better understanding of the brain kinetics of antipsychotics, we have proposed a variation of this approach, "extended" dosing, which allows for intermittent but regular dosing...

..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...

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

..Thus, [11C](+)-PHNO seems a suitable PET radiotracer to estimate D3 receptor occupancy in humans...

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..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...

..11)C]-(+)-PHNO offer new opportunities for exploring the potential therapeutic significance of the D(3) receptor in schizophrenia and the action of antipsychotics...

..This unforeseen finding suggests that their clinical effects cannot be attributed to D3 receptor blockade...

..Postmortem studies suggest decreased 5-HT(1A) receptors in patients with Alzheimer disease (AD), but this has not been confirmed in vivo. Our primary objective was to assess the extent of 5-HT(1A) receptor losses in mild to moderate AD...

..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...

..Employing a naturalistic design, we examined response rates over 3 circumscribed antipsychotic trials...

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..MAM treatment disrupted performance of the win-shift task but did not alter cocaine self-administration or cocaine-induced locomotion. Implications of these results for the MAM model of schizophrenia are discussed...

..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...

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..501, p = .017). These correlations were corroborated by a voxel-wise analysis. These results suggest that the serotonergic system may have a regulatory effect on the OFC and ACC for establishing and maintaining social relationships...

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..Comorbid major depression and tobacco dependence exacerbates this effect, suggesting an altered dopamine system in comorbid patients...

..The potential implications of this discrepancy are discussed...

..Therefore, single administration of an antipsychotic has no effect on CI or resting motor threshold. Whether chronic, repeated administration of antipsychotics has effects on CI requires further investigation...

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..It is concluded that chronic antipsychotic treatment disrupts active maternal behaviors and this disruption, most likely to lead to side effects in humans, should be avoided in future drug development...

..Given its location at the interface of limbic and motor regions, the ventral striatum may be critical in learning about motivationally salient stimuli, regardless of valence, and using that information to bias selection of actions...

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

..The present findings are in good agreement with the known gene expression data for D2 and D3 receptors in these human brain regions...

..Does this mean we need to (or should) administer antipsychotics at least daily? There is a body of evidence challenging this long-established clinical axiom...

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

..Our results suggest that actigraphy is useful as a sensitive, noninvasive tool for measuring the effect of antipsychotics on spontaneous motor activity...

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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...

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

..This effect may be intrinsic to antipsychotic activity or may be reflective of a side-effect. Since the latter is more likely, this may be an effect to avoid in the design of future antipsychotics...

..We sought to determine whether STN stimulation could release endogenous striatal dopamine...

..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...

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

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

..As the dust settles on this period and substantial data, as well as practical prescribing experience, are available, we examine what has been gained and what can be learned...

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

..These changes were not correlated with the D(2)RBP increments. The results of this study are overall consistent with previous findings by our group using the same methodology in a different cohort of six healthy subjects...

..The objective of this study was to evaluate the early response (within the first 24 h) in psychosis with ziprasidone IM treatment, and to determine whether this early effect is distinct from a reduction in agitation symptoms...

..These findings support the contention that D(2) occupancy levels induced by chronic HAL must be high and sustained through the day before significant risk of VCMs, and perhaps also TD, emerges...

..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...

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

..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...

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

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..It is suggested that the threshold level of cortical dopamine D(2) receptor occupancy for the suppression of CAR is demonstrated in the present study...

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

..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...

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..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...

..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...