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D2 and 5HT2A receptor occupancy of different doses of quetiapine in schizophrenia: A PET study

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Abstract

Quetiapine is a novel antipsychotic agent with many atypical features, including low D(2) and higher 5HT(2A) affinity in vitro, low propensity to induce extra-pyramidal side effects and minimal effects on prolactin levels. The purpose of this study was to investigate, using positron emission tomography (PET), the relationship between plasma concentrations of different doses of quetiapine and occupancy of D(2) and 5HT(2A) receptors in schizophrenic patients. Five patients were treated with quetiapine (titrated to 750 or 450 mg/day) for 28 days, subsequently reduced weekly in a descending-dose schedule. Dopamine D(2) and 5HT(2A) occupancies were determined using [(11)C] raclopride and [(11)C] N-methylspiperone as ligands, respectively, and PET imaging. Mean D(2) receptor occupancies of 41 and 30% were observed at quetiapine doses of 750 and 450 mg/day. At lower dose levels no occupancy could be determined. Quetiapine induced a consistently higher degree of 5HT(2A) receptor occupancy, with mean occupancies of 74 and 57% at doses of 750 and 450 mg/day, respectively. No EPS emerged during the trial and most of the pre-trial EPS resolved during the study. In clinically effective doses, quetiapine induced low occupancy at D(2) receptors, which is consistent with atypical antipsychotics such as clozapine, and probably explains the lack of EPS observed in this trial. Correlations between receptor occupancy and plasma concentrations of quetiapine could not be calculated, although receptor occupancy increased with higher plasma concentrations for the 450 and 750 mg doses.

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... Given the few data concerning the relationship between clinical responses and plasma QTP concentrations, some clues can be extrapolated from PET studies of receptor blockades. A number of studies have investigated the relationship between the time course of central nervous system dopamine and serotonin receptor blockade and plasma drug concentrations after the discontinuation of QTP treatment, and shown that the disappearance of QTP from plasma is much more rapid than the decrease in serotonin receptor occupancy [136,143,145]. A better, but not perfect, correspondence was observed between D 2 receptor dissociation and plasma QTP half-life. ...
... A better, but not perfect, correspondence was observed between D 2 receptor dissociation and plasma QTP half-life. These data indicate a discrepancy between the time course of receptor occupancy and plasma QTP concentrations [145]. ...
... Kapur et al. [136] found a clear curvilinear relationship between 5-HT 2A receptor occupancy and plasma QTP concentrations, but only a weak relationship between plasma QTP concentrations and D 2 receptor occupancy. In an albeit very small patient sample (n = 5), Gevfert et al. [145] found an apparently clear correlation between plasma QTP concentrations and D 2 receptor occupancy in a study that used the Positive and Negative Syndrome Scale, CGI and SAS to assess clinical outcomes. The results showed that the data at QTP doses of \ 300 and [ 450 mg/day were collected from individuals who differed clinically, in that the former were uncontrolled and the latter were controlled on QTP treatment [145]. ...
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Therapeutic drug monitoring studies have generally concentrated on controlling compliance and avoiding side effects by maintaining long-term exposure to minimally effective blood concentrations. The rationale for using therapeutic drug monitoring in relation to second-generation antipsychotics is still being discussed at least with regard to the real clinical utility, but there is evidence that it can improve efficacy, especially when patients do not respond or develop side effects using therapeutic doses. Furthermore, drug plasma concentration determinations can be of some utility in medico-legal problems. This review concentrates on the clinical pharmacokinetic data related to clozapine, risperidone, paliperidone, olanzapine, quetiapine, amisulpride, ziprasidone, aripiprazole, sertindole, asenapine, iloperidone, lurasidone, brexpiprazole and cariprazine and briefly considers the main aspects of their pharmacodynamics. Optimal plasma concentration ranges are proposed for clozapine, risperidone, paliperidone and olanzapine because the studies of quetiapine, amisulpride, asenapine, iloperidone and lurasidone provide only limited information and there is no direct evidence concerning ziprasidone, aripiprazole, sertindole, brexpiprazole and cariprazine: the few reported investigations need to be confirmed and extended.
... Since 11 C-NMSP is not competitive with endogenous dopamine [9,10] and serotonin [11], its binding can directly reflect postsyntapic monoamine receptor level more accurately compared with 11 C-raclopride. Moreover, 11 C-NMSP binds predominantly to D 2 receptors in the striatum and to 5-HT 2A receptors in the cortex, which could also be used to map the 5-HT 2A and D 2 receptors simultaneously in the same individual [12,13]. In our previous study, we have investigated monoamine receptor changes induced by frightening music using 11 C-NMSP PET, and found that significantly decreased 11 C-NMSP binding in the limbic and paralimbic regions, but increased in the cerebral cortex, compared with the baseline condition [14]. ...
... Particularly, increased 11 C-NMSP binding in the superior temporal cortex may reflect increased activity of 5-HT 2A receptors. This result is consistent with the previous studies, in which, 5-HT 2A receptor density is significant higher than that of D 2 receptor in cerebral cortices [12,13]. ...
Article
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Purpose: Music can induce different emotions. However, its neural mechanism remains unknown. The aim of this study was to use functional magnetic resonance imaging (fMRI) and position emission tomography (PET) imaging for mapping of neural changes under the most popular music in healthy volunteers. Methods: Blood-oxygen-level-dependent (BOLD) fMRI and monoamine receptor PET imaging with (11)C-N-methylspiperone ((11)C-NMSP) were conducted under the popular music Gangnam Style and light music A Comme Amour in healthy subjects. PET and fMRI images were analyzed by using the Statistical Parametric Mapping software (SPM). Results: Significantly increased fMRI BOLD signals were found in the bilateral superior temporal cortices, left cerebellum, left putamen and right thalamus cortex. Monoamine receptor availability was increased significantly in the left superior temporal gyrus and left putamen, but decreased in the bilateral superior occipital cortices under the Gangnam Style compared with the light music condition. Significant positive correlation was found between (11)C-NMSP binding and fMRI BOLD signals in the left temporal cortex. Furthermore, increased (11)C-NMSP binding in the left putamen was positively correlated with the mood arousal level score under the Gangnam Style condition. Conclusion: Popular music Gangnam Style can arouse pleasure experience and strong emotional response. The left putamen is positively correlated with the mood arousal level score under the Gangnam Style condition. Our results revealed characteristic patterns of brain activity associated with Gangnam Style, and may also provide more general insights into the music-induced emotional processing.
... Given the few data concerning the relationship between clinical responses and plasma QTP levels, some clues can be extrapolated from PET studies of receptor blockades. A number of studies have investigated the relationship between the timecourse of CNS dopamine and serotonin receptor blockade and plasma drug concentrations after the discontinuation of QTP treatment, and shown that the disappearance of QTP from plasma is much more rapid than the decrease in serotonin receptor occupancy (Gefvert et al., 1998;Kapur et al., 2000;Gefvert et al., 2001). A better, but not perfect, correspondence was observed between D 2 receptor dissociation and plasma QTP halflife. ...
... A better, but not perfect, correspondence was observed between D 2 receptor dissociation and plasma QTP halflife. These data indicate a discrepancy between the time-course of receptor occupancy and plasma QTP concentrations (Gefvert et al., 2001). Kapur et al. (2000) found a clear curvilinear relationship between 5-HT 2A receptor occupancy and plasma QTP levels, but only a weak relationship between plasma QTP levels and D 2 receptor occupancy. ...
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This review will concentrate on the clinical pharmacology, in particular pharmacodynamic data, related to atypical antipsychotics, clozapine, risperidone, paliperidone, olanzapine, quetiapine, amisulpride, ziprasidone, aripiprazole, asenapine, iloperidone, lurasidone and cariprazine. A summary of their acute pharmacokinetics properties are also reported. Four new second-generation antipsychotics are available: iloperidone, asenapine, lurasidone and in the next future cariprazine. Similar to ziprasidone and aripiprazole, these new agents are advisable for the lower propensity to give weight gain and metabolic abnormalities in comparison with older second-generation antipsychotics such as olanzapine or clozapine. Actually lurasidone seems to be best in terms of minimizing unwanted alterations in body weight and metabolic variables. Therapeutic drug monitoring is not strictly necessary for all of the new antipsychotic drugs because there are no unequivocal data supporting a relationship between plasma drug levels and clinical outcomes or side effects. The exception can be represented by clozapine for which plasma levels of 350-420 ng/ml are reported to be associated with an increased probability of a good clinical response. Also for olanzapine an established therapeutic range (20-50 ng/ml) is proposed to yield an optimal response and minimize side effects.
... 7 The dosedependent beneficiary effects of quetiapine observed in our patient, with the use of 600 mg/d and partial decline with use of 300 mg/d, may be in accordance with the fact that higher 5HT2a receptor occupancy is achieved with higher doses (57% vs 74% occupancy for doses of 450 and 750 mg/d, respectively). 8 A previous report concerning a choreaacanthocytosis case has proposed that selfmutilation symptoms are a form of motor compulsion and can be viewed as obsessivecompulsive-type behavioral disorder. 2 Some researchers have discussed that the use of serotonin reuptake inhibitors may provide beneficial results in patients with chorea-acanthocytosis, although in some reports, the use of a serotonin reuptake inhibitor did not provide a favorable outcome. ...
... [3][4][5] Dyskinetic reactions were also related to metylphenidate in the literature. [6][7][8][9][10][11][12][13][14] Dyskinesia emerged after discontinuation of risperidone and initiation of methylphenidate in a case report. 6 Dyskinesia exacerbated by ongoing stimulant treatment emerged after neuroleptic withdrawal in another case report. ...
... These results need to be confirmed in follow-up clinical trials with a longer antidepressant pretreatment time with the aim of elucidating the interactive effects on therapeutic outcomes and whether antidepressant treatment should be maintained or stopped before psilocybin administration. A similar concern applies to patients who are already on 5-HT2AR-blocking antipsychotic drugs such as quetiapine and olanzapine [51][52][53]. ...
Article
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Psilocybin has been suggested as a promising transdiagnostic treatment strategy for a wide range of psychiatric disorders. Recent findings showed that psychedelic-assisted/"psycholitic" psychotherapy should provide significant and sustained alleviation of depressive symptoms. However , to date, there have been several study limitations (e.g., small sample sizes, blinding, limited follow-up, highly screened treatment populations) and some health/political issues, including prac-titioners' experience, lack of standardized protocols, psychedelics' legal status, ethical concerns, and potential psychological/psychopathological/medical untoward effects. The focus here is on a range of clinical and methodological issues, also aiming at outlining some possible suggestions. We are confident that newer evidence, more precise protocols, and eventual reclassification policies may allow a better understanding of the real potential of psilocybin as a transdiagnostic therapeutic molecule .
... There is also evidence from animal models of low potential for extrapyramidal side effects (Cheer and Wagstaff, 2004). At low doses (up to 300mg/day), it shows a consistently higher degree of occupancy of 5-HT2A receptors than D2 receptors; the degree of occupancy of both receptors is dose-dependent (Gefvert et al., 2001b). The 5-HT2 antagonistic action of quetiapine may disinhibit the dopaminergic system and enhance dopaminergic activity at the level of forebrain and influences the mood state (Lykouras et al., 2003). ...
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We report a case of 26 years old gentleman diagnosed with bipolar affective disorder who developed mania after one week of initiation of quetiapine at 200mg/d. Induction of mania in our patient is keeping with the literature regarding induction or worsening of hypomanic or manic symptoms at a lower dose of quetiapine. Hypomanic or manic symptoms at a low dose of quetiapine are brief and seem to reverse the effect by either discontinuing the causing agent or increasing it dose. Quetiapine being an atypical antipsychotic possess antidepressant property at low doses as well as mood stabilizer at higher doses. At lower dose, due to its serotonergic antagonism property, quetiapine appears to induce or worsen hypomanic or manic symptoms. As the dosage increases its dopamine antagonistic activity become more prominent and the medication acts as a mood stabilizer. This is one of the possible explanations of disappearing of manic or hypomanic symptoms at a higher dose.
... In the treatment of schizophrenia, the antagonism of QTP to the D2 receptor in the mesolimbic pathway contributes to the weakening of productive symptoms [16,17]. At low concentrations, QTP predominantly blocks histamine receptors and α1-adrenoreceptors, providing a nonspecific sedative effect; with an increase in dosage, on the contrary, it activates the adrenergic system and strongly binds to serotonin receptors and their synaptic autoreceptors [18]. QTP is a lipophilic tetracyclic compound that is poorly soluble in water. ...
Article
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(1) Introduction: Quetiapine (QTP) is a dibenzothiazepine derivative, a second generation antipsychotic (AP), which is structurally similar to clozapine. The main indications for use are schizophrenia and depressive disorder. Under manic episodes in bipolar disorder can be used alone or in combination with lithium. The frequency of prescribing QTP is on average 11,987 per 100,000 population, with a positive trend in dynamics: a growth rate of more than 800% within the period 2002 to 2017. (2) Purpose: The review of studies of pharmacogenetic pharmacokinetic and pharmacogenetic pharmacodynamic markers of QTP efficacy and safety. (3) Materials and Methods: A search was carried out for publications of the Science Index, PubMed, Web of Science, Springer databases by keywords and their combinations over the last 10 years. In addition, the review includes earlier publications of historical interest. Despite extensive searches of these commonly used databases and search terms, it cannot be ruled out that some publications may have been missed. (4) Results: The review considers the following pharmacokinetic markers of QTP efficacy and safety: genes are coding isoforms of cytochrome P450 ( CYP2D6, CYP2C19, CYP3A4, CYP3A5 ), P-glycoprotein ( ABCB1 ); pharmacogenetic pharmacodynamic markers of the efficacy and safety of QTP : genes of dopamine receptor isoform ( DRD3 ), dopamine transporter ( SCL1A1 ) and catecholO-methyltransferase ( COMT ), serotonin receptor isoforms ( HTR2C ), melanocortin receptor ( MC4R ), NOTCH protein ( NOTCH4 ), phosphodiesterase 4D ( PDE4D ), SPoPL protein ( SPoPL ), multiple EGFlike domain ( MEGF10 ), protocadherin-7 ( PCDH7 ), contactin-associated protein 5 ( CNTNAP5 ) , TRAF2 and NCK-interacting protein kinase ( TNIK ), spermatogenesis-associated protein 6 ( SPATA6L ), neurobihin ( NBEA ), synaptic vesicle protein-2C ( SVC2 ) . (5) Conclusion: Disclosure of pharmacogenetic markers of pharmacokinetics and pharmacodynamics of QTP efficacy and safety in the treatment of patients with schizophrenia and other psychiatric disorders, may provide a key to developing a strategy for its personalized prevention of adverse grug reactions (ADRs) and therapy strategy in real clinical practice.
... 7,8 Atypical antipsychotics as a class have increased affinities for 5-HT2AR and produce relatively high occupancies at clinical doses. [9][10][11] Antidepressant benefit among antipsychotics has been hypothesized to arise from serotonin 5-HT7 receptor (5HT7R) antagonism, 12 as it is present among several antipsychotics used successfully in the treatment of bipolar disorder. [12][13][14] Compounds with selective 5-HT7R antagonist activity have been shown to reduce rapid eye movement (REM) sleep and/or increase latency to onset of REM sleep; and to have antidepressant-like effects in mouse models. ...
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In contrast to the dose-occupancy relationship in the treatment of schizophrenia, the minimal effective level of dopamine receptor 2 (D2R) blockade for antipsychotics in the treatment of bipolar depression is unknown. Lower doses aimed at relieving extrapyramidal side effects are balanced against retaining D2R benefit on emergent cycling, mixed, manic, anxiety and/or psychotic symptoms. Dose-reductions intended to lower D2R blockade however could also decrease concomitant serotonin receptor antagonism and its potential benefit on depressive symptoms. Here we uncoupled the potential antidepressant activity in amisulpride, driven by 5-HT7 receptor (5-HT7R) antagonism, from the D2R-mediated antipsychotic activity by discovering that each enantiomer favors a different receptor. Aramisulpride was more-potent at 5-HT7R relative to esamisulpride (Ki 47 vs 1,900 nM, respectively), while esamisulpride was more potent at D2R (4.0 vs 140 nM). We hypothesized that a non-racemic ratio might achieve greater 5-HT7R-mediated antidepressant effects at a lower level of D2R blockade. The dose-occupancy relationship of esamisulpride at D2R was determined by PET imaging in human volunteers. Separately the dose-relationship of aramisulpride was established in humans using suppression of rapid eye movement (REM) sleep as a marker of 5-HT7R antagonism. These results led to the discovery of an 85:15 ratio of aramisulpride to esamisulpride (SEP-4199) that maximizes the potential for antidepressant benefit of aramisulpride via 5-HT7R and reduces esamisulpride to minimize D2R-related extrapyramidal side effects while still retaining D2R-mediated effects predicted to provide benefit in bipolar depression. SEP-4199 was recently evaluated in a proof of concept trial for the treatment of bipolar depression (NCT03543410).
... In the medium dose range, it binds to the adrenergic and serotonin receptors. At the higher dose ranges, the drug provides dopamine blocking action, making it useful in psychotic disorders [17]. Page: 13 www.raftpubs.com ...
Article
The COVID-19 pandemic has led to a multitude of new medical and psychiatric complications and new presentations that were either never seen before or not seen to the extent that they are presenting now. [1,2]. Increased number of suicide attempts and worsening severity of suicide attempts have been noted in the past year since the COVID-19 pandemic has started [1]. Psychotropic medications can often have lesser-known side effects and movement disorders, including tics, can be one of them [3]. Tics are recurrent, simple or complex behaviors that can be motor or phonic in nature [4,5]. Simple motor tics are often observed as rapid movements while complex motor tics are more synchronized and elaborate. Additionally, noises or brief sounds are examples of simple vocal tics, while speaking a string of words or syllables are more characteristic of a complex vocal tic [4]. The underlying pathogenesis of tics and tic disorders has not been well elucidated, dopaminergic hypothesis being the most widely accepted; however, multiple areas of the brain are speculated to be involved [4,6]. Common treatment options for tic disorders include alpha-2 agonists, clonidine and guanfacine, and antipsychotics [4,7]. Previous literature identifies two case reports that documented tics related to quetiapine. One report described a pediatric bipolar patient who developed tics proportional to quetiapine dose [8], and the other report identified an adult patient with schizophrenia who developed tics during quetiapine therapy [9]. In this article, we describe a pediatric patient who presented after overdosing on quetiapine, lamotrigine and sertraline and developed tics after re-initiation of quetiapine at a much lower dose. To the best of our knowledge, this is the first case of its kind where tics, which were previously absent, developed on re-initiation of quetiapine after an overdose.
... However, as 150 mg quetiapine is probably insufficient to occupy dopamine D2 receptors (Gefvert et al., 2001) and as quetiapine has multiple actions ( (Hamidovic et al., 2008) or the dopamine reuptake inhibitor bupropion (150 or 300 mg) (Acheson & de Wit, 2008), did not affect either delay discounting or risk-seeking for gains. These results are comparable to other findings: haloperidol (1.5 mg) did not affect delay discounting (Pine et al., 2010), and L-DOPA had no influence on risk-seeking for gains (100 mg) (Symmonds et al., 2013), risk-seeking for losses or loss aversion as assessed with a mixed gambles task (150 mg) (Rutledge et al., 2015). ...
Thesis
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Background: The valuation of risks and the speed with which decisions are made and acted upon are important characteristics of everyone’s personality. These characteristics exist along a continuum that ranges from weak to strong expressions of impulsivity. In certain situations it is crucial to decide and react quickly. Yet these qualities can prove disadvantageous if they are expressed excessively and persistently. Self-reports, such as the Barratt Impulsiveness Scale, inquire long-term patterns of behavior to assess the level of trait impulsivity. Experimental paradigms, on the other hand, quantify specific impulsive facets, which depend rather on the current environment and state of the individual. These paradigms include decision-making tasks that capture impulsive facets such as the attitudes towards delays, risks and losses. Research indicates that these attitudes are governed by a valuation network of cortical and subcortical brain regions along with several neurotransmitters. Within this intricate network, frontostriatal circuits innervated by dopamine were identified as an important locus of control. Although a wealth of studies have subsequently examined the influence of the dopaminergic system on impulsive choice, the regulatory mechanisms remain largely unclear. This may originate from the interrelations within the valuation network but also from the complexity of the dopaminergic system itself. Seminal investigations have shown that this complicated interplay may be partly explained by an underlying inverted U-shaped function, which describes an optimal level of dopamine, flanked by increasing impulsivity in the context of sub- and supraoptimal signaling. Research Question: This work aimed to shed more light on the inverted-U theory by characterizing the contribution of dopaminergic signaling to trait and decisional impulsivity, and by clarifying whether the manipulation of decisional impulsivity through boosting striatal dopamine via L-DOPA depends on baseline signaling. We hypothesized that individuals with optimal striatal dopaminergic signaling as measured by [18F]DOPA positron emission tomography would feature low trait impulsivity as assessed with the Barratt Impulsiveness Scale. By contrast, individuals with suboptimal signaling were hypothesized to exhibit stronger trait impulsivity corresponding to higher scores on the Barratt Impulsiveness Scale. Assuming an inverted U-shaped function, we predicted that the dopamine precursor L-DOPA would 48 reduce impulsive decisions in the latter but overdose individuals with an already optimal signaling and thus make their choice behavior more impulsive. Materials and Methods: The present studies combined trait and choice measures of impulsivity with the investigation of the dopaminergic system by positron emission tomography and a pharmacological manipulation. In a double-blind, randomized, placebo-controlled, counter-balanced, repeated measures design, 87 healthy adults completed a computerized decision-making test battery. The battery includes four tasks, each of which captures one distinct dimension of impulsive choice: a delay discounting task quantifies delay discounting, a probability discounting for gains task quantifies risk-seeking for gains, a probability discounting for losses task quantifies risk-seeking for losses and a mixed gambles task quantifies loss aversion. In order to test for baseline-dependent L-DOPA effects on these dimensions, we controlled for trait impulsivity (a suggested proxy for central dopamine) as assessed with the Barratt Impulsiveness Scale (N = 87) and striatal dopamine as measured by [18F]DOPA positron emission tomography (in 60 of the 87 participants). Results: Our findings highlight the complex role of dopamine in impulsivity and the heterogeneity of its underlying biology. Participants who scored relatively high on the Barratt Impulsiveness Scale appeared to benefit from L-DOPA, indicated by a decrease in delay discounting, risk-seeking for gains and loss aversion. Participants with low levels of impulsive personality traits as assessed with the Barratt Impulsiveness Scale, on the other hand, exhibited opposite changes in choice preference. Bearing in mind that trait impulsivity may be a behavioral expression of central dopamine, our results suggest an inverted U-shaped function in which impulsive decision-making arises from both sub- and supraoptimal dopaminergic activity. We found further support for an inverted U-shaped function when accounting for baseline dopamine as measured by [18F]DOPA positron emission tomography. Participants who had higher values on the Barratt Impulsiveness Scale featured low, presumably suboptimal, striatal dopamine signaling. After enhancing and possibly optimizing the basal signaling with L-DOPA, they discounted delays less and tended to less risk-seeking for gains and loss aversion. By contrast, participants with low trait impulsivity as assessed with the Barratt Impulsiveness Scale exhibited higher striatal dopamine, 49 probably corresponding to optimal baseline activity as L-DOPA shifted their choice behavior in the opposite direction, thus indicating a dopamine overdose. The intake of L-DOPA had no influence on risk-seeking for losses, even when differences in trait impulsivity and basal levels of striatal dopamine were considered. Performance on tasks of the decision-making battery produced only few, weak intercorrelations, which implies that delay discounting, risk-seeking for gains, risk-seeking for losses and loss aversion represent dissociable aspects of choice. Conclusions: Our results endorse and extend previous findings that indicated an inverted U-shaped influence of dopamine on delay discounting and decisions under risk. Utilizing a battery of largely independent choice tasks, we were able to disentangle the effect of gains and losses on risky decisions. Whereas risk-seeking for gains seemed to depend on baseline dopamine signaling, we found no evidence for dopaminergic neurotransmission affecting risk-seeking for losses. Consistent with the literature, our data shows that self-reported trait impulsivity and experimentally measured decision-making dimensions are distinct phenomena within the multidimensional construct of impulsivity. Our analyses further revealed that choice measures were differentially related to dopaminergic activity, which suggests that they represent not merely descriptive distinctions but separable psychobiological decision-making processes. Since the regulation of choice probably spreads across neurotransmitter systems, more research on these systems is warranted. After identifying the precise mechanisms within each system, comprehensive studies of their interplay may ultimately uncover how impulsive decisions arise. Considering a series of studies that related steep delay discounting and excessive risk-seeking to poor health and mental illness, the acquired knowledge may also inform translational research on impulsivity-related maladies.
... The higher affinity of quetiapine for 5-HT 2 than D 2 receptors, and rapid dissociation from D 2 receptors, is thought to account for its low propensity to cause extra pyramidal symptoms or elevation of prolactin levels [74,79,80]. ...
... 13 Second generation antipsychotic quetiapine also has the same affinity for 5HT-2A receptors at lower dosages (below 300 mg low dose, bipolar maintenance 600-900 mg). 15,16 This drug is one of the three antipsychotics FDA approved for bipolar depression specifically, which includes two others, lurasidone and olanzapine/fluoxetine. ...
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A 22-year-old newly diagnosed patient with bipolar is discussing with her doctor the safety of starting an atypical antipsychotic as part of her treatment plan for depression. The patient was recently diagnosed with bipolar disorder after years of ups and downs making school and her relationship especially difficult. After seeking out a university student health psychiatrist for a severe depressive episode she was prescribed an antidepressant, which within a few weeks triggered a manic episode that required hospitalization. Since that time she has been compliant with her medications but has fallen into another depressive episode. Her psychiatrist encourages her to begin taking the atypical antipsychotic quetiapine because it may help with her current mood. Given her experience with antidepressants she is apprehensive. She asks, is it possible that a medication like quetiapine could trigger another manic episode?
... Since the positive effect of MPH on ADHD sym6ptoms is linked to its ability to increase dopamine efflux in the striatum (Volkow, Wang, Tomasi, et al., 2012), it may be assumed that the administration of D 2 -blocking antipsychotics could have altered challenge results in our study; however, this is unlikely, since the few patients who were on antipsychotics were receiving either aripiprazole, which is a partial dopamine agonist (Aihara et al., 2004), or quetiapine, which is a weak D 2 -dopamin receptor antagonist (Gefvert et al., 2011). ...
Article
Objective Adult and children attention deficit/hyperactivity disorder (ADHD) share similar symptoms and responses to drugs such as methylphenidate (MPH). Yet, in Europe, these drugs remain unlicensed for adults. We aimed to assess the effects of an acute MPH challenge on the four dimensions concentration, impulsivity, tension, and general well‐being in ADHD adults, and identify predictors of improvement. Methods Therapeutic Drug Monitoring was performed to measure MPH plasma levels. A Visual Analogue Scale was administered to patients before and after the acute MPH challenge to measure self‐reported changes in the four dimensions. Results After the acute MPH challenge, our 71 patients showed significant improvement in concentration and tension. The MPH challenge dose correlated with lower patients' age, greater side effects, increased concentration (p = .008) and decreased tension (p = .001). At multiple linear regression MPH plasma levels and absence of postdose side effects predicted concentration improvement, MPH plasma levels predicted tension improvement. MPH plasma levels were significantly higher in patients who reported an improvement in concentration, tension, and impulsivity compared to nonimprovers (p ’s from .001 to .004). Conclusions These findings point to the efficacy of MPH challenge in improving concentration and tension in adult ADHD, thus emphasizing the need for a broader treatment access for these patients.
... Taken together, these data indicate that dopamine dysregulation may boost a sense of embodiment. As noted, although the role of dopamine in OCD is admittedly complex (Fineberg et al., 2007), research has shown that dopamine antagonists can be useful in reducing OCD symptoms (as an adjunct to SSRIs;Vulink et al., 2009) and that dopamine agonists can generate OCD-like behaviors [Borcherding et al., 1990;Szechtman et al., 1998; of interest, ketamine per se shows affinity for dopamine D 2 in addition to serotonin 5-HT 2 receptors (Kapur and Seeman, 2002) both blocked by quetiapine, an antipsychotic sometimes used in the treatment of refractory OCD (Gefvert et al., 2001)]. ...
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Obsessive-compulsive disorder (OCD) is a deeply enigmatic psychiatric condition associated with immense suffering worldwide. Efficacious therapies for OCD, like exposure and response prevention (ERP), are sometimes poorly tolerated by patients. As many as 25% of patients refuse to initiate ERP mainly because they are too anxious to follow exposure procedures. Accordingly, we proposed a simple and tolerable (immersive yet indirect) low-cost technique for treating OCD that we call “multisensory stimulation therapy.” This method involves contaminating a rubber hand during the so-called “rubber hand illusion” (RHI) in which tactile sensations may be perceived as arising from a fake hand. Notably, Jalal et al. (2015) showed that such fake hand contamination during the RHI provokes powerful disgust reactions in healthy volunteers. In the current study, we explored the therapeutic potential of this novel approach. OCD patients (n = 29) watched as their hidden real hand was being stroked together with a visible fake hand; either synchronously (inducing the RHI; i.e., the experimental condition; n = 16) or asynchronously (i.e., the control condition; n = 13). After 5 min of tactile stimulation, the rubber hand was contaminated with fake feces, simulating conventional exposure therapy. Intriguingly, results suggested sensory assimilation of contamination sensations into the body image via the RHI: patients undergoing synchronous stimulation did not report greater contamination sensations when the fake hand was initially contaminated relative to asynchronous stroking. But contrary to expectations, they did so after the rubber hand had been contaminated for 5 min, as assessed via disgust facial expressions (a secondary outcome) and in vivo exposure (upon discontinuing the illusion). Further, to our surprise, synchronous and asynchronous stroking induced an equally vivid and fast-emerging illusion, which helps explain why both conditions initially (5 min after initiating tactile stimulation) provoked contamination reactions of equal magnitude. This study is the first to suggest heightened malleability of body image in OCD. Importantly, it may pave the way for a tolerable technique for the treatment of OCD—highly suitable for poorly resourced and emergency settings, including low-income and developing countries with minimal access to high-tech solutions like virtual reality.
... Secondly, therapeutic concentrations of all antipsychotics (typical and atypical) produce a similar D 2 receptor occupancy (13,59,64). Although this observation does not strictly apply for clozapine (21) or quetiapine (65), it has been shown that D 2 receptor occupancy in the human brain ranges between 70% and 80% within 2 h of treatment and remains elevated for over 24 h for both typical and atypical antipsychotics (21,66,67). D 2 receptor occupancy with clozapine (20) and quetiapine (68,69), on the other hand, decreases significantly within 24 h. ...
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Antipsychotic treatment resistance in schizophrenia remains a major issue in psychiatry. Nearly 30% of patients with schizophrenia do not respond to antipsychotic treatment, yet the underlying neurobiological causes are unknown. All effective antipsychotic medications are thought to achieve their efficacy by targeting the dopaminergic system. Here we review early literature describing the fundamental mechanisms of antipsychotic drug efficacy, highlighting mechanistic concepts that have persisted over time. We then reconsider the original framework for understanding antipsychotic efficacy in light of recent advances in our scientific understanding of the dopaminergic effects of antipsychotics. Based on these new insights, we describe a role for the dopamine transporter in the genesis of both antipsychotic therapeutic response and primary resistance. We believe that this discussion will help delineate the dopaminergic nature of antipsychotic treatment-resistant schizophrenia.
... Secondly, therapeutic concentrations of all antipsychotics (typical and atypical) produce a similar D 2 receptor occupancy (13,59,64). Although this observation does not strictly apply for clozapine (21) or quetiapine (65), it has been shown that D 2 receptor occupancy in the human brain ranges between 70% and 80% within 2 h of treatment and remains elevated for over 24 h for both typical and atypical antipsychotics (21,66,67). D 2 receptor occupancy with clozapine (20) and quetiapine (68,69), on the other hand, decreases significantly within 24 h. ...
... However, as 150 mg quetiapine is probably insufficient to occupy dopamine D2 receptors 13 and as quetiapine has multiple actions 14 , risk-seeking may have been promoted by effects on non-dopaminergic neurotransmission. Other contradictory findings include lack of effects of methylphenidate on hypothetical delay discounting and risk-seeking as assessed with a probability discounting for gains task in children with ADHD 12 , and of d-amphetamine (20 mg) ...
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Research has indicated a major role of dopamine in decision-making processes, but the underlying mechanisms remain largely unknown due to inconsistency in effects of dopaminergic drugs. To clarify the impact of dopamine on impulsive choice, we administered 150 mg L-DOPA to 87 healthy adults in a randomized, placebo-controlled, double-blind, crossover study, evaluating performance in four value-based decision-making tasks. We predicted that baseline impulsivity would moderate L-DOPA effects. In support of our hypothesis, L-DOPA had no main effect on impulsive choice, but reduced risk-seeking for gains in more-impulsive subjects. Because L-DOPA effects may be influenced by body weight, we repeated our analyses on data from half of the sample (n = 44) with lower weight, anticipating a stronger effect. In addition to the effect on risk-seeking for gains, low-weight participants also exhibited baseline-dependent effects of L-DOPA on loss aversion and delay discounting. Our results are consistent with the hypothesis of an inverted U-shaped dopamine function in which both low and high extremes of dopamine signaling are associated with high-impulsive choice. Consideration of differential baseline impulsivity and body weight may resolve previous seemingly paradoxical pharmacological results and might deepen our understanding of dopaminergic mechanisms underlying impulsivity.
... The majority of antipsychotic drugs exhibit efficacy at relatively high D 2 RO (>60%) and it is rare to have antipsychotic efficacy with relatively low D 2 RO (<50%), as is the case with clozapine, demonstrated with as low as 40% D 2 RO at 300 mg/day [29]. Although initial reports with quetiapine suggested relatively low occupancy [30,31], transiently high D 2 RO up to 62% has been reported with quetiapine [32,33]. In the present study, oral ITI-007 showed D 2 RO that peaked at 1 h post-dose and returned to low, but measurable trough levels within 24 h of oral dose administration. ...
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Dopamine D2 receptor occupancy (D2RO) is a key feature of all currently approved antipsychotic medications. However, antipsychotic efficacy associated with high D2RO is often limited by side effects such as motor disturbances and hyperprolactinemia. Lumateperone (ITI-007) is a first-in-class selective and simultaneous modulator of serotonin, dopamine and glutamate in development for the treatment of schizophrenia and other disorders. The primary objective of the present study was to determine D2RO at plasma steady state of 60 mg ITI-007, a dose that previously demonstrated antipsychotic efficacy in a controlled trial, administered orally open-label once daily in the morning for two weeks in patients with schizophrenia (N = 10) and after at least a two-week washout period from standard of care antipsychotics. D2RO was determined using positron emission tomography with 11C-raclopride as the radiotracer. Mean peak dorsal striatal D2RO was 39% at 60 mg ITI-007 occurring 1 h post-dose. Lumateperone was well-tolerated with a favorable safety profile in this study. There were no clinically significant changes in vital signs, ECGs, or clinical chemistry laboratory values, including prolactin levels. There were no adverse event reports of akathisia or other extrapyramidal motor side effects; mean scores on motor function scales indicated no motor disturbances with lumateperone treatment. This level of occupancy is lower than most other antipsychotic drugs at their efficacious doses and likely contributes to the favorable safety and tolerability profile of lumateperone with reduced risk for movement disorders and hyperprolactinemia. If approved, lumateperone may provide a new and safe treatment option for individuals living with schizophrenia.
... Par exemple, ces deux molécules présentent un profil de liaison au récepteur dopaminergique D2 similaire en se liant de façon labile et transitoire à ce récepteur (Seeman, 2002). De plus, leur ratio de liaison aux récepteurs sérotoninergiques de type 5-HT2 par rapport aux récepteurs D2 (ratio 5-HT2/D2) est semblable (Gefvert et al., 2001). ...
Article
Résumé Contexte : Le tabagisme est élevé chez les personnes souffrant de schizophrénie ; certains patients réclament une aide au niveau de la médication qu’ils reçoivent afin de cesser de fumer. Objectif : Parmi les traitements pharmacologiques de la schizophrénie, la clozapine peut réduire la consommation de cigarettes. Les effets de la quétiapine, un autre antipsychotique atypique partageant plusieurs propriétés structurales et pharmacologiques avec la clozapine, ont été examinés chez un groupe de fumeurs atteints de schizophrénie dans une étude exploratoire. Méthode : Vingt-et-un individus fumeurs avec un diagnostic de schizophrénie, de trouble schizo-affectif ou de trouble schizophréniforme et recevant de la quétiapine ont été évalués à l’aide du questionnaire de Fagerström pour la dépendance à la nicotine. Ils ont de plus subi des analyses de monoxyde de carbone sanguin. Résultats : Le profil tabagique des sujets n’a pas été modifié significativement par l’administration de la quétiapine, malgré une amélioration de la symptomatologie psychiatrique. Conclusion : La quétiapine ne semble pas avoir d’effet significatif sur la consommation de cigarettes chez les fumeurs souffrant de schizophrénie.
... Quetiapine is characterized by a greater affinity to 5-hydroxytryptamine-2 (5-HT 2 ) receptors than with dopamine-2 (D 2 ) receptors [6]. At low doses (up to 300 mg/day), it shows a consistently higher degree of occupancy of 5-HT 2A receptors than of D 2 receptors; the degree of occupancy of both receptors is dose dependent [7]. The 5-HT 2 antagonistic action of quetiapine may disinhibit the dopaminergic system and enhance dopaminergic activity at the level of the forebrain and influences the mood state [8]. ...
... It shares characteristics with dopaminergic (D1, D2, D3, D4 receptor) antagonists, adrenergic (α1, α2 receptor) antagonists, 5-HT1A partial agonists, high affinity 5-HT2A partial antagonists, and potentially shares properties with histamine (H1 receptor) antagonists. [2][3][4] The main indications for quetiapine are schizophrenia, bipolar disorder, and delirium. ...
Article
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Quetiapine is an atypical antipsychotic agent which is also prescribed for delirium due to its anti-dopaminergic effects; aphasia is an unusual side effect associated with the drug. Here, we report the case of an 83-year-old woman who was prescribed quetiapine (50 mg per day) for delirium. Unexpected, global aphasia occurred 3 days after treatment began. Complete recovery occurred following discontinuation of the drug. A brain computed tomography scan excluded intracranial hemorrhage and the laboratory results confirmed that no exacerbation of infection or electrolyte imbalances were present. During the aphasic episode, the patient’s condition did not deteriorate and no new neurological symptoms occurred. We suspect that the occurrence of aphasia was directly due to an adverse reaction to quetiapine. To our knowledge, this is the first case report of reversible, global aphasia as a side effect of quetiapine. We propose that this occurrence of aphasia may be due to the action of quetiapine as a dopamine receptor antagonist. Clinicians should use quetiapine with caution, especially in elderly patients. On observation of aphasia, a review of the patient’s medical history is required to assess for the usage of quetiapine.
... For QT, however, some studies show a more prominent 5HT as well as noradrenergic receptor affinity in lower dosages and a stronger dopaminergic effect in higher dosages, but binding studies show a comparable affinity for D2 and 5HT2A receptors (Richelson, 1999;Nemeroff et al., 2002). One PET binding study showed relevant DA D2 receptor occupancy even at low plasma levels in healthy controls (Nord et al., 2011), and 2 other PET studies suggest that possibly both the DA D2 and the 5HT2A receptor occupancy increase with increasing dose of QT (Kapur et al., 2000;Gefvert et al., 2001). However, other treatment studies show both a prominent cortical binding to 5HT2A receptors (Rasmussen et al., 2011) and a predominant striatal binding to dopaminergic receptors (Pavics et al., 2004) even at rather low therapeutic doses. ...
Article
Background: The dopaminergic system is implicated in many mental processes and neuropsychiatric disorders. Pharmacologically, drugs with dopamine receptor antagonistic and agonistic effects are used, but their effects on functional brain metabolism are not well known. Methods: In this randomized cross-over, placebo-controlled and rater-blinded study, 25 healthy adults received an acute dose placebo substance (starch), quetiapine (dopamine receptor antagonist), or pramipexole (dopamine agonist of the non-ergoline class) 1 hour before the experiment. Background-suppressed 2D pseudo-continuous arterial spin labeling was used to examine whole-brain baseline cerebral blood flow (CBF) differences induced by the three substances. Results: We found that quetiapine reduced perfusion in the occipital (early visual areas) and bilateral cerebellar cortex relative to placebo. In contrast, quetiapine enhanced CBF (relative to placebo) in the striatal system (putamen and caudate nucleus) but also in the supplementary motor area (SMA), insular-, prefrontal- as well as in the pre- and postcentral cortex. Pramipexole increased CBF compared to placebo in the caudate nucleus, putamen, middle frontal, SMA, and brainstem (substantia nigra), but reduced CBF in the posterior thalamus, cerebellum, and visual areas. Pramipexole administration resulted in stronger CBF relative to quetiapine in the hypothalamus, cerebellum and substantia nigra. Conclusions: Our results indicate that quetiapine and pramipexole differentially modulate regional baseline CBF. Both substances act on the dopaminergic system, although affecting distinct regions. Quetiapine altered dopaminergic function in frontal, striatal, and motor regions. In contrast, pramipexole affected CBF of the nigrostriatal (striatum and substantia nigra) dopaminergic, but less the fronto-insular system.
... In fact, in this review, almost a third of the cases of mania/hypomania suggested to have been induced by atypical antipsychotics were ziprasidone-related, of which 7 were highly suggestive of a causal link. On the other hand, quetiapine has the lowest 5-HT 2A affinity and 5-HT 2A /D 2 binding ratio, 52,56 but with a higher affinity for 5-HT 2A than D 2 receptors at lower doses, 57 it also seems to be involved in the induction of mania/hypomania. An interesting situation is mania induced by amisulpride, an antipsychotic that is generally considered to have some atypical properties and that causes minimal Table 8. ...
Article
Background: Atypical antipsychotics are widely used in clinical practice for several psychiatric disorders. Between 1994 and 1999, 26 cases of manic and hypomanic syndromes were reported with olanzapine and risperidone and were described in a previous review article. Method: An updated MEDLINE search (1999-2003) using the terms atypical antipsychotics, amisulpride, aripiprazole, clozapine, flupenthixol, olanzapine, quetiapine, risperidone, sertindole, ziprasidone, zotepine, hypomania, and mania showed that 34 new cases of induced hypomanic or manic syndromes have been published, not only with olanzapine (N = 5) and risperidone (N = 6), but also with quetiapine (N = 5) and ziprasidone (N = 11) treatment. Six cases have been reported with flupenthixol and 1 with amisulpride, two antipsychotics considered as "partial" atypicals. Results: A critical analysis of these case reports revealed that the effects on mood were insufficiently documented in some of the reports but that for 20 of them, evidence is highly suggestive of a causative role of atypical antipsychotics in the induction of manic/hypomanic symptomatology. Conclusion: This updated review continues and extends the results of the initial review and suggests that atypical antipsychotics have some intriguing effects on mood. Such effects have never been reported with conventional antipsychotics. The mechanisms involved in this phenomenon of mood switch remain to be elucidated.
... V těchto studiích byla zkoumána okupance D 2 a 5HT 2 receptorů v různých regionech mozku v různých časech po podání dávky, s popisem příslušných dosahovaných plazmatických koncentrací a dávkování léčiva a zkoumán jejich vzájemný vztah. [37][38][39][40][41][42] Nalezení vztahu mezi klinickou odpovědí a plazmatickými koncentracemi quetiapinu bylo jako jedním z primárních endpointů pouze několika studií, z nichž 2 31, 33 jsou zahrnuty v guidelines, přičemž autoři korelaci ani cut-off hodnotu pro odlišení respondérů a nonrespondérů nenalezli. Dragicevic et al. 43,44 uvádějí c trough (plazmatické koncentrace ve svém minimu, tzn. ...
Article
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Quetiapine is atypical antipsychotic with remarkable clinical and receptor-binding profile depending on dosage used. Plasma concentrations and also clinical response vary markedly after equal doses between individuals in clinical practice. Polypharmacy and suboptimal adherence is common. The drug is metabolised by cytochrome P450 and thus, clinically important pharmacokinetic drug-drug interactions are likely. There is evidence from literature about plasma concentrations obtained at therapeutically effective doses. Quetiapine is therefore suitable candidate for therapeutic drug monitoring. Here we present an overview of biotransformation and pharmacokinetic drug-drug interactions and current knowledge on therapeutic drug monitoring of quetiapine, its benefits and limitations.
... With the above in mind, utilizing neuroimaging techniques in schizophrenic patients being treated long-term with antipsychotics, it has been observed that risperidone's occupancy is approximately 80% for dopamine D 2 receptors in the striate nucleus, and between 86 and 93% for serotonin 5-HT 2A receptors in the cerebral cortex. Other authors reported similar data about clozapine, olanzapine, quetiapine, and ziprasidone [104][105][106][107][108]. In contrast, administering classical neuroleptics blocks between 70 and 90% of striatal D 2 receptors and does not significantly occupy serotonin 5-HT 2A receptors [100,109]. ...
... In line with the in vivo data (see above), most of the atypical drugs display higher 5-HT 2A than D 2 occupancy rates when dual-tracer approaches are used (Kapur et al., 1998;Nyberg et al., 1999;Gefvert et al., 2001;Mamo et al., 2004). But although it was suggested that the predominant 5-HT 2A receptor antagonism of atypical drugs protects against EPS (Meltzer, 1999), even atypical substances such as olanzapine or risperidone cause EPS when given in higher doses that lead to D 2 receptor occupancy of more than 80% (Kapur et al., 1998;Nyberg et al., 1999). ...
Chapter
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Although the serotonin hypothesis of schizophrenia is one of the oldest neurochemical hypotheses on the pathogenesis of this disease, it is still highly topical. The concept of how the serotonin system is involved in the origin and progress of schizophrenia has considerably changed over the past decades. Therefore, the present work will give an overview about the development and the current directions of the serotonin hypothesis of schizophrenia. In this regard, we will discuss the phenomenology of hallucinogenic drug action, model psychosis and translational research, post-mortem studies on receptors and transporters, imaging studies, antipsychotic drug action, neuroendocrine challenge studies, platelet and cerebrospinal fluid data, genetic association studies, developmental aspects, and the cross-talk between the glutamate and the serotonin system. In sum, there are several lines of evidence suggesting that the serotonin system plays a major role in the pathogenesis of at least a subpopulation of schizophrenia patients. Further studies are needed to better characterize patients whose psychotic symptoms are suspected to have a serotonergic origin.
... These findings suggest olanzapine and quetiapine can block more than 60 % of brain H1Rs under the clinical minimum dose. Previous PET studies of 5-HT 2 and D 2 dopamine receptor occupancy evaluated much higher doses of olanzapine (5-40 mg) and quetiapine (150-700 mg) in healthy volunteers and psychiatric patients (Gefvert et al. 2001;Kessler et al. 2006;Lako et al. 2013;Nyberg et al. 1997). From previous occupancy studies, olanzapine 2.5 mg and quetiapine 25 mg might be estimated to occupy less than 30 % of 5-HT 2 and D 2 dopamine receptors. ...
Article
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Histamine H1 antagonists have hypnotic, appetite-promoting, and sedative side effects. Most second-generation antipsychotics have potent antagonistic effects on histamine H1 receptor (H1R). Positron emission tomography (PET) can measure the H1R occupancy (H1RO) in vivo, although there are no reports regarding antipsychotics. We studied the H1RO of olanzapine and quetiapine in vivo with respect to their plasma concentrations and subjective drowsiness by performing human PET imaging studies with [(11)C]doxepin, a potent PET ligand of H1R. Six healthy Japanese male volunteers were enrolled. Cross-randomized PET imaging was performed after a single oral administration of olanzapine (2.5 mg), quetiapine (25 mg), or placebo. PET data were analyzed by region of interest and voxel-by-voxel analysis. We concurrently measured plasma drug concentrations by liquid chromatography/tandem mass spectrometry and evaluated subjective sleepiness. The binding potential ratios of olanzapine and quetiapine in the cerebral cortex were significantly lower than that of the placebo. The H1RO values of olanzapine and quetiapine in the cortex were approximately 61-80 and 56-81 %, respectively. The binding potential ratios of the drugs were significantly lower than that of the placebo in the dorsolateral prefrontal and lateral temporal cortices, and anterior and posterior cingulate gyri. The H1RO values in the cortex were significantly correlated with subjective sleepiness but not plasma drug concentrations. Olanzapine and quetiapine have high H1RO values in the human brain under their clinical minimum doses. This study provides a foundation of the properties by which new-generation antipsychotics block the central histaminergic system in humans.
... On the contrary, results on the 5-HT2A selectivity theory are more consistent and are indeed supported by PET imaging studies [71,72]. Despite this positive outcome, the fact that other SGA such as risperidone, olanzapine and quetiapine are characterized by this pharmacodynamics as well [73][74][75][76][77] but are less efficacious in SZ patients resistant to treatment makes again uncertain this theory. In reality, the peculiar antipsychotic action of clozapine does not clearly rely on factors simply related to single neurotransmitters systems or single brain areas. ...
Article
Psychopharmacological treatments for schizophrenia have always been a matter of debate and a very important issue in public health given the chronic, relapsing and disabling nature of the disorder. A thorough understanding of the pros and cons of currently available pharmacological treatments for schizophrenia is critical to better capture the features of treatment-refractory clinical pictures and plan the developing of new treatment strategies. This review focuses on brain functional changes induced by antipsychotic drugs as assessed by modern functional neuroimaging techniques (i.e. fMRI, PET, SPECT, MRI spectroscopy). The most important papers on this topic are reviewed in order to draw an ideal map of the main functional changes occurring in the brain during antipsychotic treatment. This supports the hypothesis that a network-based perspective and a functional connectivity approach are needed to fill the currently existing gap of knowledge in the field of psychotropic drugs and their mechanisms of action beyond neurotransmitter systems.
... It effectively alleviates positive and negative symptoms, cognitive dysfunction in patients with schizophrenia (Purdon, et al., 2001;Velligan, et al., 2002). It is a dibenzothiazepine, and competitively antagonizes both dopamine-2 (D 2 ) and serotonin-2 (5-HT 2 ) receptors, but with a much higher affinity for 5-HT 2 receptor than D 2 receptor (Gefvert et al., 2001). In addition to the high binding ratios of 5-HT 2 :D 2 receptor, quetiapine also has affinity for 5-HT 1A , 5-HT 6 , histamine-1 (H 1 ), α1-and α2-adrenergic receptors. ...
... PET studies in schizophrenic patients treated with quetiapine showed striatal D2/D3 receptor occupancy of up to 50%. However, 2-3 h after a single dose, a transiently high occupancy of 58-64% was observed (Kapur et al, 2000;Gefvert et al, 2001). Recently, a novel compound with fast off rate from the D2 receptor, JNJ-37822681, showed a regular saturation curve of D2/D3 receptor occupancy of up to 70% (Te Beek et al, 2012). ...
Article
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(-)-OSU6162 is a dopamine stabilizer that can counteract both hyperdopaminergic and hypodopaminergic states. In this study, D2/D3 receptor occupancy of (-)-OSU6162 in the human brain was investigated using positron emission tomography (PET). Twelve male healthy volunteers underwent [(11)C]raclopride PET scanning before and 1 h after a single oral dose of (-)-OSU6162 (15-90 mg). Blood samples for determination of (-)-OSU6162 and prolactin plasma levels were collected at Tmax. Parametric images of [(11)C]raclopride binding potential relative to nondisplaceable tissue (cerebellar grey matter) uptake (BPND) at baseline and after (-)-OSU6162 administration were generated using the simplified reference tissue model. MRI-based regions of interest were defined for the striatum, composed of caudate nucleus and putamen, and projected onto the co-registered parametric [(11)C]raclopride BPND image. Furthermore, three striatal subregions, ie, anterior dorsal caudate, anterior dorsal putamen, and ventral striatum, were defined manually and additionally analyzed. Plasma concentrations of (-)-OSU6162, ranging from 0.01 to 0.9 μM, showed a linear relationship with prolactin levels, reflecting blockade of pituitary D2 receptors. A concentration-dependent increase in striatal D2/D3 receptor occupancy was observed, reaching a value of about 20% at an (-)-OSU6162 plasma level of 0.2 μM, and which for higher concentrations leveled off to a maximal occupancy of about 40%. Findings were similar in the striatal subregions. The present data corroborate the notion that (-)-OSU6162 binds preferentially to a subpopulation of D2/D3 receptors, possibly predominantly extrasynaptic, and this may form the basis for the dopamine-stabilizing properties of (-)-OSU6162.Neuropsychopharmacology advance online publication, 24 September 2014; doi:10.1038/npp.2014.195.
... As compared to the radioligands [ 18 F]setoperone and [ 11 C]N-methylspiperone used in previous studies e.g. (Gefvert et al., 1998(Gefvert et al., , 2001Kapur et al., 2000) [ 18 F]altanserin is not limited by relatively poor selectivity for the 5HT2A. In conjunction with the poor selectivity of these tracers, a lower ratio of 5HT2A to D 2 receptors in subcortical areas compared to cortical areas makes these ligands inadequate to measure subcortical binding [ 18 F]altanserin has a 200 to 500-fold 5HT2A/D 2 selectivity measured as 1/(5HT2A Ki/D 2 ) = 1/(0.13-0.3/62 ...
Article
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Antipsychotic-induced weight gain is of major clinical importance since it is associated with severe metabolic complications and increased mortality. The serotonin2A receptor system has been suggested to be implicated in weight gain and obesity. However, no previous in vivo imaging data have related serotonin2A receptor binding to weight gain before and after antipsychotic monotherapy. Fifteen antipsychotic-naive first-episode schizophrenia patients were included and investigated before and after six months of quetiapine treatment. We examined the relationship between serotonin2A receptor binding as measured with positron emission tomography (PET) and [18F]altanserin and change in body mass index (BMI). Quetiapine was chosen because it is characterized by a moderately high affinity for the serotonin2A receptor and a fast dissociation rate from the dopamine D2 receptor. At baseline the mean BMI was 24.2 kg/m2, range 18-36 kg/m2. After six months of quetiapine treatment (mean dose: 383 mg/day) the BMI had, on average, increased by 6.7%, corresponding to an average weight gain of 5.0 kg. We found a significant positive correlation both between neocortical serotonin2A receptor binding prior to treatment and subsequent increase in BMI (rho = 0.59, p = 0.022). At follow-up, the serotonin2A receptor occupancy was positively correlated with BMI increase (rho = 0.54, p = 0.038). To our knowledge, these are the first in vivo receptor imaging data in initially antipsychotic-naive first-episode schizophrenia patients to show that the cerebral serotonin2A receptor is associated with antipsychotic-induced weight gain.
Chapter
Quetiapine (Q) is a second-generation (atypical) antipsychotic (SGA) released for the treatment of schizophrenia, bipolar disorder, and major depressive disorder (MDD). It has a broad pharmacological profile. The efficacy in treatment was established in numerous randomized, double-blind, placebo controlled studies and maintenance studies. In some RCTs Q was slightly less effective than risperidone and olanzapine with lower risk for extrapyramidal adverse effects. Common side effects include sleepiness, constipation, weight gain, and dry mouth.
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This case study reviews the pharmacotherapy of a resident in a long-term care facility being treated for poststroke seizure, hallucinations, and dementia, a geriatric syndrome that is both common in regard to its prevalence and severe in regard to its impact on the individual, families, caregivers, and health care system. This case describes the past medical history of an older resident in a skilled nursing facility that was receiving pharmacological therapy for auditory hallucinations and for poststroke seizure prophylaxis, was noted to be having side effects from drug therapy, and how the nursing staff communicated with the consultant pharmacist to resolve these issues.
Chapter
The discovery by Delay and Denicker in 1953 that chlorpromazine was highly effective in alleviating delusions, hallucinations, and disorganized thinking, was the seminal breakthrough in the treatment of schizophrenia, the first agent to produce sufficient relief of core psychotic symptoms to permit life outside of institutions for many patients with schizophrenia, and even a return to a semblance of function within normal limits. Chlorpromazine and the other related typical antipsychotic drugs which were introduced over the next 30 years have proven to be of immense benefit to vast numbers of people who experience psychotic symptoms as a component of a diverse group of neuropsychiatric and medical disorders, as well as drug-induced psychoses. These drugs have been invaluable in providing clues to the aetiology of schizophrenia and other forms of mental illness with psychotic features and as tools in understanding fundamental neural processes, especially those involving dopamine, a key neurotransmitter involved in psychosis. This class of drugs has now been supplanted by the so-called atypical antipsychotic drugs, of which clozapine is the prototype. This chapter will describe the various classes of antipsychotic agents, with emphasis on the atypical antipsychotic drugs, their benefits and adverse effects, recommendations for use in clinical practice, and mechanism of action. The drugs used to treat the extrapyramidal side-effects (EPS) produced mainly by the typical antipsychotic drugs are also considered.
Article
Background Treatment-resistant depression (TRD) is considered a common clinical condition often associated with relevant suicidal ideation and characterized by a severe functional impairment lifetime. Among the available drugs for the TRD treatment, second-generation antipsychotics (SGAs) have been reported as effective. In this context, the aim of this study was to review the clinical studies evaluating the efficacy of SGAs as add-on therapy in TRD. Methods A comprehensive search on PubMed, Medline and PsychINFO of all randomized clinical trials (RCTs) assessing the augmentation with antipsychotics in TRD, published from January 2000 until March 2020, was performed. Sixteen RCTs studies met the inclusion criteria. Results The reviewed studies showed that the add-on therapy with aripiprazole could be beneficial in the treatment of TRD. Furthermore, RCTs on quetiapine augmentation support its use in TRD, especially when comorbid anxiety or insomnia are present. The effects of risperidone and olanzapine as add-on in TRD were less studied, but preliminary data indicated an efficacy respect to placebo, making them a possible therapeutic option in TRD. Limitations The lack of consistency in the definition of TRD together with the small sample sizes and the heterogeneity of antipsychotics dosages used in the reviewed RCTs may have limited the strength of evidences obtained. Conclusion Overall, the available RCTs studies seem to support the hypothesis that the augmentation with SGAs, in particular aripiprazole and quetiapine, is a valid therapeutic option for TRD. However, to improve the therapeutic outcome of patients with TRD, larger and more homogeneous RCTs are needed.
Chapter
Clinical imaging technologies continue to develop at a rapid pace catalyzed by the desire to better understand and monitor human health and disease. Early clinical development offers a unique opportunity to apply information‐rich, quantitative imaging‐based biomarkers. This chapter reviews the challenges faced by early clinical development and considers how imaging can best contribute. Integrating imaging methodologies into early clinical development requires a step‐wise approach to consider the most appropriate technique and then to assess existing evidence around technical validation and qualification of the technique toward utilization. The aim of imaging science for drug development should be to provide tools to reliably demonstrate pharmacology in few subjects. Sufficient imaging details will need to be defined within the clinical trial protocol. Important details include timing of imaging relative to other protocol‐defined events such as dosing and clear definition of the endpoints to be derived from imaging.
Chapter
The dopamine hypothesis of schizophrenia was a major early focus of clinical molecular imaging studies. Over the years, molecular imaging has provided support for increased activity of striatal presynaptic dopaminergic neurons, as well as guidelines for optimal clinical treatment with antipsychotic drugs. Research on brain neurotransmission markers in schizophrenia has been extended also to the serotonin, GABA and cannabinoid systems. More recently, following the increased interest in the immune system as a pathophysiological factor in schizophrenia, much effort has been invested in PET studies targeting the glial marker translocator protein (TSPO). Whereas early reports in small samples found evidence for an increase in TSPO, more recent work using radioligands with higher specific to non-specific binding ratio has indicated lower levels in patients. Generally, sample sizes in clinical molecular imaging studies have been small, such that many of the individual studies are underpowered to detect even medium-sized effects. Multisite collaborations and data sharing are important ways forwards to address this issue.
Article
This systematic review and meta-analysis examined predictors of successful antipsychotic dose reduction in schizophrenia. Prospective clinical trials and randomized controlled trials (RCTs) investigating antipsychotic dose reduction in schizophrenia were selected for systematic review and meta-analysis, respectively. In total, 37 trials were identified. Only eight studies focused on second-generation antipsychotics (SGAs); no studies investigated long-acting injectable SGAs. Of 24 studies evaluating relapse or symptom changes, 20 (83.3%) met the criteria for successful dose reduction. Factors associated with successful dose reduction were study duration <1 year, age >40 years, duration of illness >10 years, and post-reduction chlorpromazine equivalent (CPZE) dose >200 mg/day. Clinical deterioration was mostly re-stabilized by increasing the dose to the baseline level (N = 7/8, 87.5%). A meta-analysis of 18 RCTs revealed that relapse rate was significantly higher in the reduction group than the maintenance group (risk ratio [RR] = 1.96; 95% confidence interval [CI], 1.23–3.12), whereas neurocognition was significantly improved (standardized mean difference = 0.69; 95% CI, 0.25–1.12). Subgroup analysis indicated that only a post-reduction CPZE dose ≤200 mg/day was associated with an increased risk of relapse (RR = 2.79; 95% CI, 1.29–6.03). Thus, when reducing antipsychotic doses, clinicians should consider the long-term risk of relapse in younger patients with a relatively short illness duration and keep the final doses higher than CPZE 200 mg/day. Further studies, particularly those involving SGAs, are warranted to determine the optimal strategies for successful antipsychotic dose reduction in schizophrenia.
Article
While positron emission tomography (PET) studies have provided invaluable data on antipsychotic effects, selection bias remains a serious concern. A systematic review of PET studies that measured dopamine D2 receptor blockade with antipsychotics was conducted to examine their inclusion/exclusion criteria, using PubMed, EMBASE, and ClinicalTrials.gov (last search, September 2016). PET studies were included if they measured D2 receptor occupancy in patients with schizophrenia and included introduction of antipsychotic treatment or antipsychotic regimen change in a systematic manner. Twenty-six studies were identified. Age limit was included in 13 studies; one study solely included geriatric patients while others targeted younger adults. Eleven, 6, and 3 studies specifically targeted clinically stable patients, patients with severe psychopathology, and antipsychotic-free patients, respectively. Nineteen and 18 studies excluded patients with physical comorbidity and substance abuse, respectively. As a result, the mean age of subjects ranged from 23 to 42 years when one study that targeted geriatric patients was excluded. Mean Positive and Negative Syndrome Scale total scores ranged from 54 to 95. No comparison active-drug or placebo arm was employed in 24 studies. Blind assessment of symptomatology was performed in 5 studies. In general, subjects participating in clinical PET studies were relatively young, presented with mild symptomatology, and were free from substance abuse or physical comorbidities. These characteristics need to be taken into account when clinical PET data are interpreted. On the other hand, it should also be noted that this study was only qualitative and conservative interpretation is necessary for possibility of subjective bias.
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Quetiapine (QTP) is an atypical antipsychotic labelled for the treatment of patients with schizophrenia, bipolar mania and bipolar depression. Nevertheless, QTP has been tried across multiple diagnosis categories and seems to be used, among other atypical antipsychotics, in clinical practice for an expanding range of disorders such as major depression, substance abuse disorders, anxiety disorders, and borderline personality disorders. The present review focuses on papers which investigated the molecular mechanism(s) of QTP antidepressant effect. In particular, preclinical studies performed by coupling the chronic mild stress, an animal model of human depression with Affymetrix microarray technology, revealed that chronic QTP administration prevented the stress-induced up- or down-regulation of 42 genes involved in the central nervous system development or having a crucial role for viability of neural cells, like regulation of signal transduction, inorganic ion transport, membrane organisation, and neurite morphogenesis. Among these, Ptgs2, Hes5, Plcb1, Senp2, Gad1, and Marcks are presumably the effectors of the QTP clinical efficacy.
Article
Dopamine (DA) signaling in the brain is mediated by two major classes of DA receptors, DA D1-type receptors which include DA D1 and DA D5 receptors and DA D2-type receptors which include DA D2-, DA D3-, and DA D4-type receptors. These receptors have differing distributions in brain and differing intracellular signaling pathways which are briefly reviewed. Because of the importance of DA signaling in a number of disease states including schizophrenia, drug abuse, movement disorders, attention deficit hyperactivity disorder, and likely depression and obesity, there has been great interest and considerable research efforts into development of methods for delineating regional levels of cerebral DA receptors and DA release in striatum, substantia nigra, limbic regions, and cortex over the past three decades. This chapter will examine the strengths and weaknesses of the currently available positron emission tomography and single-photon emission computed tomography radioligands for DA D1- and DA D2-type receptors, the methods of quantitation of receptor levels using these radioligands, and the ability of these radioligands to assess both psychostimulant-induced DA release and basal extracellular levels of DA as well as provide a limited review of their clinical research applications.
Article
Objective: To investigate the effect of long-term administration of quetiapine on the cognitive function of patients with Alzheimer's disease (AD). Methods: Fifty-one AD outpatients with psychological and behavioral symptoms were randomly divided into treatment group (taking quetiapine, n=26) and control group (n=25). Cognitive Abilities Screening Instrument (CASI) and Alzheimer's Disease Assessment Scale (ADAS-cog) were used to assess the cognitive function of two groups before treatment (baseline), and three months, six months after treatment. Results: The baseline scores of CASI and ADAS-cog of two groups were not statistically significant (P>0.05). Three months after treatment, the scores of CASI and ADAS-cog increased but were not statistically significant (P>0.05). Six months after treatment, the scores of CASI and ADAS-cog further increased. The scores of treatment group were obviously higher than those of the control group and statistically significant (P<0.05). Conclusion: Long-term administration of quetiapine may cause an adverse impact on the cognitive function of AD patients.
Chapter
This chapter seeks to document advances and controversies in relation to mechanisms underlying the therapeutic and adverse effects of antipsychotic drugs. It focuses on findings for second-generation agents, with an emphasis on neuroimaging studies in living patients; yet it is mindful of what we have learned and have still to learn from their first-generation counterparts. Thereafter, it considers putative “third-generation” agents, and then considers novel mechanisms and possible future developments.
Article
The mandate of the Centers for Medicare & Medicaid Services to decrease the use of antipsychotics in long-term care facilities requires creative solutions. Low-dose quetiapine is used for a multitude of behavioral disorders and sleep problems in the nursing facility population. Yet, at doses of 25 mg per day or less, it doesn't have strong affinity (if any) for the dopamine-2 (D2) receptor, but it does maintain affinity for the histamine-1 and alpha-1 receptors. This begs the question: If it's not antagonizing the D2 receptor, could the use of something with similar receptor-affinity produce the same result, allowing discontinuation of the antipsychotic altogether? Using knowledge of receptor affinities and the pharmacologic action of low-dose quetiapine, consultant pharmacists may have one additional tool in their armamentarium of fighting inappropriate antipsychotic use.
Article
Quetiapine (Seroquel®) is the only atypical antipsychotic approved in the US for use as monotherapy in both bipolar mania and depression, offering potential compliance advantages. Monotherapy with oral quetiapine 300 mg/day is effective in the treatment of patients with bipolar I or II depression. Rapid and sustained improvements in depressive and anxiety symptoms are seen with quetiapine, as well as improvements in health-related quality of life (HR-QOL). Quetiapine is generally well tolerated in bipolar depression and is not associated with an increased risk of treatment-emergent mania. Thus, despite the current lack of data from active comparator trials, quetiapine monotherapy should be considered a first-line option for the acute treatment of bipolar depression. Pharmacological Properties The precise mechanism of action of quetiapine in bipolar depression is unknown, although it has been suggested that its antidepressant activity may be linked to its higher affinity for serotonergic than dopaminergic receptors. Quetiapine is not associated with elevation of prolactin levels and has a low propensity to induce extrapyramidal symptoms, most likely reflecting its relatively low affinity for, and its rapid dissociation from, dopamine D2 receptors. Oral quetiapine is rapidly absorbed and undergoes extensive hepatic metabolism, meaning that dosage adjustment may be needed in patients with hepatic impairment. Caution is recommended when quetiapine is co-administered with cytochrome P450 (CYP) 3A4 inhibitors such as ketoconazole, erythromycin, itraconazole and fluconazole. In addition, higher maintenance dosages of quetiapine may be needed in patients receiving concomitant CYP3A4 inducers (e.g. phenytoin, carbamazepine). Clinical Efficacy The efficacy of monotherapy with oral quetiapine 300 or 600 mg/day in adults with bipolar I or II disorder and a major depressive episode was demonstrated in two well designed 8-week trials (the BOLDER I and II trials) [n = 511 and 467]. In both BOLDER I and II, Montgomery-Åsberg Depression Rating Scale (MADRS) total scores at week 8 were reduced from baseline to a significantly greater extent with quetiapine than with placebo (the change from baseline in MADRS total scores was the primary endpoint). In addition, the proportion of patients who had responded or were in remission at week 8 was significantly higher with quetiapine than with placebo. No additional benefit was seen in patients receiving quetiapine 600 mg/day compared with those receiving quetiapine 300 mg/day. Improvements in Hamilton Depression Rating Scale (HAM-D) total and HAM-D item 1 (depressed mood) scores were significantly greater with quetiapine than with placebo, as were improvements on the Clinical Global Impression-Severity of Illness scale. In terms of anxiety symptoms, improvements from baseline in Hamilton Anxiety Rating Scale total scores were significantly greater with quetiapine than with placebo. In both the BOLDER I and II trials, HR-QOL was improved to a significantly greater extent with quetiapine 300 mg/day than with placebo, as shown by the change from baseline in Quality of Life Enjoyment and Satisfaction Questionnaire Short Form scores. A significantly greater improvement in the quality of sleep occurred with quetiapine 300 or 600 mg/day than with placebo, as shown by the change from baseline in Pittsburgh Sleep Quality Index scores (assessed only in BOLDER I). Sheehan Disability Scale (SDS) scores (assessing functional improvement) were improved to a significantly greater extent with quetiapine 600 mg/day than with placebo, although no significant difference was seen between quetiapine 300 mg/day and placebo recipients (SDS scores were assessed only in BOLDER II). Apost hoc pooled analysis of the BOLDER I and II trials revealed significantly greater reductions in mean MADRS item 10 (suicidal thoughts) and HAM-D item 3 (suicide) scores in patients receiving quetiapine than in those receiving placebo. Among quetiapine recipients, the incidence of treatment-emergent suicidal ideation or suicide attempt was low and similar to that seen in placebo recipients. Exploratory subgroup analyses revealed that quetiapine was effective in reducing MADRS total scores in patients with bipolar I depression and patients with rapid-cycling bipolar disorder. In patients with bipolar II depression, quetiapine was significantly more effective than placebo in a combined analysis of the BOLDER I and II trials, and in BOLDER II alone, but not in BOLDER I alone (the separate BOLDER trials were not powered to detect between-treatment differences in subgroups of patients). Tolerability Quetiapine was generally well tolerated in patients with bipolar depression, according to the results of the BOLDER I and II trials. In BOLDER I, the incidence of dry mouth, sedation, somnolence, dizziness and constipation was significantly higher in patients receiving quetiapine 300 or 600 mg/day than in patients receiving placebo. Changes in scores on the Simpson-Angus Rating Scale and the Barnes Akathisia Rating Scale did not differ between quetiapine and placebo recipients. Compared with placebo, quetiapine was not associated with an increased risk of treatment-emergent mania in either trial. Only modest weight gain was seen in quetiapine recipients in these short-term studies and there were no significant differences between quetiapine and placebo recipients in terms of fasting serum glucose levels.
Article
A 24-year-old man with bipolar disorder who was started on quetiapine as an adjunct to valproate (mood stabiliser) after a depressive episode switched to a manic episode while on the drug. The manic episode resolved following the withdrawal of quetiapine. This case illustrates the rare possibility of quetiapine emergent manic episode which a clinician needs to be aware of in the context of the management of bipolar disorders.
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[11C]Raclopride binding to central D2-dopamine receptors in humans has previously been examined by positron emission tomography (PET). Based on the rapid occurrence of binding equilibrium, a saturation analysis has been developed for the determination of receptor density (Bmax) and affinity (Kd). For analysis of PET measurements obtained with other ligands, a kinetic three-compartment model has been used. In the present study, the brain uptake of [11C]raclopride was analyzed further by applying both a kinetic and an equilibrium analysis to data obtained from four PET experiments in each of three healthy subjects. First regional CBV was determined. In the second and third experiment, [11C]-raclopride with high and low specific activity was used. In a fourth experiment, the [11C]raclopride enantiomer [11C]FLB472 was used to examine the concentration of free radioligand and nonspecific binding in brain. Radio-activity in arterial blood was measured using an automated blood sampling system. Bmax and Kd values for [11C]raclopride binding could be determined also with the kinetic analysis. As expected theoretically, those values were similar to those obtained with the equilibrium analysis. In addition, the kinetic analysis allowed separate determination of the association and dissociation rate constants, kon and koff, respectively. Examination of [11C]raclopride and [11C]FLB472 uptake in brain regions devoid of specific D2-dopamine receptor binding indicated a fourth compartment in which uptake was reversible, nonstereoselective, and nonsaturable in the dose range studied.
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Quetiapine fumarate (Seroquel [ICI 204,636]) is an atypical dibenzothiazepine antipsychotic with a greater affinity for 5-hydroxytryptamine2 (5-HT2) receptors than for D2 dopamine receptors; its efficacy in patients with schizophrenia was shown in early phase 2 trials (maximum dose, 750 mg/d). In this multicenter, double-blind, placebo-controlled trial, 286 patients hospitalized with chronic or subchronic schizophrenia (DSM-III-R) were randomized to 6 weeks of treatment with high-dose quetiapine fumarate (< or = 750 mg/d), n = 96; low-dose quetiapine fumarate (< or = 250 mg/d), n = 94; or placebo, n = 96. The Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression Severity of Illness item scores were the primary efficacy variables. Secondary efficacy variables included the BPRS positive-symptom cluster score, the Modified Scale for the Assessment of Negative Symptoms summary score (United States only), and the total score from the negative scale of the Positive and Negative Syndrome Scale (Europe only). Scores were analyzed using an analysis of covariance for change from baseline at end point with last observations carried forward. The model included baseline score (covariate), center, and treatment. Extrapyramidal symptoms were assessed using the Simpson-Angus Scale and the Barnes Akathisia Scale; abnormal involuntary movements were assessed using the Abnormal Involuntary Movement Scale. Frequency distributions of grouped change-from-baseline scores were analyzed using chi 2 tests. Of 280 patients in whom the efficacy of quetiapine was evaluated, 159 (42% of those receiving high-dose treatment; 57%, low-dose treatment; and 59%, placebo) withdrew before trial completion, primarily because of treatment failure. Significant (P < .001, BPRS; P = .003, Clinical Global Impression Severity of Illness item; and P = .003, BPRS positive-symptom cluster) differences were identified between patients receiving high-dose quetiapine and placebo for both primary efficacy variables, with end point differences in the BPRS positive-symptom cluster score showing quetiapine's consistency in reducing positive symptoms. The reduction of negative symptoms was less consistent; high-dose quetiapine was superior on the Modified Scale for the Assessment of Negative Symptoms but not on the negative scale of the Positive and Negative Syndrome Scale. Quetiapine was well tolerated and did not induce extrapyramidal symptoms, sustained elevations of prolactin, or clinically significant changes in hematologic parameters. Quetiapine is an effective antipsychotic with a favorable safety profile. The optimum dose is probably greater than 250 mg/d.
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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.
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Olanzapine is a new atypical antipsychotic recently introduced for the treatment 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. Twelve patients with schizophrenia were randomly assigned to 5, 10, 15, or 20 mg/day of olanzapine in a prospective fashion. Three other subjects taking 30-40 mg/day were also included. Once steady-state plasma levels were achieved, dopamine D2 and serotonin 5-HT2 receptors were assessed by using [11C]raclopride and [18F]setoperone positron emission tomography imaging, respectively. Ratings of clinical status, extrapyramidal side effects, and prolactin levels were also obtained. Olanzapine induced near saturation of the 5-HT2 receptors, even at 5 mg/day. Its D2 occupancy increased with dose: patients taking 5-20 mg/day showed 43%-80% D2 occupancy, while patients taking 30-40 mg/day showed 83%-88%. Olanzapine is a potent 5-HT2 blocker and shows a higher 5-HT2 than D2 occupancy at all doses. However, its D2 occupancy is higher than that of clozapine and similar to that of risperidone. In the usual clinical dose range of 10-20 mg/day, its occupancy varies from 71% to 80%, and this restricted range may explain its freedom from extrapyramidal side effects and prolactin elevation. However, doses of 30 mg/day and higher are associated with more than 80% D2 occupancy and may have a higher likelihood of prolactin elevation and extrapyramidal side effects.
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In an attempt to understand the basis of early relapse after antipsychotic withdrawal, the objective of this study was to determine whether the low occupancy of dopamine D2 receptors by clozapine and by quetiapine, as seen by brain imaging, could arise from a rapid release of some of the D2-bound clozapine or quetiapine by the brain imaging compounds and by the action of a physiological concentration of dopamine. Human cloned D2 receptors were first pre-equilibrated with the [3H]antipsychotic drug, after which raclopride, iodobenzamide, or dopamine (at the physiological concentration in the synapse) was added, and the time course of release of the [3H]antipsychotic from the D2 receptor was measured. Within 5 minutes, low concentrations of raclopride and iodobenzamide displaced appreciable amounts of [3H]clozapine and [3H]quetiapine from the D2 receptors but, during the course of 1 hour, did not displace any of the other antipsychotic [[3H]ligands. [3H]Clozapine and [3H]quetiapine, moreover, were displaced by dopamine (100 nM) at least 100 times faster than the other antipsychotic [3H]ligands. Clozapine and quetiapine are loosely bound to the D2 receptor, and the injected radioactive ligand at its peak concentration may displace some of the D2-bound antipsychotic drug, resulting in apparently low D2 occupancies. Therefore, under clinical brain imaging conditions with [11C]raclopride, D2 occupancies by clozapine and by quetiapine may be higher than currently estimated. These considerations may result in high levels of the D2 receptors being occupied by therapeutic doses of clozapine or quetiapine. The rapid release of clozapine and quetiapine from D2 receptors by endogenous dopamine may contribute to low D2 receptor occupancy and to early clinical relapse upon withdrawal of these medications.
Article
One of the take-home messages from our recent report regarding the clinical and biological effects of the atypical neuroleptic, clozapine, was that the admixture of clozapine's effects on dopaminergic, serotonergic, and noradrenergic systems may underlie its unique efficacy in otherwise poorly responsive patients with schizophrenia.1 We agree with a suggestion by R. W. Pies, MD, (unpublished communication to the Archives, May 1992) that clozapine's diverse pharmacologic properties indicate strategies for augmentation of neuroleptic drugs in treatment-resistant patients and that thioridazine or mesoridazine besylate may be particularly useful, given their relatively low incidence of extrapyramidal side effects. Whereas much attention has been given to the 5-hydroxytryptamine2 (5-HT2) antagonism of clozapine, including the ratio of 5-HT2 to D2 affinities as a predictor of neuroleptic atypicality,2 we have noted that clozapine's relatively potent α2-antagonism (putatively contributing to observed increases in norepinephrine turnover) is distinct among
Article
Background: Antipsychotic drugs in depot formulations may prevent psychotic relapses, even after complete withdrawal. To examine the duration of drug remaining in the brain, central D2 dopamine receptor occupancy was measured with positron emission tomography for a year after discontinuation of depot neuroleptic treatment.Methods: Four schizophrenic patients were withdrawn from low-dose treatment with haloperidol decanoate (30-50 mg every 4 weeks). They were examined repeatedly with positron emission tomography and the radioligand carbon 11-labeled raclopride during the following year. At end point, a Scatchard analysis was performed to determine the density and affinity of D2 dopamine receptors.Results: Occupancy of D2 dopamine receptors was highest 1 week after depot injection (66%, 77%, 82%, and 78% in 4 patients) and then decreased slowly. Six months after discontinuation of treatment, D2 dopamine receptor occupancy was 24%, 32%, and 34% in 3 patients. After 1 year, D2 dopamine receptor density and affinity in 2 patients were within the ranges of control subjects, suggesting no remaining haloperidol.Conclusions: Our preliminary finding of persistence of D22 dopamine receptor occupancy indicates that commonly used doses of haloperidol decanoate (200 mg every 4 weeks) maintain antipsychotic levels of receptor occupancy even 16 weeks after discontinuation of treatment. This may explain the lower relapse rates in patients withdrawn from depot neuroleptic treatment compared with those with-drawn from oral treatment. In addition, the remaining occupancy may confound the clinical evaluation of subsequent treatments. For controlled clinical trials of new antipsychotic drugs, we suggest a minimum washout of 6 months after the last depot injection.
Article
ICI 204,636 is a new, potentially atypical antipsychotic.In early phase II trials, the antipsychotic was well tolerated and results suggested efficacy in the treatment of the positive and negative symptoms of schizophrenia. The efficacy and safety of ICI 204,636 were evaluated on a larger scale in a 6-week, multicenter, double-blind trial. Hospitalized patients who met DSM-III-R criteria for chronic or subchronic schizophrenia with acute exacerbation, as well as other criteria, were randomized to ICI 204,636 (75 to 750 mg daily) (N = 54) or placebo (N = 55). Patients were assessed weekly by use of the Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Negative Symptoms (SANS), and Clinical Global Impression Scale (CGI) for efficacy and the Simpson Scale and Abnormal Involuntary Movement Scale for extrapyramidal side effects (EPS). Significant differences (p less or equal to 0.05) between treatment groups, which favored ICI 204,636, were identified throughout the trial. Endpoint differences were significant (by analysis of covariance) for BPRS factor IV (activation) and SANS scores and were marginally significant for total BPRS, BPRS factor III (thought disturbance), BPRS positive-symptom cluster, and CGI Severity of Illness item scores (p = 0.07, 0.09, 0.06, and 0.09, respectively). ICI 204,636 was well tolerated, although it was associated with mild transient increases in alanine aminotransferase and a higher incidence of somnolence and anticholinergic effects compared with placebo. In the dose range studied, treatment with ICI 204,636 did not induce EPS as determined by analysis of Simpson Scale total scores and lack of treatment-emergent acute dystonic reactions. Furthermore, ICI 204,636 did not produce sustained levels of prolactin; the mean change from baseline at endpoint (-7.2 micro gram/L) was comparable (p = 0.44) to that for placebo (-8.2 micro gram/L). These findings distinguish ICI 204,636 from standard antipsychotics and confirm preclinical predictions that ICI 204,636 is an atypical antipsychotic. (J Clin Psychopharmacol 1996;16:158-169).
Article
Unlabelled: Movement during or between PET examinations is a common and serious problem. Consequently, there is a great need for rapid, accurate and robust methods to realign image sets. Methods: Derivative information from the image sets was used to extract areas containing edge information. Image similarity between a reference dataset and a misaligned dataset was evaluated for these areas. Powell's method for function minimization was used to find the set of translations and rotations along and around the axes that maximized image similarity. The method was validated by realigning image sets with a known misalignment. Image sets used for validation included brain studies using several different tracers and heart studies using labeled acetate or water. Results: The method was capable of labeled acetate or water. Results: The method was capable of realigning brain datasets using the same tracer with an accuracy of 0.2 mm and 0.2 degrees along and around all axes. The same accuracy was obtained for datasets with as few as a total of 800,000 counts. Brain studies utilizing different tracers with markedly dissimilar regional uptake patterns were realigned with an accuracy of 1.5 mm and 1.5 degrees. Heart studies using water or acetate were realigned with an accuracy of 0.2 mm and 0.4 degrees along and around all axes. Realignment of a heart study containing a large focal uptake defect against a dataset without defect produced errors no greater than 1.0 mm and 1.0 degree. Conclusion: The use of derivative information provides a useful method to accurately realign PET image sets. It is rapid and noise-insensitive enough to allow for its routine use in dynamic studies.
Article
Five fixed doses of the atypical antipsychotic "Seroquel" (quetiapine) were evaluated to delineate a dose–response relationship and to compare efficacy and tolerability opposite placebo and haloperidol. This was measured by changes from baseline responses in the Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression (CGI), and Modified Scale for the Assessment of Negative Symptoms (SANS) summary scores. 361 18–64 yr olds hospitalized with schizophrenia completed a single-blind, placebo washout phase and were randomized to double-blind treatment with quetiapine (75, 150, 300, 600, or 750 mg daily), haloperidol, or placebo and evaluated weekly for 6 wks. Differences in adjusted mean changes from baseline were identified between the 4 highest doses of quetiapine and placebo for BPRS total, BPRS positive-symptom cluster, and CGI Severity of Illness item scores and between quetiapine 300 mg and placebo for SANS summary score. Dose-response modeling showssignificant linear and quadratic functions of quetiapine dose for all primary efficacy variables. Quetiapine is both superior to placebo and comparable to haloperidol in reducing positive symptoms at doses ranging from 150 to 750 mg/day and in reducing negative symptoms at a dose of 300 mg/day. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Article
Clozapine has an affinity for the dopamine (DA) D2 receptor which is relatively weak but is in line with its average clinical dose when compared with typical neuroleptic drugs. A few atypical antipsychotic drugs may have high absolute affinities for the D2 receptor, but most are weak D2 blockers. The atypical antipsychotic drugs also differ from the typical antipsychotic drugs by a relatively high affinity for the serotonin (5-HT2) receptor. This is evident on both in vitro and in vivo binding to cortical 5-HT2 receptors. The atypical antipsychotics are best distinguished from the typical antipsychotics on the basis of the relationship between strong 5-HT2 and weak D2 affinities. High D1 receptor binding is not characteristic of the group of atypical drugs. A new group of putative atypical antipsychotic drugs with high affinities for 5-HT2 compared to D2 receptors is under study.
Article
Central D2-dopamine receptor occupancy was followed by repeated PET experiments after administration of single oral doses of haloperidol to four healthy men. D2-dopamine receptor occupancy was high already 3 h after administration of 4 and 7.5 mg haloperidol and remained high for at least 27 h. Akathisia appeared when D2-dopamine receptor occupancy was maximal. After initiation of neuroleptic drug treatment several days or weeks may elapse before antipsychotic effect is evident. The results of this study do not indicate that any late onset of the antipsychotic effect is related to an insufficient D2-dopamine receptor occupancy during the first days of treatment.
Article
Atypical antipsychotic drugs such as clozapine, fluperlapine, and melperone produce weak catalepsy in rodents, and minimal extrapyramidal symptoms and serum prolactin elevations in humans, compared to typical antipsychotic drugs such as haloperidol. The biological basis for these differences has been attributed to relatively weak blockade at D2 dopamine (DA) receptors, various effects at D1 receptors, or potent serotonin2 (5-HT2) antagonism, although other possibilities exist. To clarify the relative importance of actions at D1, D2, and 5-HT2 receptors for identification of candidate typical and atypical drugs, we determined the negative log of the Ki (pKi) value of 21 typical and 17 atypical antipsychotic drugs for the striatal D1 and D2 and frontal cortex 5-HT2 receptors of rodent brain. Cluster analysis identified that the 5-HT2/D2 ratio was the most successful means of utilizing this data to classify typical and atypical antipsychotic drugs correctly. A 92 percent accuracy was achieved.
Article
By means of positron emission tomography the uptake and kinetics of N-(methyl-11C)clozapine in different brain regions have been studied in Rhesus monkeys. 11C-clozapine rapidly entered the brain and maximum radioactive uptake was seen 5-12 min after administration. Highest uptake was measured in the striatum. Other regions with an uptake higher than in the cerebellum were thalamus and mesencephalon. The radioactivity from different brain regions decreased with an elimination half-life of about 5 h and parallelled the plasma kinetics of unlabelled clozapine. The striatum/cerebellum ratio of 11C-clozapine-derived radioactivity remained constant during the period studied and did not change after pretreatment with atropine. In contrast, the striatum/cerebellum ratio was somewhat lower after pretreatment with N-methylspiperone (NMSP), indicating competition for the same binding sites in the striatum. After pretreatment with increasing doses of clozapine, a dose-dependent protection of binding sites in the striatum for 11C-NMSP was seen. It is concluded that clozapine is more loosely bound to dopamine receptors in the striatum than N-methylspiperone and that the kinetics of clozapine in the brain parallel that in the plasma. The binding properties of clozapine within the brain may explain some of the clinical properties of the drug.
Article
The regional distribution of 3 11C-labelled dopamine receptor antagonists, N-methyl spiperone, raclopride and clozapine, in the brain of Rhesus monkeys was studied by positron emission tomography (PET). The measured radioactivities in the striatal area were similar for the 3 antagonists, although the highest selectivity as compared to cerebellum was found for 11C-raclopride 60 min after administration. The selectivity of the radiotracers for the serotonin and D2-dopamine receptors was evaluated after pretreatment of the monkeys with serotonin and dopamine receptor antagonists. 11C-N-methylspiperone and 11C-clozapine both bound to serotonin receptors in the frontal cortex and to D2-dopamine receptors in the striatal area. Raclopride was selectively bound to the D2-dopamine receptors. The radioactivities measured in the striatal area with cerebellum as reference were fitted to a 3-compartment model which made possible evaluation of receptor binding characteristics. The rate proportional to the association rate constant for the receptor, kon and number of receptors, Bmax, varied from 0.02-0.07 min-1 between the studied radiolabelled drugs, whereas the apparent dissociation rate was highest for clozapine. This means that clozapine had the lowest affinity for the receptors in the striatum, assuming that the Bmax values are identical. The observed difference in selective receptor binding and binding characteristics of the 3 tracers may have an influence both on the clinical efficacy and side effects of the studied dopamine receptor antagonists.
Article
The method of graphical analysis for the evaluation of sequential data (e.g., tissue and blood concentrations over time) in which the test substance is irreversibly trapped in the system has been expanded. A simpler derivation of the original analysis is presented. General equations are derived that can be used to analyze tissue uptake data when the blood-plasma concentration of the test substance cannot be easily measured. In addition, general equations are derived for situations when trapping of the test substance is incomplete and for a combination of these two conditions. These derivations are independent of the actual configuration of the compartmental system being analyzed and show what information can be obtained for the period when the reversible compartments are in effective steady state with the blood. This approach is also shown to result in equations with at least one less nonlinear term than those derived from direct compartmental analysis. Specific applications of these equations are illustrated for a compartmental system with one reversible region (with or without reversible binding) and one irreversible region.
Article
In two patients with chronic schizophrenia, who were on clozapine medication for more than 6 months, a sudden withdrawal of the drug resulted in a very pronounced deterioration of the psychosis within 24-48 h. The most prominent symptoms were auditory hallucinations and persecutory ideas and one patient tried to commit suicide. These observations are interpreted as supersensitivity psychoses induced by the very effective clozapine treatment.
Article
It has been suggested that a combined blockade of 5-HT2 and D2 dopamine receptors may be superior to D2 dopamine antagonists alone in the treatment of schizophrenia. Risperidone, which has a high affinity for 5-HT2 and D2 dopamine receptors in vitro, is a new antipsychotic drug that has been developed according to this hypothesis. The aim of this study was to examine if risperidone indeed induces 5-HT2 and D2 dopamine receptor occupancy in vivo in humans. Central receptor occupancy was examined by positron emission tomography (PET) in three healthy men after oral administration of 1 mg risperidone. [11C]N-methylspiperone ([11C]NMSP) was used as a radioligand for determination of 5-HT2 receptor occupancy in the neocortex. Both an equilibrium ratio analysis and a kinetic three-compartmental analysis indicated a 5-HT2 receptor occupancy about 60%. [11C]raclopride was used as a radioligand for determination of D2 dopamine receptor occupancy in the striatum and the calculated occupancy was about 50%. This is the first quantitative determination of 5-HT2 receptor occupancy induced by an antipsychotic drug in the living human brain. The results indicate that 5-HT2 receptor occupancy should be very high at the dose level of 4-10 mg risperidone daily, as suggested for clinical use. Risperidone is thus an appropriate compound for clinical evaluation of the benefit of combined 5-HT2 and D2 dopamine receptor blockade in the treatment of schizophrenia.
Article
Positron emission tomography (PET) and 11C-raclopride were used to measure the occupancy of central dopamine D2 receptors by a new neuroleptic, CP-88,059-1. In a double blind dose escalation study, seven healthy male subjects received a predose of between 2 mg and 60 mg CP-88,059-1, 5 h before PET scanning. One additional subject was assigned to placebo predose. Receptor occupancy was defined as the percentage reduction in binding potential compared with that seen in the subject predosed with placebo and with that seen in seven unmedicated normal volunteers previously studied. Binding of 11C-raclopride decreased in a dose dependent manner, and 85% dopamine D2 receptor occupancy was achieved with the highest dose of CP-88,059-1. The findings confirm that brain dopamine D2 receptors are blocked by CP-88,059-1 and suggest that an effective antipsychotic dose will be between 20 mg and 40 mg. The study high-lights the potential of positron emission tomography in the preclinical evaluation of new drugs.
Article
ICI 204,636 is a new, potentially atypical antipsychotic. In early phase II trials, the antipsychotic was well tolerated and results suggested efficacy in the treatment of the positive and negative symptoms of schizophrenia. The efficacy and safety of ICI 204,636 were evaluated on a larger scale in a 6-week, multicenter, double-blind trial. Hospitalized patients who met DSM-III-R criteria for chronic or subchronic schizophrenia with acute exacerbation, as well as other criteria, were randomized to ICI 204,636 (75 to 750 mg daily) (N = 54) or placebo (N = 55). Patients were assessed weekly by use of the Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Negative Symptoms (SANS), and Clinical Global Impression Scale (CGI) for efficacy and the Simpson Scale and Abnormal Involuntary Movement Scale for extrapyramidal side effects (EPS). Significant differences (p < or = 0.05) between treatment groups, which favored ICI 204,636, were identified throughout the trial. Endpoint differences were significant (by analysis of covariance) for BPRS factor IV (activation) and SANS scores and were marginally significant for total BPRS, BPRS factor III (thought disturbance), BPRS positive-symptom cluster, and CGI Severity of Illness item scores (p = 0.07, 0.09, 0.06, and 0.09, respectively). ICI 204,636 was well tolerated, although it was associated with mild transient increases in alanine aminotransferase and a higher incidence of somnolence and anticholinergic effects compared with placebo. In the dose range studied, treatment with ICI 204,636 did not induce EPS as determined by analysis of Simpson Scale total scores and lack of treatment-emergent acute dystonic reactions. Furthermore, ICI 204,636 did not produce sustained levels of prolactin; the mean change from baseline at endpoint (-7.2 micrograms/L) was comparable (p = 0.44) to that for placebo (-8.2 micrograms/L). These findings distinguish ICI 204,636 from standard antipsychotics and confirm preclinical predictions that ICI 204,636 is an atypical antipsychotic.
Article
The distribution volume ratio (DVR), which is a linear function of receptor availability, is widely used as a model parameter in imaging studies. The DVR corresponds to the ratio of the DV of a receptor-containing region to a nonreceptor region and generally requires the measurement of an arterial input function. Here we propose a graphical method for determining the DVR that does not require blood sampling. This method uses data from a nonreceptor region with an average tissue-to-plasma efflux constant k2 to approximate the plasma integral. Data from positron emission tomography studies with [11C]raclopride (n = 20) and [11C]d-threo-methylphenidate ([11C]dMP) (n = 8) in which plasma data were taken and used to compare results from two graphical methods, one that uses plasma data and one that does not. k2 was 0.163 and 0.051 min-1 for [11C]raclopride and [11C]dMP, respectively. Results from both methods were very similar, and the average percentage difference between the methods was -0.11% for [11C]raclopride and 0.46% for [11C]dMP for DVR of basal ganglia (BG) to cerebellum (CB). Good agreement between the two methods was also achieved for DVR images created by both methods. This technique provides an alternative method of analysis not requiring blood sampling that gives equivalent results for the two ligands studied. It requires initial studies with blood sampling to determine the average kinetic constant and to test applicability. In some cases, it may be possible to neglect the k2 term if the BG/CB ratio becomes reasonably constant for a sufficiently long period of time over the course of the experiment.
Article
The reference tissue model allows for quantification of receptor kinetics without measuring the arterial input function, thus avoiding arterial cannulation and time-consuming metabolite measurements. The model contains four parameters, of which the binding potential (BP) is the parameter of interest. Although BP is robust, convergence rates are slow and the other parameters can have large standard errors. To overcome this problem, a simplified reference tissue containing only three parameters was developed. This new three-parameter model was compared with the previous four-parameter model using a variety of PET studies: [11C]SCH 23390 (D1 receptor) and [11C]raclopride (D2 receptor) in humans, and [11C]SCH 23390, [11C]raclopride and [11C]RTI-121 (dopamine transporter) in rats. The BP values obtained from both models were essentially the same for all cases. In addition, the three-parameter model was insensitive to starting values, produced stable results for the other parameters (small standard errors), and converged rapidly. In conclusion, for the ligands tested the three-parameter model is a better choice, combining increased convergence rate with increased stability.
Article
A 6-week, double-blind, randomized, multicentre, parallel-group study was conducted to compare the efficacy of quetiapine ('Seroquel') (n=101) with that of chlorpromazine (n=100) in hospitalized patients with acute exacerbation of subchronic or chronic schizophrenia, or schizophreniform disorder. The tolerabilities of the two treatments were also compared. The mean daily doses of quetiapine and chlorpromazine at the end of the study were 407 mg and 384 mg, respectively. Both treatments were effective in the treatment of positive and negative symptoms, with a trend towards superior efficacy for quetiapine. The quetiapine group had a lower incidence of adverse events than the chlorpromazine group, and a low incidence of treatment-emergent extrapyramidal symptoms. Quetiapine was not associated with a sustained increase in serum prolactin. These clinical data support the preclinical profile of quetiapine as an atypical antipsychotic agent.
Article
Quetiapine (Seroquel) is a novel antipsychotic with an atypical profile in animal models and a relatively short plasma half-life of 2.5 5 h. In the present study, we used PET to compare the time course of blockade of dopamine D2 and serotonin 5HT2 receptors of quetiapine using C11-raclopride and C11-N-methyl-spiperone as ligands, parallel to monitoring plasma drug concentrations. It was an open study in 11 schizophrenic men using a fixed dose of 450 mg quetiapine. Eight men completed the 29 days treatment, followed by four PET scans performed over a 26-h period after withdrawal of the compound. Quetiapine was shown to bind to dopamine D2 receptors in striatum and 2 h (t[max]) after the last dose, 44% receptor occupancy was calculated. After 26 h it had dropped to the same level as was found in untreated healthy volunteers. Serotonin 5HT2 receptor blockade in the frontal cortex was 72% after 2 h, which declined to 50% after 26 h. The terminal plasma half-life of quetiapine was 5.3 h. Clinically, our eight patients had good antipsychotic effect without any extrapyramidal side-effects. Our data shows that quetiapine has a relatively low affinity for dopamine D2 receptors, with an occupancy half-life (10 h), which was about twice as long as that for plasma. A more prolonged blockade of the serotonin 5HT2 receptors was found in the frontal cortex, with receptor occupancy half-life of 27 h. Compared to clozapine, as demonstrated in other studies, quetiapine has much the same ratio of D2/5HT2 occupancy. This could suggest that the combination of D2/5HT2 receptor blockade contributes to the antipsychotic effect and a low incidence of EPS seen with quetiapine in comparative phase three trials. Our results also confirm the clinical data that quetiapine can be administered twice daily.
Article
The occupancy of the atypical neuroleptic quetiapine (Seroquel) at the D2 dopamine receptor was investigated using the PET tracers [11C]raclopride and N-[11C]methylspiperone in a group of five schizophrenic patients. A steady-state treatment condition was ensured by dosing the patients with 750 mg quetiapine daily during 3 weeks followed by a period of tapering off the dose. For each patient, PET examinations were performed with both tracers at two of the following doses: 750, 450, 300 and/or 150 mg. As control, a group of six healthy untreated volunteers was investigated. The D2 binding potential in the putamen and the caudate nucleus was determined by using an evaluation method based on the method proposed by Patlak and Blasberg. The receptor occupancy was determined by assuming that the group of healthy volunteers is representative of untreated drug-naive schizophrenic patients. While a significant linear trend of increasing occupancy with increasing quetiapine dose (reaching 51% +/- 10% occupancy at the 750 mg dose) was detected with [11C]raclopride (P < 0.01), no such trend was apparent for N-[11C]methylspiperone (P > 0.09, maximal occupancy values were 2% +/- 3%, measured for the group of three patients on 450 mg). The study suggests that N-[11C]methylspiperone cannot be used for the assessment of D2 receptor occupancy induced by quetiapine. The result is discussed in terms of endogenous dopamine, tracer kinetics and equilibrium dissociation constants.
Article
Schizophrenia is a chronic and debilitating disorder whose effective pharmacological management is often less than optimal. For several decades, pharmaceutical treatment for this disorder consisted of conventional neuroleptics such as haloperidol and chlorpromazine. However, the limitations of these drugs have driven the development of newer antipsychotics that are designed to be more efficacious and more tolerable than conventional agents. Newer agents available for consideration as first-line treatment options now include risperidone, olanzapine, sertindole and, more recently, quetiapine. Proper dosing has emerged as a vital factor in the effective use of these newer drugs. This report examines data derived from clinical trials and market research with risperidone and olanzapine to help clinicians determine the appropriate dose for efficacy and to appraise the adverse events associated with that efficacious dose. Current information suggests that, for most patients with schizophrenia, the optimal dose with respect to efficacy and tolerability of risperidone is < or = 6 mg/day. The optimal dose of olanzapine is less clear and may be 15 mg/day or higher. With the advent of these newer antipsychotics, clinicians now have more treatment options for the management of patients with psychotic disorders. Knowledge gained through clinical experience is needed to augment clinical trial results and to help define the most effective use of each of these agents.
Article
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. 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. 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. 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.
Article
Multicenter trials with the novel antipsychotic risperidone have suggested a standard dose of 6 mg/day. However, a dose producing the highest response rate in fixed-dose studies is likely to exceed the minimal effective dose in most patients. The aim of this positron emission tomography (PET) study was to suggest a minimal effective dose of risperidone based on measurements of dopamine D2 and serotonin 5-HT2A receptor occupancy. Eight first-episode or drug-free schizophrenic patients were treated with risperidone, 6 mg/day, for 4 weeks and then 3 mg/day for 2 weeks. PET was performed after 4 and 6 weeks, with [11C]raclopride to measure D2 receptor occupancy and [11C]N-methylspiperone to measure 5-HT2A receptor occupancy. Seven patients completed the study and responded to treatment with risperidone. No patient had extrapyramidal side effects at the time of inclusion in the study. At the 6-mg/day dose, mean D2 receptor occupancy was 82% (range = 79%-85%), 5-HT2A receptor occupancy was 95% (range = 86%-109%), and six patients had developed extrapyramidal side effects. After dose reduction to 3 mg/day, D2 receptor occupancy was 72% (range = 53%-78%), and 5-HT2A receptor occupancy was 83% (range = 65%-112%). Three patients had extrapyramidal side effects at this time. Treatment with risperidone, 6 mg/day, is likely to induce unnecessarily high D2 receptor occupancy, with a consequent risk of extrapyramidal side effects. High 5-HT2A receptor occupancy did not prevent extrapyramidal side effects completely. The authors previously suggested an optimal interval for D2 receptor occupancy of 70%-80%. To achieve this, resperidone, 4 mg/day, should be a suitable initial dose for antipsychotic effect with a minimal risk of extrapyramidal side effects in most patients.
Article
A sensitive and specific HPLC assay for the measurement of the antipsychotic compound quetiapine in human plasma has been developed and validated. The assay employs a three-step liquid liquid extraction of quetiapine and its 7-hydroxylated and 7-hydroxylated, N-dealkylated metabolites from human plasma, and utilizes ultraviolet (UV) detection of quetiapine and electrochemical detection of the metabolites. The method provides a linear response from a quantitation limit of 2.50 to 500 ng ml(-1) for each analyte using 0.4 ml plasma. The assay is applicable from 500 to 5000 ng ml(-1) by sample dilution with de-ionized water. The inter-assay precision of quetiapine in plasma calibration standards across 4 validation days averaged 11.9% relative standard deviation (RSD) over the range 2.50 to 500 ng ml(-1), with intra-assay precision averaging 16.0% RSD and mean accuracy of 98.6% of theory. Similarly, the inter-assay precision of the 7-hydroxylated metabolite in plasma calibration standards across 4 validation days averaged 13.7% RSD over the range 2.50 to 500 ng ml(-1), with intra-assay precision averaging 17.6% RSD and mean accuracy of 109% of theory. The 7-hydroxylated, N-dealkylated metabolite demonstrated inter-assay precision of 16.2% RSD, intra-assay precision of 19.9% RSD, and mean accuracy of 104% of theory over the range 2.50 to 500 ng ml(-1). The present assay method was used to support a study comparing the pharmacokinetic profile of quetiapine with the time course of dopamine D2 and serotonin 5-HT2 receptor occupancy in the brain using positron emission tomography (PET). We describe in this paper the bioanalytical method and the plasma concentrations of quetiapine and its metabolites resulting from this study.
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Risperidone and olanzapine: optimal dosing for efficacy and tolerability in patients with schizophrenia
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Time course of D2 dopamine receptor occupancy examined by PET after single oral doses of haloperidole
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A positron emission tomography study of quetiapine in schizophrenia
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Dose dependent occupancy of central dopamine D2 receptors by the novel neuroleptic CP-88,059-01: a study using positron emission tomography and 11C-raclopride
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Antipsychotic action with low D2 occupancy: a study of quetiapine
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Clozapine for the treatment-resistant schizophrenic — a double-blind comparison with chlorpromazine
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