Serotonin2A receptor blockade and clinical effect in first-episode schizophrenia patients treated with quetiapine

Rasmussen, Henrik; Ebdrup, Bjørn H; Erritzoe, David; Aggernæs, Bodil; Oranje, Bob; Kalbitzer, Jan; Pinborg, Lars H.; Baaré, William F.C.; Svarer, Claus; Lublin, Henrik; Knudsen, Gitte M.; Glenthøj, Birte

doi:10.1007/s00213-010-1941-5

Cited by 38 publications

(15 citation statements)

References 47 publications

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“…**p<0.01, significant decrease in DI compared with the vehicle group. # p<0.05, significant reversal in DI compared with PCP group study which measured 5-HT 2A receptor occupancy with [ 18 F] altanserin PET in 15 first-episode antipsychotic-naïve schizophrenia patients before and after 6 months of quetiapine treatment reported that a 5-HT 2A receptor occupancy level between 60% and 70% appeared to exert the optimal 5-HT 2A receptor-related treatment effect on positive symptoms (Rasmussen et al 2010). It is noteworthy that co-administration of LY379268 and sub-effective doses of the atypical APDs, clozapine and lurasidone, but not haloperidol or pimavanserin, ameliorated the subchronic PCP-induced NOR deficit.…”

Section: Discussionmentioning

confidence: 91%

Interaction of mGlu2/3 agonism with clozapine and lurasidone to restore novel object recognition in subchronic phencyclidine-treated rats

2011

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These results indicate that mGlu₂/₃ agonism can potentiate the ability of atypical, but not typical APDs, to ameliorate the effect of subchronic PCP on NOR, that mGlu₂/₃ agonism may contribute to the ability of atypical APDs to acutely reverse the effect of subchronic PCP on NOR, but that by itself, mGlu₂/₃ agonism, is ineffective in this model of cognitive impairment in schizophrenia. These results suggest that mGlu₂/₃ receptor agonism should be investigated as an adjunctive treatment of cognitive impairment in schizophrenia rather than as monotherapy, which may be effective for control of psychosis, but not for cognitive impairment.

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Section: Discussionmentioning

confidence: 91%

Interaction of mGlu2/3 agonism with clozapine and lurasidone to restore novel object recognition in subchronic phencyclidine-treated rats

2011

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“…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. Thus, we cannot be absolutely certain about the pharmacological specificity of the QT effects alone.…”

Section: Discussionmentioning

confidence: 98%

Baseline Perfusion Alterations Due to Acute Application of Quetiapine and Pramipexole in Healthy Adults

Michels

Scherpiet

Staempfli³

et al. 2016

IJNPPY

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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 crossover, 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 nonergoline class) 1 hour before the experiment. Background-suppressed 2D pseudo-continuous arterial spin labeling was used to examine whole-brain baseline cerebral blood flow differences induced by the 3 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 cerebral blood flow (relative to placebo) in the striatal system (putamen and caudate nucleus) but also in the supplementary motor area, insular-, prefrontal- as well as in the pre- and postcentral cortex. Pramipexole increased cerebral blood flow compared with placebo in the caudate nucleus, putamen, middle frontal, supplementary motor area, and brainstem (substantia nigra), but reduced cerebral blood flow in the posterior thalamus, cerebellum, and visual areas. Pramipexole administration resulted in stronger cerebral blood flow relative to quetiapine in the hypothalamus, cerebellum, and substantia nigra.Conclusions:Our results indicate that quetiapine and pramipexole differentially modulate regional baseline cerebral blood flow. Both substances act on the dopaminergic system, although they affect distinct regions. Quetiapine altered dopaminergic function in frontal, striatal, and motor regions. In contrast, pramipexole affected cerebral blood flow of the nigrostriatal (striatum and substantia nigra) dopaminergic, but less the fronto-insular system.

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“…With the radiotracer altanserin, a 65% block was observed after 6 month treatment with 300 mg quetiapine [56]. The affinity of altanserin and quetiapine for 5-HT 2 A receptor was described with a K i value of 0.3 nM (Tan et al, 1999) and 264 nM, respectively.…”

Section: Methodsmentioning

confidence: 99%

Simulations of symptomatic treatments for Alzheimer's disease: computational analysis of pathology and mechanisms of drug action

Roberts

Spiros

Geerts

2012

Alzheimers Res Ther

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IntroductionA substantial number of therapeutic drugs for Alzheimer's disease (AD) have failed in late-stage trials, highlighting the translational disconnect with pathology-based animal models.MethodsTo bridge the gap between preclinical animal models and clinical outcomes, we implemented a conductance-based computational model of cortical circuitry to simulate working memory as a measure for cognitive function. The model was initially calibrated using preclinical data on receptor pharmacology of catecholamine and cholinergic neurotransmitters. The pathology of AD was subsequently implemented as synaptic and neuronal loss and a decrease in cholinergic tone. The model was further calibrated with clinical Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) results on acetylcholinesterase inhibitors and 5-HT6 antagonists to improve the model's prediction of clinical outcomes.ResultsAs an independent validation, we reproduced clinical data for apolipoprotein E (APOE) genotypes showing that the ApoE4 genotype reduces the network performance much more in mild cognitive impairment conditions than at later stages of AD pathology. We then demonstrated the differential effect of memantine, an N-Methyl-D-aspartic acid (NMDA) subunit selective weak inhibitor, in early and late AD pathology, and show that inhibition of the NMDA receptor NR2C/NR2D subunits located on inhibitory interneurons compensates for the greater excitatory decline observed with pathology.ConclusionsThis quantitative systems pharmacology approach is shown to be complementary to traditional animal models, with the potential to assess potential off-target effects, the consequences of pharmacologically active human metabolites, the effect of comedications, and the impact of a small number of well described genotypes.

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Serotonin2A receptor blockade and clinical effect in first-episode schizophrenia patients treated with quetiapine

Cited by 38 publications

References 47 publications

Interaction of mGlu2/3 agonism with clozapine and lurasidone to restore novel object recognition in subchronic phencyclidine-treated rats

Interaction of mGlu2/3 agonism with clozapine and lurasidone to restore novel object recognition in subchronic phencyclidine-treated rats

Baseline Perfusion Alterations Due to Acute Application of Quetiapine and Pramipexole in Healthy Adults

Simulations of symptomatic treatments for Alzheimer's disease: computational analysis of pathology and mechanisms of drug action

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