Previous treatment as a confounding variable in studies with novel antipsychotics: two cases of high dopamine-2 receptor occupancy with quetiapine

Tauscher, Johannes; Küfferle, B.; Asenbaum, S.; Brücke, Thomas; Kasper, Siegfried

doi:10.1007/s002130050378

Cited by 19 publications

(3 citation statements)

References 10 publications

(16 reference statements)

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“…One of the most important confounding variable is premedication with typical neuroleptics and speciÞcally with depot formulations. As already previously shown, pretreatment with depot-neuroleptics with a pause for as long as 3 months is associated with higher striatal D 2 receptor occupancy rates (Harasko-van der Meer et al 1993;Tauscher et al 1997). We were also able to detect this phenomenon during sertindole treatment in two of our patients who were pretreated with depot medication.…”

Section: Discussionsupporting

confidence: 69%

Sertindole and dopamine D 2 receptor occupancy in comparison to risperidone, clozapine and haloperidol - a 123 I-IBZM SPECT study

et al. 1998

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The striatal D2 dopamine binding was studied in schizophrenic patients treated with the novel atypical antipsychotic drug sertindole (n=10). Comparisons were obtained with haloperidol (n=8), clozapine (n=6), risperidone (n=11) and untreated healthy controls (n=8) of a dataset which has partly been reported previously. 123I-Iodobenzamide (IBZM) single photon emission computerized tomography (SPECT) was used for estimation of striatal dopamine D2 receptor binding. Sertindole-treated patients exhibited significantly (P < 0.001) lower levels of striatal D2 binding (BG/FC ratio:1.28) compared with those treated with haloperidol (BG/FC ratio:1.09) and risperidone (8 mg:1.18) but significantly (P < 0.005) higher levels compared with clozapine (BG/FC ratio: 1.49). However, if patients were pretreated with a depot neuroleptic, significantly (P < 0.05) higher striatal D2 binding (BG/FC ratio:1.12) has been obtained. Since sertindole has been shown to exert distinct clinical efficacy for treatment of positive and negative symptoms, our data are indicative that antipsychotic efficacy is not associated with a high degree of striatal D2 receptor occupancy in schizophrenic patients.

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Section: Discussionsupporting

confidence: 69%

Sertindole and dopamine D 2 receptor occupancy in comparison to risperidone, clozapine and haloperidol - a 123 I-IBZM SPECT study

et al. 1998

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“…Quetiapine (QT) acts as antagonist at the DA D2 receptor, as well as at the serotonin 2A (5-HT2A) receptor (dose-dependent, besides additional effects at the H1 and other 5-HT and adrenergic receptors). Specifically, QT is characterized by a high affinity for the 5-HT2A receptor and a fast dissociation rate (and low affinity) for the DA D2 receptor (Kessler et al, 2006), although it has also been shown that QT can have a high (striatal) DA D2 receptor occupancy in some cases (Tauscher et al, 1997; Pavics et al, 2004). Based on these pharmacological targets, QT is used to treat patients with schizophrenia, bipolar disorder, autism, and depression (Wen et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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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“…This persistence of haloperidol in the brain may explain the relatively low relapse rate in patients withdrawn from depot neuroleptic treatment compared with those withdrawn from oral treatment [51]. It also suggests that previous treatment can be a confounding variable in studies with novel antipsychotics, a phenomenon which was actually observed in SPECT studies of the brain [52]. It has been suggested that a minimum washout period of 6 months should be required in controlled clinical trials of novel antipsychotic drugs [51].…”

Section: Classical Neurolepticsmentioning

confidence: 99%

Measuring Receptor Occupancy with PET

Waarde¹

2000

CPD

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Many physiological and biochemical measurements can be performed noninvasively in humans with modern imaging techniques like magnetic resonance imaging (MRI), positron emission tomography (PET) or single-photon emission computed tomography (SPECT). This review focuses on the monitoring of drug-receptor interactions in patients and healthy volunteers with PET. Such studies depend on the availability of a suitable radioligand; they are already possible for classical and atypical neuroleptics, anxiolytics, antidepressants, anticholinergics, antihistamines, antiepileptics, beta-blockers and hypnotic drugs. In Phase I-II human studies, measurements of plasma pharmacokinetics can be combined with images of receptor occupancy and be quantitatively related to pharmacologic effects which are induced in the same subjects. Optimal dosing schedules can be defined and valuable information for the design of Phase III studies can be acquired. Moreover, the effect of interventions (e.g. change of dose, additional medication) can be predicted. Medical imaging techniques will play an increasing role in clinical pharmacology and allow well-informed go/no-go decisions in future drug development.

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Previous treatment as a confounding variable in studies with novel antipsychotics: two cases of high dopamine-2 receptor occupancy with quetiapine

Cited by 19 publications

References 10 publications

Sertindole and dopamine D 2 receptor occupancy in comparison to risperidone, clozapine and haloperidol - a 123 I-IBZM SPECT study

Sertindole and dopamine D 2 receptor occupancy in comparison to risperidone, clozapine and haloperidol - a 123 I-IBZM SPECT study

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

Measuring Receptor Occupancy with PET

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