UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Therapeutic window of dopamine D2/3 receptor occupancy to treat psychosis in Alzheimer's disease

Reeves, S; McLachlan, E; Bertrand, J; D'Antonio, F; Brownings, S; Nair, A; Greaves, S; ... Howard, R; + view all (2017) Therapeutic window of dopamine D2/3 receptor occupancy to treat psychosis in Alzheimer's disease. Brain , 140 (4) pp. 1117-1127. 10.1093/brain/aww359. Green open access

[img]
Preview
Text
Reeves_Manuscript_BrainInPress.pdf - Accepted version

Download (764kB) | Preview

Abstract

Antipsychotic drugs, originally developed to treat schizophrenia, are used to treat psychosis, agitation and aggression in Alzheimer’s disease. In the absence of dopamine D2/3 receptor occupancy data to inform antipsychotic prescribing for psychosis in Alzheimer’s disease, the mechanisms underpinning antipsychotic efficacy and side effects are poorly understood. This study used a population approach to investigate the relationship between amisulpride blood concentration and central D2/3 occupancy in older people with Alzheimer’s disease by combining: (i) pharmacokinetic data (280 venous samples) from a phase I single (50 mg) dose study in healthy older people (n = 20, 65–79 years); (ii) pharmacokinetic, 18F-fallypride D2/3 receptor imaging and clinical outcome data on patients with Alzheimer’s disease who were prescribed amisulpride (25–75 mg daily) to treat psychosis as part of an open study (n = 28; 69–92 years; 41 blood samples, five pretreatment scans, 19 post-treatment scans); and (iii) 18F-fallypride imaging of an antipsychotic free Alzheimer’s disease control group (n = 10, 78–92 years), to provide additional pretreatment data. Non-linear mixed effects modelling was used to describe pharmacokinetic-occupancy curves in caudate, putamen and thalamus. Model outputs were used to estimate threshold steady state blood concentration and occupancy required to elicit a clinically relevant response (>25% reduction in scores on delusions, hallucinations and agitation domains of the Neuropsychiatric Inventory) and extrapyramidal side effects (Simpson Angus Scale scores > 3). Average steady state blood levels were low (71 ± 30 ng/ml), and associated with high D2/3 occupancies (65 ± 8%, caudate; 67 ± 11%, thalamus; 52 ± 11%, putamen). Antipsychotic clinical response occurred at a threshold concentration of 20 ng/ml and D2/3 occupancies of 43% (caudate), 25% (putamen), 43% (thalamus). Extrapyramidal side effects (n = 7) emerged at a threshold concentration of 60 ng/ml, and D2/3 occupancies of 61% (caudate), 49% (putamen) and 69% (thalamus). This study has established that, as in schizophrenia, there is a therapeutic window of D2/3 receptor occupancy for optimal treatment of psychosis in Alzheimer’s disease. We have also shown that occupancies within and beyond this window are achieved at very low amisulpride doses in Alzheimer’s disease due to higher than anticipated occupancies for a given blood drug concentration. Our findings support a central pharmacokinetic contribution to antipsychotic sensitivity in Alzheimer’s disease and implicate the blood-brain barrier, which controls central drug access. Whether high D2/3 receptor occupancies are primarily accounted for by age- or disease-specific blood–brain barrier disruption is unclear, and this is an important future area of future investigation, as it has implications beyond antipsychotic prescribing.

Type: Article
Title: Therapeutic window of dopamine D2/3 receptor occupancy to treat psychosis in Alzheimer's disease
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/brain/aww359
Publisher version: http://doi.org/10.1093/brain/aww359
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: amisulpride, Alzheimer’s, psychosis, D2/3 occupancy, 18F-fallypride
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Division of Psychiatry
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
URI: https://discovery.ucl.ac.uk/id/eprint/1544997
Downloads since deposit
75Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item