Therapeutic window of dopamine D2/3 receptor occupancy to treat psychosis in Alzheimer's disease.
See Caravaggio and Graff-Guerrero (doi:10.1093/awx023) for a scientific commentary on this article.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.
Division of Psychiatry, 149 Tottenham Court Road, London W1T 7NF, University College London, UK.|Department of Old Age Psychiatry, London, SE58AF, Kings College London, UK.
Suzanne
S
Reeves
Department of Old Age Psychiatry, London, SE58AF, Kings College London, UK.
Emma
E
McLachlan
UMR 1137 IAME INSERM University Paris 7, France; and Genetics Institute, WC1E6BT, University College London, UK.
Julie
J
Bertrand
Division of Psychiatry, 149 Tottenham Court Road, London W1T 7NF, University College London, UK.|Department of Old Age Psychiatry, London, SE58AF, Kings College London, UK.
Fabrizia
F
D'Antonio
Division of Psychiatry, 149 Tottenham Court Road, London W1T 7NF, University College London, UK.
Stuart
S
Brownings
Division of Psychiatry, 149 Tottenham Court Road, London W1T 7NF, University College London, UK.
Akshay
A
Nair
South London and Maudsley NHS Foundation Trust, London, SE58AZ, UK.
Suki
S
Greaves
South London and Maudsley NHS Foundation Trust, London, SE58AZ, UK.
Alan
A
Smith
South London and Maudsley NHS Foundation Trust, London, SE58AZ, UK.
David
D
Taylor
Division of Imaging Sciences, St Thomas Hospital, London, SE17EH, UK.
Joel
J
Dunn
Division of Imaging Sciences, St Thomas Hospital, London, SE17EH, UK.
Paul
P
Marsden
University of Alabama, Birmingham, AL 35294-4550, USA.
Robert
R
Kessler
Division of Psychiatry, 149 Tottenham Court Road, London W1T 7NF, University College London, UK.|Department of Old Age Psychiatry, London, SE58AF, Kings College London, UK.
Robert
R
Howard
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000523:psychology*; D000077582:Amisulpride; D014150:Antipsychotic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001549:Benzamides; D015259:Dopamine Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D049268:Positron-Emission Tomography; D011618:Psychotic Disorders / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000523:psychology*; D011759:Pyrrolidines; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D050637:Receptors, Dopamine D3 / Q000187:drug effects*; D012959:Socioeconomic Factors; D013469:Sulpiride / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome
D014150:Antipsychotic Agents; D001549:Benzamides; D015259:Dopamine Agents; C094948:N-((1-allyl-2-pyrrolidinyl)methyl)-5-(3-fluoropropyl)-2,3-dimethoxybenzamide; D011759:Pyrrolidines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D013469:Sulpiride; D000077582:Amisulpride
18F-fallypride; Alzheimer’s; D2/3 occupancy; amisulpride; psychosis