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

Abstract

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 20ng/ml and D2/3 occupancies of 43% (caudate), 25%(putamen), 43% (thalamus). Extrapyramidal side effects (n=7) emerged at a threshold 4 concentration of 60ng/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.5

Therapeutic D2/3 receptor occupancies and response with low amisulpride blood concentrations in very late‐onset schizophrenia‐like psychosis (VLOSLP)

“…Mild EPS (SAS score of 4) emerged at a lower threshold Caverage of 96 ng/ml (75 mg/day), and one participant developed akathisia (Barnes score of 3) at 129 ng/ml. In previously described AD participants, severe EPS (SAS scores of 11, 15 and 16) emerged at Caverage of 60, 61 and 62 ng/ml in three participants (Reeves et al, 2017). Figure 1 shows Caverage, plotted against SAS scores for (a) AD and (b) VLOSLP groups, separated on the basis of mild (scores of 3-5) and severe (scores of 6 or above) EPS.…”

“…As discussed previously (Reeves et al, 2017), tracers with higher affinity (low dissociation constant) such as [18F]fallypride require higher concentrations of competing drug to displace them from receptor sites than those of lower affinity, leading to lower apparent occupancy (Seeman, 2011;Seeman, 2014;Seeman and Van Tol, 1995). In vivo, this is particularly problematic if there is insufficient imaging time for the tracer to achieve equilibrium in the D2/3 rich striatum (Olsson and Farde, 2001;Xiberas et al, 2001;Vernaleken et al, 2011).…”

“…We have recently used an adapted [ 18 F]fallypride imaging protocol (Clark‐Papasavas et al, ; Dunn et al, ) to investigate the relationship between dose, blood drug concentration and central D2/3 receptor occupancy in older patients with Alzheimer's disease (AD) and VLOSLP who were prescribed amisulpride off label to treat psychosis symptoms, as part of an open treatment study. Amisulpride dose–concentration (Reeves et al, ), and concentration–occupancy profiles across a 25–75 mg/day dose range have been previously described in the AD group (Reeves et al, ). Low amisulpride blood concentrations (9–109 ng/ml), which in all but one individual were below the recommended optimal therapeutic range (100–319 ng/ml) (Hiemke et al, ; Sparshatt et al, ) for the treatment of positive symptoms in schizophrenia, were associated with high D2/3 receptor occupancies (43–84% in the caudate), symptomatic improvement and emergent EPS, which ranged from mild to severe (Reeves et al, ).…”

“…Amisulpride dose–concentration (Reeves et al, ), and concentration–occupancy profiles across a 25–75 mg/day dose range have been previously described in the AD group (Reeves et al, ). Low amisulpride blood concentrations (9–109 ng/ml), which in all but one individual were below the recommended optimal therapeutic range (100–319 ng/ml) (Hiemke et al, ; Sparshatt et al, ) for the treatment of positive symptoms in schizophrenia, were associated with high D2/3 receptor occupancies (43–84% in the caudate), symptomatic improvement and emergent EPS, which ranged from mild to severe (Reeves et al, ).…”

Region-specific blood-brain barrier transporter changes leads to increased sensitivity to amisulpride in Alzheimer’s disease

“…This has led to restrictions on the NHS use of this class of drugs in the pharmacological management of psychosis and agitation in dementia. Emerging evidence from research into amisulpride use in older people with Alzheimer’s disease (AD) psychosis suggests that blood-brain barrier (BBB) dysfunction may be an important contributor to this heightened sensitivity (Reeves et al 2017)(Caravaggio Fernando; Graff-Guerrero 2017).…”