Estimating dopamine D₂ receptor occupancy for doses of 8 antipsychotics: a meta-analysis.
BACKGROUND
Dose equivalents based on dopamine D₂ receptor occupancy can be used to compare antipsychotics on D₂ receptor-mediated (adverse) effects such as extrapyramidal symptoms and altered emotional experiences. Previous meta-analyses modeling the dose-occupancy relationship hardly addressed potential heterogeneity of the imaging data.


OBJECTIVE
To model the relationship between dose and D₂ receptor occupancy for a series of frequently prescribed antipsychotics while addressing the potential heterogeneity of the imaging data.


METHODS
We conducted a meta-analysis on published D₂ receptor occupancy data (positron emission tomography and single-photon emission computed tomography) in patients with schizophrenia treated with antipsychotics. A nonlinear mixed effects model estimated the median D₂ receptor occupancy for a given antipsychotic dose. Heterogeneity between studies was investigated by incorporating study as a random effect in the model, in addition to patient- and study-specific explanatory variables.


RESULTS
Included were 51 studies, describing 606 patients (mean ± SD age, 32.2 ±10.8 years; 25.7% female). The models described the dose-occupancy relationship with narrow confidence bands around the therapeutic dose range. Maximum occupancy (95% confidence interval[CI]) was estimated for haloperidol (91.9%; 95% CI, 86.1-97.8), risperidone(92.4%; 95% CI, 81.8-100), olanzapine (96.5%; 95% CI,85.8-100), clozapine (61.7%; 95% CI, 49.2-74.2), quetiapine (49.1%; 95% CI, 18.7-79.6), aripiprazole (86.9%; 95% CI, 78.2-95.7), ziprasidone (82.9%; 95% CI, 44.9-100), and amisulpride (85.0%; 95% CI, 68.5-100). Interindividual differences explained most of the variability in occupancy values, besides significant heterogeneity between studies.


CONCLUSIONS
Dose-occupancy functions estimated the median level of dopamine D₂ receptor occupancy for 8 frequently prescribed antipsychotics in patients with schizophrenia. These dose equivalents can be used to compare antipsychotic effects in epidemiological studies and clinical practice.
Pharmacotherapy and Pharmaceutical Care, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Irene M
IM
Lako
Edwin R
ER
van den Heuvel
Henrikus
H
Knegtering
Richard
R
Bruggeman
Katja
K
Taxis
D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism; D001480:Basal Ganglia Diseases / Q000139:chemically induced; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D018492:Dopamine Antagonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D004644:Emotions / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D017711:Nonlinear Dynamics; D049268:Positron-Emission Tomography; D011485:Protein Binding; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D015899:Tomography, Emission-Computed, Single-Photon; D016896:Treatment Outcome; D055815:Young Adult
D014150:Antipsychotic Agents; C581293:DRD2 protein, human; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2