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Cited by 125Schizophrenia research and treatmentNeurotransmitter Receptor Influence on BehaviorParkinson's Disease Mechanisms and Treatments

Estimating Dopamine D2 Receptor Occupancy for Doses of 8 Antipsychotics: A Meta-Analysis

Lako, Irene M., van den Heuvel, Edwin R., Knegtering, Henrikus, Bruggeman, Richard, Taxis, Katja·2013·Journal of Clinical Psychopharmacology
DOI 10.1097/jcp.0b013e3182983ffa
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Abstract

RATIONALE: 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. OBJECTIVES: 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.

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  • PET imaging demonstrates a hyperbolic relationship between doses of antipsychotic and D2 receptor blockade.

    “Furthermore, PET imaging demonstrates a hyperbolic relationship between doses of antipsychotic and D2 receptor blockade.”

    From A Method for Tapering Antipsychotic Treatment That May Minimize the Risk of Relapse (2021) · cites this paper as Lako et al.91

  • Linear decrements of 10 percentage point D2 receptor occupancy from 90% for haloperidol require hyperbolic dose reductions.

    “Linear decrements of, eg, 10 percentage point D2 receptor occupancy from 90% for haloperidol require hyperbolic dose reductions (table 3b; decrements of 20 percentage points in figure 2c), with further medications shown in table 4 and supplementary tables S3–S11.”

    From A Method for Tapering Antipsychotic Treatment That May Minimize the Risk of Relapse (2021) · cites this paper as [91]

  • Taking the example of haloperidol, linear dose reductions from therapeutic doses of 4 mg produce increasingly large reductions in percentage points of D2 dopamine antagonism: 3.5 percentage points (4 to 3 mg), 6.1 percentage points (3 to 2 mg), 13.7 percentage points (2 to 1 mg), and 55.7 percentage points (1 to 0 mg).

    “Taking the example of haloperidol (figure 2 and table 3a),91 it is notable that linear dose reductions from therapeutic doses of 4 mg produce increasingly large reductions in percentage points of D2 dopamine antagonism: 3.5 percentage points (4 to 3 mg), 6.1 percentage points (3 to 2 mg), 13.7 percentage points (2 to 1 mg), and 55.7 percentage points (1 to 0 mg; figure 2b and table 3a).”

    From A Method for Tapering Antipsychotic Treatment That May Minimize the Risk of Relapse (2021) · cites this paper as [91]

  • Even reductions from 0.5 mg of haloperidol to 0 mg will produce a reduction in D2 antagonism of 40.0 percentage points, and reduction from 0.25 mg to 0 mg will produce a 25.5 percentage point reduction (larger than the change from 20 to 2 mg [19.6 percentage points]).

    “Indeed, even reductions from 0.5 mg of haloperidol (the smallest available tablet) to 0 mg will produce a reduction in D2 antagonism of 40.0 percentage points, and reduction from 0.25 mg (half the smallest tablet) to 0 mg will produce a 25.5 percentage point reduction (larger than the change from 20 to 2 mg [19.6 percentage points]);”

    From A Method for Tapering Antipsychotic Treatment That May Minimize the Risk of Relapse (2021) · cites this paper as [91]

  • There is some heterogeneity in the meta-analysis of PET studies indicating the likelihood of interindividual differences in receptor occupancy for a given dose, emphasizing the importance of individualized tapering guided by the patient's response to reductions.

    “It should also be noted that there is some heterogeneity in the meta-analysis of PET studies91 indicating the likelihood of interindividual differences in receptor occupancy for a given dose, emphasizing the importance of individualized tapering guided by the patient’s response to reductions.”

    From A Method for Tapering Antipsychotic Treatment That May Minimize the Risk of Relapse (2021) · cites this paper as [91]

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Authors
Lako, I. M., van den Heuvel, E. R., Knegtering, H., Bruggeman, R., & Taxis, K.
Affiliations
  • University Medical Center Groningen (NL)
  • University of Groningen (NL)
Corresponding author
  • Lako, Irene M.
  • Bruggeman, Richard
  • Taxis, Katja
ORCID
Venue
Journal of Clinical Psychopharmacology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2013-10
Volume
33
Issue
5
Pages
675-681
ISSN
0271-0749 (ISSN-L)
DOI
10.1097/jcp.0b013e3182983ffa
OpenAlex
W2136998407
Cited by
125
References
48
Citations by year
2026: 13 · 2025: 10 · 2024: 13 · 2023: 13 · 2022: 6 · 2021: 16 · 2020: 7 · 2019: 10 · 2018: 6 · 2017: 14 · 2016: 6 · 2015: 5 · 2014: 6
FWCI
0.77
Type
journal article
Language
en
Open access
closed
Locations
  • Journal of Clinical Psychopharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
  • TU/e Research Portal (submittedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
Keywords
dopamine D2 receptor occupancy, antipsychotic drugs, schizophrenia, haloperidol, risperidone, olanzapine, clozapine, quetiapine, aripiprazole, ziprasidone, amisulpride, dose equivalent, extrapyramidal symptoms, nonlinear mixed-effects models
MeSH terms
Adult, Basal Ganglia Diseases, Brain, Dose-Response Relationship, Drug, Emotions, Female, Humans, Male, Protein Binding, Schizophrenia, Antipsychotic Agents, Tomography, Emission-Computed, Single-Photon, Treatment Outcome, Receptors, Dopamine D2, Nonlinear Dynamics, Dopamine Antagonists, Positron-Emission Tomography, Young Adult, Dopamine D2 Receptor Antagonists

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