Dopamine D2/3 Receptor Occupancy Following Dose Reduction Is Predictable With Minimal Plasma Antipsychotic Concentrations: An Open-Label Clinical Trial

Schizophr Bull. 2016 Jan;42(1):212-9. doi: 10.1093/schbul/sbv106. Epub 2015 Jul 28.


Background: Population pharmacokinetics can predict antipsychotic blood concentrations at a given time point prior to a dosage change. Those predicted blood concentrations could be used to estimate the corresponding dopamine D2/3 receptors (D2/3R) occupancy by antipsychotics based on the tight relationship between blood and brain pharmacokinetics. However, this 2-step prediction has never been tested.

Methods: Two blood samples were collected at separate time points from 32 clinically stable outpatients with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; mean ± SD age: 60.1 ± 7.3 years) to measure plasma concentrations of olanzapine or risperidone at baseline. Then, subjects underwent a dose reduction of olanzapine or risperidone and completed a [(11)C]-raclopride positron emission tomography scan to measure D2/3R occupancy in the putamen. The plasma concentration at the time of the scan was predicted with the 2 samples based on population pharmacokinetic model, using NONMEM. D2/3R occupancy was then estimated by incorporating the predicted plasma concentration in a hyperbole saturation model. The predicted occupancy was compared to the observed value.

Results: The mean (95% CI) prediction errors for the prediction of D2/3R occupancy were -1.76% (-5.11 to 1.58) for olanzapine and 0.64% (-6.18 to 7.46) for risperidone. The observed and predicted D2/3R occupancy levels were highly correlated (r = 0.67, P = .001 for olanzapine; r = 0.67, P = .02 for risperidone).

Conclusions: D2/3R occupancy levels can be predicted from blood drug concentrations collected prior to dosage change. Although this 2-step model is subject to a small degree of error, it could be used to select oral doses aimed at achieving optimal D2/3R occupancy on an individual basis.

Keywords: PET; antipsychotics; dopamine; olanzapine; population pharmacokinetics; prediction; risperidone; schizophrenia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antipsychotic Agents / administration & dosage*
  • Antipsychotic Agents / metabolism
  • Benzodiazepines / administration & dosage
  • Benzodiazepines / metabolism
  • Brain / diagnostic imaging*
  • Brain / metabolism
  • Carbon Radioisotopes
  • Chromatography, Liquid
  • Female
  • Humans
  • Male
  • Middle Aged
  • Olanzapine
  • Paliperidone Palmitate / metabolism
  • Positron-Emission Tomography
  • Prospective Studies
  • Raclopride
  • Receptors, Dopamine D2 / metabolism*
  • Receptors, Dopamine D3 / metabolism*
  • Risperidone / administration & dosage
  • Risperidone / metabolism
  • Schizophrenia / drug therapy*
  • Schizophrenia / metabolism
  • Tandem Mass Spectrometry


  • Antipsychotic Agents
  • Carbon Radioisotopes
  • Receptors, Dopamine D2
  • Receptors, Dopamine D3
  • Benzodiazepines
  • Raclopride
  • Risperidone
  • Olanzapine
  • Paliperidone Palmitate