Dose-finding Study of Paliperidone ER Based on Striatal and Extrastriatal Dopamine D2 Receptor Occupancy in Patients With Schizophrenia

Psychopharmacology (Berl). 2008 Apr;197(2):229-35. doi: 10.1007/s00213-007-1029-z. Epub 2007 Dec 6.

Abstract

Rationale: Paliperidone ER is a novel antipsychotic drug in an extended-release (ER) formulation. As with all antipsychotics, careful dose setting is necessary to avoid side effects.

Objectives: In this study, we measured striatal and extrastriatal dopamine D2 receptor occupancy during paliperidone ER treatment in patients with schizophrenia using positron emission tomography (PET) to compare regional occupancy and to estimate the optimal dose.

Materials and methods: Thirteen male patients with schizophrenia participated in this 6-week multiple-dose study. Six of them took 3 mg of paliperidone ER per day, four took 9 mg, and three took 15 mg. Two to 6 weeks after first drug intake, two PET scans, one with [11C]raclopride and one with [11C]FLB 457, were performed in each patient on the same day. The relationship between the dose or plasma concentration of paliperidone and dopamine D2 receptor occupancy was calculated.

Results: The dopamine D2 receptor occupancies in the striatum measured with [11C]raclopride and the temporal cortex measured with [11C]FLB 457 were 54.2-85.5% and 34.5-87.3%, respectively. ED50 values of the striatum and temporal cortex were 2.38 and 2.84 mg/day, respectively. There was no significant difference in dopamine D2 receptor occupancy between the striatum and the temporal cortex.

Conclusions: The data from this study suggest that paliperidone ER at 6-9 mg provides an estimated level of dopamine D2 receptor occupancy between 70-80% and that the magnitude of dopamine D2 receptor occupancy is similar between the striatum and temporal cortex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antipsychotic Agents / administration & dosage*
  • Antipsychotic Agents / pharmacokinetics
  • Antipsychotic Agents / therapeutic use*
  • Brain Chemistry / drug effects*
  • Data Interpretation, Statistical
  • Delayed-Action Preparations
  • Dopamine Antagonists
  • Dose-Response Relationship, Drug
  • Humans
  • Isoxazoles / administration & dosage*
  • Isoxazoles / pharmacokinetics
  • Isoxazoles / therapeutic use*
  • Male
  • Neostriatum / diagnostic imaging
  • Neostriatum / drug effects
  • Neostriatum / metabolism*
  • Paliperidone Palmitate
  • Positron-Emission Tomography
  • Psychiatric Status Rating Scales
  • Pyrimidines / administration & dosage*
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / therapeutic use*
  • Pyrrolidines
  • Raclopride
  • Radiopharmaceuticals
  • Receptors, Dopamine D2 / drug effects
  • Receptors, Dopamine D2 / metabolism*
  • Salicylamides
  • Schizophrenia / diagnostic imaging
  • Schizophrenia / drug therapy*

Substances

  • Antipsychotic Agents
  • Delayed-Action Preparations
  • Dopamine Antagonists
  • Isoxazoles
  • Pyrimidines
  • Pyrrolidines
  • Radiopharmaceuticals
  • Receptors, Dopamine D2
  • Salicylamides
  • FLB 457
  • Raclopride
  • Paliperidone Palmitate