Positron emission tomography measurement of dopamine D₂ receptor occupancy in the pituitary and cerebral cortex: relation to antipsychotic-induced hyperprolactinemia.
OBJECTIVE
Hyperprolactinemia is a common side effect of antipsychotic drugs used in the treatment of schizophrenia. However, the magnitude of hyperprolactinemia differs among antipsychotics, and there is no reliable mechanism-related marker for the risk of hyperprolactinemia that would allow us to characterize antipsychotics.


METHODS
In this study, 11 healthy male subjects taking different doses of sulpiride and 24 male patients with DSM-IV-diagnosed schizophrenia taking different antipsychotic drugs (risperidone, olanzapine, haloperidol, and sulpiride) participated. Positron emission tomography scanning using [¹¹C]FLB 457 was performed on all subjects. The dopamine D₂receptor occupancy of antipsychotics in the pituitary and temporal cortex was calculated. Correlations between plasma concentration of prolactin and dopamine D₂receptor occupancies were evaluated. The ratio of drug concentration of cerebral receptor site to that of pituitary receptor site (brain/plasma concentration ratio; B/P ratio) was calculated from the receptor occupancies in the 2 regions. Data were collected between November 2001 and September 2007.


RESULTS
Significant positive correlation was observed between the plasma concentration of prolactin and dopamine D₂receptor occupancy in the pituitary by all 4 antipsychotics (P = .001). Dopamine D₂receptor occupancies of sulpiride were markedly different between the pituitary and temporal cortex, and the B/P ratio for sulpiride (0.34) was significantly lower than for olanzapine (P = .007) and risperidone (P = .015). Olanzapine had a relatively high B/P ratio (2.70), followed by haloperidol (2.40) and risperidone (1.61).


CONCLUSIONS
Dopamine D₂receptor occupancy in the pituitary is a good indicator of hyperprolactinemia. B/P ratio, indicating the penetrating capability across the blood-brain barrier, seems to be a good characteristic biomarker of each antipsychotic drug for the risk of hyperprolactinemia at therapeutic dose.
Arakawa
Ryosuke
R
Molecular Neuroimaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba, Japan.
Okumura
Masaki
M
Ito
Hiroshi
H
Takano
Akihiro
A
Takahashi
Hidehiko
H
Takano
Harumasa
H
Maeda
Jun
J
Okubo
Yoshiro
Y
Suhara
Tetsuya
T
D000328:Adult; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001569:Benzodiazepines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D002250:Carbon Radioisotopes; D002525:Cerebellar Cortex / Q000000981:diagnostic imaging / Q000187:drug effects; D002540:Cerebral Cortex / Q000000981:diagnostic imaging* / Q000187:drug effects*; D003196:Computer Graphics; D018492:Dopamine Antagonists / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D006966:Hyperprolactinemia / Q000097:blood / Q000139:chemically induced* / Q000000981:diagnostic imaging*; D008297:Male; D008432:Mathematical Computing; D008875:Middle Aged; D000077152:Olanzapine; D010902:Pituitary Gland / Q000000981:diagnostic imaging* / Q000187:drug effects*; D049268:Positron-Emission Tomography; D011388:Prolactin / Q000097:blood; D011759:Pyrrolidines / Q000493:pharmacokinetics; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000378:metabolism; D018967:Risperidone / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D012457:Salicylamides / Q000493:pharmacokinetics; D012559:Schizophrenia / Q000097:blood / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D013223:Statistics as Topic; D013469:Sulpiride / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D013702:Temporal Lobe / Q000000981:diagnostic imaging / Q000187:drug effects; D055815:Young Adult
D014150:Antipsychotic Agents; D002250:Carbon Radioisotopes; D018492:Dopamine Antagonists; D011759:Pyrrolidines; D017448:Receptors, Dopamine D2; D012457:Salicylamides; C065065:FLB 457; D001569:Benzodiazepines; D013469:Sulpiride; D011388:Prolactin; D006220:Haloperidol; D018967:Risperidone; D000077152:Olanzapine