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.

Method: 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 D2 receptor occupancy of antipsychotics in the pituitary and temporal cortex was calculated. Correlations between plasma concentration of prolactin and dopamine D2 receptor 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 D2 receptor occupancy in the pituitary by all 4 antipsychotics (P‘ ‰=‘ ‰.001). Dopamine D2 receptor 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 D2 receptor 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.

J Clin Psychiatry

Submitted: April 17, 2008; accepted April 15, 2009.

Online ahead of print: February 23, 2010 (doi:10.4088/JCP.08m04307yel).

Corresponding author: Tetsuya Suhara, MD, PhD, Molecular Neuroimaging Group, Molecular Imaging Center, National Institute of Radiological Sciences 4-9-1, Anagawa, Inage-ku, Chiba, 263-8555, Japan (suhara@nirs.go.jp).