Is there a way to avoid hyperprolactinemia ? Prog Neuropsychpharm Biol Psychiatry. 2013.Aug


Hyper prolactinemia is a common side effect of antipsychotics with numerous consequences.Longterm prolactin elevation is associated with the risk of  decreasing bone mineral density and increasing risk of breast cancer in post-menopausal women.

Disinhibition of the lactotroph How to avoidcells in the anterior pituitary gland through dopamine D2 receptor antagonism is the mechanism of increase in prolactin.Hyperprolactinemia is common with first generation antipsychotics and high potency second generation antipsychotics often creating the idea that it is inevitable.D2 receptor occupancy in the pituitary is a predictor of hyperprolactinemia.Is there  a limit of D2 receptor occupancy below which prolactin levels will not rise at the same time retain the antipsychotic effects?

Takashi Tsuboi and colleagues answers this question in this article. They describe a method by which dopamine D2 receptor occupancy  (by risperidone, olanzapine, and ziprasidone)  can be reliably estimated from plasma concentrations of these drugs from two blood samples.They used the Clinical Antipsychotic Trials in Inter- vention Effectiveness (CATIE) (Stroup et al., 2003: dataset  ( Adult schizophrenia: randomised trial of different antipsychotics for up to 18 months) to see the relationship between D2 occupancy  and plasma prolactin levels.Data of subjects who were receiving risperidone, olanzapine, or ziprasidone is used in this analysis.Prolactin level at 3 months was measured for 481 subjects on the above three medications.

Findings: Estimated dopamine D2 receptor occupancy levels statistically showed a positive association with the serum prolactin concentration. The cut-off points for hyperprolactinemia were 68–70% for risperidone, 77% for olanzapine, and 55% for ziprasidone.This corresponded to  plasma concentrations for  risperidone (plus 9-hydroxyrisperidone) : 16.7–19.1 ng/mL,  olanzapine : 39.9 ng/mL and (ziprasidone : 54.5 ng/mL)

This is the largest study to investigate the relationship between serum prolactin concentration and estimated dopamine D2 receptor blockade.  The threshold of hyperprolactinemia is at  73% of striatal dopamine D2 receptor occupancy. Threshold seems to differ among antipsychotic drugs. Therapetic efficacy is considered to be  achieved with 65–80% occupancy in the striatal dopamine D2 receptors.PET study  has shown that that the likelihood of hyperprolactinemia increase significantly as the dopamine D2 occupancy exceeded 72% for haloperidol. All this point towards  the relevance of using low antipsychotic dosage to minimize the risk of this D2 occupancy-dependent side effect in the treatment of schizophrenia. 

The findings in the present study need to be replicated in prospective brain imaging studies that focus on the pituitary.  The clinical relevance of using the lowest possible dose of antipsychotics is highlighted.

Summary of the article:

Hyperprolactinemia and estimated dopamine D2 receptor occupancy and in patients with schizophrenia:Analysis of the CATIE data. Tsuboi T, Bies RR, Suzuki T, Mamo DC, Pollock BG, Graff-Guerrero A, Mimura M, Uchida H. Prog Neuropsychopharmacol Biol Psychiatry. 2013.Aug.



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