A pharmacogenetic study of patients with schizophrenia from West Siberia gets insight into dopaminergic mechanisms of antipsychotic-induced hyperprolactinemia

Diana Z Osmanova,Bob Wilffert,Ivan V Pozhidaev,Svetlana A Ivanova,Nikolay A Bokhan,Anastasiia S Boiko,Natalia M Vyalova,Anton J M Loonen,Maxim B Freidin,Elena G Kornetova,Arkadiy V Semke,Olga Yu Fedorenko,Vladimir V Tiguntsev

doi:10.1186/s12881-019-0773-3

Abstract

BackgroundHyperprolactinemia (HPRL) is a classical side effect of antipsychotic drugs primarily attributed to blockade of dopamine D2 receptors (DRD2s) on the membranes of lactotroph cells within the pituitary gland. Certain antipsychotic drugs, e.g. risperidone, are more likely to induce HPRL because of relative accumulation within the adenohypophysis. Nevertheless, due to competition for pituitary DRD2s by high dopamine levels may limit antipsychotic-induced HPRL. Moreover, the activity of prolactin-producing lactotrophs also depends on other hormones which are regulated by the extra-pituitary activity of dopamine receptors, dopamine transporters, enzymes of neurotransmitter metabolism and other factors. Polymorphic variants in the genes coding for these receptors and proteins can have functional significance and influence on the development of hyperprolactinemia.MethodsA set of 41 SNPs of genes for dopamine receptors DRD1, DRD2, DRD3, DRD4, the dopamine transporter SLC6A3 and dopamine catabolizing enzymes MAOA and MAOB was investigated in a population of 446 Caucasians (221 males/225 females) with a clinical diagnosis of schizophrenia (according to ICD-10: F20) with and without HPRL who were treated with classical and/or atypical antipsychotic drugs. Additive genetic model was tested and the analysis was carried out in the total group and in subgroup stratified by the use of risperidone/paliperidone.ResultsOne statistically significant association between polymorphic variant rs1799836 of MAOB gene and HPRL in men was found in the total group. Furthermore, the rs40184 and rs3863145 variants in SLC6A3 gene appeared to be associated with HPRL in the subgroup of patients using the risperidone/paliperidone, but not with HPRL induced by other antipsychotic drugs.ConclusionsOur results indicate that genetic variants of MAOB and SLC6A3 may have consequences on the modulation of prolactin secretion. A further search for genetic markers associated with the development of antipsychotic-related hyperprolactinemia in schizophrenic patients is needed.

Highlights

Hyperprolactinemia (HPRL) is a classical side effect of antipsychotic drugs primarily attributed to blockade of dopamine D2 receptors (DRD2s) on the membranes of lactotroph cells within the pituitary gland
A further search for genetic markers associated with the development of antipsychotic-related hyperprolactinemia in schizophrenic patients is needed
Based upon reviewing the literature we selected a set of 26 polymorphisms in dopamine receptors genes (DRD1, Dopamine receptor D2 (DRD2s), DRD3, DRD4), 12 polymorphic variants of dopamine transporter SLC6A3, as well as 3 polymorphisms of monoamine oxidase A and B and here we present new data on the association between them and HPRL in antipsychotic drug-treated patients with schizophrenia from West Siberia, Russian Federation

Summary

Introduction

Hyperprolactinemia (HPRL) is a classical side effect of antipsychotic drugs primarily attributed to blockade of dopamine D2 receptors (DRD2s) on the membranes of lactotroph cells within the pituitary gland. Due to competition for pituitary DRD2s by high dopamine levels may limit antipsychotic-induced HPRL. The activity of prolactin-producing lactotrophs depends on other hormones which are regulated by the extra-pituitary activity of dopamine receptors, dopamine transporters, enzymes of neurotransmitter metabolism and other factors. Treatment of schizophrenic illness usually involves the long-term usage of antipsychotic drugs [1], which have both therapeutic and side effects, related to antagonism to D2 receptors. Prolactin secretion is under a complex neuroendocrine control, in which various agents participate: neurotransmitters, biologically active neuropeptides, hormones of peripheral endocrine glands. Synthesis and secretion of prolactin are carried out by lactotrophs of the pituitary gland, which constitute an average of 20–50% of the total cell population of the pituitary cells [5]

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