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

Abstract

Background 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. 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. Methods A 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. Results One 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. Conclusions Our 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. Electronic supplementary material The online version of this article (10.1186/s12881-019-0773-3) contains supplementary material, which is available to authorized users.

Influence of the use of atypical antipsychotics in metabolic syndrome

“…Osmanova et al calcularon que un 48,1% de los pacientes en tratamiento antipsicótico presentaba una disfunción sexual como consecuencia del aumento de la prolactina en sangre, atribuida a la utilización de algunos antipsicóticos atípicos como la risperidona, que inducían con más probabilidad la hiperprolactinemia, debido al bloqueo que producían sobre los receptores dopaminérgicos tipo D2 15 . Kirino descubrió que el uso de aripiprazol (tanto en monoterapia como en combinación con otros medicamentos) era recomendable para reducir dichas repercusiones, por su baja afinidad a los mencionados receptores D2, sobre los que actuaba la dopamina, lo que le permitía actuar como agonista y antagonista funcional al mismo tiempo, dependiendo de los niveles de dopamina circulante, pero no dependiendo de los niveles de prolactina sérica, como lo son los agonistas de dopamina 16 .…”

“…Osmanova et al calculated that 48.1% of patients receiving antipsychotic treatment presented sexual dysfunctions as a result of increased prolactin in the bloodstream, attributed to the use of some atypical antipsychotics such as risperidone, which are more likely to create hyperprolactinaemia, due to the blockage they cause in type D2 dopaminergic receptors 15 . Kirino discovered that the use of aripiprazole (alone and in combination with other drugs) was advisable in that it reduced this type of effect thanks to its low affinity to D2 receptors acted on by dopamine, which enabled it to act as a functional agonist and antagonist at the same time, depending on the levels of circulating dopamine, but independently of the levels of serum prolactin, such as the dopamine agonists 16 .…”

Preliminary Pharmacogenetic Study to Explore Putative Dopaminergic Mechanisms of Antidepressant Action

“…Pharmacogenetic investigations of the dopaminergic pathway have found associations in patients with Parkinson’s disease and schizophrenia, among other psychiatric disorders [ 20 , 21 ]. However, for depression, contradictory findings have greyed the landscape to determine whether polymorphisms impact antidepressant efficacy [ 22 , 23 , 24 ].…”

Application of a Pharmacogenetics-Based Precision Medicine Model (5SPM) to Psychotic Patients That Presented Poor Response to Neuroleptic Therapy

“…One of the more widespread hypotheses to explain this interindividual variable response to treatment directs the question to a pharmacokinetic cause. Therefore, it is proposed that the metabolism of the neuroleptics administered to the patient could explain these differences [15][16][17].…”

“…In our environment, the most commonly used atypical antipsychotics are metabolized mainly through the cytochrome P 450 (CYP450) system [18]. The superfamily CYP450 is a set of highly polymorphic genes, which suggests a possible strong genetic variability among individuals and, consequently, a potential strong phenotypic variability, which translates into different enzymatic activity on the drugs administered to the individual [15,[19][20][21][22]. In addition, the therapeutic target of these drugs is found in the central nervous system, meaning they must pass through the blood-brain barrier [23], therefore, the genes involved in the absorption and transport process should be considered [24].…”