Hyperprolactinemia is a common side-effect of antipsychotics (APs), which may trigger serious secondary problems and compromise the adherence to treatment which is crucial for prognosis, especially in patients presenting with a first-episode of psychosis (FEP).
Aims:
We evaluated, in some cases for the first time, the effect of polymorphisms in multiple candidate genes on serum prolactin (PRL) levels in an AP-treated FEP cohort recruited in the multicenter PEPs study (Phenotype − genotype and environmental interaction; Application of a predictive model in first psychotic episodes).
Methods:
PRL concentration was measured in serum from 222 patients. A total of 167 polymorphisms were selected in 23 genes. Genetic association analysis was performed in the whole sample and also in homogenous subgroups of patients treated with APs with a high (N = 101) or low risk (N = 95) of increasing PRL release, which showed significant differences in their PRL levels.
Results:
After Bonferroni correction, polymorphisms in NTRK2, DRD2 and ACE genes were associated with PRL concentration.
Conclusion:
Our results give more support to the impact of DRD2, but also of other genes related to dopamine availability such as ACE. Moreover, this study provides the first evidence for the involvement of NTRK2, which suggests that pathways other than the ones related to dopamine or serotonin may participate in the AP-related PRL levels.
AklilluEKalowWEndrenyiLet al. (2007) CYP2D6 and DRD2 genes differentially impact pharmacodynamic sensitivity and time course of prolactin response to perphenazine. Pharmacogenet Genomics17: 989–993.
2.
American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders, 4th edn.Washington, DC: American Psychiatric Press.
3.
ArnoldEThebaultSBaeza-CruzGet al. (2014) The hormone prolactin is a novel, endogenous trophic factor able to regulate reactive glia and to limit retinal degeneration. J Neurosci34: 1868–1878.
4.
BalsaJASánchez-FrancoFPazosFet al. (1998) Direct action of serotonin on prolactin, growth hormone, corticotropin and luteinizing hormone release in cocultures of anterior and posterior pituitary lobes: Autocrine and/or paracrine action of vasoactive intestinal peptide. Neuroendocrinology68: 326–333.
5.
BernardoMBioqueMCabreraBet al. (2017) Modelling gene-environment interaction in first episodes of psychosis. Schizophr Res189: 181–189.
6.
BernardoMBioqueMParelladaMet al. (2013) Assessing clinical and functional outcomes in a gene-environment interaction study in first episodes of psychosis (PEPs). Rev Psiquiatr Salud Ment6: 4–16.
7.
CabaleiroTLópez-RodríguezROchoaDet al. (2013) Polymorphisms influencing olanzapine metabolism and adverse effects in healthy subjects. Hum Psychopharmacol28: 205–214.
8.
CabaleiroTLópez-RodríguezRRománMet al. (2015) Pharmacogenetics of quetiapine in healthy volunteers: Association with pharmacokinetics, pharmacodynamics, and adverse effects. Int Clin Psychopharmacol30: 82–88.
9.
CalargeCAEllingrodVLAcionLet al. (2009) Variants of the dopamine D2 receptor gene and risperidone-induced hyperprolactinemia in children and adolescents. Pharmacogenet Genomics19: 373–382.
10.
ChenCYYehYWKuoSCet al. (2016) Catechol-O-methyltransferase gene variants may associate with negative symptom response and plasma concentrations of prolactin in schizophrenia after amisulpride treatment. Psychoneuroendocrinology65: 67–75.
11.
ChienYLHwuHGFannCSet al. (2013) DRD2 haplotype associated with negative symptoms and sustained attention deficits in Han Chinese with schizophrenia in Taiwan. J Hum Genet58: 229–232.
12.
ChoongEPolariAKamdemRHet al. (2013) Pharmacogenetic study on risperidone long-acting injection: Influence of cytochrome P450 2D6 and pregnane X receptor on risperidone exposure and drug-induced side-effects. J Clin Psychopharmacol33: 289–298.
13.
ChungCMWangRYChenJWet al. (2010) A genome-wide association study identifies new loci for ACE activity: Potential implications for response to ACE inhibitor. Pharmacogenomics J10: 537–544.
14.
CorreiaCTAlmeidaJPSantosPEet al. (2010) Pharmacogenetics of risperidone therapy in autism: Association analysis of eight candidate genes with drug efficacy and adverse drug reactions. Pharmacogenomics J10: 418–430.
15.
dos Santos JúniorAHenriquesTBde MelloMPet al. (2015) Hyperprolactinemia in children and adolescents with use of risperidone: Clinical and molecular genetics aspects. J Child Adolesc Psychopharmacol25: 738–748.
16.
DuanJWainwrightMSComeronJMet al. (2003) Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. Hum Mol Genet12: 205–216.
17.
EmilianoABFudgeJL (2004) From galactorrhea to osteopenia: Rethinking serotonin-prolactin interactions. Neuropsychopharmacology29: 833–846.
18.
FitzgeraldPDinanTG (2008) Prolactin and dopamine: What is the connection? A review article. J Psychopharmacol22: 12–19.
19.
FreemanMEKanyicskaBLerantAet al. (2000) Prolactin: Structure, function, and regulation of secretion. Physiol Rev80: 1523–1631.
20.
GaoSHuZChengJet al. (2012) Impact of catechol-o-methyltransferase polymorphisms on risperidone treatment for schizophrenia and its potential clinical significance. Clin Biochem45: 787–792.
21.
GardnerDMMurphyALO’DonnellHet al. (2010) International consensus study of antipsychotic dosing. Am J Psychiatry167: 686–693.
22.
GlattSJFaraoneSVLasky-SuJAet al. (2009) Family-based association testing strongly implicates DRD2 as a risk gene for schizophrenia in Han Chinese from TaiwanMol Psychiatry14: 885–893.
23.
González-BlancoLGreenhalghAMGarcia-RizoCet al. (2016) Prolactin concentrations in antipsychotic-naïve patients with schizophrenia and related disorders: A meta-analysis. Schizophr Res174: 156–160.
24.
Grupo de trabajo de la Guía de Práctica Clínica sobre la Esquizofrenia y el Trastorno Psicótico Incipiente. Fòrum de Salut Mental cPdCpeSNd (2009) Guía de Práctica Clínica sobre la Esquizofrenia y el Trastorno Psicótico Incipiente. Madrid, Spain.
25.
HalbreichUKahnLS (2003) Hyperprolactinemia and schizophrenia: Mechanisms and clinical aspects. J Psychiatr Pract9: 344–353.
26.
HoustonJDhariaSBishopJRet al. (2011) Association of DRD2 and ANKK1 polymorphisms with prolactin increase in olanzapine-treated women. Psychiatry Res187: 74–79.
27.
HoustonJPFijalBHeinlothANet al. (2010) Genetic associations of prolactin increase in olanzapine/fluoxetine combination-treated patients. Psychiatry Res175: 171–172.
28.
HoustonJPKohlerJBishopJRet al. (2012) Pharmacogenomic associations with weight gain in olanzapine treatment of patients without schizophrenia. J Clin Psychiatry73: 1077–1086.
29.
IvanovaSAOsmanovaDZFreidinMBet al. (2017) Identification of 5-hydroxytryptamine receptor gene polymorphisms modulating hyperprolactinaemia in antipsychotic drug-treated patients with schizophrenia. World J Biol Psychiatry18: 239–246.
30.
JenkinsTA (2008) Effect of angiotensin-related antihypertensives on brain neurotransmitter levels in rats. Neurosci Lett444: 186–189.
31.
JenkinsTAMendelsohnFAChaiSY (1997) Angiotensin-converting enzyme modulates dopamine turnover in the striatum. J Neurochem68: 1304–1311.
32.
JohnstonCI (1990) Biochemistry and pharmacology of the renin-angiotensin system. Drugs39: 21–31.
33.
JönssonEGNöthenMMGrünhageFet al. (1999) Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Mol Psychiatry4: 290–296.
34.
KapurSZipurskyRJonesCet al. (2000) Relationship between dopamine D(2) occupancy, clinical response, and side effects: A double-blind PET study of first-episode schizophrenia. Am J Psychiatry157: 514–520.
35.
KuruvillaAPeedicayilJSrikrishnaGet al. (1992) A study of serum prolactin levels in schizophrenia: Comparison of males and females. Clin Exp Pharmacol Physiol19: 603–606.
36.
LeuchtSCiprianiASpineliLet al. (2013) Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: A multiple-treatments meta-analysis. Lancet382: 951–962.
37.
López-RodríguezRRománMNovalbosJet al. (2011) DRD2 Taq1A polymorphism modulates prolactin secretion induced by atypical antipsychotics in healthy volunteers. J Clin Psychopharmacol31: 555–562.
38.
MasSGassóPLafuenteAet al. (2016) Pharmacogenetic study of antipsychotic induced acute extrapyramidal symptoms in a first episode psychosis cohort: Role of dopamine, serotonin and glutamate candidate genes. Pharmacogenomics J16: 439–445.
39.
MiharaKKondoTSuzukiAet al. (2000) Prolactin response to nemonapride, a selective antagonist for D2 like dopamine receptors, in schizophrenic patients in relation to Taq1A polymorphism of DRD2 gene. Psychopharmacology149: 246–250.
40.
MiharaKSuzukiAKondoTet al. (2001) Relationship between Taq1 A dopamine D2 receptor (DRD2) polymorphism and prolactin response to bromperidol. Am J Med Genet105: 271–274.
41.
MiuraIZhangJPHagiKet al. (2016) Variants in the DRD2 locus and antipsychotic-related prolactin levels: A meta-analysis. Psychoneuroendocrinology72: 1–10.
42.
MontejoÁLArangoCBernardoMet al. (2016) Spanish consensus on the risks and detection of antipsychotic drug-related hyperprolactinaemia. Rev Psiquiatr Salud Ment9: 158–173.
43.
MontgomeryJWinterbottomEJessaniMet al. (2004) Prevalence of hyperprolactinemia in schizophrenia: Association with typical and atypical antipsychotic treatment. J Clin Psychiatry65: 1491–1498.
44.
MoralesT (2011) Recent findings on neuroprotection against excitotoxicity in the hippocampus of female rats. J Neuroendocrinol23: 994–1001.
45.
NobleEPBlumKRitchieTet al. (1991) Allelic association of the D2 dopamine receptor gene with receptor-binding characteristics in alcoholism. Arch Gen Psychiatry48: 648–654.
46.
PacchiarottiIMurruAKotzalidisGDet al. (2015) Hyperprolactinemia and medications for bipolar disorder: Systematic review of a neglected issue in clinical practice. Eur Neuropsychopharmacol25: 1045–1059.
47.
PeuskensJPaniLDetrauxJet al. (2014) The effects of novel and newly approved antipsychotics on serum prolactin levels: A comprehensive review. CNS Drugs28: 421–453.
48.
RajkumarRP (2014) Prolactin and psychopathology in schizophrenia: A literature review and reappraisal. Schizophr Res Treatment2014: 175360.
49.
RobinsonDWoernerMGAlvirJMet al. (1999) Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. Arch Gen Psychiatry56: 241–247.
50.
SakataKDukeSM (2014) Lack of BDNF expression through promoter IV disturbs expression of monoamine genes in the frontal cortex and hippocampus. Neuroscience260: 265–275.
51.
SukasemCHongkaewYNgamsamutNet al. (2016) Impact of pharmacogenetic markers of CYP2D6 and DRD2 on prolactin response in risperidone-treated Thai children and adolescents with autism spectrum disorders. J Clin Psychopharmacol36: 141–146.
52.
ThompsonJThomasNSingletonAet al. (1997) D2 dopamine receptor gene (DRD2) Taq1 A polymorphism: Reduced dopamine D2 receptor binding in the human striatum associated with the A1 allele. Pharmacogenetics7: 479–484.
53.
Yasui-FurukoriNSaitoMNakagamiTet al. (2010) Gender-specific prolactin response to antipsychotic treatments with risperidone and olanzapine and its relationship to drug concentrations in patients with acutely exacerbated schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry34: 537–540.
54.
YoungRMLawfordBRBarnesMet al. (2004) Prolactin levels in antipsychotic treatment of patients with schizophrenia carrying the DRD2*A1 allele. Br J Psychiatry185: 147–151.
55.
ZhangJPRobinsonDGGallegoJAet al. (2015) Association of a schizophrenia risk variant at the DRD2 locus with antipsychotic treatment response in first-episode psychosis. Schizophr Bull41: 1248–1255.
56.
ZhangXRZhangZJZhuRXet al. (2011) Sexual dysfunction in male schizophrenia: Influence of antipsychotic drugs, prolactin and polymorphisms of the dopamine D2 receptor genes. Pharmacogenomics12: 1127–1136.
57.
ZhuXBouzekriNSouthamLet al. (2001) Linkage and association analysis of angiotensin I-converting enzyme (ACE)-gene polymorphisms with ACE concentration and blood pressure. Am J Hum Genet68: 1139–1148.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
