Boiko, A.S.

Fedorenko, O.Y.

Freidin, M.B.

Ivanova, S.A.

Kornetova, E.G.

Loonen, A.J.M.

Osmanova, D.

Pozhidaev, I.V.

Wilffert, B.

English

Background: Long-term antipsychotic drug use remains the mainstay of treatment for patients with schizophrenia. However, pharmacotherapy with these drugs is complicated by several troublesome side effects, including hyperprolactinemia (HP). Prolactin secretion is persistently inhibited by dopamine, and antipsychotic drugs are believed to increase prolactin release by blocking dopamine receptors in the pituitary gland. Genetic factors play an important role in the development of antipsychotic induced HP [1, 2]. Genes coding for dopamine receptors and transporters are considered to be responsible for HP in schizophrenia [3]. The present study aimed to investigate the role of polymorph-isms of the dopamine receptors and transporters genes (DRD1, DRD2, SLC6A3) in the pathogenesis of antipsychotic-related HP in patients with schizophrenia. Methods: 431 Russian patients with schizophrenia were examined. The average age of patients was 42.1 ± 1.4 years. Evaluation of serum prolactin level was performed by ELISA using reagents set PRL Test System (USA). Genotyping was carried out on 17 polymorphic variants of the dopamine receptors and transporters genes DRD1 (rs4532, rs936461), DRD2 (rs4245147, rs6279, rs2734842) and SLC6A3 (rs3756450, rs2550956, rs6347, rs2617605, rs3863145, rs250686, rs464049, rs4975646, rs1048953, rs11133767, rs27048, rs40184). The SPSS sof tware was used for statistical analysis. The Hardy-Weinberg equilibrium (HWE) of genotypic frequencies was tested by the chi-square test. Results: We studied the association between HP and a set of SNPs from DRD1, DRD2 receptor genes and neurotransmitter transporter SLC6A3 in patients from Siberia with a clinical diagnosis of schizophrenia who were treated with classical and/or atypical antipsychotic drugs. All patients with schizophrenia were divided into two groups: those with and without HP. Physiological normal results for the serum prolactin levels are less than 20 ng/ml in men, and less than 25 ng/ml in women. Statistically significant result was obtained for polymorphic variant rs2550956 of the gene SLC6A3 (χ2 = 9.992; p = 0.007), which suggests its involvement in the development of HP. The heterozygous genotype TC of rs2550956 was significantly less common in patients with elevated levels of prolactin and it presumably has protective properties (OR 0.54; 95% CI: 0.36-0.81). We did not find any statistically significant associations for other polymorphisms DRD1 (rs4532, rs936461), DRD2 (rs4245147, rs6279, rs2734842) and SLC6A3 (rs3756450, rs6347, rs2617605, rs3863145, rs250686, rs464049, rs4975646, rs1048953, rs11133767, rs27048, rs40184). The group of dopamine receptors is heterogeneous and only some of them participate in the formation of psychotic symptoms and, accord ingly, in the antipsychotic action of neuroleptics. The effect of neuroleptics on other groups of dopamine receptors leads to the development of different side effects including extrapyramidal disorders [4], and their role is extremely low in the formation of the actual therapeutic response. Conclusion: Our results indicate that genetic variants of SLC6A3 may have functional consequences on the modulation of prolactin secretion. Neurotransmitter systems are involved in the mechanisms of action of antipsychotic drugs; therefore, a further search for genetic markers associated with the development of antipsychotic-related hyperprolactinemia in schizophrenic patients is needed

Proceedings - University of Groningen

   University of GroningenAssociation of polymorphism in the dopamine receptors and transporter genes withhyperprolactinemia in patients with schizophreniaOsmanova, D.; Boiko, A.S.; Fedorenko, O.Y.; Pozhidaev, I.V.; Freidin, M.B.; Kornetova, E.G.;Ivanova, S.A.; Wilffert, B.; Loonen, A.J.M.Published in:European NeuropsychopharmacologyIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2017Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Osmanova, D., Boiko, A. S., Fedorenko, O. Y., Pozhidaev, I. V., Freidin, M. B., Kornetova, E. G., Ivanova,S. A., Wilffert, B., & Loonen, A. J. M. (2017). Association of polymorphism in the dopamine receptors andtransporter genes with hyperprolactinemia in patients with schizophrenia. EuropeanNeuropsychopharmacology, 27(Suppl. 4), 923-924.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.interact with CNS receptors known to cause adverse events, and theKi of LB-102 against the 5-HT7 receptor was also similar toamisulpride. In vivo both LB-102 and LB-103 were as effective asamisulpride and risperidone in restoration of the ability to discri-minate between novel and familiar objects in NOR. In the LMAstudy, 30 mg/kg doses of LB-102 attenuated the d-amphetamine-induced increase in LMA at lower doses than amisulpride (P <0.05) while the 30 mg/kg dose was numerically more effective(p = 0.07). Plasma exposure following oral administration ofLB-102 was similar to amisulpride and should be appropriatefor oral administration. In a catalepsy bar test (an animal test ofthe=potential for extrapyramidal side effects) no difference wasobserved between LB-102 and LB-103 and vehicle control.Conclusion: LB-102 and LB-103 have CNS receptor bindingprofiles similar to amisulpride. The efficacy of both compoundswas similar to amisulpride in NOR and LB-102 was superior in theLMA study. Our initial preclinical evaluation suggests that bothLB-102 and LB-103 have meaningful potential antipsychoticproperties for the treatment of schizophrenia.References[1] Dos Santos Pereira, J.N, Tadjerpisheh, S., Abu Abed, M.,Saadatmand, A.R, Weksler, B., Romero, I.A, Couraud, P.-O.,Brockmöller, J., Tzvetkov, M. V., 2014. The Poorly MembranePermeable Antipsychotic Drugs Amisulpride and Sulpride AreSubstrates of the Organic Cation Transporters from the SLC22Family’. The AAPS Journal 16, 1247–1258.[2] Castelli, M.P, Mocci, I., Sanna, A.M, Gessa, G.L, Pani, L., 2001. (–)SAmisulpride Binds With High Affinity To Cloned Dopamine D3 AndD2 Receptors. European J Pharmacol 432, 143–147.Disclosure statement: VG, MB, MSH, ZP, and AV own shares of LBPharmaceuticals. VG is on the Board of Directors of LB Pharmaceuticals,ZP and AV are employees of LB Pharmaceuticals, and MB and MH areconsultants to LB Pharmaceuticals. JCN has received expenses to attendconferences and fees for lecturing and consultancy work (includingattending advisory boards) from themanufacturers of various antipsychoticdrugs. JCN, BG, GP and DC are employees of the University ofManchester. Acknowledgements: This research was supported by LBPharmaceuticals Inc. (NY USA) and Rivopharm SA (Lugano,Switzerland).P.3.c.006 Association of polymorphism in thedopamine receptors and transporter geneswith hyperprolactinemia in patients withschizophreniaD. Osmanova1*, A.S. Boiko1, O.Y. Fedorenko1, I.V. Pozhidaev1,M.B. Freidin2, E.G. Kornetova3, S.A. Ivanova1, B. Wilffert4,A.J.M. Loonen5 1Mental Health Research Institute- TomskNRMC, Laboratory of Molecular Genetics and Biochemistry,Tomsk, Russia; 2Research Institute of Medical Genetics, TomskNRMC, Laboratory of Population Genetics, Tomsk, Russia;3Mental Health Research Institute- Tomsk NRMC, Department ofClinical and Social Psychiatry and Addiction, Tomsk, Russia;4Groningen Research Institute of Pharmacy, Pharmacotherapyand Clinical Pharmacology, Groningen, The Netherlands;5Groningen Research Institute of Pharmacy, Pharmacotherapy inPsychiatric Patients, Groningen, The NetherlandsBackground: Long-term antipsychotic drug use remains themainstay of treatment for patients with schizophrenia. However,pharmacotherapy with these drugs is complicated by severaltroublesome side effects, including hyperprolactinemia (HP).Prolactin secretion is persistently inhibited by dopamine, andantipsychotic drugs are believed to increase prolactin release byblocking dopamine receptors in the pituitary gland. Geneticfactors play an important role in the development of antipsychoticinduced HP [1,2]. Genes coding for dopamine receptors andtransporters are considered to be responsible for HP inschizophrenia [3].The present study aimed to investigate the role of polymorph-isms of the dopamine receptors and transporters genes (DRD1,DRD2, SLC6A3) in the pathogenesis of antipsychotic-related HPin patients with schizophrenia.Methods: 431 Russian patients with schizophrenia wereexamined. The average age of patients was 42.1 ± 1.4 years.Evaluation of serum prolactin level was performed by ELISAusing reagents set PRL Test System (USA). Genotyping wascarried out on 17 polymorphic variants of the dopamine receptorsand transporters genes DRD1 (rs4532, rs936461), DRD2(rs4245147, rs6279, rs2734842) and SLC6A3 (rs3756450,rs2550956, rs6347, rs2617605, rs3863145, rs250686, rs464049,rs4975646, rs1048953, rs11133767, rs27048, rs40184). The SPSSsoftware was used for statistical analysis. The Hardy-Weinbergequilibrium (HWE) of genotypic frequencies was tested by thechi-square test.Results: We studied the association between HP and a set ofSNPs from DRD1, DRD2 receptor genes and neurotransmittertransporter SLC6A3 in patients from Siberia with a clinicaldiagnosis of schizophrenia who were treated with classical and/oratypical antipsychotic drugs. All patients with schizophrenia weredivided into two groups: those with and without HP. Physiologicalnormal results for the serum prolactin levels are less than 20 ng/mlin men, and less than 25 ng/ml in women. Statistically significantresult was obtained for polymorphic variant rs2550956 of the geneSLC6A3 (χ2 = 9.992; p = 0.007), which suggests its involvementin the development of HP. The heterozygous genotype TC ofrs2550956was significantly less common in patients with elevatedlevels of prolactin and it presumably has protective properties(OR 0.54; 95% CI: 0.36–0.81). We did not find any statisticallysignificant associations for other polymorphisms DRD1 (rs4532,rs936461), DRD2 (rs4245147, rs6279, rs2734842) and SLC6A3(rs3756450, rs6347, rs2617605, rs3863145, rs250686, rs464049,rs4975646, rs1048953, rs11133767, rs27048, rs40184). The groupof dopamine receptors is heterogeneous and only some of themparticipate in the formation of psychotic symptoms and, accord-ingly, in the antipsychotic action of neuroleptics. The effect ofneuroleptics on other groups of dopamine receptors leads to thedevelopment of different side effects including extrapyramidaldisorders [4], and their role is extremely low in the formation of theactual therapeutic response.Conclusion: Our results indicate that genetic variants ofSLC6A3 may have functional consequences on the modulationof prolactin secretion. Neurotransmitter systems are involved in themechanisms of action of antipsychotic drugs; therefore, a furthersearch for genetic markers associated with the development ofantipsychotic-related hyperprolactinemia in schizophrenic patientsis needed.References[1] Ivanova, S.A., Osmanova, D.Z., Boiko, A.S., Pozhidaev, I.V.,Freidin, M.B., Fedorenko, O.Y., Semke, A.V., Bokhan, N.A.,Kornetova, E.G., Rakhmazova, L.D., Wilffert, B., Loonen, A.J.,2016. Prolactin gene polymorphism (-1149G/T) is associated withhyperprolactinemia in patients with schizophrenia treated withP.3.c Psychotic disorders and treatment – Treatment (basic) S923antipsychotics. Schizophrenia Research Oct 21, pii: S0920-9964 (16)30473-X. doi: 10.1016/j.schres.2016.10.029.[2] Ivanova, S.A., Osmanova, D.Z., Freidin, M.B., Fedorenko, O.Y.,Boiko, A.S., Pozhidaev, I.V., Semke, A.V., Bokhan, N.A., Agarkov, A.A., Wilffert, B., Loonen, A.J., 2017. Identification of 5-hydroxy-tryptamine receptor gene polymorphisms modulating hyperprolacti-naemia in antipsychotic drug-treated patients with schizophrenia.World J Biol Psychiatry 18 (3), 239–246.[3] Miura, I., Zhang, J.P., Hagi, K., Lencz, T., Kane, J.M., Yabe, H.,Malhotra, A.K., Correll, C.U., 2016. Variants in the DRD2 locus andantipsychotic-related prolactin levels: A meta-analysis.Psychoneuroendocrinology 72, 1–10.[4] Al Hadithy, A.F.Y., Ivanova, S.A., Pechlivanoglou, P., Semke, A.,Fedorenko, O., Kornetova, E., Ryadovaya, L., Brouwers, J.R.B.J.,Wilffert, B., Bruggeman, R., Loonen, A.J.M., 2009. Tardive dyski-nesia and DRD3, HTR2A and HTR2C gene polymorphisms inRussian psychiatric inpatients from Siberia. Progress inNeuroPsychopharmacology and Biological Psychiatry 33, 475–481.P.3.c.007 GPR52 agonists represent a novel approachto treat psychotic disorders and improvecognitive functionA.J. Grottick1, N. Schülert2, H. Rosenbrock2,M. Von Heimendahl2, R. Arban2, S. Hobson2* 1BeaconDiscovery Inc., CNS Drug Discovery, San Diego, USA;2Boehringer Ingelheim Pharma GmbH & Co KG, Department ofCNS Discovery Research, Biberach a.d. Riss, GermanyBackground: There is increasing awareness that key symptomdomains within defined psychiatric and neurological diseases areunder-treated. For example, cognitive impairments associated withschizophrenia (CIAS) are key predictors of functional outcome butantipsychotic drugs are ineffective. Similarly, in neurodegenera-tive diseases such as Alzheimer’s and Parkinson’s disease,psychotic symptoms occur frequently and are associated withpoorer functional outcomes, but antipsychotics are not indicatedfor dementia-related psychosis and are contra-indicated for long-term use due to increased risk of death. Therefore, novelmechanisms to address these undertreated symptom domains arein need, and are currently under investigation.Based largely on its expression pattern and functional coupling,the Gs-coupled orphan g-protein coupled receptor GPR52 iscurrently being investigated as a potential drug target for bothCIAS and psychosis in AD. GPR52 is selectively expressed inbrain, most strikingly in the striatum where it co-localizes almostexclusively with D2-expressing dopamine (DA) receptors, butadditionally in cortex where it co-localizes with DA D1 receptorson glutamatergic neurons. Based on GPR52’s g-protein coupl-ing, agonists would be predicted to functionally resemble D2receptor antagonists in the striatum, and to resemble D1 agonists incortical areas, thus holding the promise to be efficacious andprovide a novel treatment for both psychosis as well as cognitivedysfunction.Methods: GPR52 agonists were tested in three separateassays. 1. Cortical electrophysiology: Rat medial prefrontalcortical slices (n = 4–6) were stimulated in layer II and excitatorypostsynaptic potentials recorded in layer V in the presence orabsence of a GPR52 agonist. To demonstrate the GPR52specificity of any effect on synaptic potentials, slices were pre-treated with a GPR52 antagonist. 2. Social recognition task: AGPR52 agonist was administered to rats prior to interaction with ajuvenile conspecific. 24h later, the same two rats were paired andinteraction times at the first and second intervals compared. 3.Blockade of amphetamine-stimulated locomotor activity: Ratswere treated with a GPR52 agonist prior to administration ofamphetamine and subsequent locomotor activity recorded.Statistical significance for each of these measurements wasascertained by one or two-way ANOVA.Results: GPR52 agonists produced a robust, long-lasting andconcentration-dependent increase in synaptic potentiation whichwas prevented by pre-treatment with an antagonist (p = 0.0017 andp < 0.0001, respectively). In vivo, GPR52 agonists significantlyreduced interaction time in the rat social recognition task after a 24hintertrial interval (p = 0.008 and 0.034), and reduced amphetaminestimulated locomotor activity in the absence of any appreciableeffect on baseline activity when dosed alone (p = 0.0007).Conclusions: Increased memory of a social interaction andpotentiation of cortical synaptic transmission suggest enhancedcognitive function, whereas the ability to block amphetamine-induced locomotion is indicative of antipsychotic activity. Thesedata underscore the potential of GPR52 agonists to treat bothcognitive and psychotic symptoms associated with certain CNSdisorders.P.3.c.008 Long-term antipsychotic treatment andcorpus callosum volume: an MRI study inpatients with schizophreniaM. Trehout1,2*, E. Leroux2, N. Delcroix3, S. Dollfus1,2 1Servicede psychiatrie adulte- Centre Esquirol, Centre HospitalierUniversitaire, Caen, France; 2Normandie Univ- UNICAEN- ISTS,GIP Cyceron, Caen, France; 3Normandie Univ, UNICAEN,CNRS, UMS, GIP Cyceron, Caen, FranceBackground:White matter volume changes have been evidencedin patients with schizophrenia (SZ) [1]. Nevertheless, studies onthe corpus callosum, which is the main interhemisphericcommissure of white matter, remain divergent [2,3]. One issueconcerns the reasons of these changes and the question is to knowif these changes are specific of the disease or are due to long-termantipsychotic treatment. Indeed, it has been revealed that chronicexposure to antipsychotic medication could significantly contrib-ute to white matter volume change in SZ [4]. Therefore, theobjective of the present study was to determinate CC volumechanges in SZ compared to healthy controls (HC) and to evaluatethe potential contribution of long-term exposure to antipsychoticson these changes.Methods:The study included 19SZand 40HC, all right-handedwhich did not differ significantly on education level, age andgender. All patients were stabilized outpatients with no change intheir treatment over the last month. For each participant, thevolumes of total CC and three sub-regions (anterior CC; middleCC; posterior CC) were extracted (in cm3) using an automated in-house segmentation method. The callosal volume was defined onten sagittal slices (1mm thick). To test group differences, threeANCOVAs were run with the CC volumes as dependent variablesand group as independent variable. Gender and brain volume wereused as covariates. In SZ, ANCOVAs were conducted to evaluatethe relationships between CC volumes and antipsychotic doses inchlorpromazine equivalents (mg/day) controlled by illnessduration.Results: ANCOVAs did not reveal any differences between SZand HC for all CC volumes (anterior CC: p = 0.59; middle CC: p =0.92; posterior CC: p = 0.29; total CC: p = 0.43). However, therewere significant, negative correlations between antipsychoticP.3.c Psychotic disorders and treatment – Treatment (basic)S924

Association of polymorphism in the dopamine receptors and transporter genes with hyperprolactinemia in patients with schizophrenia

https://pure.rug.nl/ws/files/52226224/1_s2.0_S0924977X17316401_main_1_.pdf

Association of polymorphism in the dopamine receptors and transporter genes with hyperprolactinemia in patients with schizophrenia

Abstract

Similar works

Full text

Available Versions

Proceedings - University of Groningen