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01-01-2015 | Psychiatry and Preclinical Psychiatric Studies - Original Article

Genetics of psychotropic medication induced side effects in two independent samples of bipolar patients

Authors: Chiara Fabbri, Daniel Souery, Raffaella Calati, Concetta Crisafulli, Armando Chierchia, Diego Albani, Gianluigi Forloni, Alberto Chiesa, Rosalba Martines, Othman Sentissi, Julien Mendlewicz, Giovanni De Girolamo, Alessandro Serretti

Published in: Journal of Neural Transmission | Issue 1/2015

Abstract

The treatment of bipolar disorder (BD) usually requires combination therapies, with the critical issue of the emergence of adverse drug reactions (ADRs) and the possibility of low treatment adherence. Genetic polymorphisms are hypothesized to modulate the pharmacodynamics of psychotropic drugs, representing potential biological markers of ADRs. This study investigated genes involved in the regulation of neuroplasticity (BDNF, ST8SIA2), second messenger cascades (GSK3B, MAPK1, and CREB1), circadian rhythms (RORA), transcription (SP4, ZNF804A), and monoaminergic system (HTR2A and COMT) in the risk of neurological, psychic, autonomic, and other ADRs. Two independent samples of BD patients naturalistically treated were included (COPE-BD n = 147; STEP-BD n = 659). In the COPE-BD 34 SNPs were genotyped, while in the STEP-BD polymorphisms in the selected genes were extracted from the genome-wide dataset. Each ADRs group was categorized as absent-mild or moderate-severe and logistic regression with appropriate covariates was applied to identify possible risk genotypes/alleles. 58.5 and 93.5 % of patients were treated with mood stabilizers, 44.2 and 50.7 % were treated with antipsychotics, and 69.4 and 46.1 % were treated with antidepressants in the COPE-BD and STEP-BD, respectively. Our findings suggested that ST8SIA2 may be associated with psychic ADRs, as shown in the COPE-BD (rs4777989 p = 0.0017) and STEP-BD (rs56027313, rs13379489 and rs10852173). A cluster of RORA SNPs around rs2083074 showed an effect on psychic ADRs in the STEP-BD. Trends supporting the association between HTR2A and autonomic ADRs were found in both samples. Confirmations are needed particularly for ST8SIA2 and RORA since the few available data regarding their role in relation to psychotropic ADRs.

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Al-Qudah M, Anderson CD, Mahavadi S, Bradley ZL, Akbarali HI, Murthy KS, Grider JR (2014) Brain-derived neurotrophic factor enhances cholinergic contraction of longitudinal muscle of rabbit intestine via activation of phospholipase C. Am J Physiol Gastrointest Liver Physiol 306:G328–G337PubMedCrossRef

Anderson CA, Pettersson FH, Clarke GM, Cardon LR, Morris AP, Zondervan KT (2010) Data quality control in genetic case-control association studies. Nat Protoc 5:1564–1573PubMedCentralPubMedCrossRef

Angata K, Nakayama J, Fredette B, Chong K, Ranscht B, Fukuda M (1997) Human STX polysialyltransferase forms the embryonic form of the neural cell adhesion molecule. Tissue-specific expression, neurite outgrowth, and chromosomal localization in comparison with another polysialyltransferase, PST. J Biol Chem 272:7182–7190PubMedCrossRef

Baldessarini R, Henk H, Sklar A, Chang J, Leahy L (2008) Psychotropic medications for patients with bipolar disorder in the United States: polytherapy and adherence. Psychiatr Serv 59:1175–1183PubMedCrossRef

Balog Z, Kiss I, Keri S (2011) ZNF804A may be associated with executive control of attention. Genes Brain Behav 10:223–227PubMedCrossRef

Basile VS, Ozdemir V, Masellis M, Meltzer HY, Lieberman JA, Potkin SG, Macciardi FM, Petronis A, Kennedy JL (2001) Lack of association between serotonin-2A receptor gene (HTR2A) polymorphisms and tardive dyskinesia in schizophrenia. Mol Psychiatry 6:230–234PubMedCrossRef

Beaulieu JM, Gainetdinov RR, Caron MG (2009) Akt/GSK3 signaling in the action of psychotropic drugs. Annu Rev Pharmacol Toxicol 49:327–347PubMedCrossRef

Black AR, Black JD, Azizkhan-Clifford J (2001) Sp1 and kruppel-like factor family of transcription factors in cell growth regulation and cancer. J Cell Physiol 188:143–160PubMedCrossRef

Bouwman P, Philipsen S (2002) Regulation of the activity of Sp1-related transcription factors. Mol Cell Endocrinol 195:27–38PubMedCrossRef

Cacabelos R, Martinez-Bouza R, Carril JC, Fernandez-Novoa L, Lombardi V, Carrera I, Corzo L, McKay A (2012) Genomics and pharmacogenomics of brain disorders. Curr Pharm Biotechnol 13:674–725PubMedCrossRef

Calati R, Crisafulli C, Balestri M, Serretti A, Spina E, Calabro M, Sidoti A, Albani D, Massat I, Hofer P, Amital D, Juven-Wetzler A, Kasper S, Zohar J, Souery D, Montgomery S, Mendlewicz J (2013) Evaluation of the role of MAPK1 and CREB1 polymorphisms on treatment resistance, response and remission in mood disorder patients. Prog Neuropsychopharmacol Biol Psychiatry 44:271–278PubMedCrossRef

Crisafulli C, Drago A, Sidoti A, Serretti A (2013) A genetic dissection of antipsychotic induced movement disorders. Curr Med Chem 20:312–330PubMed

de Leon J, Susce MT, Pan RM, Fairchild M, Koch WH, Wedlund PJ (2005) The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation. J Clin Psychiatry 66:15–27PubMedCrossRef

Demyttenaere K, Albert A, Mesters P, Dewe W, De Bruyckere K, Sangeleer M (2005) What happens with adverse events during 6 months of treatment with selective serotonin reuptake inhibitors? J Clin Psychiatry 66:859–863PubMedCrossRef

Drago A, Crisafulli C, Serretti A (2011) The genetics of antipsychotic induced tremors: a genome-wide pathway analysis on the STEP-BD SCP sample. Am J Med Genet B Neuropsychiatr Genet 156B:975–986PubMedCrossRef

Esslinger C, Kirsch P, Haddad L, Mier D, Sauer C, Erk S, Schnell K, Arnold C, Witt SH, Rietschel M, Cichon S, Walter H, Meyer-Lindenberg A (2011) Cognitive state and connectivity effects of the genome-wide significant psychosis variant in ZNF804A. Neuroimage 54:2514–2523PubMedCrossRef

Fabbri C, Di Girolamo G, Serretti A (2013) Pharmacogenetics of antidepressant drugs: an update after almost 20 years of research. Am J Med Genet B Neuropsychiatr Genet 162B:487–520PubMedCrossRef

Foltynie T, Cheeran B, Williams-Gray CH, Edwards MJ, Schneider SA, Weinberger D, Rothwell JC, Barker RA, Bhatia KP (2009) BDNF val66met influences time to onset of levodopa induced dyskinesia in Parkinson’s disease. J Neurol Neurosurg Psychiatry 80:141–144PubMedCrossRef

Frederic F, Chianale C, Oliver C, Mariani J (2006) Enhanced endocrine response to novel environment stress and lack of corticosterone circadian rhythm in staggerer (Rora sg/sg) mutant mice. J Neurosci Res 83:1525–1532PubMedCrossRef

Garfield LD, Dixon D, Nowotny P, Lotrich FE, Pollock BG, Kristjansson SD, Dore PM,Lenze EJ (2013) Common selective serotonin reuptake inhibitor side effects in older adults associated with genetic polymorphisms in the serotonin transporter and receptors: data from a randomized controlled trial. Am J Geriatr Psychiatry [Epub ahead of print]

Girgenti MJ, LoTurco JJ, Maher BJ (2012) ZNF804a regulates expression of the schizophrenia-associated genes PRSS16, COMT, PDE4B, and DRD2. PLoS One 7:e32404PubMedCentralPubMedCrossRef

Gollner H, Bouwman P, Mangold M, Karis A, Braun H, Rohner I, Del Rey A, Besedovsky HO, Meinhardt A, van den Broek M, Cutforth T, Grosveld F, Philipsen S, Suske G (2001) Complex phenotype of mice homozygous for a null mutation in the Sp4 transcription factor gene. Genes Cells 6:689–697PubMedCrossRef

Grimes CA, Jope RS (2001) The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling. Prog Neurobiol 65:391–426PubMedCrossRef

Gunes A, Scordo MG, Jaanson P, Dahl ML (2007) Serotonin and dopamine receptor gene polymorphisms and the risk of extrapyramidal side effects in perphenazine-treated schizophrenic patients. Psychopharmacology 190:479–484PubMedCrossRef

Hammonds MD, Shim SS (2009) Effects of 4-week treatment with lithium and olanzapine on levels of brain-derived neurotrophic factor, B-cell CLL/lymphoma 2 and phosphorylated cyclic adenosine monophosphate response element-binding protein in the sub-regions of the hippocampus. Basic Clin Pharmacol Toxicol 105:113–119PubMedCrossRef

Hauser RA, Molho E, Shale H, Pedder S, Dorflinger EE (1998) A pilot evaluation of the tolerability, safety, and efficacy of tolcapone alone and in combination with oral selegiline in untreated Parkinson’s disease patients. Tolcapone De Novo Study Group. Mov Disord 13:643–647PubMedCrossRef

Heldt SA, Zimmermann K, Parker K, Gaval M, Weinshenker D, Ressler KJ (2014) BDNF deletion or TrkB impairment in amygdala inhibits both appetitive and aversive learning. J Neurosci 34:2444–2450PubMedCentralPubMedCrossRef

Hess JL, Glatt SJ (2014) How might ZNF804A variants influence risk for schizophrenia and bipolar disorder? A literature review, synthesis, and bioinformatic analysis. Am J Med Genet B Neuropsychiatr Genet 165:28–40CrossRef

Ikeda E, Matsunaga N, Kakimoto K, Hamamura K, Hayashi A, Koyanagi S, Ohdo S (2013) Molecular mechanism regulating 24-hour rhythm of dopamine D3 receptor expression in mouse ventral striatum. Mol Pharmacol 83:959–967PubMedCrossRef

Joels M, Pasricha N, Karst H (2013) The interplay between rapid and slow corticosteroid actions in brain. Eur J Pharmacol 719:44–52PubMedCrossRef

Journiac N, Jolly S, Jarvis C, Gautheron V, Rogard M, Trembleau A, Blondeau JP, Mariani J, Vernet-der Garabedian B (2009) The nuclear receptor ROR(alpha) exerts a bi-directional regulation of IL-6 in resting and reactive astrocytes. Proc Natl Acad Sci USA 106:21365–21370PubMedCentralPubMedCrossRef

Kato M, Serretti A (2010) Review and meta-analysis of antidepressant pharmacogenetic findings in major depressive disorder. Mol Psychiatry 15:473–500PubMedCrossRef

Lafuente A, Bernardo M, Mas S, Crescenti A, Aparici M, Gasso P, Deulofeu R, Mane A, Catalan R, Carne X (2008) Polymorphism of dopamine D2 receptor (TaqIA, TaqIB, and-141C Ins/Del) and dopamine degradation enzyme (COMT G158A, A-278G) genes and extrapyramidal symptoms in patients with schizophrenia and bipolar disorders. Psychiatry Res 161:131–141PubMedCrossRef

Leclerc E, Mansur RB, Brietzke E (2013) Determinants of adherence to treatment in bipolar disorder: a comprehensive review. J Affect Disord 149:247–252PubMedCrossRef

Lingjaerde O, Ahlfors UG, Bech P, Dencker SJ, Elgen K (1987) The UKU side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatr Scand Suppl 334:1–100PubMedCrossRef

Lisowski P, Juszczak GR, Goscik J, Stankiewicz AM, Wieczorek M, Zwierzchowski L, Swiergiel AH (2013) Stress susceptibility-specific phenotype associated with different hippocampal transcriptomic responses to chronic tricyclic antidepressant treatment in mice. BMC Neurosci 14:144PubMedCentralPubMedCrossRef

Liu MT, Kuan YH, Wang J, Hen R, Gershon MD (2009) 5-HT4 receptor-mediated neuroprotection and neurogenesis in the enteric nervous system of adult mice. J Neurosci 29:9683–9699PubMedCentralPubMedCrossRef

Lotta T, Vidgren J, Tilgmann C, Ulmanen I, Melen K, Julkunen I, Taskinen J (1995) Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry 34:4202–4210PubMedCrossRef

McCarthy MJ, Wei H, Marnoy Z, Darvish RM, McPhie DL, Cohen BM, Welsh DK (2013) Genetic and clinical factors predict lithium’s effects on PER2 gene expression rhythms in cells from bipolar disorder patients. Transl Psychiatry 3:e318PubMedCentralPubMedCrossRef

McClay JL, Adkins DE, Aberg K, Bukszar J, Khachane AN, Keefe RS, Perkins DO, McEvoy JP, Stroup TS, Vann RE, Beardsley PM, Lieberman JA, Sullivan PF, van den Oord EJ (2011) Genome-wide pharmacogenomic study of neurocognition as an indicator of antipsychotic treatment response in schizophrenia. Neuropsychopharmacology 36:616–626PubMedCentralPubMedCrossRef

Muller DJ, Chowdhury NI, Zai CC (2013) The pharmacogenetics of antipsychotic-induced adverse events. Curr Opin Psychiatry 26:144–150PubMedCrossRef

Pinacho R, Villalmanzo N, Lalonde J, Haro JM, Meana JJ, Gill G, Ramos B (2011) The transcription factor SP4 is reduced in postmortem cerebellum of bipolar disorder subjects: control by depolarization and lithium. Bipolar Disord 13:474–485PubMedCentralPubMedCrossRef

Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575PubMedCentralPubMedCrossRef

Racaniello M, Cardinale A, Mollinari C, D’Antuono M, De Chiara G, Tancredi V, Merlo D (2010) Phosphorylation changes of CaMKII, ERK1/2, PKB/Akt kinases and CREB activation during early long-term potentiation at Schaffer collateral-CA1 mouse hippocampal synapses. Neurochem Res 35:239–246PubMedCrossRef

Ray MT, Shannon Weickert C, Webster MJ (2014) Decreased BDNF and TrkB mRNA expression in multiple cortical areas of patients with schizophrenia and mood disorders. Transl Psychiatry 4:e389PubMedCentralPubMedCrossRef

Sachs GS, Guille C, McMurrich SL (2002) A clinical monitoring form for mood disorders. Bipolar Disord 4:323–327PubMedCrossRef

Sachs GS, Thase ME, Otto MW, Bauer M, Miklowitz D, Wisniewski SR, Lavori P, Lebowitz B, Rudorfer M, Frank E, Nierenberg AA, Fava M, Bowden C, Ketter T, Marangell L, Calabrese J, Kupfer D, Rosenbaum JF (2003) Rationale, design, and methods of the systematic treatment enhancement program for bipolar disorder (STEP-BD). Biol Psychiatry 53:1028–1042PubMedCrossRef

Saiz PA, Susce MT, Clark DA, Kerwin RW, Molero P, Arranz MJ, de Leon J (2008) An investigation of the alpha1A-adrenergic receptor gene and antipsychotic-induced side-effects. Hum Psychopharmacol 23:107–114PubMedCrossRef

Sato C, Kitajima K (2013) Impact of structural aberrancy of polysialic acid and its synthetic enzyme ST8SIA2 in schizophrenia. Front Cell Neurosci 7:61PubMedCentralPubMed

Segman RH, Heresco-Levy U, Finkel B, Goltser T, Shalem R, Schlafman M, Dorevitch A, Yakir A, Greenberg D, Lerner A, Lerer B (2001) Association between the serotonin 2A receptor gene and tardive dyskinesia in chronic schizophrenia. Mol Psychiatry 6:225–229PubMedCrossRef

Serretti A, Chiesa A, Calati R, Fabbri C, Sentissi O, De Ronchi D, Mendlewicz J, Souery D (2013) Side effects associated with psychotropic medications in patients with bipolar disorder: evidence from two independent samples. J Psychopharmacol 27:616–628PubMedCrossRef

Shaw AD, Tiwari Y, Kaplan W, Heath A, Mitchell PB, Schofield PR, Fullerton JM (2014) Characterisation of genetic variation in ST8SIA2 and its interaction region in NCAM1 in patients with bipolar disorder. PLoS One 9:e92556PubMedCentralPubMedCrossRef

Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC (1998) The mini-international neuropsychiatric interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 59((Suppl 20)):22–33 (quiz 34–57)PubMed

Sikander A, Rana SV, Prasad KK (2009) Role of serotonin in gastrointestinal motility and irritable bowel syndrome. Clin Chim Acta 403:47–55PubMedCrossRef

Simons CJ, van Winkel R, Group (2013) Intermediate phenotype analysis of patients, unaffected siblings, and healthy controls identifies VMAT2 as a candidate gene for psychotic disorder and neurocognition. Schizophr Bull 39:848–856PubMedCentralPubMedCrossRef

Souery D, Zaninotto L, Calati R, Linotte S, Sentissi O, Amital D, Moser U, Kasper S, Zohar J, Mendlewicz J, Serretti A (2011) Phenomenology of psychotic mood disorders: lifetime and major depressive episode features. J Affect Disord 135:241–250PubMedCrossRef

Souery D, Zaninotto L, Calati R, Linotte S, Mendlewicz J, Sentissi O, Serretti A (2012) Depression across mood disorders: review and analysis in a clinical sample. Compr Psychiatry 53:24–38PubMedCrossRef

Srivastava V, Varma PG, Prasad S, Semwal P, Nimgaonkar VL, Lerer B, Deshpande SN, Bk T (2006) Genetic susceptibility to tardive dyskinesia among schizophrenia subjects: IV. Role of dopaminergic pathway gene polymorphisms. Pharmacogenet Genomics 16:111–117PubMedCrossRef

Staeker J, Leucht S, Laika B, Steimer W (2014) Polymorphisms in serotonergic pathways influence the outcome of antidepressant therapy in psychiatric inpatients. Genet Test Mol Biomark 18:20–31CrossRef

Staudt MD, de Oliveira CV, Lehman MN, McKenna KE, Coolen LM (2010) Activation of MAP kinase in lumbar spinothalamic cells is required for ejaculation. J Sex Med 7:2445–2457PubMed

Stojkov NJ, Janjic MM, Baburski AZ, Mihajlovic AI, Drljaca DM, Sokanovic SJ, Bjelic MM, Kostic TS, Andric SA (2013) Sustained in vivo blockade of alpha(1)-adrenergic receptors prevented some of stress-triggered effects on steroidogenic machinery in Leydig cells. Am J Physiol Endocrinol Metab 305:E194–E204PubMedCrossRef

Utge SJ, Soronen P, Loukola A, Kronholm E, Ollila HM, Pirkola S, Porkka-Heiskanen T, Partonen T, Paunio T (2010) Systematic analysis of circadian genes in a population-based sample reveals association of TIMELESS with depression and sleep disturbance. PLoS One 5:e9259PubMedCentralPubMedCrossRef

Van Den Bossche MJ, Docx L, Morrens M, Cammaerts S, Strazisar M, Bervoets C, Smolders S, Depreeuw V, Lenaerts AS, De Rijk P, Del-Favero J, Sabbe BG (2012) Less cognitive and neurological deficits in schizophrenia patients carrying risk variant in ZNF804A. Neuropsychobiology 66:158–166CrossRef

van der Heijden KB, de Sonneville LM, Swaab H (2013) Association of eveningness with problem behavior in children: a mediating role of impaired sleep. Chronobiol Int 30:919–929PubMedCrossRef

Van Rheenen TE, Rossell SL (2013) Genetic and neurocognitive foundations of emotion abnormalities in bipolar disorder. Cogn Neuropsychiatry 18:168–207PubMedCrossRef

Whiteford HA, Degenhardt L, Rehm J, Baxter AJ, Ferrari AJ, Erskine HE, Charlson FJ, Norman RE, Flaxman AD, Johns N, Burstein R, Murray CJ, Vos T (2013) Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet 382:1575–1586PubMedCrossRef

Wilffert B, Al Hadithy AF, Sing VJ, Matroos G, Hoek HW, van Os J, Bruggeman R, Brouwers JR, van Harten PN (2009) The role of dopamine D3, 5-HT2A and 5-HT2C receptor variants as pharmacogenetic determinants in tardive dyskinesia in African-Caribbean patients under chronic antipsychotic treatment: curacao extrapyramidal syndromes study IX. J Psychopharmacol 23:652–659PubMedCrossRef

Yamashita S, Tai P, Charron J, Ko C, Ascoli M (2011) The Leydig cell MEK/ERK pathway is critical for maintaining a functional population of adult Leydig cells and for fertility. Mol Endocrinol 25:1211–1222PubMedCentralPubMedCrossRef

Yuan P, Zhou R, Wang Y, Li X, Li J, Chen G, Guitart X, Manji HK (2010) Altered levels of extracellular signal-regulated kinase signaling proteins in postmortem frontal cortex of individuals with mood disorders and schizophrenia. J Affect Disord 124:164–169PubMedCentralPubMedCrossRef

Zai CC, Tiwari AK, Muller DJ, De Luca V, Shinkai T, Shaikh S, Ni X, Sibony D, Voineskos AN, Meltzer HY, Lieberman JA, Potkin SG, Remington G, Kennedy JL (2010) The catechol-O-methyl-transferase gene in tardive dyskinesia. World J Biol Psychiatry 11:803–812PubMedCrossRef

Zhou X, Long JM, Geyer MA, Masliah E, Kelsoe JR, Wynshaw-Boris A, Chien KR (2005) Reduced expression of the Sp4 gene in mice causes deficits in sensorimotor gating and memory associated with hippocampal vacuolization. Mol Psychiatry 10:393–406PubMedCrossRef

Zivkovic M, Mihaljevic-Peles A, Bozina N, Sagud M, Nikolac-Perkovic M, Vuksan-Cusa B, Muck-Seler D (2013) The association study of polymorphisms in DAT, DRD2, and COMT genes and acute extrapyramidal adverse effects in male schizophrenic patients treated with haloperidol. J Clin Psychopharmacol 33:593–599PubMedCrossRef

Title: Genetics of psychotropic medication induced side effects in two independent samples of bipolar patients
Authors: Chiara Fabbri
Daniel Souery
Raffaella Calati
Concetta Crisafulli
Armando Chierchia
Diego Albani
Gianluigi Forloni
Alberto Chiesa
Rosalba Martines
Othman Sentissi
Julien Mendlewicz
Giovanni De Girolamo
Alessandro Serretti
Publication date: 01-01-2015
Publisher: Springer Vienna
Published in: Journal of Neural Transmission / Issue 1/2015
Print ISSN: 0300-9564
Electronic ISSN: 1435-1463
DOI: https://doi.org/10.1007/s00702-014-1290-3

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Genetics of psychotropic medication induced side effects in two independent samples of bipolar patients

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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