PHARMACOGENETIC PREDICTORS FOR TREATMENT OUTCOME
A prospective longitudinal study in the NESDA population.
Project leader / Applicant: Witte Hoogendijk, VUMC psychiatry
Promovendus: Pierre Bet, VUMC pharmacology
Background: The variation in individual clinical response to psychotropic drugs is an important drawback in the management of mentally ill patients. Using clinical variables as predictors for success have shown limited effect. The availability of genomic information as well as molecular biological techniques has boosted research to determine relationships between genotype and drug response. This pharmacogenetic research has identified pharmacokinetic and pharmacodynamic polymorphisms to be predictors of short-term psychotropic drug response and adverse effects. Many studies have shown the influence of cytochrome P450 (CYP) 2D6 and 2C19 polymorphism on pharmacokinetics of antidepressant and anxiolytic drugs. Approximately 50% of these drugs should be used in distinctly different dosages in patients, who are poor or ultra fast metabolisers for CYP 2D6 and 2C19 (Kirchheimer 2001). In the Caucasian population the incidence of poor and ultra fast metabolisers for CYP 2D6 is 8% and 1-10% respectively. The incidence of poor metabolisers for CYP 2C19 is 1-3% in Caucasians and about 20 % among Orientals (Tamminga 2003). Retrospective studies have shown that altered CYP 2D6 status is a risk factor for adverse drug reactions (ADRs) (Phillips 2001, Tamminga 2003) or therapeutic failure (Kawanishi 2004, Rau 2004, Wedlund 2004). Altered CYP2D6 status was also associated with increased duration of hospital stay and costs (Chou 2000). Carcillo et al. suggested a relationship between the 2D6 mRNA-expression in peripheral blood mononuclear cells and the metabolic phenotype as measured by standard 2D6 debrisoquine recovery ratio (Carcillo 2003). Important pharmacodynamic polymorphisms could be the serotonin 2a receptor (S2aR) T102C and the polymorphism in the promotor region of the serotonin transporter (ST) gene, SLC6A4. S2aR T102C polymorphism has been linked to increased incidence of side effects in patients on paroxetin treatment (Murphy 2003) and poor response to serotonergic antidepressants (Malhotra 2004-ref 108). The ST gene polymorphism, SLC6A4, has a long and a short variant. The long/long genotype has been linked to better response to short-term serotonergic antidepressants in several populations (Malhotra 2004) and less antidepressant- induced mania in patients with bipolar depression (Malhotra 2004-ref 124). Another important set of pharmacodynamic polymorphisms is situated in the glucocorticoid receptor (GR), that regulates hypothalamus–pituitary-adrenal (HPA) axis feedback. Previous research Recently we, together with the department of Endocrinology and Psychiatry of the AMC and the ErasmusMC, found that in depressed patients the response to paroxetine was associated with measures of HPA axis hyperactivity and that these measures, and partly also treatment response, were associated with the presence of polymorphisms in the GR DNA sequence (BclI, ER22/23EK, N363S, 9 beta) (Brouwer et al, submitted). Moreover, relapse rates were higher in patients with measures of post-treatment HPA axis hyperactivity. At present we are performing association studies in the same cohort testing other (HPA axis and 5-HT) related candidate genes, which may also appear to be relevant for the NESDA population, such as the FKBP5 gene. Three polymorphisms in this gene where published in Nature Genetics to be functional (i.e. altered concentrations of the corresponding chaperone protein) and strongly associated to a faster treatment response (Binder et al., 2004). It is, however, unknown whether the polymorphisms described above also influence (long term) disease outcome in patients with depression and anxiety disorders. Therefore, our overall aim is to find predictors for treatment response and outcome by studying their association with pharmacokinetic and pharmacodynamic polymorphisms in patients participating in NESDA. Research questions are: 1) Are polymorphisms in known and newly found pharmacokinetic and pharmacodynamic
candidate genes, such as CYP2D6, CYP2C19, ST, S2aR and GR, associated with clinical factors, such as severity of depression and anxiety,suicidal ideation, medication use, relapse rates, treatment response and adverse effects?
2) Are these associations stronger when related biological endophenotypes are taken into
account, such as HPA axis activity and autonomous nervous system measures?
Previous research
Recently we, together with the department of Endocrinology and Psychiatry of the AMC and
the ErasmusMC, found that in depressed patients the response to paroxetine was associated
with measures of HPA axis hyperactivity and that these measures, and partly also treatment
response were associated with the presence of polymorphisms in the GR DNA sequence
(BclI, ER22/23EK, N363S) (Brouwer et al, submitted). Moreover, relapse rates were higher in
patients with measures of post-treatment HPA axis hyperactivity. At present we are performing
association studies in the same cohort testing other (HPA axis and 5-HT related) related
candidate genes, which may also appear to be relevant for the NESDA population.
Brouwer, Appelhof, van Rossum, Koper, Fliers, Huyser, Schene, Tijssen, Van Dyck, Lamberts, Wiersinga and
Hoogendijk. Prediction of Treatment Response by HPA-axis and Glucocorticoid Receptor Polymorphisms in Major Depression. Submitted
Binder EB, Salyakina D, Lichtner P, Holsboer F, Muller-Myhsok B. Polymorphisms in FKBP5 are associated with
increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet. 2004 Dec;36(12):1319-25. Epub 2004 Nov 21
Carcillo JA, Adedoyin A, Burckart GJ et al. Coordinated intrahepatic and extrahepatic regulation of cytochrome
P4502D6 in healthy subjects and in patients after liver transplantation. Clin Pharmacol Ther 2003;73:456-67.
Chou WH, Yan FX, de Leon J et al. Extension of a pilot study: impact from the cytochrome P450 2D6 polymorphism
on outcome and costs associated with severe mental illness. J Clin Psychopharmacol. 2000 Apr;20(2):246-51.
Kawanishi C, Lundgren S, Agren H et al. Increased incidence of CYP2D6 gene duplication in patients with persistent
mood disorders: ultrarapid metabolism of antidepressants as a cause of nonresponse. A pilot study. Eur J Clin Pharmacol. 2004 Jan;59(11):803-7. Epub 2003 Dec 02.
Kirchheiner J, Brosen K, Dahl M et al. CYP2D6 and CYP2C19 genotype-based dose recommendations for
antidepressants: a first step towards subpopulation-specific dosages. Acta Psychiatr Scand. 2001 Sep;104(3):173-92. Erratum in: Acta Psychiatr Scand 2001 Dec;104(6):475.
Malhotra AK, Murphy GM, Kennedy JL: Pharmacogenetics of psychotropic drug response. Am J Psychiatry 2004;
Murphy GM, Kremer C, Rodriques HE et al. Pharmacogenetics of antidepressant medication intolerance. Am J
Phillips KA, Veenstra DL, Oren A et al. Potential role of pharmacogenomics in reducing adverse drug reactions. JAMA
Rau T, Wohlleben G, Wuttke H et al. CYP2D6 genotype: impact on adverse effects and nonresponse during treatment
with antidepressants-a pilot study. Clin Pharmacol Ther. 2004 May;75(5):386-93.
Tamminga WJ, Wemer J, Oosterhuis B et al. Polymorphic drug metabolism (CYP2D6) and utilisation of psychotropic
drugs in hospitalised psychiatric patients: a retrospective study. Eur J Clin Pharmacol. 2003 May;59(1):57-64. Epub 2003 Mar 18.
Wedlund PJ, de Leon J. Cytochrome P450 2D6 and antidepressant toxicity and response: what is the evidence? Clin
Research plan:
Several pharmacogenetically relevant polymorphisms will be determined and associated with
clinical factors (i.e. treatment outcome and side-effects), biological endophenotypes, and (long
term) outcome in patient samples that will become available in NESDA (N=2800). In the first
wave a large number of items on psychiatric diagnosis (CIDI) and on symptomatology
(through the IDS, BAI, Beck suicide and Fear questionnaires) and the use of antidepressants
(type, frequency, dosage, duration) is collected. Relapse rates and treatment response will be
assessed by examining changes in depressive and anxiety symptomatology and psychiatric
diagnoses after the first and second follow-up waves. The biological endophenotypes will be
assessed through the VU-AMS system (for indicators of the autonomic nervous system) and
through cortisol determination in saliva samples (for indicators of the HPA-axis). After
selection and validation of the analytical methods, the collected DNA-samples will be analysed
First year: 2005 An additional questionaire will be selected or composed to specifically address side effects (will be proposed and to be approved by the ‘NESDA vervolgmetingen werkgroep’), so that these additional items will be collected during the follow-up visits. Selection and validation of the analytical DNA methods. For each polymorphism a choice can be made from several techniques: GeneChip technology, Sniplex, Taqman, etc. The eventual selection of polymorphisms to be associated will be made after an update of the literature by that time. Moreover, new candidate genes may emerge from own human and animal genetic studies. For this reason no genes can be ruled out at this point in time and it is almost certain that enough association data will become available to initiate additional pharmacogenetic studies. However, since the LUMC/LU research group has a long standing tradtion in mineralocorticoid receptor (MR) research polymorphisms in the corresponding gene will be studied by this group (see project outline Prof. Zitman). Since our group already published on genetic association studies with GR polymorphisms in depression and the LUMC/LU group also has a focus on this gene, in the present project these genetic variations will be studied in close collaboration with the LUMC/LU group. Second year: Preparations will be made for data analyses in de NESDA database and selection of patients Third and fourth year: Patient samples will become available in NESDA (after final approval by the board; N=2800). This will allow us to study differences in DNA polymorphisms. Relationships between the DNA and clinical outcome measures will be determined. Justification of methods and personnel Analytical platforms will be chosen per polymorphism The PhD student will perform all data analyses and publish the results in international journals. Sample collection will all be performed by research nurses within the framework of NESDA, and will not be described here.
Date: September 20th 2004 the applicant: W.J.G. Hoogendijk
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