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Abstract

Objective:

To assess potential genetic influences on citalopram treatment efficacy for agitation in individuals with Alzheimer dementia (AD). Six functional genetic variants were studied in the following genes: serotonin receptor 2A (HTR2A-T102C), serotonin receptor 2C (HTR2C-Cys23Ser), serotonin transporter (5HTT-LPR), brain-derived neurotropic factor (BDNF-Val66Met), apolipoprotein E (ε2, ε3, ε4 variants), and cytochrome P450 (CYP2C19). Treatment response by genotype was measured by (1) the agitation domain of the Neurobehavioral Rating Scale, (2) the modified Alzheimer Disease Cooperative Study—Clinical Global Impression of Change scale (mADCS-CGIC), (3) the agitation domain of the Neuropsychiatric Inventory (NPI), and (4) the Cohen-Mansfield Agitation Inventory.

Method:

We utilized data from the Citalopram for Agitation in Alzheimer’s Disease (CitAD) database. CitAD was a 9-week randomized, double-blind, placebo-controlled multicenter clinical trial showing significant improvement in agitation and caregiver distress in patients treated with citalopram. Proportional odds logistic regression and mixed effects models were used to examine the above-mentioned outcome measures.

Results:

Significant interactions were noted on the NPI agitation domain for HTR2A (likelihood ratio [LR] = 6.19, df = 2, P = .04) and the mADCS-CGIC for HTR2C (LR = 4.33, df = 2, P = .02) over 9 weeks.

Discussion:

Treatment outcomes in CitAD showed modest, although statistically significant, influence of genetic variation at HTR2A and HTR2C loci. Future studies should continue to examine the interaction of known genetic variants with antidepressant treatment in patients with AD having agitation.

Keywords

Alzheimer disease citalopram agitation randomized trial dementia antidepressant genetics

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References

Hebert

Weuve

Scherr

Evans

. Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology. 2013;80(19):1778–1783.

Steinberg

Corcoran

Tschanz

. Risk factors for neuropsychiatric symptoms in dementia: the cache county study. Int J Geriatr Psychiatry. 2006;21(9):824–830.

Steinberg

Shao

Zandi

. Point and 5-year period prevalence of neuropsychiatric symptoms in dementia: the Cache County Study. Int J Geriatr Psychiatry. 2008;23(2):170–177.

Aalten

de Vugt

Jaspers

Jolles

Verhey

. The course of neuropsychiatric symptoms in dementia. Part I: findings from the two-year longitudinal Maasbed study. Int J Geriatr Psychiatry. 2005;20(6):523–530.

Ryu

Katona

Rive

Livingston

. Persistence of and changes in neuropsychiatric symptoms in Alzheimer disease over 6 months: the LASER-AD study. Am J Geriatr Psychiatry. 2005;13(11):976–983.

Lyketsos

Colenda

Beck

. Position statement of the American Association for Geriatric Psychiatry regarding principles of care for patients with dementia resulting from Alzheimer disease. Am J Geriatr Psychiatry. 2006;14(7):561–572.

Drye

Ismail

Porsteinsson

. Citalopram for agitation in Alzheimer’s disease: design and methods. Alzheimers Dement. 2012;8(2):121–130.

Porsteinsson

Drye

Pollock

. Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. JAMA. 2014;311(7):682–691.

Peters

Vaidya

Drye

. Sertraline for the treatment of depression in Alzheimer disease: genetic influences. J Geriatr Psychiatry Neurol. 2011;24(4):222–228.

10.

Wilkosz

Kodavali

Weamer

. Prediction of psychosis onset in Alzheimer disease: the role of depression symptom severity and the HTR2A T102C polymorphism. Am J Med Genet B Neuropsychiatr Genet. 2007;144B(8):1054–1062.

11.

Lappalainen

Long

Virkkunen

Ozaki

Goldman

Linnoila

. HTR2C Cys23Ser polymorphism in relation to CSF monoamine metabolite concentrations and DSM-III-R psychiatric diagnoses. Biol Psychiatry. 1999;46(6):821–826.

12.

Durham

Webb

Milos

Clary

Seymour

. The serotonin transporter polymorphism, 5HTTLPR, is associated with a faster response time to sertraline in an elderly population with major depressive disorder. Psychopharmacology (Berl). 2004;174(4):525–529.

13.

Easteal

Tan

Schweitzer

Aziz

. Serotonin transporter polymorphisms and clinical response to sertraline across ethnicities. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30(5):953–957.

14.

Ramanathan

Glatt

. Serotonergic system genes in psychosis of Alzheimer dementia: meta-analysis. Am J Geriatr Psychiatry. 2009;17(10):839–846.

15.

Serretti

Benedetti

Zanardi

Smeraldi

. The influence of Serotonin Transporter Promoter Polymorphism (SERTPR) and other polymorphisms of the serotonin pathway on the efficacy of antidepressant treatments. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29(6):1074–1084.

16.

Hwang

Tsai

Hong

Yang

Lirng

Yang

. The Val66Met polymorphism of the brain-derived neurotrophic-factor gene is associated with geriatric depression. Neurobiol Aging. 2006;27(12):1834–1837.

17.

Tsai

Cheng

Chen

Hong

. Association study of a brain-derived neurotrophic-factor genetic polymorphism and major depressive disorders, symptomatology, and antidepressant response. Am J Med Genet B Neuropsychiatr Genet. 2003;123B(1):19–22.

18.

Murphy

Kremer

Rodrigues

Schatzberg

; Mitrazapine versus paroxetine Study Group. The apolipoprotein E epsilon4 allele and antidepressant efficacy in cognitively intact elderly depressed patients. Biol Psychiatry. 2003;54(7):665–673.

19.

Jin

Pollock

Frank

. Effect of age, weight, and CYP2C19 genotype on escitalopram exposure. J Clin Pharmacol. 2010;50(1):62–72.

20.

Borroni

Grassi

Archetti

. BDNF genetic variations increase the risk of Alzheimer’s disease-related depression. J Alzheimers Dis. 2009;18(4):867–875.

21.

Myers

Schaefer

Wilson

. Apolipoprotein E epsilon4 association with dementia in a population-based study: The Framingham study. Neurology. 1996;46(3):673–677.

22.

Christidis

Liberopoulos

Kakafika

. The effect of apolipoprotein E polymorphism on the response to lipid-lowering treatment with atorvastatin or fenofibrate. J Cardiovasc Pharmacol Ther. 2006;11(3):211–221.

23.

Harangi

Seres

Balogh

. Effect of apolipoprotein E genotypes on the efficacy of ezetimibe monotherapy in patients with statin induced adverse effects. Int J Clin Pharmacol Ther. 2013;51(9):746–752.

24.

McKhann

Knopman

Chertkow

. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):263–269.

25.

Folstein

McHugh

. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189–198.

26.

Cummings

Mega

Gray

. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology. 1994;44(12):2308–2314.

27.

Avramopoulos

Mikkelsen

Vassilopoulos

Grigoriadou

Petersen

. Apolipoprotein E allele distribution in parents of Down’s syndrome children. Lancet. 1996;347(9005):862–865.

28.

Levin

High

Goethe

. The neurobehavioural rating scale: assessment of the behavioural sequelae of head injury by the clinician. J Neurol Neurosurg Psychiatry. 1987;50(2):183–193.

29.

Schneider

Olin

Doody

. Validity and reliability of the Alzheimer’s disease cooperative study-clinical global impression of change. The Alzheimer’s Disease Cooperative Study. Alzheimer Dis Assoc Disord. 1997;11(suppl 2):S22–S32.

30.

Cohen-Mansfield

. Conceptualization of agitation: results based on the Cohen-Mansfield Agitation Inventory and the Agitation Behavior Mapping Instrument. Int Psychogeriatr. 1996;8(Suppl 3):309–315; discussion 351-354.

31.

Schwab

Kaschka

Spina

. Pharmacogenomics in Psychiatry (Advances in Biological Psychiatry). Basel, Switzerland: Karger Publishers; 2010.

Citalopram for the Treatment of Agitation in Alzheimer Dementia

Abstract

Objective:

Method:

Results:

Discussion:

Keywords

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References