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Genetic Variation and the Risk of Haloperidol-Related Parkinsonism in Elderly Patients: A Candidate Gene Approach

Knol, Wilma MD, PhD*†‡; van Marum, Rob J. MD, PhD; Jansen, Paul A.F. MD, PhD*; Strengman, Eric MSc; Al Hadithy, Asmar F.Y. PharmD, PhD; Wilffert, Bob PhD#; Schobben, Alfred F.A.M. PharmD, PhD; Ophoff, Roel A. PhD**††; Egberts, Toine C.G. PharmD, PhD‡‡‡

Journal of Clinical Psychopharmacology: June 2013 - Volume 33 - Issue 3 - p 405–410
doi: 10.1097/JCP.0b013e3182902708
Brief Reports

Factors that influence the variation in occurrence of antipsychotic-related parkinsonism in elderly have not been well elucidated. The aim of this study was to investigate whether previous identified and studied genetic polymorphisms at DRD2, ANKK1, DRD3, HTR2A, HTR2C, RGS2, COMT, and BDNF genes are associated with antipsychotic-related parkinsonism in elderly patients.

This cross-sectional study included 150 inpatients aged 65 years and older who were treated with haloperidol. Parkinsonism assessed by the Simpson Angus Scale was present in 46% of the included patients. The investigated predictors were polymorphisms in DRD2 (141CIns/Del and C957T), ANNK1 (TaqIA), DRD3 (Ser9Gly), HTR2A (−1438G>A and His452Tyr), HTR2C (Cys23Ser and −759C/T), RGS2 (+2971C>G), COMT (G158A), and BDNF (Val66Met). Frequencies of the −759 T allele of the HTR2C gene and the 158A allele of the COMT gene were significantly higher in patients without antipsychotic-induced parkinsonism (AIP) (nominal P = 0.03 and P = 0.02, respectively). −759 T allele carriership in females was associated with a lower risk of AIP (adjusted odds ratio, 0.31; 95% confidence interval, 0.11-0.85). The decrease in risk of AIP in carriers of the COMT 158A allele did not reach statistical significance. No significant associations were found between AIP and the remaining selected polymorphisms.

Although validation is needed, this study suggests that carriership of the −759 T allele of the HTR2C gene in females may be protective against development of parkinsonism in elderly patients during treatment with haloperidol.

Supplemental digital content is available in the text.

From the *Department of Geriatrics and Expertise Center Pharmacotherapy in Old Persons, University Medical Center Utrecht, Utrecht; †Department of Geriatrics, Tergooiziekenhuizen, Hilversum; ‡Department of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht; §Department of Geriatrics, Jeroen Bosch Ziekenhuis, ’s-Hertogenbosch; ∥Department of Medical Genetics, University Medical Center Utrecht, Utrecht; ¶Hospital Pharmacy, Erasmus University Medical Center, Rotterdam; #Unit of Pharmacotherapy and Pharmaceutical Care, Department of Pharmacy, University of Groningen, Groningen; **Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands; ††Center for Neurobehavioral Genetics, University of California Los Angeles, Los Angeles, CA; and ‡‡Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, the Netherlands.

Received September 13, 2011; accepted after revision November 28, 2012.

Reprints: Wilma Knol, MD, Department of Geriatrics, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, the Netherlands (e-mail:

The authors have not published any related paper from the same study and no copies of related or possibly duplicative materials are under consideration elsewhere.

References 32 to 39 were cited in the Supplemental Material on the Journal’s Web site.

Supplemental digital contents are available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (

© 2013 Lippincott Williams & Wilkins, Inc.