Serotonin transporter genotype interacts with paroxetine plasma levels to influence depression treatment response in geriatric patients

Serotonin transporter genotype interacts with paroxetine plasma levels to influence depression treatment response in geriatric patients

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J Psychiatry Neurosci 2008;33(2):123-30

Francis E. Lotrich, MD, PhD; Bruce G. Pollock, MD, PhD; Margaret Kirshner, BA; Robert F. Ferrell, PhD; Charles F. Reynolds III, MD

Lotrich, Pollock, Kirshner, Reynolds — NIMH Advanced Center in Interventions and Services Research for Late-Life Mood Disorders and the John A. Hartford Foundation Center of Excellence in Geriatric Psychiatry, Department of Psychiatry, Western Psychiatric Institute and Clinics, University of Pittsburgh Medical Center; Ferrell — Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pa.; Pollock — Rotman Research Institute, Baycrest Centre for Geriatric Care, University of Toronto, Toronto, Ont.

Abstract

Objective: To investigate whether variable antidepressant response may be influenced by an interaction between the serotonin transporter promoter polymorphism (5-HTTLPR) and antidepressant concentration.

Methods: Elderly subjects with depression treated with paroxetine (n = 110) were genotyped and assessed with the Hamilton Rating Scale for Depression (HAMD). A mixed-effect analysis of repeated measures was used.

Results: There was an interaction between early paroxetine concentration and 5-HTTLPR genotype on symptomatic improvement over 12 weeks (F 18,59.5 = 1.8, p < 0.05), as well as main effects of both paroxetine concentration (F 68,55.3 = 2.4, p < 0.005) and genotype (F 2,74.2 = 5.7, p < 0.005). Paroxetine concentrations were correlated with change in HAMD scores after 2 weeks of treatment in subjects with the short (s) allele (r = 0.31, p < 0.05) but not in subjects homozygous for the long (l) allele. Conclusion: The results demonstrate a concentration–response relation for paroxetine in late-life depression and support the hypothesis for both a direct main effect and a moderating influence of 5-HTTLPR alleles on this concentration–response relation.

Résumé

Objectif : Savoir si la réponse variable aux antidépresseurs peut être influencée par une interaction entre le polymorphisme du promoteur du transporteur de la sérotonine (5 HTTLPR) et la concentration d’antidépresseur.

Méthodes : On a déterminé le génotype de sujets âgés atteints de dépression traitée à la paroxétine (n = 110) et on les a évalués au moyen de l’échelle de dépression de Hamilton (HAMD). On a utilisé une analyse à effets mixtes de mesures répétées.

Résultats : On a constaté qu’une interaction entre la concentration de paroxétine au début et le génotype de la 5 HTTLPR était associée à une amélioration des symptômes en 12 semaines (F 18,59,5 = 1,8, p < 0,05), et que la concentration de paroxétine (F 68,55,3 = 2,4, p < 0,005) et le génotype (F 2,74,2 = 5,7, p < 0,005) étaient associés à des effets principaux. On a établi une corrélation entre les concentrations de paroxétine et l'évolution des résultats du test HAMD après deux semaines de traitement chez les sujets qui avaient l'allèle (s) court (r = 0,31, p < 0,05), mais non chez les sujets homozygotes pour l'allèle long (l). Conclusion : Les résultats démontrent l’existence d’un lien concentration-réponse pour la paroxétine dans le cas de la dépression chez les personnes âgées et appuient l’hypothèse selon laquelle les allèles de la 5 HTTLPR ont à la fois un effet principal direct et une influence modératrice sur cette relation concentration-réponse.


Medical subject headings: serotonin; paroxetine; depression; aged.

Competing interests: Bruce Pollock has received research support from Janssen Pharmaceuticals and is a consultant to Lundbeck and Forest Pharmaceuticals and until August 2004 was a consultant to SmithKline Beecham. Charles Reynolds has received research support from GSK, Forest, Pfizer, BMS and Lilly. SmithKline Beecham donated the paroxetine used in the trials.

Submitted May 24, 2007; Revised Aug. 27, 2007; Accepted Sept. 5, 2007

Contributors: Dr. Lotrich designed the study. Drs. Pollock, Ferrell and Reynolds, and Ms. Kirshner acquired the data, which Drs. Lotrich, Pollock and Reynolds analyzed. Dr. Lotrich wrote the article, and Drs. Pollock, Ferrell and Reynolds, and Ms. Kirshner revised it. All authors gave final approval for the article to be published.

Acknowledgements: This research was supported by NIMH grants K23MH074012, K24MH065416, R01MH043832, P30MH071944, the John A. Hartford Foundation Center of Excellence in Geriatric Psychiatry, the University of Pittsburgh Medical Center Endowed Chair in Geriatric Psychiatry and the Sandra A. Rotman Chair in Neuropsychiatry. The results were preliminarily reported in abstract form at Collegium Internationale Neuropsychopharmacologicum 2006.

Correspondence to: Dr. F.E. Lotrich, Western Psychiatric Institute and Clinics, 3811 O’Hara St., Pittsburgh PA 15213; fax 412 246-6260; lotrichfe@upmc.edu