title: R- and S-citalopram concentrations have differential effects on neuropsychiatric scores in elders with dementia and agitation.
abstract: The aim was to determine the relationship between (R) and (S)-citalopram enantiomer exposure (AUC(0,24 h)) and therapeutic response in agitated individuals greater than 60 years old with Alzheimer's dementia (AD).
  
  
  
  Citalopram enantiomer exposures (AUC(0,24 h)) derived from an established population pharmacokinetic analysis were utilized to explore the relationship between (R)- and (S)-citalopram area under the curve (AUC(0,24 )) and Mini-Mental State Examination (MMSE), Neurobehavioural Rating Scale-Agitation Subscale (NBRS-A), modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC) and Neuropsychiatric Inventory Agitation subscale (NPIA) scores. Time dependent changes in these scores (disease progression) were accounted for prior to exploring the exposure effect relationship for each enantiomer. These relationships were evaluated using a non-linear-mixed effects modelling approach as implemented in nonmem v7.3.
  
  
  
  (S)-AUC(0,24 h) and (R)-AUC(0,24 h) each contributed to improvement in NBRS-A scores (k3(R) -0.502; k4(S) -0.712) as did time in treatment. However, increasing (R)-AUC(0,24 h) decreased the probability of patient response (maximum Δ -0.182%/AUC(0,24 h)) based on the CGIC while (S)-AUC(0,24 h) improved the probability of response (maximum Δ 0.112%/AUC(0,24 h)). (R)-AUC(0,24 h) was also associated with worsening in MMSE scores (-0.5 points).
  
  
  
  Our results suggest that citalopram enantiomers contributed differentially to treatment outcomes. (R)-citalopram accounted for a greater proportion of the adverse consequences associated with racemic citalopram treatment in patients with AD including a decreased probability of treatment response as measured by the CGIC and a reduction in MMSE scores. The S-enantiomer was associated with increased probability of response based on the CGIC.
authors.affiliation: Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Thang
authors.initials: T
authors.lastname: Ho
authors.affiliation: Campbell Family Mental Health Research Institute, CAMH, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Pollock
authors.affiliation: Campbell Family Mental Health Research Institute, CAMH, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Benoit H
authors.initials: BH
authors.lastname: Mulsant
authors.affiliation: Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Oliver
authors.initials: O
authors.lastname: Schantz
authors.affiliation: Division of Geriatric Psychiatry, Colleges of Physicians and Surgeons, Columbia University, New York, New York.
authors.forename: Devangere P
authors.initials: DP
authors.lastname: Devanand
authors.affiliation: Clinical Biotechnology Research Institute, Roper St. Francis Healthcare, Charleston, South Carolina.
authors.forename: Jacobo E
authors.initials: JE
authors.lastname: Mintzer
authors.affiliation: Alzheimer's Disease Care, Research and Education Program (AD-CARE), University of Rochester School of Medicine and Dentistry, Rochester, New York.
authors.forename: Anton P
authors.initials: AP
authors.lastname: Porsteinsson
authors.affiliation: Department of Psychiatry and Behavioral Science, Keck School of Medicine, University of Southern California, California.
authors.forename: Lon S
authors.initials: LS
authors.lastname: Schneider
authors.affiliation: Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Daniel
authors.initials: D
authors.lastname: Weintraub
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, California.
authors.forename: Jerome
authors.initials: J
authors.lastname: Yesavage
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Lea T
authors.initials: LT
authors.lastname: Drye
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Department of Neurology, Johns Hopkins Bayview and Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Munro
authors.affiliation: Department of Medicine (Pulmonary) and Epidemiology (Center for Clinical Trials), Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: David M
authors.initials: DM
authors.lastname: Shade
authors.affiliation: Memory and Alzheimer's Treatment Center, Johns Hopkins Bayview and Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
authors.forename: Constantine
authors.initials: C
authors.lastname: Lyketsos
authors.affiliation: Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, USA.|Campbell Family Mental Health Research Institute, CAMH, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Bies
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000097:blood / Q000150:complications / Q000188:drug therapy; D015283:Citalopram / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D003704:Dementia / Q000150:complications / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007536:Isomerism; D008297:Male; D011569:Psychiatric Status Rating Scales / Q000706:statistics & numerical data*; D011595:Psychomotor Agitation / Q000150:complications / Q000188:drug therapy; D017367:Selective Serotonin Reuptake Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D015283:Citalopram; D017367:Selective Serotonin Reuptake Inhibitors
keywords: Alzheimer's disease; agitation; citalopram; escitalopram; pharmacodynamics