Thang Ho1, Bruce G Pollock2, Benoit H Mulsant2, Oliver Schantz1, Devangere P Devanand3, Jacobo E Mintzer4, Anton P Porsteinsson5, Lon S Schneider6, Daniel Weintraub7, Jerome Yesavage8, Lea T Drye9, Cynthia A Munro10, David M Shade11, Constantine Lyketsos12, Robert Bies1,2. 1. Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, USA. 2. Campbell Family Mental Health Research Institute, CAMH, University of Toronto, Toronto, Ontario, Canada. 3. Division of Geriatric Psychiatry, Colleges of Physicians and Surgeons, Columbia University, New York, New York. 4. Clinical Biotechnology Research Institute, Roper St. Francis Healthcare, Charleston, South Carolina. 5. Alzheimer's Disease Care, Research and Education Program (AD-CARE), University of Rochester School of Medicine and Dentistry, Rochester, New York. 6. Department of Psychiatry and Behavioral Science, Keck School of Medicine, University of Southern California, California. 7. Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. 8. Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, California. 9. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. 10. Department of Psychiatry and Behavioral Sciences, Department of Neurology, Johns Hopkins Bayview and Johns Hopkins School of Medicine, Baltimore, Maryland. 11. Department of Medicine (Pulmonary) and Epidemiology (Center for Clinical Trials), Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. 12. Memory and Alzheimer's Treatment Center, Johns Hopkins Bayview and Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
Abstract
AIMS: 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). METHODS: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. RESULTS: (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). CONCLUSIONS: 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.
RCT Entities:
AIMS: 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). METHODS: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. RESULTS: (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). CONCLUSIONS: 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: Michael D Hurd; Paco Martorell; Adeline Delavande; Kathleen J Mullen; Kenneth M Langa Journal: N Engl J Med Date: 2013-04-04 Impact factor: 91.245
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Authors: Ayman Akil; Robert R Bies; Bruce G Pollock; Dimitrios Avramopoulos; D P Devanand; Jacobo E Mintzer; Anton P Porsteinsson; Lon S Schneider; Daniel Weintraub; Jerome Yesavage; David M Shade; Constantine G Lyketsos Journal: J Pharmacokinet Pharmacodyn Date: 2015-11-26 Impact factor: 2.745
Authors: Thang Ho; Bruce G Pollock; Benoit H Mulsant; Oliver Schantz; Devangere P Devanand; Jacobo E Mintzer; Anton P Porsteinsson; Lon S Schneider; Daniel Weintraub; Jerome Yesavage; Lea T Drye; Cynthia A Munro; David M Shade; Constantine Lyketsos; Robert Bies Journal: Br J Clin Pharmacol Date: 2016-06-20 Impact factor: 4.335
Authors: M Sano; M Soto; M Carrillo; J Cummings; S Hendrix; J Mintzer; A Porsteinsson; P Rosenberg; L Schneider; J Touchon; P Aisen; B Vellas; C Lyketsos Journal: J Prev Alzheimers Dis Date: 2018
Authors: Stephan Ehrhardt; Anton P Porsteinsson; Cynthia A Munro; Paul B Rosenberg; Bruce G Pollock; Davangere P Devanand; Jacobo Mintzer; Tarek K Rajji; Zahinoor Ismail; Lon S Schneider; Sheriza N Baksh; Lea T Drye; Dimitri Avramopoulos; David M Shade; Constantine G Lyketsos Journal: Alzheimers Dement Date: 2019-10-03 Impact factor: 16.655