Effect of Citalopram on Agitation in Alzheimer Disease: The CitAD Randomized Clinical Trial

• Published in: JAMA : the journal of the American Medical Association Vol. 311; no. 7; pp. 682 - 691
• Main Authors: Porsteinsson, Anton P, Drye, Lea T, Pollock, Bruce G, Devanand, D. P, Frangakis, Constantine, Ismail, Zahinoor, Marano, Christopher, Meinert, Curtis L, Mintzer, Jacobo E, Munro, Cynthia A, Pelton, Gregory, Rabins, Peter V, Rosenberg, Paul B, Schneider, Lon S, Shade, David M, Weintraub, Daniel, Yesavage, Jerome, Lyketsos, Constantine G
• Format: Journal Article
• Language: English
• Published: Chicago, IL American Medical Association 19-02-2014
• Subjects: Activities of Daily Living; Adult and adolescent clinical studies; Aged; Aged, 80 and over; Alzheimer Disease - complications; Alzheimer Disease - nursing; Alzheimer Disease - physiopathology; Alzheimer's disease; Arrhythmias, Cardiac - chemically induced; Biological and medical sciences; Caregivers - psychology; Citalopram - adverse effects; Citalopram - therapeutic use; Clinical trials; Cognition - drug effects; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Double-Blind Method; Drug therapy; Drugs; Female; General aspects; Humans; Male; Medical sciences; Neurology; Organic mental disorders. Neuropsychology; Psychology. Psychoanalysis. Psychiatry; Psychomotor Agitation - drug therapy; Psychomotor Agitation - etiology; Psychopathology. Psychiatry; Serotonin Uptake Inhibitors - adverse effects; Serotonin Uptake Inhibitors - therapeutic use; Severity of Illness Index; Stress, Psychological; Treatment Outcome; Nervous system diseases; Agitation; Serotonin; Alzheimer disease; Psychotropic; Reuptake inhibitor; Selective serotonin reuptake inhibitor; Cerebral disorder; Citalopram; Medicine; Central nervous system disease; Neurotransmitter; Antidepressant agent; Clinical trial; Degenerative disease
• ISSN: 0098-7484; 1538-3598
• DOI: 10.1001/jama.2014.93

IMPORTANCE Agitation is common, persistent, and associated with adverse consequences for patients with Alzheimer disease. Pharmacological treatment options, including antipsychotics are not satisfactory. OBJECTIVE The primary objective was to evaluate the efficacy of citalopram for agitation in patients with Alzheimer disease. Key secondary objectives examined effects of citalopram on function, caregiver distress, safety, cognitive safety, and tolerability. DESIGN, SETTING, AND PARTICIPANTS The Citalopram for Agitation in Alzheimer Disease Study (CitAD) was a randomized, placebo-controlled, double-blind, parallel group trial that enrolled 186 patients with probable Alzheimer disease and clinically significant agitation from 8 academic centers in the United States and Canada from August 2009 to January 2013. INTERVENTIONS Participants (n = 186) were randomized to receive a psychosocial intervention plus either citalopram (n = 94) or placebo (n = 92) for 9 weeks. Dosage began at 10 mg per day with planned titration to 30 mg per day over 3 weeks based on response and tolerability. MAIN OUTCOMES AND MEASURES Primary outcome measures were based on scores from the 18-point Neurobehavioral Rating Scale agitation subscale (NBRS-A) and the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC). Other outcomes were based on scores from the Cohen-Mansfield Agitation Inventory (CMAI) and the Neuropsychiatric Inventory (NPI), ability to complete activities of daily living (ADLs), caregiver distress, cognitive safety (based on scores from the 30-point Mini Mental State Examination [MMSE]), and adverse events. RESULTS Participants who received citalopram showed significant improvement compared with those who received placebo on both primary outcome measures. The NBRS-A estimated treatment difference at week 9 (citalopram minus placebo) was −0.93 (95% CI, −1.80 to −0.06), P = .04. Results from the mADCS-CGIC showed 40% of citalopram participants having moderate or marked improvement from baseline compared with 26% of placebo recipients, with estimated treatment effect (odds ratio [OR] of being at or better than a given CGIC category) of 2.13 (95% CI, 1.23-3.69), P = .01. Participants who received citalopram showed significant improvement on the CMAI, total NPI, and caregiver distress scores but not on the NPI agitation subscale, ADLs, or in less use of rescue lorazepam. Worsening of cognition (−1.05 points; 95% CI, −1.97 to −0.13; P = .03) and QT interval prolongation (18.1 ms; 95% CI, 6.1-30.1; P = .01) were seen in the citalopram group. CONCLUSIONS AND RELEVANCE Among patients with probable Alzheimer disease and agitation who were receiving psychosocial intervention, the addition of citalopram compared with placebo significantly reduced agitation and caregiver distress; however, cognitive and cardiac adverse effects of citalopram may limit its practical application at the dosage of 30 mg per day. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00898807