Citalopram for Agitation in Alzheimer's Disease (CitAD)

A Multi-Center Randomized Placebo-Controlled Clinical Trial Study of Citalopram for the Treatment of Agitation in Alzheimer's Disease

The purpose of this study is to evaluate the safety and efficacy of citalopram for agitation in Alzheimer's dementia.

Study Overview

• Status: Completed
• Conditions: Alzheimer's Disease; Agitation
• Intervention / Treatment: Drug: citalopram; Drug: placebo

Detailed Description

This study is designed to examine the efficacy and safety of citalopram as treatment for clinically significant agitation in Alzheimer's dementia (AD) patients. It will also investigate pharmacogenomic, genetic, and clinical predictors of response to citalopram therapy. The management of agitation is a major priority in treating patients with AD. Non-pharmacologic options have limited effectiveness. Several pharmacologic options have been explored, but findings for anticonvulsants, antipsychotics, and cholinesterase inhibitors are disappointing or associated with questionable risk-benefit ratio. Better pharmacologic options are needed. Selective serotonin reuptake inhibitors (SSRIs) show promise as a treatment for agitation in AD, based on evidence of a link between agitation and brain serotonin system abnormalities in AD patients, and on preliminary clinical data from a single-site, randomized controlled trial (RCT) in which citalopram was superior to perphenazine and placebo.

• Study Type: Interventional
• Enrollment (Actual): 186
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M6J1H4
      • Centre for Addiction and Mental Health
• United States
  • California
    • Los Angeles, California, United States, 90089
      • University of Southern California Keck School of Medicine Memory and Aging Center
    • Palo Alto, California, United States, 94304
      • VA Palo Alto Health Care System
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Johns Hopkins University
  • New York
    • New York, New York, United States, 10032
      • Columbia University
    • Rochester, New York, United States, 14559
      • Monroe Community Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania, Section of Geriatric Psychiatry, Ralston House
  • South Carolina
    • Charleston, South Carolina, United States, 29406
      • Medical University of South Carolina Alzheimer's Research and Clinical Programs

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: ADULT; OLDER_ADULT; CHILD
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria

• Probable Alzheimer's disease (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria), with Mini-Mental score of 5-28 inclusive
• A medication for agitation is appropriate, in the opinion of the study physician

• Clinically significant agitation for which either

  1. the frequency of agitation as assessed by the Neuropsychiatric Inventory (NPI) is 'Very frequently', or
  2. the frequency of agitation as assessed by the NPI is 'Frequently' AND the severity of the agitation as assessed by the NPI is 'Moderate', or 'Marked'
• Provision of informed consent for participation in the study by patient or surrogate (if necessary) and caregiver
• Availability of primary caregiver, who spends several hours a week with the patient and supervises his/her care, to accompany the patient to study visits and to participate in the study
• No change to Alzheimer's disease (AD) medications within the month preceding randomization, including starting, stopping, or dosage modifications

Exclusion criteria

• Meets criteria for Major Depressive Episode by Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV (TR)) criteria
• Presence of a brain disease that might otherwise explain the presence of dementia, such as extensive brain vascular disease, Parkinson's disease, dementia with Lewy bodies, traumatic brain injury, or multiple sclerosis
• Psychosis (delusions or hallucinations) requiring antipsychotic treatment in the opinion of the study physician
• Prolonged measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle (QT interval)
• Treatment with citalopram is contraindicated in the opinion of the study physician
• Failure of past treatment with citalopram for agitation after adequate trial at a minimally accepted dose (greater than or equal to 20 mg/day)
• Treatment with a medication that would prohibit the safe concurrent use of citalopram, such as Monoamine oxidases (MAO) inhibitors
• Need for psychiatric hospitalization or suicidal
• Current participation in a clinical trial or in any study that may add a significant burden or affect neuropsychological or other study outcomes
• Current treatment with antipsychotics, anticonvulsants (other than dilantin), other antidepressants (other than trazodone, less than or equal to 50 mg per day at bedtime), benzodiazepines (other than lorazepam), or psychostimulants
• Any condition that, in the opinion of the study physician, makes it medically inappropriate or risky for the patient to enroll in the trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Citalopram and psychosocial intervention; Target dose of 30 mg per day of citalopram, oral, and psychosocial intervention	Drug: citalopram; target dose 30mg daily for 9 weeks; Other Names: Celexa
PLACEBO_COMPARATOR: Placebo and psychosocial intervention; Matching placebo, oral, and psychosocial intervention	Drug: placebo; daily for 9 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
NeuroBehavior Rating Scale-- Agitation	NeuroBehavioral Rating Scale- Agitation(NBRS-A) assesses multiple types of psychopathology common in dementia and is based on a seven point Likert scale of increasing severity for each item(i.e., 0=not present, 1=very mild, 2-mild, 3=moderate, 4=moderately severe, 5=severe, 6=extremely severe). The NBRS agitation subscore includes NBRS 'inhibition', 'agitation', and 'hostility'. The range is 0 to 18 points. Higher scores indicate more symptoms.	9 weeks
Modified Alzheimer's Disease Cooperative Study- Clinical Global Impression of Change in Agitation(CGIC)	Modified Alzheimer's Disease Cooperative Study- Clinical Global Impression of Change in agitation(CGIC) accesses clinically significant change in agitation. A trained clinician, blind to treatment assignment, uses a 7-point Likert scale to rate change of each patient along a continuum from "marked improvement"(1), "no change"(4), and "marked worsening"(7). A number of aspects of the agitation is considered such as emotional agitation, mood liability/distress, psychomotor agitation, verbal aggression, and physical aggression. Range is 1-7.	Baseline to 9 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cohen-Mansfield Agitation Inventory (CMAI)	CMAI examines several agitated behaviors including verbal, physical agitation, and other behaviors. Sub-items are summed. Range is 14-70. Higher scores indicate more severe symptoms.	9 weeks
Neuropsychiatric Inventory (NPI)-- Agitation Subscore	NPI agitation score is based on responses from an informed caregiver involved in the patient's life. Symptom severity (1=mild, 2=moderate, 3=severe) is multiplied by frequency (1=occasionally, less than once/week; 4 = very frequently, once or more/day or continuously) to obtain the NPI agitation score.Range is 0-12. Higher scores indicate more severe symptoms.	9 weeks

Collaborators and Investigators

• Sponsor: JHSPH Center for Clinical Trials
• Collaborators: National Institute of Mental Health (NIMH); National Institute on Aging (NIA)
• Investigators: Principal Investigator: Lon Schneider, MD, University of Southern California Keck School of Medicine Memory and Aging Center; Principal Investigator: Bruce Pollock, MD, Centre for Addiction and Mental Health; Principal Investigator: Jacobo Mintzer, MD, Medical University of South Carolina Alzheimer's Research and Clinical Programs; Principal Investigator: David Shade, Esq, Johns Hopkins University; Principal Investigator: Davengere Devanand, MD, Columbia University; Principal Investigator: Anton Porsteinsson, MD, University of Rochester

Publications and helpful links

General Publications

• Drye LT, Ismail Z, Porsteinsson AP, Rosenberg PB, Weintraub D, Marano C, Pelton G, Frangakis C, Rabins PV, Munro CA, Meinert CL, Devanand DP, Yesavage J, Mintzer JE, Schneider LS, Pollock BG, Lyketsos CG; CitAD Research Group. Citalopram for agitation in Alzheimer's disease: design and methods. Alzheimers Dement. 2012;8(2):121-30. doi: 10.1016/j.jalz.2011.01.007. Epub 2012 Feb 1.
• Porsteinsson AP, Drye LT, Pollock BG, Devanand DP, Frangakis C, Ismail Z, Marano C, Meinert CL, Mintzer JE, Munro CA, Pelton G, Rabins PV, Rosenberg PB, Schneider LS, Shade DM, Weintraub D, Yesavage J, Lyketsos CG; CitAD Research Group. Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. JAMA. 2014 Feb 19;311(7):682-91. doi: 10.1001/jama.2014.93.
• Drye LT, Spragg D, Devanand DP, Frangakis C, Marano C, Meinert CL, Mintzer JE, Munro CA, Pelton G, Pollock BG, Porsteinsson AP, Rabins PV, Rosenberg PB, Schneider LS, Shade DM, Weintraub D, Yesavage J, Lyketsos CG; CitAD Research Group. Changes in QTc interval in the citalopram for agitation in Alzheimer's disease (CitAD) randomized trial. PLoS One. 2014 Jun 10;9(6):e98426. doi: 10.1371/journal.pone.0098426. eCollection 2014.

Study record dates

Study Major Dates

• Study Start: July 1, 2009
• Primary Completion (ACTUAL): September 1, 2013
• Study Completion (ACTUAL): September 1, 2013

Study Registration Dates

• First Submitted: May 11, 2009
• First Submitted That Met QC Criteria: May 11, 2009
• First Posted (ESTIMATE): May 12, 2009

Study Record Updates

• Last Update Posted (ESTIMATE): June 27, 2014
• Last Update Submitted That Met QC Criteria: June 26, 2014
• Last Verified: June 1, 2014

More Information

Terms related to this study

• Keywords: neuropsychiatric symptoms; aggression; mood lability
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Neurocognitive Disorders; Neurodegenerative Diseases; Dyskinesias; Psychomotor Disorders; Dementia; Tauopathies; Psychomotor Agitation; Alzheimer Disease; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Antidepressive Agents, Second-Generation; Citalopram
• Other Study ID Numbers: IA0155; R01AG031348 (NIH)