Agitation, Alzheimer's Disease
Conditions
Keywords
neuropsychiatric symptoms, aggression, mood lability
Brief summary
The purpose of this study is to evaluate the safety and efficacy of citalopram for agitation in Alzheimer's dementia.
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.
Interventions
DRUGcitalopram
target dose 30mg daily for 9 weeks
DRUGplacebo
daily for 9 weeks
Sponsors
National Institute on Aging (NIA)
National Institute of Mental Health (NIMH)
JHSPH Center for Clinical Trials
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| NeuroBehavior Rating Scale-- Agitation | 9 weeks | 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. |
| Modified Alzheimer's Disease Cooperative Study- Clinical Global Impression of Change in Agitation(CGIC) | Baseline to 9 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cohen-Mansfield Agitation Inventory (CMAI) | 9 weeks | 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. |
| Neuropsychiatric Inventory (NPI)-- Agitation Subscore | 9 weeks | 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. |
Countries
Canada, United States
Participant flow
Recruitment details
Recruitment activities included chart review, telephone interviews and screens, discussion with physicians, and recruitment in the clinic waiting areas and assisted living facilities affiliated with the clinics. The recruitment period lasted from August 2009 to December 2012.
Participants by arm
| Arm | Count |
|---|---|
| Citalopram and Psychosocial Intervention Target dose of 30 mg per day of citalopram, oral, and psychosocial intervention
citalopram : target dose 30mg daily for 9 weeks | 94 |
| Placebo and Psychosocial Intervention Matching placebo, oral, and psychosocial intervention
placebo : daily for 9 weeks | 92 |
| Total | 186 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 1 |
| Overall Study | Family pressure to discontinue | 2 | 2 |
| Overall Study | Lost to Follow-up | 1 | 3 |
| Overall Study | Withdrawal by Subject | 5 | 3 |
Baseline characteristics
| Characteristic | Citalopram and Psychosocial Intervention | Placebo and Psychosocial Intervention | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 88 Participants | 85 Participants | 173 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 7 Participants | 13 Participants |
| Age, Continuous | 78 years STANDARD_DEVIATION 9 | 79 years STANDARD_DEVIATION 8 | 78 years STANDARD_DEVIATION 8 |
| Region of Enrollment Canada | 12 participants | 13 participants | 25 participants |
| Region of Enrollment United States | 82 participants | 79 participants | 161 participants |
| Sex: Female, Male Female | 44 Participants | 41 Participants | 85 Participants |
| Sex: Female, Male Male | 50 Participants | 51 Participants | 101 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 90 / 90 | 86 / 86 |
| serious Total, serious adverse events | 8 / 94 | 7 / 92 |
Outcome results
Primary
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.
Time frame: Baseline to 9 weeks
Population: The primary analysis was an intention-to-treat analysis; analysis was conducted as randomized. Data from the 186 randomized participants were used in the analytic model. 167 of the 186 patients had week 9 data on CGIC.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Citalopram and Psychosocial Intervention | Modified Alzheimer's Disease Cooperative Study- Clinical Global Impression of Change in Agitation(CGIC) | 40 percentage moderate/marked improvement |
| Placebo and Psychosocial Intervention | Modified Alzheimer's Disease Cooperative Study- Clinical Global Impression of Change in Agitation(CGIC) | 26 percentage moderate/marked improvement |
Comparison: Primary assessment of efficacy was based on intention-to-treat comparison of the difference in the NBRS-A scores at week 9 and comparison at week 9 for the CGIC. For the CGIC proportional odds analysis, the study was designed to have power greater than 80% to detect a difference of 20% between citalopram and placebo in the proportions of patients who improve (or worsen).p-value: 0.00795% CI: [1.23, 3.69]Proportional odds
Primary
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.
Time frame: 9 weeks
Population: The primary analysis was an intention-to-treat analysis; analysis was conducted as randomized. Data from the 186 randomized participants were used in the analytic model. 167 of the 186 patients had week 9 data on the NBRS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Citalopram and Psychosocial Intervention | NeuroBehavior Rating Scale-- Agitation | 4.33 units on a scale | Standard Error 0.31 |
| Placebo and Psychosocial Intervention | NeuroBehavior Rating Scale-- Agitation | 5.26 units on a scale | Standard Error 0.31 |
Comparison: Primary assessment of efficacy was based on intention-to-treat comparison of the difference in the NBRS-A scores at week 9 and comparison at week 9 for the CGIC. For the NBRS-A, the study was designed to have 85% power to detect a standardized difference at week 9 of 40% for citalopram compared to placebo at week 9.p-value: 0.03695% CI: [-1.8, -0.06]Mixed Models Analysis
Secondary
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.
Time frame: 9 weeks
Population: The primary analysis was an intention-to-treat analysis; analysis was conducted as randomized. Data from the 186 randomized participants were used in the analytic model. 169 of the 186 patients had week 9 data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Citalopram and Psychosocial Intervention | Cohen-Mansfield Agitation Inventory (CMAI) | 27.7 units on a scale | Standard Deviation 6.7 |
| Placebo and Psychosocial Intervention | Cohen-Mansfield Agitation Inventory (CMAI) | 28.7 units on a scale | Standard Deviation 6.7 |
Secondary
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.
Time frame: 9 weeks
Population: The primary analysis was an intention-to-treat analysis; analysis was conducted as randomized. Data from the 186 randomized participants were used in the analytic model. 169 of the 186 patients had week 9 data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Citalopram and Psychosocial Intervention | Neuropsychiatric Inventory (NPI)-- Agitation Subscore | 7.8 units on a scale | Standard Deviation 2.2 |
| Placebo and Psychosocial Intervention | Neuropsychiatric Inventory (NPI)-- Agitation Subscore | 8.0 units on a scale | Standard Deviation 2.4 |