Daily oral citalopram improved agitation in patients with Alzheimer’s disease and reduced caregiver stress but was associated with a higher rate of cardiac adverse effects than was placebo at the dose used in a multicenter, double-blind, randomized trial.
This benefit was of "clinically meaningful" magnitude and comparable to that reported for treatment with antipsychotic drugs. In addition, 40% of the study participants who received citalopram were deemed to be much or very much improved on a measure of clinically significant change in agitation, compared with 26% of those who received placebo, Dr. Anton P. Porsteinsson of the department of psychiatry at the University of Rochester (N.Y.) and his associates reported Feb. 18 in JAMA.
Cognitive decline, however, was slightly greater with citalopram than with placebo, and the active treatment was associated with QT-interval prolongation. These adverse effects are concerning, so citalopram, at least at the 30-mg daily dose used in this trial, "cannot be generally recommended as an alternative treatment option," the investigators said.
Citalopram, a selective serotonin reuptake inhibitor (SSRI), has been proposed as a safer alternative to antipsychotic drugs for agitation and aggression in dementia patients, even though until now there has only been limited evidence supporting its safety and efficacy. Dr. Porsteinsson and his colleagues conducted the Citalopram for Agitation in Alzheimer Disease (CitAD) study at eight U.S. and Canadian academic medical centers to further test the drug’s safety and efficacy in 186 AD patients who had significant agitation but no depression.
The average age of these study participants was 78 years; 46% were women, 65% were white and non-Hispanic, and 89% were community dwelling. All had dementia of at least 5 years’ duration. Approximately two-thirds took cholinesterase inhibitors and 42% took memantine (Namenda). All were allowed to receive lorazepam or trazodone as rescue medications for significant agitation or sleep disturbance.
A total of 94 patients were randomly assigned to receive 30 mg oral citalopram daily and 92 to receive a matching placebo in a double-blind fashion for 9 weeks. All the participants and their caregivers also received psychosocial support in the form of educational materials; 24-hour crisis management; a supportive-care plan; and 20- to 30-minute counseling sessions during study visits for individualized emotional support, skill building, and problem solving (JAMA 2014;311:682-91).
The trial took place between 2009 and 2013. Midway through in 2011, the U.S. Food and Drug Administration published an advisory that warned of a dose-dependent risk of QT prolongation with citalopram. The CitAD protocol was then amended to exclude participants with high QTc, to include ECG exams for all future participants, and to add serum magnesium to routine electrolyte monitoring.
The primary outcome measures were scores on the agitation subscale of the Neurobehavioral Rating Scale (NBRS-A) – which assesses agitation, hostility/uncooperativeness, and disinhibition – and scores on a modified version of the Alzheimer Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) scale. Participants receiving citalopram showed significant improvement on the NBRS-A, compared with those receiving placebo. Overall, 40% of the citalopram group, compared with only 26% of the placebo group, showed moderate to marked improvement on ADCS-CGIC scores.
Citalopram also offered significant improvement over placebo in scores on the Cohen-Mansfield Agitation Inventory and the Neuropsychiatric Inventory (NPI), notably in the caregiver distress ratings on the NPI. There were no significant differences between the two study groups in scores on the Alzheimer Disease Cooperative Study-Activities of Daily Living scale or in the use of rescue lorazepam.
"Adverse events were generally modest and consistent with known SSRI-mediated adverse events (increases in gastrointestinal complaints, respiratory tract infections, and falls), except that no weight loss or hyponatremia was seen," the authors wrote, and the rate of serious adverse events was comparable between the two study groups. However, results on the Mini-Mental State Exam (MMSE) showed greater cognitive worsening with citalopram, and patients in that group also had more frequent falls and upper respiratory tract infections than did those in the placebo group.
There was no difference between the two study groups on measures of somnolence or confusion. The degree of cognitive worsening was small, and its clinical significance is uncertain. "Also unknown are whether this cognitive effect continues beyond 9 weeks and whether citalopram adversely affects the course of AD," Dr. Porsteinsson and his associates wrote.
The results of ECG monitoring initiated partway through CitAD were available for 24 patients in the citalopram group and 24 in the placebo group. They showed a greater increase in QTc interval and more patients with a high increase in QTc interval with the active drug (12.5%) than with placebo (4.3%), which is in line with the FDA advisory and current prescribing information.