Citalopram cut Alzheimer’s agitation, upped heart risk

Daily oral citalopram improved agitation in patients with Alzheimer’s disease and reduced caregivers’ stress, but was associated with higher rate of cardiac adverse effects than was a placebo at the dose used in a multicenter, double-blind, randomized trial.

This benefit was of “clinical meaningful” magnitude and comparable to that reported for treatment with antipsychotic drugs. In addition, 40 percent 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 percent of those who received placebo, the department of psychiatry at the University of  Rochester (NY) and associates reported.

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 trial, cannot be generally recommended as an alternative treatment option.

Citalopram, a selective serotonin reuptake inhibitor (SRRI), has been proposed as a safer alternative to antipsychotic drugs for agitation and aggression in dementia patients. They conducted the Citalopram for Agitation in Alzheimer Disease study at eight US and Canadian academic medical centers to further test the drug’s safety and efficiency in 186 AD patients who had significant agitation but no depression.

The average age of the study participants was 78 years; 46 percent were women, 65 percent were white and Hispanic, and 89 percent were community dwelling. All had dementia of at least five years duration. Approximately two-thirds took cholinesterase inhibitors and 42 percent took mematine. All were allowed to receive lorazapam or trazodone as rescue medications.

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-minded fashion for nine weeks. All the participants and their caregivers also received psychosocial support in the form of educational material; 24 hours 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.

The trial took place between 2009-2013. Midway through 2011, the US 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 score 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 to those receiving placebo. Overall, 40 percent of the citalopram group, compared to only 26 percent of the placebo group, showed moderate to marked improvement on ACD-CGIC scores.

Citalopram also offered significant improvement over placebo in scores on the Cohen-Mansfield Agitation 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 com plaints, respiratory tract infections, and falls), except that weight loss or hyponatremia was seen,” the authors wrote. However, results on the Mini-Mental State Exam (MMSE) showed greater cognitive worsening with citalopram, and patients 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.

The results of ECG monitoring initiated partway through CitAD were available for 24 patients in the citalopram group and 24 placebo groups. They showed a greater increase in QTc interval and more patients with a high increase in QTc interval with active drug (12.5percent) than with placebo (4.3percent) which is in line with the FDA advisory and current prescribing information.

A maximum daily dose of 20 mg of citalopram I recommended for patients older than 60 years. But the trial didn’t have enough patients treated with 20 mg per day “to assess efficacy at that level.”