Citalopram Reduces Agitation in Patients With Alzheimer's

Pauline Anderson

February 18, 2014

The antidepressant citalopram (Celexa, Forest Laboratories) reduces agitation in older patients with Alzheimer's disease (AD), but at the expense of increased cardiac adverse effects and mildly reduced cognition, a new randomized trial shows.

After the start of the study, which used 30 mg of citalopram daily as the target dose, the US Food and Drug Administration (FDA) advised that this drug should not be prescribed at doses over 20 mg in patients older than 60 years because higher doses prolong the QT interval on electrocardiography (ECG).

That means that another study should be carried out in the same population using a target dose of 20 mg of the drug, said lead author, Anton P. Porsteinsson, MD, professor, psychiatry, University of Rochester, New York.

"The big issue, the unanswered question, is whether 20 mg, which is a dose that is FDA-approved for use in older individuals with depression, is just as effective for agitation as 30 mg," said Dr. Porsteinsson.

The study is published in the February 19 issue of JAMA.

Agitation in AD a "Huge Challenge"

A selective serotonin reuptake inhibitor, citalopram is the most widely used antidepressant for older patients anywhere in the world.

Dr. Anton P. Porsteinsson

There's currently no good treatment for agitation in patients with AD. "It's a huge challenge," said Dr. Porsteinsson. "Alzheimer's disease is laced with serious behavioral disruptions that are unbearable for caregivers and for patients themselves. There are no approved treatments and you get limited benefit from nonpharmacological interventions, although these should always be tried first."

The Citalopram for Agitation in Alzheimer Disease (CitAD) study enrolled 186 patients with probable AD, mean age 78 years, at 8 centers in the United States and Canada. None had major depression or psychosis requiring treatment.

Researchers randomly assigned participants to citalopram at a target dose of 30 mg — a dose that was selected because of prior evidence of response and tolerability, said Dr. Porsteinsson — or placebo. The 2 groups were equal in terms of baseline characteristics except that the placebo group had a lower mean Mini-Mental Status Examination (MMSE) score (lower scores indicate worse functioning).

All participants received a psychosocial intervention that included education materials, 24-hour availability of crisis management, and counseling sessions.

Two thirds of the way through the study, the FDA issued an advisory that citalopram can prolong the QT interval and that older patients should no longer use doses greater than 20 mg. This led investigators to institute "strict ECG monitoring," said Dr. Porsteinsson; for example, men with a corrected QT interval (QTc) greater than 450 milliseconds and women with a QTc greater than 475 milliseconds were excluded from the study, and the frequency of ECG monitoring was increased.

At week 9 of the study, the analysis, which included 83 patients in the placebo group and 86 in the treatment group, found a significant improvement in the treatment group compared with the placebo group on the 18-point Neurobehavioral Rating Scale-Agitation (NBRS-A), which assesses agitation, hostility/uncooperativeness, and disinhibition, with higher scores indicating more severe symptoms. The mean estimated treatment effect on the NBRS-A (the difference in scores at week 9, controlling for baseline score and MMSE score) was –0.93 (95% confidence interval, –1.80 to –0.06; P = .04).

As well, 40% of the patients receiving citalopram had moderate or marked improvement from baseline severity on the 7-point modified Alzheimer's Disease Cooperative Study–Clinical Global Impression of Change score, which assesses items specific to agitation in AD. This compared to 26% of the patients taking placebo.

This effect of citalopram on agitation is about the same as that of atypical antipsychotic drugs, such as olanzapine and risperidone, said Dr. Porsteinsson. However, research shows that atypical antipsychotics are associated with an increased risk for death, primarily from cardiac-related events or infections.

Dr. Porsteinsson noted that while the treatment group had better outcomes, the placebo response, too, "was quite robust." He attributed much of this, and the high proportion of patients (90%) completing the study, to the psychosocial assistance offered to study participants.

"We met with participants and their families, tried to understand what was going on, what some of the triggers were, or what was particularly upsetting to them. We tried to get caregivers to change the approach they were using and to allow patients to talk about what was going on, or to vent their feelings. Basically, we tried to train both caregivers and patients to handle things in a different way."

The treatment drug was associated with significantly better outcomes compared with placebo on many secondary measurements, including the Cohen-Mansfield Agitation inventory (P = .008), Neuropsychiatric Inventory (NPI) total score (P = .01), and the NPI caregiver distress subscore (P = .02). The treatment group did not, however, fare significantly better on the NPI agitation subscale (P = .12) or the AD Cooperative Study–Activities of Daily Living scale (P = .32).

QT Difference

The researchers found that among the 48 patients for whom data were available at study end, 12.5% of the treatment group and 4.3% of the placebo group had a prolonged QT interval on ECG. Despite other studies showing that citalopram doesn't increase cardiac arrhythmia or cardiac death, and the fact that questions surround the FDA restrictions on citalopram dosing, Dr. Porsteinsson is behind the move to limit citalopram dosing.

"Our findings support the FDA," he said. "If nonpharmacological intervention is not beneficial, judicious use of citalopram appears to have a role in managing agitation in patients with Alzheimer's disease, but generally, the dose should not surpass 20 mg per day."

In the "rare cases" where physicians decide to go with a higher dose, they need to monitor for cardiac adverse effects, he added.

The study didn't include enough patients taking 20 mg of the drug to determine whether this dose affected the QT interval or whether it also led to reduced agitation.

The study showed a decline on the MMSE in patients taking citalopram (mean estimated score of 17.0 at baseline to 16.83), while it increased in the placebo group (from 14.4 at baseline to 15.33), for a mean estimated treatment effect of –1.05 (P = .03).

This outcome, said Dr. Porsteinsson, was "quite surprising" as other studies haven't picked this up and, in fact, some found an improvement on cognitive measures. The cognitive decline in the current analysis could be explained by the unbalanced MMSE scores at baseline and a "drift toward the mean," said Dr. Porsteinsson.

The decline, he added, was "not so different" from that seen with atypical antipsychotics, "where the mean change over multiple studies is about 0.7 points on the MMSE."

It's not known whether this decline will revert at some point or continue to worsen, said Dr. Porsteinsson. "That's one of the questions that should be raised in future studies with citalopram in this population."

Difficult to Interpret

The clinical relevance of the group difference in MMSE scores is "difficult to interpret," partly because the sensitivity of this tool is "limited" in patients with more severe dementias, according to Gary W. Small, MD, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, who contributed an accompanying editorial.

"In practice, individual patients often fluctuate on this measure by several points depending on the time of day, minor distractions during an examination, level of fatigue, or variations in methods of administering the scale," he writes.

Although Dr. Small concluded that the study results support a role for citalopram in the management of agitation in dementia, he said more research is needed to answer the many remaining questions. "Such studies should determine the duration of adverse effects and benefits beyond 9 weeks, dose ranges that influence mortality risk as well as QT prolongation, and predictors of response."

As did Dr. Porsteinsson, Dr. Small said physicians should continue to emphasize nonpharmacologic strategies. As well, he said doctors should carefully document their treatment plans and aim for short-term treatment to minimize the possible added risks of long-term use.

Next on the research agenda is applying for funding to look at 20 mg as the target dose, said Dr. Porsteinsson. "The aim is to treat people with clinically meaningful agitation and see if that dose has similar agitation efficacy and if it reduces caregiver burden to the same degree, but without the QTc findings or the cognitive findings, that we saw."

The study was supported by the National Institute on Aging and National Institute of Mental Health, and in part by the National Institutes of Health. Dr. Porsteinsson reports receipt of a grant to his institution from Avanir, Baxter, BMS, Elan, EnVivo, Genentech/Roche, Janssen Alzheimer Initiative, Merck, Pfizer, Toyama, Medivation, the National Institutes of Health, the National Institute of Mental Health, the National Institute on Aging, and the Department of Defense; paid consultancy for Elan, Janssen Alzheimer Initiative, Pfizer, and TransTechPharma; membership on data safety and monitoring boards for Quintiles, Functional Neuromodulation, and the New York State Psychiatric Institute; participation on a speaker's bureau for Forest; and development of educational presentations for CME Inc. Dr. Small reports being among the inventors of FDDNP-PET (2-(1-{6-[(2-[fluorine-18]fluoroethyl)(methyl)amino]-2-naphthyl}-ethylidene)malono nitrile–positron emission tomography). The University of California, Los Angeles, owns a US patent for FDDNP-PET, which has been licensed to TauMark LLC. He reports having a financial interest in Taumark LLC and having served as an advisor and receiving lecture fees from Lily, Herbalife, Jansssen, Novartis, and Pfizer.

JAMA. 2014;311:682-691, 677-678. Abstract Editorial

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