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Antidepressant Reportedly Quells Alzheimer's Agitation, but Raises Safety Concerns



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Among patients with probable Alzheimer disease and agitation who were receiving psychosocial intervention, citalopram significantly reduced agitation and caregiver distress; however, cognitive and cardiac adverse effects of citalopram may limit its practical application at the dosage of 30 mg daily.

Citalopram (Celexa), one of the most widely used antidepressants, quells the agitation commonly found in Alzheimer's patients, but a dosage of 30 mg per day can disrupt normal heart rhythms and cause slight cognitive decline, according to a paper published in the Feb. 19 issue of the Journal of the American Medical Association (JAMA).

The Citalopram for Agitation in Alzheimer Disease Study (CitAD) randomized 186 patients with probable Alzheimer's disease (AD) and agitation into two groups. Ninety-four received citalopram for nine weeks, while 92 received a placebo. Both groups also received psychological counseling and other assistance. In addition to assessing the effect of citalopram on agitation, the study sought to measure the effects of the drug on patient functionality and caregiver distress, and to identify any safety concerns.

However, on Aug. 22, 2011 — about two-thirds of the way through the study — the Food and Drug Administration (FDA) issued an advisory stating that citalopram carried a dose-dependent risk of QT prolongation, which can cause palpitations and sudden death due to ventricular fibrillation. Prescribing information advises against a dose above 40 mg per day in adults, and over 20 mg per day in anyone 60 years or older.

In response, the researchers excluded recruits with QTc greater than 450 ms for men and greater than 475 ms for women, included an electrocardiogram at week three and after the first dose increase to 30 mg, and added serum magnesium to routine electrolyte monitoring.

Although patients taking citalopram showed a 40 percent reduction in agitation according to one measure, compared with 26 percent on placebo, the researchers observed changes in the electrical activity of the heart in the form of QTc prolongation in the citalopram group and, to their surprise, a modest worsening of cognitive function.

As a result they concluded that citalopram “cannot be generally recommended as an alternative treatment” at a dose of 30 mg per day.

“In most instances citalopram should be kept at 20 mg or lower in individuals who are 60 years of age and older,” said lead author Anton P. Porsteinsson, MD, William B. and Sheila Konar professor of psychiatry at the University of Rochester School of Medicine and Dentistry, and director of the University of Rochester Alzheimer's Disease Care, Research and Education Program. “The FDA recommendations are accurate.”

While the study showed robust effects at a dose of 30 mg per day, Dr. Porsteinsson suspects 20 mg per day would also be beneficial, “but in our study we just didn't have enough participants at lower doses to say anything about efficacy,” he said.

He advised physicians who prescribe a dose above 20 mg per day to take into account the potential for QT prolongation. For patients with a normal QTc, the risk of heart irregularities “is probably not a big deal,” at least if the patient is checked before and after taking citalopram, Dr. Porsteinsson said. “For myself, I would certainly consider citalopram one of the first-line agents, but I would start someone at 10 mg and take them to 20 mg, and then keep them at that dose, and only in very rare circumstances push above that dose,” he added.

DR. ANTON P. PORSTEINSSON. DR. ANTON P. PORSTEINSSON: “In most instances citalopram should be kept at 20 mg or lower in individuals who are 60 years of age and older.”

The cognitive impact of citalopram was much more of a surprise to the researchers. Patients taking citalopram showed a one-point drop on the Mini-Mental State Examination (MMSE), while those taking a placebo improved somewhat after nine weeks.

“We did not expect that, and we don't quite know what to make of it,” Dr. Porsteinsson said. “One possibility is that we are just seeing a drift toward the mean as there were baseline differences on the MMSE score between the two groups.”

In an accompanying editorial, Gary W. Small, MD, a professor of psychiatry and biobehavioral sciences and the Parlow-Solomon professor on aging at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA), acknowledged that the difference in scores is hard to interpret, but he did not consider it problematic. “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,” said Dr. Small, who is also the founding director of the UCLA Memory Clinic, and director of the UCLA Center on Aging.

Dr. Porsteinsson agreed with that assessment. “You could say that a 1.4 decline on the MMSE is a minimally significant change,” he said. “But again, it's something to keep in mind, and if you have a patient who has more of a cognitive change, you would need to consider the possibility that it's related to the medication.”

However, co-author Lon Schneider, MD, a professor of psychiatry, the behavioral sciences, and neurology at the University of Southern California (USC) Keck School of Medicine, pointed out that a 1-point change in the positive direction has made cholinesterase inhibitors very popular drugs.

“On the one hand, with Aricept [donepezil] we say a one-point change is great,” said Dr. Schneider, who is also the director of the USC California Alzheimer's Disease Center and the clinical core director of the USC NIH Alzheimer's Disease Research Center. “Here some say (a one-point drop) is only a small level, but seeing this level of cognitive worsening in a relatively small study should be concerning.”

Dr. Schneider advised viewing agitation as a heterogeneous problem that requires a multi-pronged approach. “Agitation itself is not a simple behavior. Rather, it's code for disruptive behaviors of all kinds,” such as aggression, sundowning, confusion, irritability, or simple non-compliance. “Without even attending to adverse events, one has to ask, what are we treating and what is getting better?” he said.

“We found that about 40 percent on citalopram improved vs. 25 percent on placebo, and this is significant. However, this is also about the same level as what one has seen with antipsychotics and other drugs. We need to weigh risks and benefits. Does this person have agitation that requires medication? Are you prepared to prescribe 30 mg off-label to someone with dementia who's over 60? And are you prepared to take this risk to get this added benefit over non-pharmacological treatment? Treatment, as always, has to be individualized.”


Jeffrey Cummings, MD, the Camille and Larry Ruvo chair for brain health at the Neurological Institute of Cleveland Clinic in Las Vegas and in Cleveland, also expressed uncertainty about how to apply the results of CitAD to individual patients.

“I think it's an important, well-conducted study from which the appropriate recommendations for care of these patients are ambiguous,” he said. “Although citalopram appears to quell agitation quite well, the negative effects on cognition combined with the prolongation of the QT interval should make clinicians reluctant to prescribe a 30 mg dose, and it remains unknown if a 20 mg dose would be as effective. Only a weak recommendation can come from this study because of safety issues that emerged.”


DR. LON SCHNEIDER: “We need to weigh risks and benefits. Does this person have agitation that requires medication? Are you prepared to prescribe 30 mg off-label to someone with dementia whos over 60? And are you prepared to take this risk to get this added benefit over non-pharmacological treatment? Treatment, as always, has to be individualized.”

Dr. Cummings would like to see a double-blind placebo-controlled study of the efficacy of the 20 mg dose to see if it produced sufficient benefit without serious side-effects. The danger of QT prolongation, for example, does not render a drug useless. “It's a known problem with many chemicals you introduce into the body,” he said. “It is a worry, but it's not uncommon.”

Despite its potential for causing QT prolongation, citalopram still may be the best first drug for agitation, said Bruce Miller, MD, who holds the A.W. and Mary Margaret Clausen distinguished professorship in neurology at the University of California, San Francisco (UCSF).

“The truth is, anything we try is disappointing, but I would consider citalopram better than antipsychotics,” said Dr. Miller, who is also the director of the UCSF Memory and Aging Center. “This is a very good study by a very good group of investigators, so I think the results will decrease the likelihood that we'll give a higher dose of citalopram to patients with agitation, with the caveat that sometimes we face desperate situations.”

Agitation, after all, can be considered toxic in itself, he added.


•. Porsteinsson AP, Drye LT, Pollock BG, et al. for the CitAD Research Group. Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. JAMA 2014;311(7):682–691.
    •. Small GW. Editorial: Treating dementia and agitation. JAMA 2014: 311(7):677–678.
      •. Neurology archive on dementia and agitation: