SSRI May Help Alzheimer's Agitation, but Caveats Abound

Nancy A. Melville

April 12, 2016

The antidepressant citalopram (multiple brands) may reduce agitation in patients with Alzheimer's disease (AD). However, these benefits are only obtained at higher doses, which the US Food and Drug Administration (FDA) has warned against.

"The take-home message from this research is that there is a signal that citalopram is an effective treatment for agitation, but that signal was achieved at a dose that we generally don't recommend (30 mg/day) and that the FDA has warned against. So in general, we can't advise this dose to be used routinely," coauthor Anton P. Porsteinsson, MD, director of the Alzheimer's Disease Care, Research and Education Program at the University of Rochester, in New York, told Medscape Medical News.

Neuropsychiatric symptoms, including delusions, anxiety, or irritability/lability, are common in early AD and are associated with more rapid disease progression. However, treatment with antipsychotics is a concern because of side effects.

The analysis was published online April 1 in the American Journal of Psychiatry.

Best Responders

The first results from the Citalopram for Agitation in Alzheimer's Disease (CitAD) study, a 9-week, randomized, double-blind, placebo-controlled multicenter trial, showed that the drug, a selective serotonin reuptake inhibitor (SSRI), was effective in the treatment of AD-related agitation.

In the current secondary analysis, Dr Porsteinsson and colleagues set out to further evaluate the drug's effectiveness in reducing other neuropsychiatric symptoms, as assessed by Neuropsychiatric Inventory (NPI) domains.

For the study, 196 patients with probable AD were randomly assigned to receive citalopram at a target dosage of 30 mg/day (n = 94), titrated over 3 weeks, or placebo (n = 92).

All patients also received psychosocial intervention, including counseling and educational materials.

After 9 weeks, those receiving citalopram were significantly less likely to experience delusions compared with the placebo group (odds ratio [OR] = .40), as well as anxiety (OR = .43) and irritability/lability (OR = .38).

Rates were also lower with the citalopram group for hallucinations (OR = .63). However, as has been documented with SSRIs, sleep/nighttime behavior disorders occurred at a higher rate than inthe placebo group.

Patients in the study were not receiving antipsychotic treatment, and most participants did not have severe psychiatric symptoms. Only 19% in the citalopram group and 23% in the placebo group had hallucinations at baseline, and the rates dropped to 13% and 16%, respectively, at week 9.

"We found the subgroup that responded best to citalopram were those with agitation and cognitive impairment that wasn't too severe; who lived in the community and not in nursing homes; and who had agitation associated with symptoms, including anxiety, irritability, moodiness, but not the type of executive agitation that could include confusion or problem-solving issues," said Dr Porsteinsson.

Side effects reported in the preliminary analysis of the CitAD trial were described as generally modest. However, effects of cognitive worsening and QT prolongation have raised concern about the 30 mg/day dosage, and the FDA has warned against the use of doses higher than 20 mg/day for older patients.

Dr Portsteinsson said that too few patients in the study were treated with 20 mg to allow reporting on benefits for neuropsychiatric symptoms with agitation. The evidence also pointed to the potential benefits of a generic form of citalopram.

"We did learn in a subgroup analysis that side effects appear to correlate with plasma levels in terms of the inactive version of CIT, called R-CIT, while the benefits correlated better with the active isomer S-CIT, which happens to be available as a generic SSRI depressant, so that is what we are examining moving forward," he said.

"It absolutely makes sense to take this class to the next step, and we think it makes more sense to explore S-CIT, which in the US does not have a dose warning, and our findings suggest the benefits are more correlated with that molecule than the inactive component."

Encouraging Findings

Commenting on the findings for Medscape Medical News, Robert Roca, MD, vice president and medical director of Sheppard Pratt Health System, in Baltimore, Maryland, said the study contributes important insights into potential treatments for Alzheimer's patients, with several notable limitations.

"It is encouraging to see that symptoms that we tend to think would only respond to antipsychotics might indeed respond to this class of medications as well, so that is a finding that's very useful," said Dr Roca, who is the chair of the American Psychiatric Association's Council on Geriatric Psychiatry.

"However, patients who were sufficiently psychotic as to need antipsychotics were not included, so that is a limitation, and at the higher doses, citalopram is clearly not without its own set of side effects in older patients," he added.

The authors note that the improvement observed with citalopram in reducing delusions is consistent with reports linking serotonin loss and psychosis in AD and suggests a role for citalopram in that effect. Dr Roca agreed that the role of serotonin could explain the effects of citalopram seen in the study.

"Because of the interaction with serotonin and dopamine systems in the brain, there has been reason to think that drugs that enhanced the activity of serotonin might be helpful in ameliorating symptoms of psychosis, so that was a theoretical reason to think these medications might be helpful in these patients," he said.

The study received funding from National Institute on Aging, the National Institute of Mental Health, and the National Institutes of Health. The authors' disclosures are included in the original article. Dr Roca reports no relevant financial relationships.

Am J Psychiatry. Published online April 1, 2016. Abstract

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