Alzheimer’s disease can make patients disruptive and aggressive, leaving distraught caregivers with little option but to place their loved ones in nursing homes. Clinicians have few choices for treating these behavioral disorders. No drug has been approved to mitigate these symptoms in AD patients, and drugs used off-label have serious health risks. Several research groups are searching for alternatives. In the February 19 Journal of the American Medical Association, researchers led by Anton Porsteinsson at the University of Rochester, New York, report mixed results from a clinical trial of one such medication. They found that the antidepressant citalopram calms Alzheimer’s patients, which reduces stress for caregivers. However, at the tested dose of 30 mg daily, citalopram comes with safety risks of its own, including abnormal heart rhythms. The Food and Drug Administration now recommends that elderly patients take no more than 20 mg citalopram daily for any indication. Further study will have to sort out whether this lower dose will be equally effective at quieting agitation, the authors note.

Commentators agreed that citalopram shows promise for treating agitation in AD, but said more research is needed and urged clinicians to use the drug with caution. “Although the results from this study support a role for citalopram in the management of agitation in dementia, when and how to prescribe the drug so that benefits are optimized and risks minimized are not straightforward,” wrote Gary Small at the University of California, Los Angeles, in an accompanying editorial.

With no FDA-approved treatment for agitation in Alzheimer’s, clinicians frequently fall back on atypical antipsychotics, a newer class of drugs that are believed to have fewer side effects than first-generation antipsychotics. Atypical antipsychotics carry a “black box” warning from the FDA because they increase the risk of death in people with dementia and can have other negative consequences such as sleepiness and parkinsonism (see Oct 2005 news storyJan 2009 news story). Moreover, some studies have questioned how well these drugs work (see Oct 2006 news story). Other alternatives tested so far, such as donepezil and antiepileptics like valproate, have failed to show a benefit (see Oct 2007 news story; Nov 2009 conference story).

Previous studies hinted that citalopram, a selective serotonin reuptake inhibitor (SSRI), helped calm elderly patients who had dementia or anxiety (see, e.g., Nyth and Gottfries, 1990Ragneskog et al., 1996). To more thoroughly test the drug, Porsteinsson, in collaboration with colleagues at numerous clinical centers across the United States and Canada, recruited 186 Alzheimer’s patients with moderate to severe agitation. All participants in the CitAD trial received a non-pharmacological intervention consisting of educational materials and counseling sessions for patients and caregivers during clinic visits. Half the participants took citalopram at doses up to 30 mg daily, the remainder placebo, for nine weeks.

On the positive side, the medication worked to lower agitation. Clinicians rated participants on the drug as significantly less agitated than those on placebo on four out of five measures, with the fifth measure showing a trend in the same direction. Primary endpoints were the Neurobehavioral Rating Scale agitation subscale (NBRS-A) and the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC); secondary measures comprised the Cohen-Mansfield Agitation Inventory (CMAI), the total Neuropsychiatric Inventory (NPI), and the NPI agitation subscale, which showed the trend. It is not clear why that scale measured less change, but it may be less sensitive than the others, Porsteinsson said. In addition, caregivers of patients on the drug reported feeling less stress than did those in the placebo group, indicating the improvement was meaningful to them.

On the flip side, some patients on citalopram developed an abnormal heart rhythm known as a “long QT interval,” which slows heartbeat. This increases the risk for cardiac arrhythmias, which can lead to sudden death. In August 2011, the FDA warned of the QT interval problem at doses over 40 mg citalopram. A March 2012 update recommended that people over 60 take no more than 20 mg daily, although there is no evidence of increased death among people taking citalopram. In CitAD, participants received doses from 10 to 30 mg based on how well they tolerated the drug. Because side effects were few, only about 20 percent of the participants received 20 mg citalopram or less, too small a sample to tell if the drug was effective at these levels. Porsteinsson told Alzforum that he is applying for funding to test lower doses of the drug. The only death in CitAD occurred in the placebo group. 

The study turned up another harmful side effect as well: Cognitive scores on the Mini Mental State Examination declined by about a point in the treatment group compared to placebo. Porsteinsson noted that the significance of this is unclear, since the treatment group started with a higher baseline score and the change could represent a drift toward the mean. More studies are needed to see if this represents a real effect, he said. Commentators agreed that this bears watching but does not rule out using the drug at this point. Chris Fox at the University of East Anglia, U.K., wrote to Alzforum, “The impact on cognition may be spurious, but the data support the need to monitor for side effects and discontinue citalopram once the agitation has improved.”

Given the safety issues with current drugs, what then is the best option for Alzheimer’s patients whose agitation becomes disruptive? Across the board, researchers said that non-pharmacological, behavioral approaches should be tried first. Such methods often work well (see Mar 2009 news story). In Porsteinsson’s study, about 25 percent of the placebo group improved markedly, compared with 40 percent of the treatment group, showing that the behavioral intervention alone provided a benefit. “We should focus on environmental, psychosocial interventions and other ways of mitigating agitation, such as distracting patients or avoiding triggers,” said co-author Lon Schneider at the University of Southern California, Los Angeles. Robert Howard at King’s College London wrote to Alzforum, “Excellent trained nursing care remains the most effective and least harmful treatment course” (see full comment below).

However, for patients with severe agitation who do not respond to behavioral interventions, many commentators supported limited, cautious use of citalopram at 20 mg while watching for side effects. “I think we need a drug, and citalopram at 20 mg represents a reasonable choice, although at this point we lack data on efficacy,” said Jeffrey Cummings at the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas. 

Several other drugs to treat agitation in AD are currently in clinical trials, including an NIH-funded study of the antihypertensive drug prazosin (see Jan 2013 news story); a Phase 2 trial of the combination drug Nuedexta, which is approved to treat uncontrollable crying or laughing; a Phase 2 study of the small molecule scyllo inositol; and a Phase 3 study of the dopamine agonist brexpiprazole

“I’m excited that we are actively looking for solutions for behavioral disruptions again,” Porsteinsson said, noting that research in this area lagged for nearly a decade after the health risks of the atypical antipsychotic drugs were revealed.—Madolyn Bowman Rogers.

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Comments on News and Primary Papers

  1. This is an important study, well-conducted by a “dream team” of U.S. researchers in the area. I expect that it will have a major impact upon practice in the field. Having said this, citalopram is clearly not a magic bullet for the treatment of agitation in AD. It joins a list of agents that have shown statistically significant superiority over placebo in the treatment of behavioral symptoms in dementia. But, as for the other agents, the benefits compared with placebo only just scraped over the margins of what might be considered a clinically significant difference. The field still needs to look for treatments that convincingly improve these distressing symptoms in a way that impacts positively on the experience of patients and their caregivers. Agitation is such a compound symptom that it is unlikely that there will be a pharmacological solution. Excellent trained nursing care remains the most effective and least harmful treatment course.

    As regards safety, we only discovered the risks associated with the use of atypical antipsychotics in this indication from trial databases that were an order of magnitude larger than what is available from this study, so I think it is too early to comment on safety. The significance of the prolonged QT interval seen in 1 of 8 treated patients isn’t yet apparent. I suspect that the cognition difficulty may have more to do with the placebo patients improving their MMSE score (change over nine weeks 14.4 to 15.33), rather than citalopram patients worsening their score (17.0 to 16.83). I’d be relaxed about this.  

    View all comments by Robert Howard

References

News Citations

  1. More Trouble for Atypical Antipsychotics—Dementia Patients at Risk
  2. Antipsychotics on Trial Again—DART-AD Confirms Increased Mortality
  3. Rethinking Antipsychotics for Alzheimer Patients—Again
  4. Donepezil BeCALMed? Drug Fails to Relieve Agitation
  5. Chicago: AD and Epilepsy—Lessons from the Clinic, Animals
  6. CADRES Trial—Tempering Agitation by Non-pharmacological Means
  7. NIH Funds Four Clinical Trials in ADCS Renewal

Therapeutics Citations

  1. ELND005
  2. Brexpiprazole

Paper Citations

  1. . The clinical efficacy of citalopram in treatment of emotional disturbances in dementia disorders. A Nordic multicentre study. Br J Psychiatry. 1990 Dec;157:894-901. PubMed.
  2. . Long-term treatment of elderly individuals with emotional disturbances: an open study with citalopram. Int Psychogeriatr. 1996;8(4):659-68. PubMed.

External Citations

  1. March 2012 update
  2. study of the antihypertensive drug prazosin
  3. Phase 2 trial
  4. Phase 2 study
  5. Phase 3 study

Further Reading

Primary Papers

  1. . Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. JAMA. 2014 Feb 19;311(7):682-91. PubMed.