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Should SSRIs for Depression in Patients with Dementia Be Revisited?

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discuss the limitations of SSRI antidepressants for the first-line treatment of depression in patients with Alzheimer disease and other forms of dementia.

Even at low doses, selective serotonin reuptake inhibitors (SSRIs) are associated with increased risk of injurious falls among nursing home residents with dementia, according to a Dutch retrospective study published in the British Journal of Pharmacology in January.

Patients on any type of antidepressant medication faced a threefold risk of falls, the authors found; but when investigators analyzed the drugs by class, only SSRIs posed an increased risk. The study, which analyzed antidepressant use and falls among 248 nursing home residents with dementia over a two-year period, also established a dose-response relationship between SSRIs and falls: fall risk increased by 31 percent at 0.25 of a defined daily dose of an SSRI, and by 73 percent at the 0.50 defined daily dose. At one defined daily dose, fall risk jumped by 198 percent (HR 2.98, 95% CI 1.94 to 4.57).

DR. MURRAY RASKIND

: “One has to be selective about prescribing or withholding these medications from people with depression in the context of Alzheimer disease. You dont want the people who are more likely to respond to be denied treatment. That said, its hard to argue for the mild depression group, or even the mild to moderate [cohort], to receive antidepressant medication in light of the evidence. For them, perhaps the behavioral and environmental interventions are more appropriate.”

[Indeed, an AAN practice parameter, published in 2008 in Neurology, found strong evidence associating antidepressants with falls. And falling once would often put patients at risk for more falls. The practice parameter noted that pooled data from several studies indicate that a history of falls increases the risk of falling by more than two-fold, that is, the relative risk is 2.4. The absolute risk of falling was 55 percent for these subjects during follow-up, which was about a year for most studies. For the Neurology Today story about the parameter, see “AAN Practice Guidelines: Neurologists Can Take Simple Steps to Reduce Fall injuries,” http://bit.ly/zLZT7E.]

The British Journal of Pharmacology study comes on the heels of another paper — published last July in the Lancet — based on the results of the placebo-controlled, double-blinded Health Technology Assessment Study of the Use of Antidepressants for Depression in Dementia (HTA-SADD) trial, conducted in Britain. The earlier study compared sertraline and mirtazapine against placebo for depression in patients with Alzheimer disease, and found an absence of benefit combined with an increased risk of adverse events.

Given the results of these and other papers, should the use of SSRI antidepressants for the first-line treatment of depression in patients with Alzheimer disease and other forms of dementia be reconsidered, as the authors of the HTA-SADD trial suggest?

“Obviously, it's a really difficult problem,” said Michael Friedman, MD, a clinical assistant professor in the department of psychiatry and human behavior and the department of neurology at Brown University Medical School. “Depression affects the quality of life terribly. We see earlier entry into assisted living, increased frequency of hospitalization, accelerated cognitive decline, and lower quality of life for patients and their caregivers. Indeed, people in the geriatric population who develop depression are at a higher risk for developing dementia over the next few years. Depression is often considered to be one of the earliest symptoms of cognitive impairment and is considered by some to be a prodromal symptom of dementia.”

WHAT ARE THE OPTIONS?

So data suggesting that antidepressant medication may not be beneficial in these patients leaves many clinicians in a quandary. Most other medications used to treat depression in patients with dementia, such as antipsychotics, come with even more side effects. What are the options?

The question is a complicated one, said Murray Raskind, MD, director of the VA Northwest Network's Mental Illness, Research and Education Clinical Center and professor of psychiatry and behavioral sciences at the University of Washington. Dr. Raskind was one of the lead investigators on a 1989 double-blind trial of imipramine in dementia patients with depression published in the American Journal of Psychiatry, a trial that was also negative.

“Conducting that trial gave me some insight into doing placebo-controlled trials in this population,” Dr. Raskind observed. “There are some things that one needs to be cautious about when interpreting the data.”

Recruitment poses a significant challenge for placebo-controlled trials in people who have depression associated with dementia. “Persons with severe depression that is worrisome to the caregivers and the providers are rarely referred to trials, because everybody wants to get them treated,” Dr. Raskind said. “So what happens is that the more mildly depressed patients, the ones who often don't have the more persistent, intractable symptoms, get referred to trials.”

Dr. Raskind pointed to the Cornell scale scores cited in the Lancet paper. “The mean score was 13.6 at baseline, but the mean score for definite major depressive disorder in the initial 1988 paper for the Cornell scale is 22 — substantially higher.” (The Cornell Scale for Depression in Dementia is considered one of the most reliable tools for assessing depression in this population, Dr. Raskind noted. Each of the 19 items on the scale is ranked as “absent,” “mild or intermittent,” or “severe.” The mean score for probable major depressive disorder is 12.6, but for “definite major depressive disorder,” which Dr. Raskind calls “the more convincingly and severely depressed patients,” the mean score is 21.6)

“One has to be selective about prescribing or withholding these medications from people with depression in the context of Alzheimer disease,” Dr. Raskind said. “You don't want the people who are more likely to respond to be denied treatment. That said, it's hard to argue for the mild depression group, or even the mild to moderate [cohort], to receive antidepressant medication in light of the evidence. For them, perhaps the behavioral and environmental interventions are more appropriate.”

Some depressive symptoms in people with dementia may be traced to environmental factors rather than an underlying pathophysiology, said David S. Knopman, MD, professor of neurology at the Mayo Clinic in Rochester, MN. “Depression in dementia patients often occurs because of social isolation. People don't visit them and they miss out on favorite activities like church groups, and they just sit at home. It may be the case that medication doesn't work very well when mood changes are associated with social isolation. To the extent that it would be feasible, going to adult day care or scheduled activities to enhance social engagement might have greater success.”

“Studies like these really reinforce the need for other interventions in many of these patients, before turning to medications,” Dr. Friedman agreed. “Repetitive, structured activities and psychosocial interventions are invaluable, and especially in early dementia, likely to be more helpful than medications. I recommend adult centers for many of my patients with cognitive impairment.”

‘STANDARD’ CRITERIA MAY NOT APPLY

Dr. Raskind suggested that neurologists and psychiatrists be wary of applying standard criteria for depression to demented patients. “Apathy is an early sign of Alzheimer disease, and it can easily be confused with the loss of interest and decreased ability to experience pleasure that is a major symptom of depression in persons without dementia,” he said. “Similarly, two other primary symptoms of depression are decreased ability to think and concentrate, and sleep problems. Well, all dementia patients have the first symptom, and even happy dementia patients often have sleep disturbances. Using those major criteria for depression can steer one in the wrong direction and lead toward overuse.”

It may be that the people with mild to moderate depression in the context of dementia don't actually have the pathophysiologic changes in the CNS that would make them responsive to medication. Dr. Raskind said that neurologists instead should look for other criteria that tend to signal more severe depression: “Very persistent, long-lasting unresponsiveness to stimuli that were previously pleasurable; being sad or distressed almost constantly, no matter when they're observed; decreasing food intake, and losing weight. These people may be more likely to have an underlying pathophysiology that responds to medication.”

While the Lancet study is clearly negative, Dr. Raskind said, it's worth noting that all of the groups who went through the experimental protocol showed improvement in their depression scores. “That reinforces the probable efficacy of devoting increased attention, as well as careful evaluations of clinical status, to the people who meet criteria for depression in the context of Alzheimer's disease.”

REFERENCES:

• Sterke CS, Ziere G, van der Cammen TJ, et al. Dose-response relationship between selective serotonin reuptake inhibitors and injurious falls: A study in nursing home residents with dementia. Br J Clin Pharmacol 2012; E-pub 2012 Jan. 18.
    • Banerjee S, Hellier J, Burns A, et al. Sertraline or mirtazapine for depression in dementia (HTA-SADD): A randomized [sic], multicentre, double-blind, placebo-controlled trial. Lancet 2011;378(9789):403-411.
      • Reifler BV, Teri L, Raskind M, et al. Double-blind trial of imipramine in Alzheimer's disease patients with and without depression. Am J Psychiatry 1989; 146: 45–49.
        • Alexopoulos G. Cornell scale for depression in dementia. Biol Psych 1988; 23: 271-284.
          • Thurman DJ, Stevens JA, Rao JK. Practice parameter: Assessing patients in a neurology practice for risk of falls (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2008;70:473-479.