22 July 2011. For the many people with Alzheimer’s disease who are depressed, the most commonly prescribed treatment is an antidepressant. Now, results from a large, randomized clinical trial, reported online July 18 in the Lancet, call that practice into question. Researchers led by Sube Banerjee at King’s College London, U.K., tested representative drugs from the two classes of antidepressants most commonly prescribed for AD, and found that the medications were no more effective than placebo at relieving depression. Intriguingly, however, most of the participants in the trial improved in mood, which the authors attribute to the psychosocial interventions that all participants received. The findings indicate that medication should not be the first-line treatment for depression in most cases, the authors suggest. Instead, Banerjee supports more research into specific non-drug interventions to develop the most effective standard of care for depression associated with dementia.
In an accompanying editorial, Henry Brodaty at the University of New South Wales, Australia, calls this a “landmark study” and notes it is “the largest trial of antidepressant drugs in dementia ever and almost equaling the combined total from previously published work.”
Another Lancet paper on dementia, published online July 19, carries significant public health implications. Researchers Deborah Barnes and Kristine Yaffe at the University of California, San Francisco, reviewed data from observational trials on seven modifiable AD risk factors that have been most consistently associated with dementia. Assuming that societal and lifestyle changes could reduce the number of people with each susceptibility factor by one-fourth, they projected that as many as three million worldwide AD cases could be prevented, for a drop of about 10 percent of the total. Their findings could focus attention on the most promising targets for health policy changes and public education campaigns.
One such target is depression, the focus of the first Lancet paper. About one-fifth of people with dementia are depressed. Prior trials of antidepressants in this population have produced mixed results or negative data. The Depression in Alzheimer Disease Study (DIADS) found some benefit from the selective serotonin reuptake inhibitor (SSRI) sertraline (see Lyketsos et al., 2003), but a subsequent larger trial came up negative (see Rosenberg et al., 2010 and Weintraub et al., 2010).
To try to clarify the issue, Banerjee and colleagues recruited more than 300 volunteers around 80 years old with moderately severe AD who had been referred to psychiatry services across England for treatment of depression. To be eligible for the trial (dubbed the Health Technology Assessment Study of the Use of Antidepressants for Depression in Dementia, or HTA-SADD), volunteers had to score eight points or higher on the Cornell scale for depression in dementia (CSDD; see also Alexopoulos et al., 1988). More than half the participants had scores of 12 or higher (a score of 10 or higher indicates probable major depression). This scale is the best validated instrument for measuring depression in dementia, and takes into account the fact that some symptoms of dementia can mimic those of depression, Banerjee told ARF (see also Moniz-Cook et al., 2008).
One-third of the participants took a placebo, while another third got the SSRI sertraline (trade name Zoloft), one of the antidepressants most commonly prescribed for AD. The remaining third took mirtazapine (trade name Remeron), which belongs to the older class of tetracyclic antidepressants. After 13 weeks, people in all three groups dropped around five points on the CSDD—more than a 40 percent improvement in depression scores—but there was no significant difference between those on placebo and those taking drugs. The drop in depression scores stayed stable in all groups at 39 weeks. The biggest difference between the groups was that people on the antidepressants experienced more adverse reactions than people on placebo, with some evidence that patients taking sertraline had more neuropsychiatric symptoms and a lower quality of life than those on mirtazapine.
What explains the improvement in depression scores? All participants, and the people who cared for them, received psychosocial treatments, which included such things as education about dementia, problem-solving and coping mechanisms, and support from psychiatric nurses, Banerjee said. He believes these services were responsible for the consistent improvement in patients’ moods. Symptoms probably did not improve spontaneously, Banerjee added, as most participants had been depressed for more than six months before seeking treatment.
“It is not that depressive symptoms in dementia are not treatable,” Banerjee emphasized, but instead that drugs are not the most effective approach for people with AD. In addition, he noted that good dementia care has to include support and education for the person caring for the patient, as this trial did. “I think a lot of the power of the intervention is mediated through the carers,” he said. In future studies, Banerjee would like to look in detail at various psychosocial treatments to isolate which interventions are most effective. This data could help researchers and clinicians develop better standards for treatment of depression in dementia, he suggested.
In his commentary, Brodaty noted that several non-drug interventions have been shown to lessen depression in AD patients, including problem-solving therapy, exercise, interpersonal therapy, and occupational therapy (see Teri et al., 1997; Teri et al., 2003; Graff et al., 2007; and Miller and Reynolds, 2007).
Antidepressant drugs may still be useful for some dementia patients, Banerjee said. His trial excluded severely depressed people, for example, and it is possible that this group could benefit from medications. It is also possible that other classes of antidepressants might have an effect, or that people with other types of dementia might be more responsive to drugs than those with AD. “Anecdotally, clinicians report successful treatment of patients with antidepressants,” Brodaty wrote. Banerjee suggested that antidepressants should be a second-line treatment for those whose depression is severe or does not resolve with three months of standard care.
Speaking at the Alzheimer's Association International Conference on Alzheimer's Disease (ICAD) 2011 in Paris, France, held 16-21 July, Constantine Lyketsos at Johns Hopkins University, Baltimore, Maryland, pointed out that depression worsens dementia and also accelerates the conversion of mild cognitive impairment to dementia, highlighting the importance of treating it effectively. Together with David Miller at Bracket (formerly United BioSource Corporation), Lyketsos is chairing a group that will take a systematic approach to finding better treatments for depression and other neuropsychiatric syndromes common in dementia, such as psychosis, apathy, and agitation.
One implication of the negative HTA-SADD trial results is that different pathogenic mechanisms may be at play in depression in Alzheimer’s disease compared to depression in the general population, Brodaty wrote. Banerjee agrees this is probable. “There is increasing evidence that the neural damage you get in dementia or cerebrovascular disorder means that depressive symptoms are less treatable, or act in a different way,” he said.
In the second Lancet paper, Barnes and Yaffe focused on seven modifiable risk factors for AD, choosing those that have most consistently shown an association with dementia in reviews and meta-analyses. These included depression, diabetes, hypertension, obesity, current smoking, physical inactivity, and cognitive inactivity or low educational achievement. For each factor, they calculated the population attributable risk, that is, the proportion of dementia cases that can be attributed to that factor, based on how common the risk factor is in the population and how strongly it is linked to dementia. This allowed them to project how many AD cases might be prevented by reducing the number of people who have each risk factor.
Worldwide, lack of education potentially contributes the largest number of AD cases, followed by smoking and physical inactivity, the authors found. In the U.S., physical inactivity contributes the greatest number of cases, followed by depression. If the prevalence of all seven risk factors was reduced by 25 percent, it could theoretically drop worldwide AD cases by three million, or about 10 percent of the total, Barnes and Yaffe calculated.
The review has several limitations, the authors acknowledge. If future studies show that one of these factors is not causally linked to dementia, the estimates would change. Also, although the researchers focused on AD, they also included studies that looked at total dementia, so the results are not specific for Alzheimer’s.
The findings stand in contrast to a 2010 National Institutes of Health State of the Science panel that concluded no definitive evidence exists for any health intervention that might prevent or delay AD (see ARF related conference story). Barnes does not disagree with that conclusion, but notes: “What our study says, based on the best available data we have today, is that these are the things we think matter the most. I am hoping people take home a positive message. If we could reduce these risk factors, then it is possible we could prevent or mitigate the dementia epidemic that we see coming down the road.”
The next step, Barnes told ARF, is to conduct randomized clinical trials to see if lowering the prevalence of these risk factors does indeed reduce or delay AD. In an accompanying commentary, Laura Fratiglioni at the Karolinska Institutet-Stockholm University, Sweden, and Chengxuan Qiu at the Stockholm Gerontology Research Center note that several such intervention studies are underway in Europe (see, e.g., Richard et al., 2009 and Gillette-Guyonnet et al., 2009). However, “in the U.S., such research will simply not be done because there are inadequate resources to support it,” said Alzheimer’s Association representative Bill Thies, speaking at the conference in Paris. Barnes agrees that more funding is essential, but notes that reducing these dementia risk factors would be good for public health in many ways. Even in the absence of randomized clinical trials, “I think we can still recommend those things to people,” she said.—Madolyn Bowman Rogers.
Banerjee S, Hellier J, Dewey M, Romeo R, Ballard C, Baldwin R, Bentham P, Fox C, Holmes C, Katona C, Knapp M, Lawton C, Lindesay J, Livingston G, McCrae N, Moniz-Cook E, Murray J, Nurock S, Orrell M, O’Brien J, Poppe M, Thomas A, Walwyn R, Wilson K, Burns A. Sertraline or Mirtazapine for depression in dementia (HTA-SADD): a randomised, multicentre, double-blind, placebo-controlled trial. Lancet. 2011 Jul 18. Abstract
Brodaty H. Antidepressant treatment in Alzheimer’s disease. Lancet. 2011 Jul 18. Abstract
Barnes DE, Yaffe K. The projected effect of risk factor reduction on Alzheimer’s disease prevalence. Lancet. 2011 Jul 19. Abstract
Fratiglioni L, Qiu C. Prevention of cognitive decline in ageing: dementia as the target, delayed onset as the goal. Lancet. 2011 Jul 19. Abstract