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Do antidepressants work in the damaged brain?

Results have been discouraging for Alzheimer’s disease, but they may help stroke patients in a variety of ways.

Alzheimer’s disease and the depression that often affects people starting at about age 65 can easily be mistaken for one another. Depression can cause dementia-like deficits in memory and other mental functions, and Alzheimer’s disease can cause depressive-like apathy and withdrawal.

But many Alzheimer’s patients don’t just appear to be depressed. Perhaps up to 30% of them are depressed, although depression in people with dementia may be expressed in atypical ways (see sidebar below). Some studies have also found depression to be common among people with mild cognitive impairment, a condition that may precede full-blown Alzheimer’s disease.

Many people with Alzheimer’s disease are prescribed antidepressant medication. Antidepressants have become more widely used in general because the selective serotonin reuptake inhibitors (SSRIs), like fluoxetine (Prozac) and sertraline (Zoloft), often have more tolerable side effects than earlier generations of antidepressants. The fact that there are so few treatments available to improve the quality of life of Alzheimer’s patients may also be a contributing factor in the use of antidepressants. Doctors and patients and their families may jump at the chance to treat depression, a problem that may seem more amenable to treatment.

The depressed Alzheimer’s disease patient

The symptoms of depression include sadness, an inability to get pleasure out of pleasurable things, difficulty sleeping, poor self-esteem, and suicidal thoughts.

People with Alzheimer’s disease who get depressed have many of the same symptoms but others as well. Delusions, agitation, and irritability may be more common than in depressed people without Alzheimer’s disease. In 2011, Norwegian researchers reported that complaints about physical problems (indigestion, joint pain, and so on) stood out in their study of depressed Alzheimer’s patients. Alzheimer’s patients may not be able to articulate their thoughts very well, so they may describe physical problems and sensations instead. It’s also possible that depression brings on these physical problems or vice versa: the physical problems, many of which cause some pain, bring on the depression.

Doubts about antidepressants

But is it? There have been relatively few studies of antidepressants as a treatment for depression in people with Alzheimer’s disease. Those that have been done haven’t included very many patients, and the results have been mixed. Some of the most favorable outcomes have come from studies of the tricyclic antidepressants, not the SSRIs. One exception was a 2003 report by researchers at Johns Hopkins that sertraline was effective in a small (44 patients) study of people with probable Alzheimer’s and major depression. But in 2010, results from a different trial showed sertraline wasn’t effective. All in all, the evidence for antidepressants alleviating the depression of people with Alzheimer’s disease has looked pretty thin and patchy.

Study results published in 2011 in The Lancet make it seem even more so. British researchers enrolled 326 people with “probable or possible” Alzheimer’s and depression that had lasted at least four weeks. They were randomly assigned to take sertraline; mirtazapine (Remeron), a second-line antidepressant that affects a different mix of brain chemicals than the SSRIs; or a placebo. After 13 weeks, the researchers measured the depression of the study subjects using an assessment method developed at Cornell that involves interviewing an “informant” — a family member or close friend — as well as direct observation and questioning of the patient. The depression scores of the patients taking sertraline and mirtazapine were no better than those of the patients taking the placebo pills. Several months later, there was still no difference. And, as you might expect, the people taking the antidepressant medications experienced more side effects than those taking the placebo.

The more people in a clinical trial, the less likely the outcome might be due to chance and the more reliable the result. So it’s noteworthy that this British study had — by far — more people in it than other studies of antidepressants for people with Alzheimer’s and depression. One important caveat, though, is that the patients in the study had been referred for special psychiatric services, so they may not be representative of the larger population of people with Alzheimer’s and depression.

Still, this study, along with inconclusive and negative results from the ones that came before it, sows some doubt about what has become a fairly common practice. The take-home message from the British researchers seems about right: it’s time to reconsider routinely prescribing SSRIs for depressed Alzheimer’s patients. As well-intentioned as the practice might be, there isn’t a whole lot of evidence that they make depressed Alzheimer’s patients feel better. Perhaps the changes in the brain that occur with Alzheimer’s disease render the SSRI antidepressants ineffective. (Some doctors think other kinds of antidepressants might be a better choice for dementia patients.)

The British researchers argue that psychological and social services should be provided before antidepressants are prescribed. That may be a realistic option in Britain because the National Health Service there provides universal coverage, but those kinds of services, tailored to older people and their problems, aren’t readily available to many Americans. And in health care, as in other walks of life, a lack of an alternative leads to inertia, even if there’s good evidence that people should change their ways.

Explaining the depression–dementia connection: Five possibilities

Depression and dementia are associated with each other in studies, but why? There’s no definitive answer to that question, but here are five hypotheses.

1. Depression unleashes stress-related hormones called glucocorticoids that may damage structures in the brain — perhaps, most importantly, the hippocampus — that are crucial to memory and other brain functions. So a large depressive burden (the number of depressive episodes, their duration and their severity) and the release of large amounts of glucocorticoids over a lifetime may damage the hippocampus in a way that makes cognitive deficits and dementia more likely. Depression-induced glucocorticoids may also accelerate the production of beta-amyloid deposits in the brain, which is the hallmark of Alzheimer’s.

2. Depression and dementia may be outward signs of the same disease process, with depression occurring earlier on, when the damage to brain cells is relatively minor, and dementia happening later, when it’s more extensive.

3. Depression and dementia may both originate in the ische mic brain damage that occurs when the blood vessels that supply brain cells narrow or get blocked. Many studies have linked ischemic brain damage to depression. If the ischemic damage is more serious — or if it occurs in certain areas of the brain — the result may be dementia.

4. Depression may be an early, emotion-laden response to the beginning stages of dementia. Eventually, the dementia may get worse and become more apparent, so it seems to have come after the depression when actually it was the other way around.

5. People with cognitive deficits sometimes find ways to hide their forgetfulness and mental lapses. Depression may unmask the deficits by making it difficult for people to maintain those coping mechanisms.

But good results after stroke

In contrast to the disappointing results for Alzheimer’s disease, antidepressants are showing real promise as medications that might help people recover from strokes — and their positive effects may go beyond depression.

Depression is common after a stroke; putting an exact number on the proportion affected is difficult, but 35% falls in the middle of reported ranges. Depression may seem to pale in comparison with the physical difficulties facing people recovering from a stroke, but the mental anguish of depression isn’t a minor concern. Besides, depression after a stroke is associated with poorer outcomes a year after the stroke has occurred, and also with a higher death rate in subsequent years. These kinds of associations don’t prove cause and effect, but in this case, they should provide some added incentive for dealing with post-stroke depression.

Fortunately, antidepressants seem to be fairly effective. Over a dozen studies have been done, and a 2008 review of the research came to the conclusion that the medications had a “small but significant” treatment effect on post-stroke depression. The evidence that antidepressants can prevent post-stroke depression from occurring in the first place isn’t as strong, so for now, it seems like antidepressants would be limited to recovering stroke patients with depressive symptoms.

Even so, the benefits of antidepressants may not be limited to relieving depression. Successful treatment of depression may have “downstream” benefits that go beyond mental health. Antidepressants may also positively affect areas and networks in the brain that improve other impaired functions, not just mental outlook and depression.

In 2011, French investigators reported that fluoxetine and physical therapy improved people’s recovery from stroke-induced paralysis and muscle weakness. And at about the same time, a team of researchers from Japan and the University of Iowa published findings that showed fluoxetine or nortriptyline (Aventyl, Pamelor, other brands), one of the tricyclic antidepressants, helped with overall disability.

Treatment of stroke has improved greatly in this country. People who would have died or been severely disabled now do quite well because, among many reasons, blocked blood vessels in the brain can be reopened quickly with tissue-plasminogen activator (tPA) drugs. Perhaps the next major gains in stroke care will come during the recovery period. Current guidelines don’t recommend antidepressants, but if the trend of positive results continues, they might be revised so they do.

Posted by: Dr.Health

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