Depression in Late-Life: New Ideas About an Old Problem

By the year 2030, there will be 65 million Americans over the age of 65 representing 22 percent of the population. In the same time period, the number of Americans 85 and older will more than double. Although individuals are living longer, the quality of these years is impacted by the increased prevalence of illness. According to the Centers for Disease Control, 25 percent of individuals over the age of 65 are considered in fair or poor health; for example, over 30 percent of this population suffers from heart disease. Thus identifying those syndromes or diseases that result in the greatest decrements in the quality of these latter years is of the utmost importance for individuals, families, and society as a whole.

One of the most common disorders of late life associated with decrements in functional ability and increased mortality risk is depressive illness. Major Depressive Disorder (MDD) is a leading cause of disability, morbidity, and mortality across the lifespan but represents a particularly severe public health problem in late life.[i]The prevalence of MDD is 3 percent of community-dwelling adults over 60 years old, and 15 percent of older adults living in the community have clinically significant depressive symptoms. Diagnosis with MDD increases an older adult’s risk of disability by 67-73 percent over 6-year follow-up, causes twice the functional impairment compared to those without MDD,[ii] increases the risk of mortality in patients with heart disease, and is associated with high rates of completed suicide in individuals over 65 (16.9/100,000 overall and 62/100,000 in white men).

Antidepressant medication, adjunctive pharmacologic treatments, and evidence-based psychotherapeutic modalities are all treatments that are used for the treatment of depression in older patients but their effectiveness is limited. There are unique safety concerns about the use of antidepressants in older adults including excess mortality, cardiovascular risks, and falls and fall-related injuries. Understanding the risks and benefits of antidepressant strategies in older adults could vastly improve the quality of life of seniors and save billions of dollars each year in health care costs. The relative paucity of depression treatment studies that focus on older patients is incomprehensible given the prevalence, morbidity, and mortality of this illness in the late-life population

The consequence of not having effective and safe treatments for late-life depression is that the illness is highly recurrent, can become chronic, and residual symptoms place patients at increased risk of suicide as well as cardiovascular morbidity and mortality.

However, it is not simply an issue of doing more studies of the currently available treatments but rather how we develop and study innovative interventions that have the promise of working when our current treatments fail. This is the goal of personalized medicine, to be able to know which treatment is for which patient.

One of the problems that limit our ability to develop new treatments for late-life depression is that models of depression are primarily based on studies of younger adults even though the symptoms and physiology change with age. Thus we do not have sufficient knowledge of how the aging process—with respect to social and interpersonal dimensions, physical and functional capacities such as mobility or cognitive status, or with respect to how neurotransmitters such as dopamine—affect the psychobiology of depression.

In fact, a current hypothesis is that depression in older patients is a heterogeneous group of subtypes that results from the interaction between the aging process and depressive illness.

Perhaps the best-established subtype is vascular depression that results from ischemic damage in the brain caused by small vessel disease. Fewer of these patients report depressed mood and they more often report apathy, somatic concerns, cognitive deficits, and anergia, giving rise to the description of this subtype as ‘depression without sadness”. Patients with vascular depression invariably have a cognitive impairment, specifically executive dysfunction. These patients respond poorly to some classes of antidepressants and there are studies that suggest that Problem Solving Therapy is particularly helpful.

Another example of how the aging process affects the presentation of depression in late life relates to cellular energy production. Mitochondria produce most of the body’s energy and their age-related decline constitutes part of the biological basis for physical fatigue. In younger adults with depression, fatigue presents as “mental fatigue”, whereas in older adults with depression, the presentation of fatigue is more “physical fatigue”. The question is whether the older patient with marked physical fatigue would be helped by an exercise program to augment antidepressant treatment.

Finally one of the most consistent abnormalities in older individuals is an age-dependent increase in inflammatory markers, especially interleukin-6, often referred to as the “cytokine for gerontologists. Interleukin-6 levels are typically low or undetectable in young people, begin increasing as healthy individuals exceed 50 years of age, and are often found to be very high in extremely aged adults. This chronic, low-grade state of inflammation in older adults was termed “inflammaging.” It has been associated with adverse structural and functional changes in the aging central nervous system and symptoms of low energy, apathy, and motor slowing. The motor slowing is particularly intriguing because inflammation decreases dopaminergic functioning, which itself declines linearly with age. Perhaps most striking is that inflammation, depression, and slow gait are defining features for a high-risk mortality phenotype in late life.

There are some data that suggest that patients with depression and inflammation benefit from treatment with anti-inflammatory agents although caution is necessary because it is not yet clear whether the benefit outweighs the risks associated with these medications. Furthermore, there are studies underway to see if depressed patients with slow gait and inflammation are in a low dopamine state and may benefit from dopaminergic agents.

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We have long accepted that depression in children and adolescents presents differently and requires special treatment considerations. It is now compelling that we recognize that depression in late life can only be understood if we consider the impact of the aging process on the illness, and equally interesting is the growing evidence of how the illness may accelerate the aging process. If we do so it will open up many new pathways to develop innovative and effective treatments so that we can indeed have the knowledge to be able to know what treatment may work best for each type of patient.