Inflammation and the 3 Paths of Depression in Older Adults

Action points from research with a large group of older adults across 10 years.

Posted Sep 21, 2019

By Grant H. Brenner

You can't help getting older, but you can help yourself from becoming old and infirm, in mind as well as body. —Joan Collins

Depression is a serious mental illness which, according to the World Health Organization, affects over 300 million people total, is the leading cause of global disability, and affects women more than men. In many countries, less than 10 percent of people with depression are diagnosed and treated, leading to chronic suffering.

According to Greenberg and colleagues, the economic burden of depression is on the rise, up to $210 billion in 2015 by over 20 percent from 2010:

The composition of these costs remained stable, with approximately 45 percent attributable to direct costs, 5 percent to suicide-related costs, and 50 percent to workplace costs. Only 38 percent of the total costs were due to MDD itself as opposed to comorbid conditions.

Depression is different in older adults. According to the Centers for Disease Control and Prevention, older adults are at increased risk for depression and are less likely to be assessed and properly treated. Depressed older adults may have different symptoms; for example, older adults with depression may have such impaired cognition as to appear to have dementia, improving with antidepressant treatment and/or psychosocial interventions. And not only is depression treatable if diagnosed properly, it is also preventable in many cases.

Depression is not normal in later life, but because of stigma and a lack of education, many people believe feeling depressed is normal for older adults, as some also do for people diagnosed with serious illnesses. Clinical depression is never normal.

What Causes Depression?

The causes of depression are not fully known, and include genetic factors, neurobiological influences such as brain network activity, differences in the way signals in the brain are processed, psychological and social factors, developmental influences like childhood adversity and resilience, the impact of lifestyle, nutrition and gut-related factors such as the microbiome, and inflammation in the brain and body. Some of these factors are more fully researched, and a better understanding of how depression starts and is sustained in order to develop more effective treatments.

Inflammation has gained more recent attention as an important factor in depression as studies have shown that antidepressant treatment could be targeted to reduce inflammation, that treating inflammation may improve depression, that depression is more common with certain inflammatory diseases, and because inflammation can be modified in a variety of ways, ranging from medications and other medical treatments, and lifestyle factors including social support, diet and nutrition, environmental factors, and exercise.

Researching Inflammation, Metabolism, and Late-Life Depression

In order to look more deeply into late-life depression and the impact of inflammation in particular, scientists de la Torre-Luque, Ayuso-Mateos, Sanchez-Carro, de la Fuente and Lopez-Garcia at the Centre for Biomedical Research in Mental Health, in Madrid, Spain (2019) conducted a study of 13,203 people between the ages of 50 and 90 years old, using data from the English Longitudinal Study of Ageing (ELSA).

Participants, approximately half women, were followed every 2 years for 10 years, in several waves between 2002 and 2012. Information collected included different sociodemographic factors such as marital status, education, income; questions about physical and mental health; antidepressant use, and measures of disability and disease, and ability to function well on a day-to-day basis. Depression was measured using the Center for Epidemiologic Studies Depression Scale (CES-D). 

Direct biological measures included body mass index (BMI), blood pressure and blood samples (from a subset of 1,526 participants). Among other things, they measured inflammatory markers including white blood cell (WBC) count, C-reactive protein (CRP), and fibrinogen, an important molecule in forming blood clots, the level of which is elevated in inflammation.

They also looked at markers including triglyceride, cholesterol and lipid levels; and hemoglobin A1C, which reflects chronically elevated blood sugar levels by measuring how much glucose is attached to hemoglobin (“glycoslylated hemoglobin”), the oxygen-bearing protein in red blood cells. Dietary sugar intake is believed by many to contribute to inflammation. Metabolic factors also reflect systemic inflammation, as well as having specific significance for health, for example diabetic blood sugar control, cardiovascular disease risk, and the like.

Researchers used statistical analyses to see how different measures trended over time, whether there were any significant relationships (e.g. with sex and depression), and in particular in this report, whether inflammation was a significant factor.

How Do Inflammation and Metabolic Factors Interact with Later Life Depression?

They found that across the sample, there were three paths (or trajectories) in depression trends in this cohort of older adults. Overall, they found that 25 percent of people in this study were affected by clinically significant depressive symptoms. The three trajectories were:

  1. Low-symptom or “normative” (74 percent): minimal symptoms, rising gradually over time without reaching clinical significance;
  2. Moderate-symptom (18 percent): rising over time to reach probable diagnostic significance, meaning that this group became clinically depressed over the course of the study. Depression in the moderate-symptom group was accounted for by female sex, being separated or widowed, having a lower level of education, and by having a prior history of emotional and functional problems;
  3. High-symptom (7.4 percent): clinically significant symptoms at the beginning of the survey, which remained elevated but dipped slightly over time. Depression in the high-symptom group was explained by the same factors as in the moderate-symptom group, but with higher “doses” (“heavy loading” in statistic-speak) of each of those factors. The high-symptom group had elevated levels of inflammatory markers as well as increased metabolic risk.

The data showed positive correlations between inflammatory marker levels and CES-D (depression) symptoms across the whole study. Correlations were modest but significant with inflammatory markers and depressed mood, and inflammation and somatic symptoms of depression (those felt as bodily sensations e.g. headaches, fatigue, aches, and pains, etc.). Inflammatory and metabolic factors were also modestly but significantly correlated.

Action-Steps for Individuals, Clinicians, and the Healthcare System

This study supported and extended previous research on inflammation. More severe depression is driven by inflammatory and metabolic factors. In turn, depression is likely to cause elevation of, and prevent improvement in, those same factors, leading to a vicious cycle. For instance, people with more severe depression are likely to have difficulty with self-care.

Due to reduced motivation and energy, low self-esteem, pessimistic views, and so on, people with more severe depression are less likely to eat well and are more likely to eat poorly, exercise less, avoid seeking social support, and fail to ensure they get regular check-ups and follow treatment recommendations intended to improve health. 

They are less likely to recognize something is wrong, and instead interpret depression as proof, for example, of their worthlessness rather than as a clinical condition requiring assessment and care. Though depression interferes with self-care in any age group, these factors are worsened in older adults, who are more likely to have health problems and social issues purely as a function of age.

The authors also note that high levels of inflammation over time cause problems with mood regulation and depression via direct effects on the brain.

These effects included altered neuroplasticity, decreasing resilience and learning, and increasing the chances of chronic depression; and cognitive impairment, due to decrease neurotransmitter availability from increased clearance of serotonin; and direct neurotoxic effects due to higher free radical level (related to increased oxidative stress), and disturbances in astrocyte function (the support cells which help keep the neurons and brain environment functioning properly). 

Metabolic issues can also make depression more likely, for example by altering stress hormone systems in the HPA-axis (hypothalamic-pituitary-adrenocortical) and affecting insulin-resistance, leptin level (a hormone involved with appetite regulation), and worsening contributing issues like weight gain and diabetes risk.

Future research is required to develop methods for identifying and intervening with high-risk groups. For example, developing a clinical algorithm for a high-risk combo of clinical and lifestyle issues, alongside biological markers, would allow the healthcare system to identify patients early on and prevent future problems.

For example, a person with the risk of entering the high-symptom group is identified at a younger age. Resources are directed to prevention for that specific person, and public health and clinician education efforts are designed to make people aware of modifiable risks and steps to take, while doctors and other clinicians are trained to screen patients based on risk factors (even without an algorithm) and educate and treat accordingly.

Resource: NIHM—Older Adults and Depression.

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