How Stress Lays the Groundwork for Depression

Depression is a pervasive and debilitating mental health disorder that affects more than 300 million people, with a myriad of factors that underlie its development. This week, we examine how stress itself — often thought of as merely a symptom — actually lays the groundwork for depression by changing the structure of key regions of the brain. See last week’s post here.

The Impact of Stress on Biology 

Perhaps someone is constantly worried about money, performance at work, or there is a romantic relationship that produces persistent anxiety — maybe there is a mix of the three, and maybe even a few more. Though it might appear as if this type of omnipresent stress merely affects one’s mood in the short-term, the reality is that this kind of chronic stress may be wreaking havoc on a much deeper level — an epigenetic level, thus leading to long-term changes in protein expression in the brain. Being exposed to stress, especially on a long-term basis, can cause pathophysiologic changes in the brain that may lead to behavioral, cognitive, and/or mood disorders — depression being of them

One of these changes is neuronal loss and impaired functioning of the hippocampus. Pathological anxiety and chronic stress can lead to neuron death and structural degeneration of the hippocampus. The hippocampus provides inputs to other brain regions — such as the prefrontal cortex, cingulate cortex, and amygdala — that significantly contribute to altered mood and emotion in depression. It is therefore thought that altered neurogenesis in the hippocampus contributes directly to some aspects of depression, and may indirectly influence other symptoms of mood disorders including post-traumatic stress disorder (PTSD).

Another significant biological impact of stress is on the hypothalamic-pituitary-adrenal (HPA) axis — the body’s central stress response system. While the stress response is intended to promote survival, prolonged exposure to stressors may cause changes in HPA axis reactivity that can lead to overproduction or underproduction of cortisol — both of which have been linked to depression. Research has also shown that early-life stress can be particularly harmful, as it can alter the lifelong responsiveness of the HPA axis to stressors. Studies that examine the consequences of childhood trauma on the stress response have found strong links to mental and physical health problems in adulthood, as well as with alterations in HPA axis function. This is thought to be one explanation as to why childhood adversity is such a risk factor for depression in adulthood, as well as alcohol and other drug abuse. Between 35% and 65% of depressed individuals demonstrate clear HPA axis abnormalities, and persistent HPA dysfunction has been associated with higher rates of relapse and chronicity. 

Stressful and Major Life Events 

The finding that stressful and/or major life events significantly increases a person’s risk for depression is perhaps one of the most well-documented in depression research. A great financial loss, the termination of a close relationship, physical or emotional abuse, major health setbacks, the death of a loved one, and the loss of a job all fall into this category, and can lead to severe cognitive upheaval that greatly alters a person’s goals, plans, and hopes for the future.

When solely considering events unrelated to a person’s actions or behaviors, researchers estimate that there is a 2.5-fold greater likelihood that a depressed patient experienced a major life event prior to the onset of the disease versus someone who was not depressed during the same time period. When considering any type of major life event prior to the onset of the disease (i.e., even those directly caused or affected by a patient’s behavior, such as substance abuse), the risk estimate significantly increases to an odds ratio of 9.38. Based on such data, major life stress is thought to be one of the greatest risk factors for depression, with upwards of 80% of cases in the general population preceded by such events. Findings such as these have been witnessed across all age groups and have been found to be particularly strong for women.

Perhaps one of the most troubling findings concerning major life stress is the subsequent and lasting effects produced when it occurs in early life. Adverse events experienced by children, adolescents, and young adults create deeper and longer lasting impacts than when they occur later in life, as they often negatively impact the crucial developmental processes happening during these life stages. Research on the topic indicates that: 

People who experience childhood abuse are three to four times more likely to develop major depression in their lifetime.

Adults with major depression are much more likely to have a history of emotional abuse, neglect, and physical abuse compared with healthy adults.

Those who experience early childhood abuse often have earlier onset, longer duration, more severe symptoms, greater impairment, and more episodes of depression

Modern life stresses, such as cyberbullying and problematic mobile phone use, were likely contributors to significant rises in the prevalence of depression in adolescent girls between 2004 and 2014 — from 13.1% to 17.3%, respectively. 

Join us as we continue to examine the top 8 factors contributing to the depression epidemic (and don’t forget to sign up for our weekly newsletter to stay up to date with all the latest news in biotech, mental health innovation, and much more). See last week’s post here.