Stress, Cortisol, and Depression

What’s the evidence to think there’s a link between stress and depression?

There are 23,000 references in PubMed if you type in stress and depression.

The first type of evidence is epidemiological: People who have just had major stressful events are statistically more likely to fall into a depression.

Stressors are 2.5 times more likely in depressed patients compared to controls.

In community samples, 80% of depressed cases were preceded by major life events

Most episodes of major depression are preceded by stressful life events (although
most people do not become depressed even if they experience a negative life event).

It all seems so obvious that stress could lead people to be depressed. But actually it’s not.

For example, why doesn’t excessive stress cause something else? Why doesn’t it cause us to run amok, doing all sorts of wild and crazy things? Why depression?

Why doesn’t stress cause us to work harder? That would be logical–for our bodies to pump out more adrenalin and make us work harder to fix the problems we face.

The answer is we don’t know.

But to have any chance of understanding the human stress response and depression, we have to start with the basic nature of the human stress response.

We have a generalized response to a variety of stresses. Psychological stress and physical stress on the body generally lead to the same set of hormonal responses within the body, which is in itself unusual, or at least, counterintuitive.

We have one main stress response syndrome in our body:
Perception of threat
Hypothalamus activation
Pituitary activation
Adrenal gland activation
Adrenalin+Noradrenalin+Cortisol

During stress, a chain reaction of physical and chemical processes prepares the body for a fight or flight situation. After the logical, thinking part of the brain recognizes that danger is present, another part of the brain, the hypothalamus releases Corticotropin Hormone Releasing Factor (CRF). This in turn stimulates the pituitary (the “master gland”) to release Adrenocorticotrophic Hormone (ACTH). The release of ACTH triggers the secretion of cortisol from the adrenal cortex (the adrenals are located on the kidneys) to provide energy and to help suppress inflammation. Through a neural pathway (that is, via a nerve rather than chemical release in the blood stream), the adrenals are also stimulated to produce more chemicals called adrenaline and noradrenaline. These in turn serve to accelerate the pulse rate, elevate blood pressure, and stimulate the central nervous system.

The fight or flight response is a good thing. It has saved many of our forbears from saber tooth tigers and other dangers. But what is good for us in the short run is not necessarily good for us in the long run.

And cortisol is one of those things. I believe that our best bet at the current time to understand why stress would lead to depression is cortisol.

We do have some evidence that that may be true.

Cortisol like drugs, i.e., steroids, can cause depression as one of their side effects.
People who are given high levels of synthetic glucocorticoids for autoimmune disorders or inflammatory issues have greatly increased risk of going into a depression.

Secondly, we know that long term exposure to cortisol results in some really nasty effects on the brain, particularly the hippocampus. The hippocampus is the memory center of the brain. It also does something else. It modulates the release of cortisol. Long term exposure of the hippocampus to stress leads to loss of neural branches called dendrites. And it leads to problems with memory loss.

If cortisol has a damaging effect on the hippocampus, then it also might have a damaging effect on other parts of the brain. There is only one article I found on this , but it could be true. The negative effects of prolonged cortisol exposure occur throughout the body, so it is not a far stretch to believe that we have only begun to understand the negative effects of it on the brain.

Thirdly, about 50% of people with depression hypersecrete cortisol. Of course, by itself this proves nothing. But it would be consistent with the hypothesis that too much cortisol leads to – too much cortisol. In other words, stress leads to too much cortisol, which can lead to damage of the hippocampus, which unleashes more cortisol.

By the way, elevated cortisol levels occur in mania as well as depression.

Now, let’s transition from looking at depression as a biological disorder to looking at the psychological aspects of depression.

It is certainly possible that once we become depressed, the depression itself stresses us. It enhances our negative thoughts, which increase our perception of threat and stress, which increases our cortisol output, which in turn would further cause disorder of brain functioning.

There is some evidence that the anterior cingulate, a curved bundle of nerves around the corpus callosum between the limbic system and the prefrontal cortex is affected by or is causing depression. And there is a small amount of evidence that high cortisol levels can cause atrophy or smaller volume in the anterior cingulate.

And there, the physiological trail runs cold. We just don’t know the rest. But sometimes a bad theory is better than no theory at all.

So here is the theory in my head when I am working with patients.

Stress begins for most people as a psychological process, although there are also physical components. If my wife is in the hospital, I may sleep different hours, eat different meals, and so on. But also there is mainly psychological stress.

Then the HPA axis causes the release of cortisol. If this is on a sustained basis, the long term effects of cortisol affect the hippocampus and perhaps the anterior cingulate.

Since the hippocampus is supposed to help regulate the HPA axis, if it is impaired, then the HPA axis may get further out of control leading to more cortisol.

Ultimately, the anterior cingulate and the serotonin pathways are affected, leading the person to become depressed if this goes on for too long, and the person has certain genetics.

But even if the trail runs cold, we may know enough to inform our decision making. Stress, particularly prolonged and severe stress is not our friend. Combatting stress takes time and energy, and in some ways it is simply easier to let ourselves be stressed out, even if that is more painful. But it is not good for our brains and it is not good for us. And depending on our genetics, it is often a luxury that we just can’t afford.

Thinking about stress psychologically.

Stress is not just the result of a situation. It is the combination of the situation and our way of perceiving the situation.

We used to think of, or I used to think of, stress as something which could go away. And once it went away, then everything would return back to normal. This way of thinking clearly has gone out the window. Memory will sometimes return back to normal after exposure to chronic stress is over, but not always.

And multiple depressions leave us even more vulnerable to further depressions. Thus, we cannot conclude that we simply return back to normal.

I sometimes say to my patients that stress is a luxury that we can’t afford. What do I mean by that? Because oftentimes, there is little that we can do about stress. Either we are stressed or we aren’t.

But that’s not quite true. There are things we can do about stress.

Cognitive therapy, for example, is aimed at helping people to be less stressed by situations than they otherwise would be.

So there is some sense in saying that stress is a luxury that we can’t afford. To the degree that we do have any control at all over our stress, we cannot afford to let ourselves sink to the bottom of the pit, with the idea that we will eventually bounce out. For some of us, this undoubtedly triggers a genetic response of biological depression. For others of us, it may impair our hippocampus if this goes on for months or years. And for others of us, it may do both.

So if stress is a luxury that we cannot afford, what can we do about it?

This is where the panoply of typical depressive therapies comes in.

Cognitive therapy works to reduce irrational negative thoughts. Why is this important? Because without excessive negative thinking, our body just might turn off the stress response. Which could turn off the cortisol. Which would give our brains a chance to heal.

Behavior therapy sometimes works on assertiveness training. Why is this important? Because assertiveness often fixes situations that we perceive as threatening, which means we don’t have to be stressed, which means that our bodies can turn off the cortisol, which lets our brains heal.

Interpersonal therapy works on improving interpersonal relationships. Which again often fixes situations that we perceive as threatening, which means we don’t have to be stressed, which means that our bodies can turn off the cortisol, which lets our brains heal.

Therapy sometimes helps the person to gain control, or at least enhance their feeling of control, which etc etc.

Get the picture? We cannot afford the luxury of stress. If there is anything that we can do which can turn off the stress response, then we need to do it. If we can divert our attention for a few hours, so much the better. If we can fix the situation, so much the better. If we can find more adaptive ways of thinking about the problem so much the better.