Evolutionary Psychiatry

The hunt for evolutionary solutions to contemporary mental health problems.

How Stress Makes You Sick and Sad

The link between depression, anxiety, diabetes, and stress

Stressed Out
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Whenever you talk about the body's response to stress, it is best to start with the HPA axis. That's hypothalamic-pituitary-adrenal axis, or master glands of stress and how they rule the body and the world.  We have a stress response system in the first place just in case something dangerous happens. Back in the day, when a bear wandered into camp, our fight or flight systems flipped into high gear.  And it works great for that kind of situation - send out a wave of stress hormone, a grandmother can lift the car off the trapped toddler. We can run faster, have better stamina, bleed less. Our senses are heightened.  The body shunts blood away from the digestive system and to our heart and large muscles.  What actually happens is that glucocorticoids (cortisol) and epinephrine (adrenaline) are released from the adrenal glands, and these hormones have a wide variety of effects on the body - increasing our cardiovascular capacity, decreasing our immune function, and increasing our ability to mobilize energy. Our own personal temporary superhero juice.

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Acute stress has effects in the brain, too. Glucocorticoids bind to receptors in particular regions of the brain that encode memory (the hippocampus and the amygdala), so that years later, we can often remember stressful events as if they happened yesterday. This mechanism is part of the basis of flashbacks for people with PTSD.

And then there's chronic stress. Exposure to adrenaline and cortisol on a chronic basis can have disastrous effects on the body and brain. It is thought to contribute to the pathology of cardiovascular disease, high blood pressure, the spreading of cancer, immune system problems, and type I and type II diabetes. Chronic stress is of course also thought to cause, in part, many anxiety disorders and depressive disorders.

Cushing's syndrome is a disease caused by excess cortisol. Imaging studies have shown that people with Cushing's syndrome have a shrunken hippocampus. People with PTSD and depression also tend to have a shrunken hippocampus. The hippocampus is the epicenter of how depression is toxic to the brain, which I will describe in detail in future posts.

It's hard to study neurochemical goings-on in the the brains of living people, as we have the tedious tendency to be using our brains (though sometimes it is not obvious). For that reason, animal models are often used for experiments to really find out what is going on in a depressed or anxious brain. And the typical way to induce depression in a rat, for example, is to expose it to stress. Sure enough, the rat will begin to have changes in weight, disrupted sleep cycles, altered HPA axis function, and neurological changes in the hippocampus and the amygdala. Chronic stress also causes an increase in glutamate in rat brains. Glutamate is a neurochemical that, in excess, is known to cause depression and anxiety, and probably migraines and seizures.  Humans will have elevated glutamate in their spinal fluid if they have anxiety.


All right. Blah blah blah. I know, news flash!  Stress makes you depressed.  But here's where it gets interesting. Because, turns out, people with diabetes have many of the same neurological and morphological changes in the brain as depressed and anxious people do. Hyperglycemia accelerates brain aging and causes irreversible neuron loss in the hippocampus - the center of where anxiety and depression act in the brain.

Cortisol seems to cause insulin resistance not only in the muscles and liver, but also in the hippocampus. Diabetics with poor glucose control have elevated cortisol, too. It's all a disastrous circle of sugary hormonal bodily terror. In an insulin-sensitive person, increases in insulin levels cause our cells to whip out the GLUT4 transporter, so that glucose is sucked from the blood into the muscle and fat. (Any GLUT transporter is a shuttle for glucose in or out of cells). Cortisol seems to wreck the function of the GLUT4 transporters to some extent, leaving increasing levels of glucose floating around in the blood. Once you have hyperglycemia, you begin to favor oxidation systems, which can be toxic, over antioxidation systems, which protect and repair. In the brain, glutathione (supreme antioxidant) levels are decreased in the hippocampus, leading to the rule of toxic glutamate.  Not favorable to a healthy state of mind. All these changes decrease synaptic plasticity and repair. Exercise, estrogen, and antidepressants seem to be protective against this effect.

Now let's talk about the insulin receptor itself. The cerebellum, hypothalamus, and hippocampus all have insulin receptors, and insulin itself seems to be involved in mood states and cognition. If someone is insulin-resistant (such as a prediabetic or a type II diabetic), adding insulin will help a person think more clearly. Insulin sensitivity seems to be associated with appropriate movement of glucose transporters GLUT4 and GLUT8 in the hippocampus to the cell membrane and the glucose-burning machinery in the neuron.  That means that when everything is working correctly, insulin helps your brain burn sugar.  If you are insulin resistant, all of these processes work more inefficiently.  That means diabetes will affect your cognition.

Okay. Well, none of these findings are a huge surprise. We knew stress was bad. We knew insulin resistance was bad. Experimental animal models show that pharmacological interventions can reverse or slow down some of the damage. But hey, wouldn't it be better to avoid the chronic stress and insulin resistance in the first place? Better for the brain, better for the body.

Modern life requires work before play. Productivity before relaxation. Ability to afford the time to exercise before one actually gets the time to exercise. Hey, that's life, but take it to the automaton extreme (and add processed food and partially hydrogenated fat), and it rots our brains and ruins our bodies. But we will spend and spend until we have no more credit left. We need to change some of the incentives out there. Chronic, expensive disease is on the back burner, and it will bankrupt us.

Reagan LP, Grillo CA, Piroli GG. The As and Ds of stress: Metabolic, morphological and behavioral consequences.Eur J Pharmacol 2008;585:64-75.

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Copyright Emily Deans, MD

Emily Deans, M.D., is a psychiatrist with a practice in Massachusetts.

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