Science Commentary

What is Depression?

t's fashionable these days to think of depression as a physical disease. And there is some reason to think so. Depression causes sleep disturbances, fatigue, changes in appetite, and other physical symptoms like difficulty concentrating. We tend to think of depression as a type of decreased excitation that somehow resembles sadness. But this only underscores how little we actually know about it.

The cause of major clinical depression is a highly emotionally charged issue for some people. They are strongly motivated to accept the idea that it's a disease, perhaps because of the strong social stigma attached to psychological disorders, or because they reject the psychology establishment and their early unsuccessful psychoanalytic models. Some of them express intense anger when anyone suggests that depression is not a purely physical disease.

Others insist that depression is purely psychological. They emphasize that suicide is a deliberate, voluntary act that has devastating consequences to those around them. One blogger got into a pile of controversy by trying to make this point. Typical of the nasty responses was Charlie Martin's criticism of him as a “damn fool” for saying that suicide is a choice, not a disease. These people believe a clinically depressed person has little or no control over their own actions.

But medically, the question of whether depression is a physical or mental disease is essentially meaningless. Or, as scientists prefer to say, “uninformative.” Everything that happens in our mind has a physical basis, and everything we think changes our brain chemistry. The APA produces a list of symptoms of clinical depression in its famous (or infamous) Diagnostic and Statistical Manual of Mental Disorders (DSM). But this list, which includes seemingly contradictory things like weight loss or weight gain, insomnia or increased desire to sleep, and so forth, does not define the disease itself, but only the patient's reaction to it. We need to know what is really going on.

The medical establishment does not have a good handle on this question. For example, the National Alliance on Mental Illness says “Researchers believe that more than one-half of people who die by suicide are experiencing depression.” The National Institute of Mental Health says “Depression is caused by a combination of genetic, biological, environmental, and psychological factors.” These statements are very reassuring, and undoubtedly true, but essentially uninformative.

Psychological aspects of depression

On a psychological level, there are at least three factors:

1. Failure of coping strategies
A person may become clinically depressed when their strategies for coping with life's stresses fail. In response they avoid using the failed strategies. They may withdraw from others, sitting for hours alone, and stop communicating with others. When forced into a conversation, they may be uncommunicative or rejecting. People might not even realize that the person is severely depressed, and are shocked when the person commits suicide. Such was the case with comedian Robin Williams, and it was the case with two people that I knew quite well.

One of these was a beloved college professor, admired and respected by his students. He wasn't stuck in some miserable slum town, but a nice leafy college community. He didn't have a boss who was evil or a wife who hated him. He made a good salary, had an enviable career solving the mysteries of life, and lived in a time when the country was reasonably free and its future looked rosy. He had a family and children. Yet one day he threw it all away.

The other was a young man with a bright future and three small kids who idolized him. He lived in a house he had built himself. He was intelligent, skillful, and witty. By any standard, he had what many of us today can only dream about. But he too threw it away. In so doing he destroyed his family and subjected his children to a lifetime of pain that those who have not experienced it can only imagine.

It is difficult to overstate the amount of suffering that suicide victims bequeath on their surviving family members. Spouses suffer, of course, but the children often become depressed themselves; they can also develop an inability to trust others, or an inability to experience happiness (anhedonia). Or they may blame the surviving parent for not supporting the suicide victim enough or even for contributing to his or her death. For the surviving parent, the children are a continuing reminder of the spouse, and the parent may come to resent them for eliciting painful memories. Such families rarely remain close.

Perhaps it is because those who commit suicide seemed to have so much, and yet spread so much destruction, that there is so little understanding of their motivations.

2. Passivity
The depressed person may appear passive. But inside the depressed person's mind there are powerful feelings of aggression and hatred that are directed inward instead of outward. Although the patient appears apathetic, this is clearly not the case. What could be a more convincing expression of violent aggression and hatred than the act of killing oneself?

Although we think of depression as a passive event—something that happens to you—it's worth asking how much of this idea comes from the current fad of passivization and medicalization. There is some merit to the idea that we must resist the fad of calling everything a disease, because doing so creates the idea that depression is something that just happens to you and there's little you can do to escape.

At its heart, depression is an emotion that consumes a person's life. But emotions are the body's way of getting you to do something. If depression had no purpose, it wouldn't be there. After four billion years of evolution, anything that served no purpose would be long gone. Anger, for instance, is how the body prepares us to fight for survival. The affective component of depression might be a clue about what the brain wants you to do. Maybe depression is the brain's way of getting you to stop caring about something that is harming you, such as your career or bad social relationships, so you can do something different.

If so, depression is the result of frustrated aggression preparing us to make radical changes in our lives. To survive, the patient might have to lose their job, change their socioeconomic status, reorganize their belief systems, or live among unfamiliar surroundings. These things are unpleasant, but the loss of a career would be a small price to pay when the alternative is death.

Many times, though, making these changes is impossible. For example, the patient might have a progressive or debilitating illness. Or they may be so afraid of change they are paralyzed. The sense of overwhelming hopelessness and inadequacy produced by depression undoubtedly can contribute to the paralysis.

Psychologist Aaron Beck, the founder of cognitive therapy, hypothesized that depression could be triggered by personal setbacks in individuals possessing dysfunctional attitudes—that is, unrealistic expectations. People who excessively value social relationships and approval become depressed after social rejection, while people who value autonomy become depressed when they experience loss of personal control.

Today we would say people who have rigid, inappropriate expectations are most at risk for depression. For such people, the robustness of their coping strategies determines whether their identity can survive contact with reality.

Physiological aspects of depression

There are also physiological factors that accompany depression. In his chapter in Handbook of Depression, Michael E. Thase and his co-authors theorize that depression is a dysregulation of the brain's response to stress. They say that 20-40% of depressed outpatients and 60-80% of depressed inpatients exhibit signs of increased cortisol secretion. This may explain why depression is correlated with post-traumatic stress disorder. But it does not tell us whether depression is a problem of the brain or of the mind, which is to say it does not tell us why the response is dysregulated. Still, there are some big clues here.

1. Neurotransmitters
One of the earliest findings was that some depressed patients excrete low levels of metabolites of norepinephrine, a monoamine neurotransmitter linked to cortical arousal and reward-seeking behavior. Antidepressants that elevate brain levels of monoamines like norepinephrine and 5-hydroxytryptamine (5HT) are very effective in reducing feelings of depression.

Neurotransmitters also control, and are affected by, a person's response to stress. Depressed people have elevated levels of the stress hormone cortisol, while chronic stress depletes 5HT levels. Stress early in life can interfere in these biochemical pathways, causing lifelong problems in dealing with stressful situations. Cortisol is well known to cause memory impairments like those seen in depression.

2. Loss of synapses
Depressed individuals have difficulty concentrating, remembering details, and making decisions. It has always been assumed that this is because the neurons are less active than they should be: they are tired and listless, like the patient. But recent research suggests that the fundamental physical change in depression may be loss of synapses.

Synapses are formed when small bumps on the neuron called dendritic spines grow and touch other neurons. These dendritic spines change at incredible speed: the proteins in a dendritic spine turn over in minutes or seconds. Compare this to proteins in other cells, which last for weeks or months, and it's easy to see how a gradual change here could have a big effect.

Patients with Parkinson's and Alzheimer's disease are frequently depressed. It has been found that such patients often have a profound loss of synapses. Some scientists believe that this is not just caused by the patient's knowledge that they have the disease, but that it may be telling us something important about its causes.

3. Genetics
In this age of molecular biology, it's inevitable that some studies have found evidence suggesting a genetic component. However, many other things besides genes are passed down from parent to child: their coping strategies, their outlook on life, their physical maladies, and even the fact that they are depressed. These psychological factors are learned and imitated by the children, but they are difficult to control in a genetic study.

4. Inflammation
There is evidence that inflammation influences the progression of major depressive disorder. Given the interactions between the brain and the immune system, it is unclear what this means. So far, there is little evidence that depression is an infectious disease. But depression must carry some survival value, or we wouldn't have it. Some researchers have speculated that depression may somehow protect against infection, perhaps by keeping people apart. In times of plague, sitting alone for days at a time, refusing food, and avoiding people might just save your life.

5. Electroconvulsive therapy
Electroconvulsive therapy (ECT) is a drastic but sometimes effective treatment for severe depression. Previously, it was assumed that ECT works by disrupting existing neural pathways and erasing painful memories. Like so many of our modern medical treatments, the idea is that losing some memories and a few brain cells is a small price to pay for keeping you alive.

But ECT, as unpleasant as it may be, may be giving us a clue. There is some evidence suggesting that brain injury or toxic chemicals can sometimes trigger the growth of new synapses. Is it possible that this, not the brain injury itself, is why ECT is sometimes effective? It is a question, like many other questions about depression, that deserves more research.