In this 52 minute lecture Robert Sapolsky argues that "depression is the worst disease you can get". About 15% of us will experience a major depression in our lives. The World Health Organization (WHO) reports that depression is the #4 cause of disability on this planet and it is projected to reach #2 by 2025 after obesity/diabetes related diseases. The talk surveys the biology and psychology of depression.

His conclusion is sobering: A major depression is as real a biological disorder as is diabetes. But people tend not to talk about psychiatric disorders. Depression is one of the hardest diseases for people to admit to despite the fact that it is so widespread.

"Depression is absolutely crippling" and its widely pervasive.

Sapolsky is mainly referring to major depression not the kind of being bummed for a few days after getting bad news. More serious legitimate bad news such as the death of a loved one, loss of a job, etc., can lead to serious impairment for several weeks until you come out the other end. The most serious forms of depression involve not coming out the other end after months of serious impairment. Once suffering a major depression, the triggers for a recurrence can be much less serious than the first time.

Sapolsky's one sentence definition of a major depression "it's a biochemical disorder with a genetic component with early experience influences where somebody can't appreciate sunsets." It is surprising that since humans can derive pleasure and satisfaction out of terrible experiences like dying of cancer, "what could possibly be worse than a disease whose defining symptom is the inability to feel pleasure"?


Anhedonia: the inability to feel pleasure

The grief and guilt in a major depression can become so severe that they take on a delusional quality.

Self-injury is a common symptom of major depression, suicide being the extreme form.

Psychomotor retardation: everything is exhausting; even thinking about things can be exhausting resulting in a paralyzed state. This is not the stage of the disease when self-injury is a risk. Usually self-injuries happen after one starts to have more energy to actually do something about how horrible one is feeling.

Vegetative symptoms show that the bodies of depressives work differently. Sleep: depressives often wake up early and their whole structure of sleeping is out of wack; appetite decrease (for most of us we eat more when we are somewhat depressed); stress response: overactivation of the sympathetic nervous systems with elevated adreneline and glucocorticoids (the body is acting like it was just gored by an elephant but it can't get out of bed).

Rhythmic patterns to a person's depression are common

Seasonal affective disorders (only getting depressed in the Winter)

Neurotransmitters are the chemical signals neurons use to communicate with other neurons across the space between them (the synapse). There are probably hundreds of neurotransmitters, but only a few are implicated in depression.

MAO inhibitors were the first antidepressants in the 1960s. They suppress the activity of enzymes that break down norepinephrine (and epinephrine, serotonin, and dopamine). Their antidepressant activity suggests that the problem in depression is too little norepinephrine to support synaptic function.

Tricyclic antidepressants block the reabsorption (recycling) of norepinephrine further supporting the theory of inadequate neurotransmitter function in depression (the norepinephrine hypothesis).

Reserpine was used for treating high blood pressure because it depletes norepinephrine with the side effect of causing depression.

Norepinephrine affects the pleasure circuit in the brain (known from both rat studies and unanesthetized brain surgery patients). So shortages of norepinephrine (at least in that part of the brain) can cause anhedonia.

But the antidepressive effects of these treatments took weeks to have an impact. Then dopamine was discovered to be even more important than norepinephrine in the pleasure pathway.

In the late 1980s prozac is introduced. Prozac is an SSRI (selective serotonin reuptake inhibitor) which like the MAO inhibitors and tricyclic antidepressants increases neurotransmitter availability in the synapse. It affects serotonin instead of norepinephrine or dopamine.

The current thinking is that dopamine affects anhedonia, norepinephrine affects psychomotor retardation, and serotonin affects the (obsessive) feeling of grief.

Substance P is involved in pain. Inhibiting Substance P can help depressives feel better. The brain is apparently using the same chemistry for physical and mental feelings of pain.

Neuroanatomy: the structure of the brain

The concept of the triune brain (1960s): Paul D. MacLean developed the model of the triune brain with three layers of brain function: reptilian (automatic / regulatory which includes the hypothalamus & pituitary), the paleomammalian or limbic system (about emotion, prominent in mammals), and the neocortex or neomammalian (the analytical brain; present in all vertebrates but more developed in some). See

The cortex is able to control the limbic system through abstract thoughts and impressions. At some level depression is the cortex whispering to the rest of the brain that you are feeling as bad as if assaulted by a predator. "On a very simplistic level, what a depression is is the cortex having too many sad thoughts and getting the rest of the brain to go along with it."

A cingulotomy is a surgical procedure to sever a pathway between the cortex and the limbic system and people get less depressed (it is only used in desperate cases after all other therapies and their combinations have been tried and the person continues to harm themselves every few months).


Thyroid hormones are about maintaining metabolism. A shortage of thyroid hormones (hypothyroidism) causes a major depression. Hashimoto's disease is an auto-immune disease attacking the thyroid and results in depression. 20% of major depressions are undiagnosed hypothyroidism instead.

Women suffer major depression at about twice the rate of men. The most likely times women suffer depression are after giving birth (postpartem depression), around the time of their period, and around the time of menopause. All of these situations are characterized by major biological changes. Also, on the average women ruminate more about their emotions. Estrogen and progesterone, and most likely their ratio, appear to be the hormones that can knock the rest of the brain out of wack causing a depression in women.

Stress hormones. Adreneline is vastly overrated according to Sapolsky. He thinks the glucocorticoids are much more important (he's devoted the last 30 years of his life to them), Glucocorticoids come out of the adrenal glands. Hydrocortisone or cortisol in humans. They are secreted when we are under stress.

Half the people with depression have elevated glucocorticoid levels. People exposed to elevated glucocorticoid levels are at a greater risk of a major depression. Most people come out of stress induced depressions with no long term impact. But after the third or fourth stress induced depression, the person is at a higher risk of suffering further major depressions without major stressors triggering them.

Cushing's syndrome or hypercortisolism is a disease where people secrete lots of glucocorticoids. People with Cushing's fall into depressions. Lengthly treatments with glucocorticoids depletes the brain of dopamine and leads to more major depressions.

Only 30-40% of depressives can be treated with this biological knowledge. The psychology of depression, Sapolsky argues, is essential for helping the rest of depressives.

Sigmund Freud asked what is the difference between mourning (being depressed for a few weeks) and melancholia (major depression)? Freud suggested that melancholia is roiling in the ambiguities of love and loss being unable to put the negative feelings in the background. Sound bite: "depression is aggression turned inward".

Experimental psychology suggests that as you feel more stress and activate the stress response system for longer times, the chance of suffering stress-related diseases including major depressions is surprising small UNLESS you don't have outlets for the frustration caused by the stressor, and/or you feel you have no control over what's happening, and/or any predictability for the stressor, and/or you don't have anyone with a shoulder to cry on. Depression is pathological extremes of these factors that challenge our ability to cope with stress. The cognitive psychology soundbite for depression is "learned helplessness". Depression is making what's wrong into the whole world: feeling that you have no control and that it is hopeless and I'm helpless to do anything about it.

One of the most reliable findings in the epidemiology of depression is lose a parent to death before age 10, and the risk of a major depression is higher. Kids at that age are learning about cause and effect and the loss teaches them that there are awful things that you cannot control bringing you one step closer to the cliff of learned helplessness that is a major depression.

Stress is the intersection of the modern biological understanding of depression with the psychology.

Depression has some degree of heritability implying that it is a genetic disorder. Depression runs in families. Identical twins have a 50% chance of having a depression if their twin has one. Full siblings have a 25% chance. Person off the street only has a 2% incidence of depression. So there is a genetic component. But since identical twins have a 50% chance of NOT getting a depression if their twin does, that implies that genes are no more important than other factors.

Genes for depression are not about inevitability, they are about vulnerability. A major study showed that having the bad version of a serotonin regulating gene means you are no more likely to have a major depression unless you also have a history of major life stressors. The effect is 30-fold greater. "This is a gene that is relevant to how readily we pick ourselves up after life has dumped us on our rear ends. How readily we recover from stressors." Glucocorticoids regulate the function of this gene.

Conclusion: A major depression is as real a biological disorder as is diabetes. But people tend not to talk about psychiatric disorders. Depression is one of the hardest diseases for people to admit to despite the fact that it is so widespread.