The obvious answer has been that it's because they selectively block the reuptake of serotonin. This explanation is appealing because of its simplicity; however, as is so often true of explanations about drugs that affect the brain, this explanation is probably inadequate.
One problem is that no one is quite sure what causes depression. Everyone knows, or will likely know one day, what it feels like to be depressed. This is why depression is often referred to as "the common cold of mental illness." This reference reveals some fundamental insights into why we become depressed when we are suffering with the flu or a bacterial infection. Bacteria induce our bodies to release an ancient form of chemical warfare called cytokines. These cytokines are part of our immune system's defensive arsenal to protect us from invading bacteria or viruses. When we become sick we demonstrate what scientists call sickness behaviors: we remove ourselves from the company of others and become less active while our bodies attempt to heal. When your dog is sick it might hide under the bed and sleep for many days; not even eating. Humans do the same thing. When a person feels depressed they demonstrate many of the same symptoms. The depression-like behaviors are now thought to be caused by the release of cytokines into the body and brain. This response for dealing with an illness has evolved to help us survive infections and be healthy.
Sometimes, however, cytokines and other pro-inflammatory chemicals are released inappropriately and for prolonged periods of time and this leads to the appearance of depression-like behaviors that last too long. Many recent scientific studies have shown that cytokine-induced processes are active in our brain during depression and that these processes lead to an imbalance in the metabolism of serotonin. A few years ago it was discovered that SSRIs have anti-inflammatory actions that can counteract the depressive effects of cytokines. This insight may also explain why SSRIs are less effective in elderly people because their brains demonstrate quite elevated levels of inflammation.
As their name suggests, SSRIs enhance the actions of serotonin by preventing its inactivation by reuptake. One nagging problem has been that SSRIs block reuptake of serotonin as soon as they enter the brain, yet the depression is not resolved for many weeks. This does not make sense. Why shouldn't we feel better immediately? After all, cocaine can also block the reuptake of serotonin and we feel its effects within minutes. The resolution of this conundrum lies in recognizing that SSRIs actually induce a cascade of slowly evolving changes in the brain that involve changes in our DNA and the production of new chemicals that alter how the brain works. One important chemical that is induced into production by taking an SSRI is called BDNF.
BDNF is critical for helping our brain cells grow, make new connections with other cells and survive throughout life. The classic anti-depressant treatments all seem to induce our brains to make more BDNF. For example, exercise increases the production of BDNF. Depressed people often find some modest relief by exercising; which of course is exactly the last thing they feel like doing! Blocking the reuptake of the neurotransmitter norepinephrine by the new anti-depressants called SNRIs also induce the production of more BDNF. On the flip side, things that tend to cause depression reduce BDNF, such as stress, sickness, obesity and inactivity (which always seem to occur simultaneously). Overall, then the best advice for being happy is to keep active: you'll have less stress, be thinner and live longer.
© Gary L. Wenk, Ph.D. Author of Your Brain on Food (Oxford, 2010)