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How Antidepressants Work: History and Brain Chemistry

by Matthew S. Koval, M.D.

mi-brainfactoryThey're used to treat bipolar disorder, depression, even severe PMS. Chances are, you know someone who's on them. Heck, even Brooke Shields and Tom Cruise battled it out over these little pills.

But just how do antidepressants work?

The simple answer is, we don’t know for sure. In fact, scientists discovered antidepressants by accident. But before we can get to that story, we must have a basic understanding of brain neurochemistry. Perhaps in the process we can discover a few clues ...


In the human brain, nerve cells, or neurons, must be able to communicate with each other. They do this by passing along neurochemical signals.

Brain ChemistryTo understand this process, imagine two neurons very close together. Between them is a tiny space called the synapse.

The first neuron (called presynaptic) has a small factory inside making chemical messengers (neurotransmitters). These messengers are packaged into small bubbles, sent to the neuron’s outer surface and dumped into the synapse.

The messengers then travel across the synapse and connect to receptors on the second neuron (called postsynaptic), delivering their message. The message typically triggers various activities in that neuron, including making more neurotransmitters. This process continues down the line of nerve cells.

If any excess neurotransmitters get out into the synapse, the presynaptic neuron has a neat little reuptake pump, or recycle bin, that it uses to scoop up the excess and take it back. That way, the leftovers can be sent to the neuron’s incinerator, where they can be destroyed and converted back into raw materials for the neuron to use in other endeavors.

This is the way most nerve cells work in your brain and body.


Now back to the story.

History of MAOI Antidepressants

One of the first drugs that treated depression was the tuberculosis medicine iproniazid. Doctors discovered that not only did it treat the disease, but it improved mood and increased activity. After additional research, they used it to treat depression in the late 1950s and early 1960s.

This pioneer antidepressant, it turns out, was able to block the incinerator in nerve cells. Specifically, it blocked an enzyme that breaks down norepinephrine, serotonin and dopamine. Researchers widely came to believe that deficiencies in one or more of these neurotransmitters led to depression. A sufficient amount of feel-good chemicals, they concluded, meant relief from depression. And the class of antidepressants known as the monoamine oxidase inhibitors, or MAOIs, was born.

History of Tricyclic Antidepressants

The next drug class, developed at about the same time, was the tricyclic antidepressant, or TCA. Imipramine was the first TCA used clinically. Researchers developed this medication to treat schizophrenia, but it didn’t show promising results. However, they recognized its ability to treat depression.

The TCAs work by blocking the reuptake, or recycling, of norepinephrine and serotonin, allowing more chemical messengers to stay out in the synapse and increase the likelihood of the message getting to the postsynaptic neuron.

Doctors prescribed the MAOIs and TCAs heavily for mood disorders over the next 20 years. Unfortunately, with them came side effects, such as weight gain, increased heart rate and blood pressure, and the fact that they were dangerous in overdose.

History of SSRI Antidepressants

At the time, most scientists relied on the belief that norepinephrine was the chemical messenger that was really involved in the depression. However, interest began to develop in serotonin as well. Due to that increasing interest, as well as interest in finding antidepressants that would have more tolerable side effects, the serotonin-specific reuptake inhibitors, or SSRIs, came about. The first drug in this class was fluoxetine (Prozac), and there have been many since. As their name suggests, these drugs work by only blocking the reuptake of serotonin, thereby reducing side effects.

Today, there are even more types of antidepressants, such as bupropion (Wellbutrin), which works by blocking the reuptake of norepinephrine and dopamine.


So now you’re saying, “Well, it’s obvious; antidepressants work by increasing those neurotransmitters.”

But wait, there’s more!

Antidepressants have an almost immediate chemical effect. Over hours to days, neurotransmitters increase. However, it takes anywhere from two to six weeks before the symptoms of depression start showing improvement. This implies a more complex explanation for the cause of depression, as well as how the antidepressants work.

Perhaps increased neurotransmitter levels lead to other changes in brain neurons or chemistry that we have not yet been able to measure. It is possible newsletter-graphicthat antidepressants take a broad approach by increasing neurotransmitters that trigger other processes that then alleviate symptoms.

In the future, as we come to understand these fascinating medications more thoroughly, we hope we can look forward to treatments that will have a more focused approach—making specific, pinpoint brain changes—and know exactly how they work!

, is a practicing psychiatrist and associate professor at the Medical University of South Carolina. Disclosure: He was formerly on the speakers bureau for GlaxoSmithKline, a pharmaceutical company that makes antidepressants (Wellbutrin and Paxil).

Last updated and/or approved: April 2010. Original article appeared in September/October 2007 former print magazine. Bio current as of September 2007. This article is not meant as individual advice. Please see our disclaimer. Source for drug names: FDA Office of Women's Health.


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