HOW DO ANTIDEPRESSANTS WORK?

 

In the 1950s, the discovery of two new drugs sparked what would become a multibillion dollar market for antidepressants. Neither drug was intended to treat depression at all— in fact, at the time, many doctors and scientists believed psychotherapy was the only approach to treating depression. The decades-long journey of discovery that followed revolutionized our understanding of depression— and raised questions we hadn’t considered before. One of those first two antidepressant drugs was ipronaizid, which was intended to treat tuberculosis. In a 1952 trial, it not only treated tuberculosis, it also improved the moods of patients who had previously been diagnosed with depression. 

In 1956, a Swiss clinician observed a similar effect when running a trial for imipramine, a drug for allergic reactions. Both drugs affected a class of neurotransmitters called monoamines. The discovery of these antidepressant drugs gave rise to the chemical imbalance theory, the idea that depression is caused by having insufficient monoamines in the brain’s synapses. Ipronaizid, imipramine, and other drugs like them were thought to restore that balance by increasing the availability of monoamines in the brain.

These drugs targeted several different monoamines, each of which acted on a wide range of receptors in the brain. This often meant a lot of side effects, including headaches, grogginess, and cognitive impairments including difficulty with memory, thinking, and judgment. Hoping to make the drugs more targeted and reduce side effects, scientists began studying existing antidepressants to figure out which specific monoamines were most associated with improvements in depression. In the 1970s, several different researchers converged on an answer: the most effective antidepressants all seemed to act on one monoamine called serotonin.

This discovery led to the production of fluoxetine, or Prozac, in 1988. It was the first of a new class of drugs called Selective Serotonin Reuptake Inhibitors, or SSRI’s, which block the reabsorption of serotonin, leaving more available in the brain. Prozac worked well and had fewer side effects than older, less targeted antidepressants.

The makers of Prozac also worked to market the drug by raising awareness of the dangers of depression to both the public and the medical community. More people came to see depression as a disease caused by mechanisms beyond an individual’s control, which reduced the culture of blame and stigmatization surrounding depression, and more people sought help. In the 1990s, the number of people being treated for depression skyrocketed.

Psychotherapy and other treatments fell by the wayside, and most people were treated solely with antidepressant drugs. Since then, we’ve developed a more nuanced view of how to treat depression and of what causes it. Not everyone with depression responds to SSRIs like Prozac— some respond better to drugs that act on other neurotransmitters, or don't respond to medication at all. For many, a combination of psychotherapy and antidepressant drugs is more effective than either alone. We’re also not sure why antidepressants work the way they do:

they change monoamine levels within a few hours of taking the medication, but patients usually don’t feel the benefit until weeks later.

And after they stop taking antidepressants, some patients never experience depression again, while others relapse. We now recognize that we don’t know what causes depression, or why anti-depressants work. The chemical imbalance theory is at best an incomplete explanation.

It can’t be a coincidence that almost all the antidepressants happen to act on serotonin, but that doesn’t mean serotonin deficiency is the cause of depression. If that sounds odd, consider a more straightforward example: steroid creams can treat rashes caused by poison ivy— the fact that they work doesn’t mean steroid deficiency

was the cause of the rash? We still have a way to go in terms of understanding this disease. Fortunately, in the meantime, we have effective tools to treat it.