Antidepressants have been a staple in mental health treatment for decades, but researchers never knew exactly how they worked on a molecular level — until now. A team of scientists has discovered the precise process behind the effectiveness of two popular antidepressants, and broken down an important wall on the road to developing safer, more effective medications in the future.

Americans are taking more antidepressants than ever; studies estimate 8 to 10 percent of the population are on the medication, the third most common in the United States. The most popular class of antidepressants is selective serotonin reuptake inhibitors (SSRIs), and though clinicians prescribe them widely, the exact mechanisms that allow the medications to work were not fully understood.

A new study published Wednesday in Nature details the molecular structure of the human serotonin transporter (SERT), the target of many antidepressants, including SSRIs. Serotonin performs a variety of functions in the brain including regulation of sleep, appetite, sexual desire, mood, and social behavior. SSRIs are designed to boost serotonin levels in the brain by blocking the neurotransmitter from being absorbed back into the cell. By doing this, the medication increases the amount of serotonin available in the brain.

The paper describes how SERT behaves when presented with two of the most popular SSRIs on the market — citalopram and paroxetine.

A Serotonin Problem

Depression as an illness, like the drugs used to treat it, is not fully understood. One major theory focuses on how the neurotransmitter serotonin can even affect bodily functions, including the cardiovascular system and various endocrine tasks. Many researchers believe that an imbalance in serotonin can influence these different aspects, which led to the development of SSRIs.

The current study, led by Dr. Eric Gouaux, a senior scientist in the Vollum Institute at Oregon Health and Science University, offers brand new insight into the inner workings of this process. Thanks to X-ray crystallography, the research literally provides a picture of the moment SERT is bound to both citalopram and paroxetine. The researchers found the antidepressants directly block serotonin from binding to SERT’s membrane protein, a finding they suggest will have a major impact on future SSRI development.

Looking Ahead

When tricyclic antidepressants were first developed in the 1950s, they provided relief in 60 to 80 percent of patients, but were also responsible for serious side effects like weight gain, sluggishness, and even some deaths from overdose. Scientists knew something had to be done, and a more targeted class of antidepressants hopped onto the market in 1987. The difference between the old drugs and these was specificity — instead of smothering an entire brain region in chemicals, the new medications focused on the serotonin transporter. The new formula was a success, with the same number of patients claiming improvement with fewer side effects.

Even though SSRIs were working, Gouaux and his colleagues knew that better understanding that process would allow for growth and improvements.

“Taken together, the structures of the SERT shed fresh insight into antidepressant recognition,” the authors wrote in the paper. This, they said, would allow researchers to design small molecules that target the binding sites specifically involved in blocking serotonin reuptake, or being absorbed back into the cell.

Better therapies would be welcome; depression and other disorders for which SSRIs are prescribed still need more consistent, focused treatments. SSRIs may be effective for 60 to 80 percent of patients, but that means millions of people are still struggling.

“The heavy toll that devastating illnesses like anxiety and depression have on families and communities is, in many ways, incalculable,” said Gouaux. “Revealing the precise structure of the serotonin transporter holds tremendous promise for the development of life-changing drug treatments for these diseases.”

Source: Coleman J, Green E, Gouaux E. X-ray structures and mechanism of the human serotonin transporter. Nature. 2016.

Correction: A previous version of this article incorrectly stated that SSRIs were developed in the 1950s instead of tricyclics.