Rethinking Serotonin Reuptake

Gregory Reid / Gallery Stock

A new study questions whether depression is really caused by a chemical imbalance.

A bombshell new study published in the journal Molecular Psychiatry on July 20 has concluded that there is no scientific evidence to support the idea that depression is caused by an imbalance of serotonin in the brain. This claim flies in the face of decades of psychiatric thinking, and it is not yet clear what it means for people with depression. 

Antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs) have long been thought to reverse such chemical imbalances, and this research raises questions about how they work. 

“The assumption that depression is a chemical imbalance of the brain caused by low serotonin levels or serotonin activity is not supported by decades of scientific research,” according to the study’s lead author Joanna Moncrieff, a professor of psychiatry at University College London. “The importance of our study is that as many as 85–90 percent of the public believes that depression is caused by low serotonin or a chemical imbalance. It is not. Yet, people are being prescribed antidepressants in huge quantities.”

In fact, antidepressants as a class are among the most prescribed medications in the world. A 2015–2018 survey from the Centers for Disease Control and Prevention found that 13.2 percent of U.S. adults had used antidepressant medications within the past 30 days, and the World Health Organization estimates 280 million people in the world suffer depression. The global market for depression medication is projected to surpass $21 billion per year by 2030, with SSRIs being the most prescribed antidepressant, according to the National Institutes of Health.   

And yet, Moncrieff says, “evidence from randomized trials suggests that antidepressants are only marginally better than a placebo tablet when it comes to improving depression.”

Moncrieff cautions those who want to get off SSRIs to consult with their prescribing physician due to the known adverse effects that can occur after withdrawal. Experts spoke to insist that antidepressants do in fact work for many people—even if we don’t know how they work. 

Not everyone agrees

Moncrieff and her colleagues conducted an “umbrella” review of the principal areas of relevant research on serotonin and depression. The study team used the databases of PubMed, Embase, and PsycInfo using search terms relevant to their study from their inception until 2020. They identified reviews, meta-analyses, and large dataset analyses that compared levels of serotonin and its breakdown products in the blood or brain fluids. “The genetic studies involved tens of thousands of participants and the others involved several thousand. Our goal was to find if these studies supported a role for serotonin in the etiology of depression and specifically whether depression was associated with lowered serotonin concentrations or activity.” We could not find it, Moncrieff said.

“Given that the serotonin theory of depression is not supported by the evidence, this suggests we need a different approach to depression.”

Additionally, the review did not find a difference in serotonin levels between people diagnosed with depression and people without depression who participated in clinical trials as control subjects, according to Moncrieff. They also looked at studies where serotonin levels were artificially lowered in hundreds of people by giving them a special amino acid drink that reduces the level of the protein precursors required to make serotonin and thereby reduced their levels of brain serotonin. “Although these studies have been cited as demonstrating that a serotonin deficiency is linked to depression, both a 2007 meta-analysis and recent studies found that lowering serotonin in this way did not produce depression in hundreds of healthy volunteers,” she says.

“Given that the serotonin theory of depression has been one of the most researched and influential biological theories of depression and is not supported by the evidence, this suggests we need a different approach to depression,” Moncrieff says. “We need a more individual approach that involves addressing the personal causes of depression rather than adjusting people’s brain chemistry.”

What exactly this means for the estimated 37 million people taking SSRIs and related medicines in the United States is unclear. Some experts disagree with the research and its conclusions, pointing out that millions of people have been treated with antidepressant drugs safely and effectively. asked Robert Klitzman, professor of psychiatry at Columbia University, his thoughts on Moncrieff’s study.  “There has been a long debate over whether SSRIs are effective. Most psychiatrists, including myself, agree that many patients have been helped by antidepressants. I disagree with the authors of this report that patients should not be prescribed these medications.”

As to the study authors’ claim that there is no evidence of a chemical imbalance with depression, Klitzman also disagrees. “Psychiatrists use the term chemical imbalance as a metaphor so the public can understand it. It is more accurate to say that rather than an ‘imbalance’ that something chemical is going on in the brains of people with depression.” 

Klitzman notes that a key criticism of the new work is its focus on serotonin levels in the bloodstream. If depression is caused by low serotonin levels in the brain, would such low levels of this neurochemical be found in the bloodstream? “I would argue that depression may be caused by low serotonin levels in the microscopic spaces or synapses between neurons in various parts of the brain, but that such low levels might not necessarily be found in the bloodstream,” he says.

“Depression may thus result from lack of serotonin in particular microscopic parts of the brain, rather than a global lack of serotonin in the body as a whole,” Klitzman says.

According to Murali Doraiswamy, a psychiatry professor at Duke University School of Medicine, the study is not surprising given we still don’t fully understand what causes depression or how treatments work in the brain—despite the fact that it’s been 40 years since the introduction of the first antidepressant. “At the end of the day, clinicians go by the clinical trial evidence as to whether the drugs work,” Doraiswamy says. “If a drug is clinically effective, we can live with the fact that we don’t fully know how [it works].”

What should people on SSRIs do?

Given the huge number of people who take SSRIs, many wonder what people who are taking them will think of this new study. Experts contacted about this study reiterated that people already prescribed antidepressant medicines should speak to their health care professionals before making any changes. Stopping suddenly is not recommended by the experts. You must slowly taper off SSRIs—and only do so under the care of a professional. But if they are doing you good, you and your doctor might decide not to change course. 

This reporter asked several people who took SSRIs whether they thought they helped. Most said yes. One person, we’ll call her Angela (not her real name), is a 40-year-old woman with a long history of depression. “At one point my depression was so bad that I had to receive ECT (electroconvulsive therapy). Since then, I’ve been taking an SSRI and I have never gone back to that dark place again.”

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