Researchers Find No Evidence That Depression is Caused by Low Serotonin

Researchers have found no clear evidence that serotonin levels or activity cause depression, according to a review of prior research published in Molecular Psychiatry.

The findings suggest that depression is most likely not caused by a chemical imbalance, calling into question how antidepressants work and what they do, according to the study authors. Most antidepressants are selective serotonin reuptake inhibitors (SSRIs), which were believed to work by correcting low serotonin levels. According to the study, there is no other accepted pharmacological mechanism by which antidepressants affect symptoms of depression.

“It is always difficult to prove a negative, but I think we can safely say that after a vast amount of research conducted over several decades, there is no convincing evidence that depression is caused by serotonin abnormalities, particularly by lower levels of reduced activity of serotonin,” lead author Joanna Moncrieff, MD, said in a press release.

Moncrieff added that the chemical imbalance theory of depression led to a significant increase in the use of antidepressants. Prescriptions have risen dramatically since the 1990s, with 1 in 6 adults in England and 2% of teenagers now being prescribed an antidepressant in a given year. The new research, however, suggests that the use of SSRIs may not be grounded in scientific evidence.

This could be important because other studies have shown that as many as 85% to 90% of the public believes that depression is caused by low serotonin levels or a chemical imbalance. However, a growing number of experts and professional bodies are recognizing the chemical imbalance framing as an over-simplification.

“Thousands of people suffer from side effects of antidepressants, including the severe withdrawal effects that can occur when people try to stop them, yet prescription rates continue to rise,” Moncrieff said in the press release. “We believe this situation has been driven partly by the false belief that depression is due to a chemical imbalance. It is high time to inform the public that this believe is not grounded in science.”

To investigate the issue, researchers conducted an umbrella review aimed to capture all relevant studies that have been published in the most important fields of research on serotonin and depression. Taken together, the studies in the review included tens of thousands of participants.

According to the study, research that compared levels of serotonin and its breakdown products in the blood or brain fluids did not find a difference between individuals diagnosed with depression and health control participants.

Similarly, research on serotonin receptors and the serotonin transporter, the protein targeted by most antidepressants, found weak and inconsistent evidence suggesting higher levels of serotonin activity in individuals with depression. However, the investigators said the findings are likely explained by the use of antidepressants among the study population, since such effects were not reliably ruled out.

The investigators also examined studies in which serotonin levels were artificially lowered in hundreds of participants by depriving their diets of the amino acid required to create serotonin. These studies have been cited as demonstrating that a serotonin deficiency is linked to depression, but a meta-analysis conducted in 2007 and a sample of recent studies found that lowering serotonin in this way did not produce depression in hundreds of healthy volunteers. There was very weak evidence in a small subgroup of individuals with a family history of depression, but the authors noted that this only involved 75 participants and more recent evidence was inconclusive.

Larger studies with tens of thousands of participants have examined gene variation, including the gene for the serotonin transporter. These studies found no difference in these genes between individuals with depression and healthy controls, and also looked at the impacts of stressful life events. They found that these events exerted a strong influence on individuals’ risk of becoming depressed—the more stressful a life event, the more likely they would become depressed.

Taken together, the authors of the umbrella review said this evidence suggests that there is “no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations.”

“I had been taught that depression was caused by low serotonin in my psychiatry training and had even taught this to students in my own lectures,” co-author Mark Horowitz, MBBS, PhD, said in the press release. “Being involved in this research was eye-opening and feels like everything I thought I knew has been flipped upside down.”

Other evidence suggests that individuals who believe that a low mood is caused by a chemical imbalance could lead them to have a pessimistic outlook on the likelihood of recovery, as well as the possibility of managing moods without medical assistance. This is important because most individuals will meet criteria for anxiety or depression at some point in their lives.

Notably, the authors found evidence from a large meta-analysis that individuals who used antidepressants had lower levels of serotonin in their blood. They concluded that some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentrations, implying that the short-term increase in serotonin produced by some antidepressants could lead to compensatory long-term changes in the brain.

Although the study did not review the efficacy of antidepressants, the authors encouraged further research into treatments that might focus on managing stressful or traumatic events, such as with psychotherapy, alongside other practices, such as exercise or mindfulness. Research could also investigate the efficacy of addressing underlying contributors such as poverty, stress, and loneliness.

“Our view is that patients should not be told that depression is caused by low serotonin or by a chemical imbalance, and they should not be led to believe that antidepressants work by targeting these unproven abnormalities,” Moncrieff said in the press release. “We do not understand what antidepressants are doing to the brain exactly and giving people this sort of misinformation prevents them from making an informed decision about whether to take antidepressants or not.”

Reference

No evidence that depression is caused by low serotonin levels, finds comprehensive review. News release. University College London; July 20, 2022. Accessed July 27, 2022. https://www.ucl.ac.uk/news/2022/jul/no-evidence-depression-caused-low-serotonin-levels-finds-comprehensive-review