It is commonly believed that depression is commonly caused by a chemical imbalance of serotonin in the brain—but a comprehensive new study argues there is "no clear evidence" to suggest serotonin levels or activity are associated with depression.

Study details and key findings

Serotonin is a neurotransmitter that plays a key role regulating digestion, mood, sleep, and other body functions. For several decades, many scientists have believed that a chemical imbalance of serotonin is an important cause of depression. This belief has also been endorsed by official medical institutions, such as the American Psychiatric Association.

Patients with depression are often treated with antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), which increase the level of serotonin in the brain. Prescriptions for antidepressants have been on the rise since 1990s, and today millions of patients with depression routinely take SSRIs.

However, a new study published in Molecular Psychiatry pushes back on the serotonin hypothesis of depression, arguing that there is "no clear evidence" serotonin levels or activity contribute to depression.

For the study, the researchers conducted a comprehensive umbrella review, which analyzed existing systematic reviews and meta-analyses across six different areas of research related to serotonin and depression. Overall, the researchers found that the studies largely did not support an association between serotonin and depression.

For example, studies in the review that examined levels of serotonin and its breakdown products in the blood or brain fluid did not find a significant difference between patients who had depression and those who did not.

Similarly, studies that examined serotonin receptors, which can transmit or inhibit serotonin, found no difference between people with depression and those without. In fact, some studies found increased serotonin activity among people with depression.

In addition, several large studies, which involved tens of thousands of patients, found that there were no differences in the genes that contain instructions for serotonin transporters between people with depression and healthy controls. According to the researchers, these "high-quality genetic studies effectively exclude an association between genotypes related to the serotonin system and depression, including a proposed interaction with stress."

The researchers also examined studies where participants had their serotonin levels artificially lowered and found that doing so did not cause depression in hundreds of healthy volunteers. Although one systematic review found weak evidence of an effect in a subgroup of people who had a family history of depression, the sample involved just 75 participants.

Commentary

Writing in The Conversation, Joanna Moncrieff and Mark Horowitz, two of the study's authors from University College London (UCL), said the study's findings call "into question the basis for the use of antidepressants" since many that are currently in use "are presumed to act via their effects on serotonin."

According to Moncrieff, "[p]atients 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 hypothetical and unproven abnormalities" since it could prevent "them from making an informed decision about whether to take antidepressants or not."

However, Moncrieff and Horowitz said that people who are currently taking antidepressants should consult their doctors before making a decision to stop treatment. Similarly, a spokesperson for the Royal College of Psychiatrists in the United Kingdom said it "would not recommend for anyone to stop taking their antidepressants based on this review, and encourage anyone with concerns about their medication to contact their GP."

Michael Bloomfield, a consultant psychiatrist and principal clinical research fellow at UCL, who was not involved in the study, noted that there is "consistent evidence that antidepressant medicines can be helpful in the treatment of depression and can be life-saving."

According to Mitch Prinstein, chief science officer for the American Psychological Association, the study's findings highlight a need to develop and test a variety of personalized treatments for depression and other psychological disorders.

"This research offers analyses to summarize some well-known facts about depression. First, depression is a very heterogeneous disorder; there are many different expressions of depression that come from a wide array of causal factors and present themselves differently from person to person," Prinstein said. "Second, there is no single treatment approach that works for everyone with depression." (Lane, Psychology Today, 7/19; Guzman, "Changing America," The Hill, 7/21; Gregory, The Guardian, 7/20; Moncrieff/Horowitz, The Conversation, 7/21)