Depression May Not Be Linked to Low Serotonin, New Analysis Finds

The serotonin hypothesis, proposed decades ago, says that a chemical imbalance in the brain — including a deficiency of serotonin — causes depression.

The most common antidepressants, known as selective serotonin reuptake inhibitors (SSRIs), are thought to make serotonin more available in the brain by blocking the reabsorption of serotonin into neurons.

However, in their recent analysis, Joanna Moncrieff, MD, a professor of psychiatry at University College London, and her colleagues found that there is no “consistent evidence” that serotonin is involved in depression.

Their findings, which were published July 20 in Molecular Psychiatry, included:

• Research on serotonin and its breakdown products in the blood and brain fluids found that the level of these chemicals was similar in people with and without depression.
• Research on serotonin receptors and the serotonin transporter, a protein targeted by many antidepressants, offered “weak and inconsistent” evidence that people with depression had higher levels of serotonin activity.
• Studies in which healthy people’s serotonin levels were artificially lowered through a special diet found that this did not increase their risk of developing depression.
• Genetic studies found no difference in serotonin-related genes between people with depression and healthy participants.

“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 or reduced activity of serotonin,” Moncrieff said in a news release.

Anthony King, PhD, a neuroscientist and licensed psychologist and psychotherapist at The Ohio State University’s College of Medicine, who was not involved in the new review, agrees that the role of serotonin in depression has been overblown.

“The idea that depression is a chemical imbalance characterized by a deficit or a lower level of serotonin in the synapses is just not correct,” he said. “It never was, and it’s not now.”

However, “I’m not saying serotonin is not involved and I’m not saying SSRIs don’t help,” he added.

Serotonin is likely involved in some way, he said, but the relationship between depression and other brain chemicals is complex. Likewise, he said SSRIs can help some people — just not everyone.

King also noted that stress can play a role in the development of depression

Dr. Srijan Sen, a professor of depression and neurosciences and director of the Frances and Kenneth Eisenberg and Family Depression Center at the University of Michigan, said he doesn’t think the new review entirely eliminates serotonin from the picture.

“Whether serotonin plays a role in depression in some way is an open question,” he said. “The brain is so complicated and complex, it would be surprising if serotonin wasn’t involved at all.”

He pointed to a recent meta-analysis of studies looking at the link between serotonin-related gene variants, stress, and depression as evidence that the case for serotonin is far from closed.

In that study, researchers found that people who carry a certain serotonin-related gene variant are at higher risk of developing depression in response to a stressful life event. However, this was only true for chronic stress and for depression assessed within a year of the stressor.

This meta-analysis was published this month, so it was not included in the review by Moncrieff and her colleagues.

There is, however, one thing that Sen agrees with Moncrieff and her colleagues on: “[Chemical imbalance] is not an accurate representation of our understanding of what happens in the brain,” he said.

“It’s probably more likely that there are certain circuits and loops of connections in the brain that are changed that are important,” he said. “But we don’t know exactly what is happening.”

King said there are other ways to think about depression that can help people break free of the downward spiral that often accompanies this condition.

“[Stressful life events] can lead to emotional upset and a big change,” he said. “That can be accompanied by a sort of pessimism and a certain habit of behavior and thinking.”

Basically, “people get into a rut — they get into a rut mentally and behaviorally,” he said. “And a sense of inertia sets in.”

While this may sound like a hard cycle to get out of, King said several types of treatment can help people get moving again, including cognitive behavioral therapy, behavioral activation, and mindfulness.

The new review also challenged whether it’s helpful to talk about SSRIs as fixing a chemical imbalance.

“Many people take antidepressants because they have been led to believe their depression has a biochemical cause, but this new research suggests this belief is not grounded in evidence,” said Moncrieff.

Sen, though, cautioned against making decisions about depression treatments based on this review.

“We generally don’t make clinical decisions about treatments based on the molecular and biological understanding of what the treatments do,” said Sen. “It’s much more based on the results of clinical trials.”

Scientists use rigorous clinical trials to see if a treatment works, as well as under what conditions and for which people. These trials can produce useful results even without a good understanding of how a treatment works, said Sen.

That said, “understanding the biology in the long term, I hope, will help us develop better medications and advancements in personalized treatments,” he added.

To date, clinical trials of SSRIs have shown that “they are moderately effective and help some people,” said Sen. “But we definitely do need better drugs.”

For people who don’t benefit from SSRIs, he said there are other potential treatments for depression, such as improved sleep routines, regular exercise, and stronger social connections. Recently using psychedelic drugs like ketamine has become more common as a potential option for people with depression.

“With all these things, there is observational and clinical trial evidence showing that they really help with depression,” he said.