The Evidence Is In: Depression Might Not Be Linked to Low Serotonin After All

A new review of prior research on depression is causing a stir in the medical community. Led by University College London (UCL), scientists found no clear evidence that serotonin levels or serotonin activity are responsible for depression. 

Published in Molecular Psychiatry, the findings come after decades of scrutinizing existing meta-analyses and systematic reviews. Researchers suggest that depression is not likely caused by a chemical imbalance in the brain, and challenge the role of antidepressants as the first line of treatment.

“For decades people have been given the impression that the idea that depression is caused by low serotonin is an established scientific fact,” says lead author Professor Joanna Moncrieff, a Professor of Psychiatry at UCL.

This idea or hypothesis was the original justification for the use of modern antidepressants (selective serotonin reuptake inhibitors, known as SSRIs) and the pharmaceutical industry heavily promoted it in the 1990s and 2000s, Moncrieff explains. “Many scientists have known that the evidence to support it was weak and contradictory but because no one had done a systematic overview of the evidence before, it was difficult to say whether it was or wasn’t true,” she adds. 

A Closer Look at the Review 

The studies involved in the review included tens of thousands of participants and adopted several different approaches to the relationship between serotonin and depression. 

Research comparing levels of serotonin and its breakdown products in the blood or brain fluids did not find a difference between people diagnosed with depression and healthy control (comparison) participants. 

The team also analyzed studies involving hundreds of participants whose serotonin levels were artificially lowered by withdrawing the amino acid required to make serotonin from their diets. A 2007 meta-analysis and a sample of recent studies found that this method of reducing serotonin levels didn’t cause depression in healthy participants, discrediting a link between serotonin deficiency and the condition.  

Several large studies looked at gene variation, including the serotonin transporter gene, but they identified no difference in the genes of people with depression and healthy controls. 

Many studies considered how stressful life events impact the risk of depression and found that people who had experienced more stressful life events were more likely to have depression. 

“The current study allows us to come to a proper evidence-based verdict on the serotonin theory of depression, which we believe is important for the scientific community and for the general public,” Moncrieff says. 

What Does This Mean for Depression Care?

The bottom line is that we can't say for certain that antidepressants work in the way that most people have been led to believe, says Moncrieff. "That is, they do not correct an underlying serotonin deficiency or abnormality, because the latter has not been demonstrated," she explains.

Aron Tendler, MD, C.BSM, BrainsWay Chief Medical Officer, says that while the recent review challenges the serotonin theory, it doesn't challenge the efficacy of mental health treatment.

"Many psychiatrists and neuroscientists suspected that serotonin theory was invalid from the NIMH-funded Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, which was completed in 2004, or even before that," Dr. Tendler says.

He points out that this is why there are different classes of antidepressants that work on other neurotransmitters, plus other treatments such as psychotherapy, transcranial magnetic stimulation, and electroconvulsive therapy.

"This review reminds all scientists to be humble and focus on the data rather than the theory," Dr. Tendler adds.

A New Understanding of Depression?

Moncrieff hopes that rather than throw yet more money at trying to find the ever elusive chemical origins of depression, the medical community will accept that depression is not a biological state but an emotional reaction to difficult life circumstances and past experiences.

"There is strong evidence that adverse life events, such as divorce, poverty, debt, loneliness, child abuse, unemployment, etc, make people more vulnerable to depression," Moncrieff says. "What this means is that we should stop seeing depression as a medical condition and view it as a human reaction. Of course the brain is involved in depression, as it is involved in all our moods and actions. But that does not mean that we can find the origin of depression in the brain, or even a part of its origin."

Mental health treatment that is tailored to each individual is key, Moncrieff says, because every case involves a different set of difficult circumstances.

"Things like exercise and psychological therapy may have some general use and have shown to be effective," she adds.