No evidence that depression is caused by low serotonin levels, finds comprehensive review

According to a comprehensive analysis of previous studies undertaken by UCL experts, there is still no conclusive proof that serotonin levels or serotonin activity are the cause of depression after decades of research.

The new umbrella review, which provides a summary of previous meta-analyses and systematic reviews, was just published in Molecular Psychiatry. It questions the effects of antidepressants and contends that depression is not likely the result of a chemical imbalance. Selective serotonin reuptake inhibitors (SSRIs), which make up the majority of antidepressants, were once believed to function by restoring unusually low serotonin levels. No other recognized chemical mechanism exists for how antidepressants influence the signs and 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 or reduced activity of serotonin," said lead author Professor Joanna Moncrieff, a Professor of Psychiatry at UCL and a consultant psychiatrist at North East London NHS Foundation Trust (NELFT).

"There has been a sharp rise in the usage of antidepressants at the same time as the 'chemical imbalance' explanation of depression has gained acceptance. Antidepressant prescriptions have increased significantly during the 1990s, with one in six people in England and 2% of teens now receiving one in a given year.

Many individuals take antidepressants because they have been told that their depression is caused by a biochemical imbalance, but this new study reveals that this view is not supported by the facts.

In order to include all pertinent papers that have been published in the key areas of serotonin and depression research, an umbrella review was conducted. Tens of thousands of people participated in each of the research that made up the review.

People with depression did not vary from healthy control (comparison) individuals in studies that evaluated serotonin levels and its breakdown products in blood or brain fluids.

Weak and contradictory data pointing to greater levels of serotonin activity in depressed individuals has been reported in studies on serotonin receptors and the serotonin transporter, the protein targeted by the majority of antidepressants. The findings, according to the researchers, are most likely explained by antidepressant usage among those who have been diagnosed with depression, as such effects could not be conclusively ruled out.

The scientists also looked at trials in which hundreds of individuals had their serotonin levels artificially decreased by denying them the amino acid needed to produce serotonin from their meals. These findings have been used to support the notion that depression and serotonin deficit are related. However, reducing serotonin in this manner did not result in depression in a large number of healthy volunteers, according to a meta-analysis done in 2007 and a sample of more recent investigations. Only 75 participants in a small subset of individuals with a family history of depression provided extremely poor evidence, and more recent research proved equivocal.

Gene variation, including the serotonin transporter gene, was studied in very large studies including tens of thousands of patients. They discovered no distinction in these genes between depressed individuals and healthy controls. These studies also examined how stressful life experiences affected people's chance of developing depression and discovered that the more stressful life events a person has gone through, the higher their likelihood of developing depression. A well-known early study discovered a connection between stressful situations, a person's type of serotonin transporter gene, and their risk of developing depression. But more extensive, bigger investigations contend that this result was erroneous.

The scientists came to the conclusion that there is "no evidence for the concept that depression is caused by reduced serotonin activity or concentrations" as a result of these data taken together.

According to surveys, up to 85%–90% of the general population believes that low serotonin levels or a chemical imbalance are to blame for depression. The researchers claim their findings are significant in light of this. The chemical imbalance framework is being recognized by an increasing number of scientists and professional organizations as being oversimplified. There is evidence that persons who think that a chemical imbalance is the source of their poor mood are less optimistic about their chances of recovering and less likely to use self-management techniques. This is significant since the majority of individuals will at some point in their lives fit the criteria for anxiety or depression.

The scientists also discovered evidence in support of the idea that antidepressant users had decreased blood levels of serotonin. They came to the conclusion that some data supported the idea that long-term antidepressant usage could lower serotonin levels. According to the researchers, this may signal that the short-term rise in serotonin that some antidepressants cause might result in compensatory alterations in the brain that have a long-term opposite impact.

Despite the fact that the study did not examine the effectiveness of antidepressants, the authors encourage more research and guidance into therapies that might instead concentrate on helping people manage traumatic or stressful life events, such as with psychotherapy, in addition to other practices like exercise or mindfulness, or by addressing underlying causes like poverty, stress, and loneliness.

According to Professor Moncrieff, patients shouldn't be informed that low serotonin levels or chemical imbalances are what causes depression, and they shouldn't be encouraged to believe that antidepressants work by addressing these unsubstantiated abnormalities. Giving individuals this kind of inaccurate information prohibits them from making an educated decision about whether or not to take antidepressants since we do not fully understand what exactly antidepressants do to the brain.

"I had been taught that depression was caused by low serotonin in my psychiatric training and had even taught this to students in my own lectures," said co-author Dr. Mark Horowitz, a trainee psychiatrist and Clinical Research Fellow in Psychiatry at UCL and NELFT. Being a part of this research was enlightening, and it feels as though everything I previously believed has been turned on its head.

Unfavorable life events had a significant impact on depression in the research we looked at, which suggests that depression is a response to people's lives and cannot be explained by a straightforward chemical equation.

Professor Moncrieff continued: "Thousands of people experience antidepressant side effects, including the severe withdrawal symptoms that can happen when someone tries to stop taking the medication, yet prescription rates are still rising. We think that this scenario has been influenced in part by the myth that depression is brought on by a chemical imbalance. It is past time to let people know that this idea is not supported by science.

Given the possibility of negative side effects after antidepressant discontinuation, the researchers advise anybody thinking about doing so to see a health practitioner. The optimal way to taper off antidepressants is the subject of continuing study by Professor Moncrieff and Dr. Horowitz.