Contrary to popular belief, depression is likely not caused by a chemical imbalance and is instead seemingly caused more by trauma and stress, scientists from University College London (UCL) found after reviewing decades worth of data in a new, peer-reviewed umbrella review published in Nature Molecular Psychiatry on Wednesday.
The umbrella review aimed to cover all relevant studies published on serotonin and depression, with the studies covered involving tens of thousands of participants.
Research that compared levels of serotonin and its breakdown products in the blood or brain fluids failed to find a difference between people diagnosed with depression and healthy control participants, according to the review.
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 people with depression, although the researchers say that this is likely explained by the use of antidepressants by these people.
The scientists also looked at studies where serotonin levels were artificially lowered in hundreds of people, but a meta-analysis conducted in 2007 and a number of recent studies found that lowering serotonin in this way in healthy volunteers did not produce depression. Very weak evidence was found in a small subgroup of people with a family history of depression, but the subgroup only consisted of 75 participants and more recent evidence was inconclusive.
Additionally, very large studies involving tens of thousands of patients that looked at gene variation, including the gene for the serotonin transporter, failed to find a difference between people with depression and healthy people. These studies also looked at the effects of stressful life events and found that these exerted a strong effect on people's risk of depression.
"Our comprehensive review of the major strands of research on serotonin shows there is no convincing evidence that depression is associated with, or caused by, lower serotonin concentrations or activity," wrote the scientists in the review.
“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 Prof. Joanna Moncrieff, a professor of psychiatry at UCL, in a press statement.
Despite the findings of the UCL scientists, the belief that serotonin levels are responsible for depression is widespread, with both practitioners and the general public subscribing or at least expressing support for the belief, according to the review. Surveys cited by the umbrella review found that 80% or more of the general public believe depression is caused by a "chemical imbalance."
The scientists stressed that while it is often assumed that the effects of antidepressants show that depression must be at least partially caused by a chemical imbalance, there have been other theories put forth concerning why these drugs work, including an amplified placebo effect or their ability to restrict or blunt emotions in general.
The scientists warned that the belief that chemical imbalances are behind depression often leads to a pessimistic outlook and negative expectancies about the likelihood of recovery.
Additionally, some of the studies cited by the review found evidence that serotonin levels were actually lower in people who had been taking antidepressants for an extended period, suggesting that the use of such drugs for a long time could produce compensatory changes opposite to their intended effects.
The authors of the review encouraged further research and advice into treatments focusing on managing stressful or traumatic events in people's lives, such as psychotherapy, exercise or mindfulness, or 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," said Moncrieff. "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.”
"It is high time to inform the public that this belief is not grounded in science."Prof. Joanna Moncrieff, a professor of psychiatry at UCL
The professor added that prescription rates for antidepressants continue to rise despite the fact that thousands of people suffer from side effects of the drugs. "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 belief is not grounded in science.”
Serotonin's link to depression promoted by pharmaceutical industry
In a blog post on the study, Moncrieff explained that the idea that serotonin levels may be related to depression was first proposed in the 1960s and gained traction with public messaging from the pharmaceutical industry in the 1990s as new antidepressant drugs were released.
The professor additionally claimed that when you look at trials that compare antidepressants to placebos, the antidepressants are "a little bit better than a placebo, but not much." She added that there are methodological problems with these studies, such as patients possibly realizing that they got the real drug due to side effects, and that many of these trials are conducted by drug companies and usually only last a few weeks.
Moncrieff stressed that people should not suddenly stop taking antidepressants and should instead make a list of positives and negatives and consult their doctor or knowledgeable health professional to reach a decision whether to stop and then very gradually stop taking the medication as stopping suddenly can cause severe withdrawal symptoms.
Co-author Dr Mark Horowitz, a training psychiatrist and Clinical Research Fellow in Psychiatry at UCL and NELFT, stated in a press statement that “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. Being involved in this research was eye-opening and feels like everything I thought I knew has been flipped upside down."
“One interesting aspect in the studies we examined was how strong an effect adverse life events played in depression, suggesting low mood is a response to people’s lives and cannot be boiled down to a simple chemical equation,” added Horowitz.
An article published by UCL scientists Benjamin Ang, Horowitz and Moncrieff in the SSM - Mental Health journal earlier this year cited a 1987 paper by psychiatrist David Healy who noted that the idea that a chemical imbalance causes depression was perpetuated because "it served the professional purpose of convincing patients that depression is a biological condition."
"Since then, the vast resources of the pharmaceutical industry have enabled the idea that depression is a biochemical condition to be deeply implanted in the public psyche. The success of this endeavor has obscured the resistance associated with alternative ways of understanding depression. The idea of the chemical imbalance and serotonin deficiency had to replace people's deeply rooted common-sense view of depression as an understandable human reaction, rather than a disease," said the scientists in the article.
Some scientists critical of the new review
In an article in SSM-Mental Health responding to the article from earlier this year, professor of psychiatry Ronald Pies and psychiatrist George Dawson stressed that most academic psychiatrists and psychopharmacologists have already known for decades that the causes of depression are "much more complicated" than just the hypothesis linking it to serotonin levels.
The two stressed that chemical imbalance as a cause of mood disorders has only ever been a hypothesis (what they described as "essentially, an informed guess") and has never been posited as a "sweeping 'chemical imbalance theory.'" The article added that the chemical imbalance trope had largely been spread by "pharmaceutical television advertising literature that reached a very wide audience in the period from 1990 to 2010."
In a Psychiatric Times article in 2011, Pies described the chemical imbalance idea as "a kind of urban legend - never a theory seriously propounded by well-informed psychiatrists."
"This review...has lumped together depression as if it is a single disorder, which from a biological perspective does not make any sense."Dr. Michael Bloomfield, a psychiatrist and UCL research fellow
A collection of expert reactions from the Science Media Center reflected Pies' opinion, with Dr. Michael Bloomfield, a psychiatrist and UCL research fellow, stating that it "remains possible...that for some people with certain types of depression, that changes in the serotonin system may be contributing to their symptoms. The problem with this review is that it isn’t able to answer that question because it has lumped together depression as if it is a single disorder, which from a biological perspective does not make any sense."
Additionally, Prof David Nutt, Edmond J Safra Chair and head of the Center for Neuropsychopharmacology at Imperial College London, stressed that "It is only recently that we have developed the technology to measure serotonin release in the living human brain and in the first study of this type (currently under review) we did find decreased serotonin release capacity in people with depression. So, to dismiss the serotonin hypothesis of depression at this point is premature."
A 2014 peer-reviewed study by scientists from the Weizmann Institute of Science found a microRNA (small, non-coding RNAs that often "fine-tune" which products of genes are expressed or silenced) that acts on serotonin-producing nerve cells and then genetically engineered mice to produce higher-than-average amounts of the microRNA. The mice did not develop the behaviors associated with chronic stress, such as anxiety or depression, which would normally appear in other mice. Mice with low levels of the microRNA exhibited more of these behaviors and responded weakly to antidepressants.
The Weizmann Institute researchers additionally found that human subjects who suffered from depression had unusually low levels of the microRNA in their blood and found a connection between the microRNA and genes linked to bipolar and mood disorders.