(ORDO NEWS) — For millions of people around the world, salvation from long periods of gloomy thoughts and oppressive feelings comes in the form of pills, each dose of which does its best to keep the balance of a humble neurotransmitter called serotonin under relative control.
Despite their popularity as a treatment for mood disorders, most of the mechanisms of action of antidepressants are a complete black box. We can only speculate about how they work in treating bad moods.
Even more shocking is that these hunches may be completely wrong, calling into question whether depression is actually caused by a significant decrease in serotonin levels.
A new umbrella review of past meta-studies and systematic analyzes of the relationship between depression and serotonin levels concluded that there is simply not enough evidence to support an association between the two variables.
This does not necessarily mean that serotonin treatment does not work by some other mechanism that we do not yet understand. And no one should stop taking medication without consulting a doctor. But since so many people rely on these drugs, it’s important to find out what’s really going on.
“It’s always difficult to prove a negative result,” said study lead author Joanna Moncrieff, a psychiatrist at University College London.
“But I think we can say with confidence that after a huge amount of research done over several decades, there is no conclusive evidence that depression is caused by abnormalities in serotonin, in particular, a decrease in its level or a decrease in its activity.”
The origins of the idea that mood disorders are due to chemical imbalances in the brain can be traced even further back to the mid-20th century, when it was suggested that a monoamine neurotransmitter called norepinephrine was malfunctioning in people with depression.
Serotonin, another known monoamine, has also been viewed with suspicion, leading to the monoamine hypothesis.
With the advent of selective serotonin reuptake inhibitor (SSRI) antidepressants on the market in the 1980s, the idea that depression is a relatively simple deficiency of some kind of neurological “happy juice” became popular.
The popularity of the “chemical imbalance” theory of depression has coincided with a huge rise in the use of antidepressants, Moncrieff says.
“Since the 1990s, the number of prescriptions for antidepressants has skyrocketed, and now one in six adults in England and two per cent of teenagers are prescribed an antidepressant within a year.”
It is not difficult to see why this hypothesis is so wholeheartedly accepted as fact. It’s a simple problem with a simple solution that can be sold profitably.
Marketing and commercial benefits aside, about one in five people with depression who take antidepressants actually experience symptom relief.
This idea is so ingrained in our social psyches that about 80 percent of the general population considers depression to be a chemical imbalance.
If you’re one of those who’s hearing about all this for the first time, the hypothesis has been on shaky ground almost since its inception in the 1990s, when study after study failed to support the idea.
Recognizing that there may be enough research to support the hypothesis, Moncrieff and her team searched prominent scientific archives such as PubMed and PsycINFO using terms related to meta-analyses of studies on depression and serotonin, excluding those associated with other conditions. such as bipolar disorder.
Independent reviewers assessed the quality of the studies using generally accepted scientific standards, and then made a final calculation of the confidence level of each study.
A total of 17 studies made it to the list, which included a genetic association study, another umbrella review, and a dozen systematic reviews and meta-analyses.
Overall, evidence for a role for serotonin in depression has been weak at best. Comparison of serotonin levels (and its breakdown products in the blood) in people with and without depression revealed no difference. Large-scale studies comparing the genetics of serotonin and the proteins that support it have not helped either.
Studies looking directly at the behavior of neurotransmitter receptors and its transporter were slightly more supportive of a role for serotonin, but were generally inconsistent in their conclusions, leaving conflicting explanations open.
Looking closely at people who successfully take antidepressants, it seems that they may have lower levels of serotonin. On the other hand, this can be expected over time as the body compensates for changes in biochemistry.
And what does it give us?
Research like this is a good reminder that differences in our bodily functions can rarely be reduced to a simple deficiency. Depression is a complex condition potentially arising from a range of factors (only a few of which we as humans have much control over).
“We believe that patients should not be told that depression is caused by low serotonin levels or a chemical imbalance, nor should they be convinced that antidepressants work on these unproven disorders,” says Moncrieff.
Critics of the review point out, however, that many of the included studies did not use direct measurements of brain serotonin activity, which has only recently become possible. Thus, more research is needed to determine how many of them are placebos and how many are some other weird tangle of neurochemistry.
It also means we need to have an honest conversation about how blind we are to the nature of chronic depression and the questions that remain about the true costs and benefits of antidepressants.
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