A chemical imbalance in the brain is most likely not the root of depression.

Rose Remi

There's been a constant stream of material on how depression is caused by a "chemical imbalance" in the brain—specifically, an imbalance of the brain chemical serotonin—for the last 30 years. Our most recent review of the research, however, shows that this claim is not supported by the data.

As a result of pharmaceutical companies' attempts to sell new antidepressants known as selective serotonin reuptake inhibitors (SSRIs) in the 1990s, the serotonin hypothesis of depression was extensively pushed in the 1960s. Even so, the American Psychiatric Association tells people that "differences in certain chemicals in the brain may contribute to feelings of depression." The message has been repeated by countless doctors around the world, both in their private practices and in the media. People just go along with whatever is told to them. People who believe they have a mental health problem and need an antidepressant to fix it are among those who first turn to antidepressants. During this time, the number of prescriptions for antidepressants went through the roof.

For example, one in six adults in England got one during this time. Psychiatrists and other academics have argued for years that there is insufficient evidence to support the idea that depression is caused by abnormally low or inactive serotonin levels. The theory is still supported by several people. So far, there hasn't been enough research on serotonin and depression to say for sure one way or the other. At first glance, the serotonin theory of depression appears to be supported by the fact that SSRI antidepressants act on the serotonin system. SSRIs may increase the amount of serotonin in the brain for a short period, but this does not necessarily mean that depression is caused by the opposite effect. Antidepressant effects can be explained by other mechanisms as well, of course. Clinical trials show that antidepressants are virtually indistinguishable from placebos in the treatment of major depressive disorder (MDD). Even though we don't know exactly how antidepressants produce this generalized emotion-numbing effect, it appears to have an impact on people's moods.

It's the beginning of the end.

Serotonin research has been going on since the 1990s, but it has never been done in such a methodical way. With the use of a method known as an "umbrella review," we were able to compile a comprehensive summary that included findings from all major subfields of study into serotonin and depression. In the past, there have been systematic evaluations of certain areas, but none of them have used data from all the different areas in this way. Serotonin and its breakdown products have been studied as a potential biomarker for depression.

In general, there was no difference between individuals with and without depression in this study. Another field of study has concentrated on serotonin receptors, which are proteins on the endings of the neurons that serotonin connects up with and that may transmit or suppress serotonin's actions. In contrast to what the serotonin theory said would happen, research on the most studied serotonin receptor found either no difference between people with depression and those who didn't have it or that people with depression had much more serotonin activity.

For those who suffer from depression, research suggests that serotonin "transporter" activity may be boosted. This protein, which acts as a "terminator" for serotonin, is what SSRIs work on. According to the authors, antidepressant usage or current use among study participants might account for these results.

We looked through studies to see whether depression can be caused in volunteers by artificially reducing their levels of serotonin. Hundreds of healthy volunteers were not depressed when serotonin levels were lowered, according to two systematic reviews and a sampling of the ten most recent studies at the time of the present study. An impact was seen in a small sample of patients with a history of depression, but the study only included 75 people. Gene variation, including instructions for manufacturing the serotonin transporter, was examined in large investigations, including tens of thousands of patients. Study participants with depression were found to have a similar number of variants of this gene as their healthy peers.

Serotonin transporter genes have been linked to stressful life experiences in the past, but more recent research has revealed no such correlation. People's later chances of getting depression, however, were strongly influenced by stressful life experiences.

People who were taking or had previously taken antidepressants were shown to have decreased levels of serotonin activity in several of the trials we reviewed.

Claims like this are based only on speculation.

Biological theories of depression, such as the serotonin hypothesis, have been among the most important and thoroughly explored. According to our research findings, scientific data does not support this belief. It also puts into question the rationale for antidepressant prescriptions in the first place.

Serotonin is thought to be the primary mechanism of action for most antidepressants currently on the market. Noradrenaline, another neurotransmitter, is influenced by several of these drugs. Most experts think that there is less evidence that noradrenaline plays a role in depression than there is for serotonin.

Antidepressants' ability to combat depression through any other known pharmacological mechanism remains a mystery. If antidepressants have a placebo effect or make the person feel nothing, it's not clear if they help. It may seem that treating depression as a medical condition would lessen its stigma, but in reality, research shows that the reverse is true, and those who feel that their sadness is caused by a chemical imbalance are less optimistic about their prospects for recovery.

People need to be aware that the assumption that depression is caused by a "chemical imbalance" is a speculative one. We also don't know what the brain does as a result of antidepressant-induced elevations in serotonin or other biochemical changes. To sum up: Taking SSRI antidepressants is neither beneficial nor safe. To make an educated choice on whether or not to take antidepressants, people need all of this information.

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