Depression is probably not caused by a chemical imbalance in the brain

For three decades, people have been inundated with information suggesting that depression is caused by a “chemical imbalance” in the brain — namely, an imbalance of a brain chemical called serotonin. However, our newest research review shows that the evidence does not support this.

Although first suggested In the 1960s, the serotonin theory of depression began to be widely promoted by the pharmaceutical industry in the 1990s in connection with its efforts to market a new line of antidepressants known as selective serotonin reuptake inhibitors, or SSRIs. The idea has also been endorsed by official institutions such as the American Psychiatric Association, which continues to tells the audience that “differences in certain brain chemicals may contribute to symptoms of depression”.

Countless doctors have echoed the message around the world, in their private practices and in the media. People accepted what they were told. And many started taking antidepressants because they thought there was something wrong with their brain that needed an antidepressant to make up for it. During the period of this marketing push, the use of antidepressants has risen dramatically, and now they are prescribed to one in six of the adult population in Englandfor example.

For a long time, certain academicsincluding some leading psychiatrists, have suggested that there is no satisfactory evidence to support the idea that depression results from abnormally low or inactive serotonin. Others stay endorse the theory. To date, however, there has been no comprehensive review of the research on serotonin and depression that could provide definitive conclusions anyway.

At first glance, the fact that SSRI-type antidepressants act on the serotonin system seems to support the serotonin theory of depression. SSRIs temporarily increase the availability of serotonin in the brain, but this does not necessarily mean that depression is caused by the opposite of this effect.

There are other explanations for the effects of antidepressants. In fact, drug studies show that antidepressants are: barely distinguishable from a placebo (dummy pill) when it comes to treating depression. Antidepressants also appear to be a generalized emotion-numbing effect that can affect people’s mood, although we don’t know how this effect is produced or much about it.

First comprehensive review

Extensive research has been done on the serotonin system since the 1990s, but it has not been collected systematically before. We performed a review “umbrella” that involved systematically identifying and collecting existing overviews of the evidence from each of the major areas of research on serotonin and depression. While there have been systematic reviews of individual areas in the past, none have combined the evidence from all the different areas taking this approach.

One area of ​​research we included was research comparing the levels of serotonin and its breakdown products in the blood or cerebrospinal fluid. Overall, this study showed no difference between people with depression and people without depression.

Another area of ​​research has focused on: serotonin receptorsThese are proteins at the ends of the nerves to which serotonin is connected that can transmit or inhibit the effects of serotonin. Research on the most studied serotonin receptor suggested either no difference between people with depression and people without depression, or that serotonin activity was actually increased in people with depression – the opposite of the prediction of the serotonin theory.

Research into the serotonin “transporter”, which is the protein that helps to end the effect of serotonin (this is the protein that SSRIs act on), also suggested that there was at least increased serotonin activity in people with depression. However, these findings may be explained by the fact that many participants in these studies were taking or were currently taking antidepressants.

We also looked at research that looked at whether depression in volunteers can be caused by: artificially lowering serotonin. Two systematic reviews of 2006 and 2007 and a sample of the ten most recent studies (at the time the current study was conducted) found that lowering serotonin did not cause depression in hundreds of healthy volunteers. One of the reviews showed very weak evidence of an effect in a small subgroup of people with a family history of depression, but involved only 75 participants.

Very large studies involving tens of thousands of patients looked at gene variation, including the gene that has the instructions for making the serotonin transporter. They found no difference in the frequency of variants of this gene between people with depression and healthy controls.

Although a famous early study found a link between the serotonin transporter gene and stressful life events, larger, more comprehensive studies suggest no such relationship exists. However, stressful life events in themselves had a strong effect on the later risk of developing depression.

Some of the studies in our review of people who were taking or had previously taken antidepressants showed evidence that antidepressants can actually lower the concentration or activity of serotonin.

Not supported by the evidence

The serotonin theory of depression is one of the most influential and extensively researched biological theories about the origins of depression. Our research shows that this view is not supported by scientific evidence. It also questions the basis for taking antidepressants.

Most of the antidepressants in use today are believed to work through their effects on serotonin. Some also affect the chemical norepinephrine in the brain. But experts agree that the evidence for norepinephrine’s involvement in depression is: weaker than that for serotonin.

There is no other accepted pharmacological mechanism for the influence of antidepressants on depression. If antidepressants exert their effects as placebos or by numbing emotions, it’s not clear that they do more good than harm.

While seeing depression as a biological condition may seem like it would reduce stigma, in fact, research has shown the oppositeand also that people who think their own depression is due to a chemical imbalance, they are more pessimistic about their chances of recovery.

It is important for people to know that the idea that depression is the result of a ‘chemical imbalance’ is hypothetical. And we don’t understand what temporarily increasing serotonin or other biochemical changes caused by antidepressants does to the brain. We conclude that it is impossible to say that taking SSRI antidepressants is worth it, or even completely safe.

If you are taking antidepressants, it is very important that you do not stop taking them without talking to your doctor first. But people need all of this information to make informed decisions about whether or not to take these drugs.

Article by Joanna Moncrieff, Senior Clinical Lecturer, Critical and Social Psychiatry, UCL, and Mark Horowitz, Clinical Research Fellow in Psychiatry, UCL.

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