Depression Is Probably Not Caused by a Chemical Imbalance in the Brain

Summary: Researchers explain why the serotonin hypothesis for depression may not be as accurate as previously believed.

Source: The Conversation

For three decades, people have been deluged 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 latest research review shows that the evidence does not support it.

Although first proposed in the 1960s, the serotonin theory of depression started to be widely promoted by the pharmaceutical industry in the 1990s in association with its efforts to market a new range of antidepressants, known as selective serotonin-reuptake inhibitors or SSRIs.

The idea was also endorsed by official institutions such as the American Psychiatric Association, which still tells the public that “differences in certain chemicals in the brain may contribute to symptoms of depression”.

Countless doctors have repeated the message all over the world, in their private surgeries and in the media. People accepted what they were told. And many started taking antidepressants because they believed they had something wrong with their brain that required an antidepressant to put right. In the period of this marketing push, antidepressant use climbed dramatically, and they are now prescribed to one in six of the adult population in England, for example.

For a long time, certain academics, including some leading psychiatrists, have suggested that there is no satisfactory evidence to support the idea that depression is a result of abnormally low or inactive serotonin. Others continue to endorse the theory. Until now, however, there has been no comprehensive review of the research on serotonin and depression that could enable firm conclusions either way.

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

There are other explanations for antidepressants’ effects. In fact, drug trials show that antidepressants are barely distinguishable from a placebo (dummy pill) when it comes to treating depression. Also, antidepressants appear to have a generalised emotion-numbing effect which may influence people’s moods, although we do not know how this effect is produced or much about it.

First comprehensive review

There has been extensive research on the serotonin system since the 1990s, but it has not been collected systematically before.

We conducted an “umbrella” review that involved systematically identifying and collating existing overviews of the evidence from each of the main areas of research into serotonin and depression. Although 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 levels of serotonin and its breakdown products in the blood or brain fluid. Overall, this research did not show a difference between people with depression and those without depression.

Another area of research has focused on serotonin receptors, which are proteins on the ends of the nerves that serotonin links up with and which can transmit or inhibit serotonin’s effects.

Research on the most commonly investigated 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 serotonin theory’s prediction.

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

We also looked at research that explored whether depression can be induced in volunteers by artificially lowering levels of serotonin. Two systematic reviews from 2006 and 2007 and a sample of the ten most recent studies (at the time the current research was conducted) found that lowering serotonin did not produce 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 this only involved 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 varieties of this gene between people with depression and healthy controls.

Although a famous early study found a relationship between the serotonin transporter gene and stressful life events, larger, more comprehensive studies suggest no such relationship exists. Stressful life events in themselves, however, exerted a strong effect on people’s subsequent risk of developing depression.

This shows the outline of a head
Around one in six people in England are prescribed antidepressants. Image is in the public domain

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

Not supported by the evidence

The serotonin theory of depression has been one of the most influential and extensively researched biological theories of the origins of depression. Our study shows that this view is not supported by scientific evidence. It also calls into question the basis for the use of antidepressants.

Most antidepressants now in use are presumed to act via their effects on serotonin. Some also affect the brain chemical noradrenaline. But experts agree that the evidence for the involvement of noradrenaline in depression is weaker than that for serotonin.

There is no other accepted pharmacological mechanism for how antidepressants might affect depression. If antidepressants exert their effects as placebos, or by numbing emotions, then it is not clear that they do more good than harm.

Although viewing depression as a biological disorder may seem like it would reduce stigma, in fact, research has shown the opposite, and also that people who believe their own depression is due to a chemical imbalance are more pessimistic about their chances of recovery.

It is important that people know that the idea that depression results from a “chemical imbalance” is hypothetical. And we do not understand what temporarily elevating serotonin or other biochemical changes produced by antidepressants do to the brain. We conclude that it is impossible to say that taking SSRI antidepressants is worthwhile, or even completely safe.

If you’re taking antidepressants, it’s very important you don’t stop doing so without speaking to your doctor first. But people need all this information to make informed decisions about whether or not to take these drugs.

About this depression research news

Author: Joanna Moncrieff and Mark Horowitz
Source: The Conversation
Contact: Joanna Moncrieff and Mark Horowitz – The Conversation
Image: The image is in the public domain

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  1. Ok, I would rather have this so-called “numbing effect” than go through hell inside my head when I am off my low-dose anti-depressant! Rumination of negative self-thinking ramps up, and anxiety and depression come back. Back into a rabbit hole, I would go. I isolate myself and become so preoccupied with self-doubt that it causes me to get stuck in a continual cycle of anxiety and panic attacks.

  2. What about other classes of antidepressants? MAOIs? NDRIs? What about the role of dopamine and norepinephrine?

    This is an extremely weak article. Which is a shame, because it could be important to lot of people.

  3. Antidepressants seem to work as anesthesia for the brain..they just numbs things for us. They don’t cure anything.

  4. And he we arrive at one of the fundamental shortcomings in our gloriously splendid framework of studying and addressing behavioral health… Validation can only be based on statistical data or experimentally tested theory. We know that whatever is going on with serotonin, depression, and antidepressants is an extremely variable process, person to person, month to month, and dosage to dosage. Statistical data can’t give you clean conclusions on wether anti-depressants are helpful, harmful, or useless. Experimentation can’t give you a valid explanation for their effects. So our hyper-rational model for validation points to the binary conclusion that they are not a valid treatment.

    But sometimes they are. Anyone who knows more than a handful of people who have suffered depression, knows someone who’s life would be worse and perhaps shorter without the right dosage of the right SSRI. The experiential aspect of pharmacology is the most important, and the most resistant to study.

    Regardless of the rigor with which this study was conducted, the conclusions of this study will meet a harsh and resistant ear from people who know that their antidepressants work for them, and the various health and pharma professionals that have a stake in making sure people who want those meds get them.

    Which leads me to the same conclusion most things lead me to… Make all drugs legal over the counter, and inundate users with as much data and counseling as they’re willing to receive. Make prescriptions recommendations, not permissions. Having the health care industry serve as the gatekeeper for which informed risks we get to take with incomplete data and which ones we don’t introduces a boatload of bad incentives for patients, providers, and researchers. Advice helps, but personal experimentation is the only way to figure what works. It’s never without risk, and it usually isn’t scientifically verifiable.

  5. This article is dangerous and extremely unprofessional! In order to complete a real study you need to have two sets of people and there needs to be a large set in both. I have seen anti-depressants work for some clients and not for others. Those that it has not worked for usually needed either an additional supplemental medication or a different medication all together (i.e. a mood stabilizer or antipsychotic). So before they go and publish an article that could cause millions of people to suddenly stop taking there much needed anti-depressants; which, would result in extreme suicidal ideation/attempts. Maybe, they might want to perform, and check, recheck, their research like a true doctorate is required too.

    Oh and to the gentleman who asked the question about why do people on anti-depressants have suicidal thoughts; it’s most likely because they are not taking them daily.

  6. I’ve never believed in the practice of taking anti depression drugs. If they are so great, and work so well, why do people that take them have suicidal thoughts? I think it’s just another pharmaceutical scam like the ADD drugs being pushed on children. It’s all profit based.

  7. Nobody has ever suggested to me there were less than three aspects to depression: mind, body, spirit are the loose terms. Some SSRI actually worsened my state until a psychiatrist tried something else (after three different types of SSRI) also a reuptake inhibitor but for other chemicals. Some people are allergic to peanuts, some aren’t. What works for me may well be detrimental to another. The generalizations of this article are extremely unprofessional.

  8. I got off anti depressents albeit low in dosage to get a better reading for persistent low cortisol (or anything else for that matter ).
    I often don’t hear about serotonin, depression, and low cortisol . Any direction on information would be appreciated .

    1. This study is incorrect. They are relying on results from studies that try to reduce the level of serotonin in the brain. These studies do not find increased depression. But, that is because the method they are using to try and reduce serotonin, reducing tryptophan in the participants diet, has never been shown to significantly change the serotonin level. I corrected my post-stroke depression with an over the counter supplement. See my video:

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