Scientists Find No Evidence That Depression Is Caused by “Chemical Imbalance” or Low Serotonin Levels

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Despite the popularity of the ‘chemical imbalance’ theory of depression, scientists say there is no clear evidence that serotonin levels or serotonin activity cause depression.

After decades of research, there remains no clear evidence that serotonin levels or serotonin activity are responsible for depression, according to a comprehensive review of prior research led by University College London (UCL) scientists.

The major new umbrella review – an overview of existing meta-analyses and systematic reviews – was published on July 20 in the journal Molecular Psychiatry. It suggests that depression is not likely caused by a chemical imbalance, and calls into question what antidepressant medications do. This is because most antidepressants are selective serotonin reuptake inhibitors (SSRIs), which were originally said to function by correcting abnormally low serotonin levels. In fact, there is no other accepted pharmacological mechanism by which antidepressants affect the symptoms of depression.

Lead author Professor Joanna Moncrieff, a Professor of Psychiatry at UCL and a consultant psychiatrist at North East London NHS Foundation Trust (NELFT), said: “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.

“The popularity of the ‘chemical imbalance’ theory of depression has coincided with a huge increase in the use of antidepressants. Prescriptions for antidepressants have risen dramatically since the 1990s, with one in six adults in England and 2% of teenagers now being prescribed an antidepressant in a given year.

“Many people take antidepressants because they have been led to believe their depression has a biochemical cause, but this new research suggests this belief is not grounded in evidence.”

This comprehensive umbrella review aimed to capture all relevant studies that have been published in the most important fields of research on serotonin and depression. The research included in the review involved tens of thousands of participants.

Studies that compared levels of serotonin and its breakdown products in the blood or brain fluids did not find any notable differences between people diagnosed with depression and healthy control (comparison) participants.

Weak and inconsistent evidence suggestive of higher levels of serotonin activity in people with depression was found by studies on serotonin receptors and the serotonin transporter, the protein targeted by most antidepressants. However, the scientists say the findings are likely explained by the use of antidepressants among people diagnosed with depression, since such effects were not reliably ruled out.

The researchers also investigated studies where serotonin levels were artificially lowered in hundreds of people by depriving their diets of the amino acid required to make serotonin. These studies have been cited as demonstrating that a serotonin deficiency is linked to depression. However, a meta-analysis conducted in 2007 and a sample of recent studies found that lowering serotonin in this way did not produce depression in hundreds of healthy volunteers. Very weak evidence was found in a small subgroup of people with a family history of depression, but this only involved 75 participants, and more recent evidence was inconclusive.

Some very large studies involving tens of thousands of patients looked at gene variation, including the gene for the serotonin transporter. No difference in these genes between people with depression and healthy controls were found. These studies also looked at the effects of stressful life events and found that these exerted a strong effect on people’s risk of becoming depressed – the more stressful life events a person had experienced, the more likely they were to be depressed. A famous early study found a relationship between stressful events, the type of serotonin transporter gene a person had, and the chance of depression. But larger, more comprehensive studies suggest this was a false finding.

These findings together led the researchers to conclude that there is “no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations.”

The authors say their findings are important as studies show that as many as 85-90% of the public believes that depression is caused by low serotonin or a chemical imbalance. A growing number of scientists and professional bodies are recognizing the chemical imbalance framing as an over-simplification. There is also evidence that believing that low mood is caused by a chemical imbalance leads people to have a pessimistic outlook on the likelihood of recovery, and the possibility of managing moods without medical help. This is important because most people will meet criteria for anxiety or depression at some point in their lives.

The scientists also found evidence from a large meta-analysis that people who used antidepressants had lower levels of serotonin in their blood. They concluded that some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentrations. The researchers say this may imply that the increase in serotonin that some antidepressants produce in the short term could lead to compensatory changes in the brain that produce the opposite effect in the long term.

While the study did not review the efficacy of antidepressants, the authors encourage further research and advice into treatments that might focus instead on managing stressful or traumatic events in people’s lives, such as with psychotherapy, alongside other practices such as exercise or mindfulness, or addressing underlying contributors such as poverty, stress, and loneliness.

Professor Moncrieff said: “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. 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.”

Co-author Dr. Mark Horowitz, a training psychiatrist and Clinical Research Fellow in Psychiatry at UCL and NELFT, said: “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.”

Professor Moncrieff added: “Thousands of people suffer from side effects of antidepressants, including the severe withdrawal effects that can occur when people try to stop them, yet prescription rates continue to rise. 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.”  

The authors caution that anyone considering withdrawing from antidepressants should seek the advice of a health professional, given the risk of adverse effects following withdrawal. Professor Moncrieff and Dr. Horowitz are conducting ongoing research into how best to gradually stop taking antidepressants.

Reference: “The serotonin theory of depression: a systematic umbrella review of the evidence” by Joanna Moncrieff, Ruth E. Cooper, Tom Stockmann, Simone Amendola, Michael P. Hengartner and Mark A. Horowitz, 20 July 2022, Molecular Psychiatry.
DOI: 10.1038/s41380-022-01661-0

16 Comments on "Scientists Find No Evidence That Depression Is Caused by “Chemical Imbalance” or Low Serotonin Levels"

  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: https://youtu.be/LXKAfX5DNcI

  2. The book “Listening To Prozac” by Peter D Kramer (June 1993) came to a similar conclusion, if I understood it and remember it correctly (I read it just after publication).
    He said that his patients given Prozac did not show signs of their depression dissipating. Rather, he saw their personality types change from “introverted” to “extroverted”. Then they started talking about how they got new friends at work, started going out with them to have fun; or became otherwise involved in some “extra-curricular” activity. Only then, after many months of living this new “extroverted” life, did they show signs of their depression dissipating.
    He concluded that it was our (modern industrial) society that shuns “introverts” and glorifies “extroverts,” as opposed to the “tribal” societies that we evolved in, that require the “quiet stay-at-home” type to keep the hearth burning and the lamp in the window lit – but a tribe includes them and all tribal members in all tribal activities by default, whereas modern society’s “tribes” do not. He said he would keep prescribing the pills because many of his patients did see improvement; it just wasn’t what the “textbooks” said it was.
    In my humble opinion of observations of friends (back when we were teen-agers and in our early 20s and 30s) given antidepressants, I had to concur with Dr. Kramer. I saw them change. But I would say for the worst. (would they? THAT is the real question!) They became more cold-hearted.
    Many warnings have been issued about antidepressants possibly causing aggressive or even violent behavior in teens; (? and suicide too, if I remember correctly ?). This is what I saw. My friends became more aggressive in general. Not outright mean or violent.
    My opinion is that, yes, these drugs do “switch” personality types (introverted to extroverted). But the truth still remains that they suffered high levels of “trauma or stress” in their early life. In my imagination, I see a violent or otherwise threatening person (all my friends mentioned here were males, and I would also hypothesize that the aggressive person in their life was also male) in their everyday life – likely a parent figure – who was also very extroverted themselves.
    The friends given the antidepressant pills, switched to extroverted, simply patterned their behavior and personality, like we all do, on the influential adults in their childhood.
    The kids who get suicidal from A.D. pills simply are rejecting their own personality’s “expression of extrovertness” – they don’t want to be or feel like the person who abused them, and they only see one way out. IDK. Just a guess.

    QUOTE from article:
    Co-author Dr. Mark Horowitz, a training psychiatrist and Clinical Research Fellow in Psychiatry at UCL and NELFT, said: “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.”

    That’s because pharmaceutical companies are the biggest industry in the world – I forget if it is by 10 or 100 times bigger than the next biggest: the “defense” (offensive weapons) industry; and they pay the universities big big big $$$$$$ to teach a specific science of medicine that keeps them in profits, and ignores the science behind real treatments for depression; for instance see “The Infinite Mind” by Valerie V. Hunt – a treatment that cures patients in ONE treatment with long-term results.

    The reviews of this book are lame. They do not talk about the real contents of what she found in her research and the multi-million dollar work with the NIMH. The Wikipedia article on her is watered down also. They don’t want you to know! Antidepressants hit the market big-time about the same time as her research hit its pinnacle. It is the single most important book on psychology and cognitive science and health and being HUMAN and ALIVE that I’ve ever read.

  3. Forem Lapsiwala | July 27, 2022 at 2:40 am | Reply

    If its not chemical imbalance then what is it and why is it that depressed people feel better after taking antidepressants? If there is no knowledge on how antidepressants work, how can you counter it without knowing how it works in the first place?

  4. Here’s an idea (and I am not a professional or something). Maybe the cause of depression is indeed not a chemical imbalance, but rather adverse life events. But maybe using SSRIs (that increase levels of serotonin more than the normal person) helps to overcome this state of mind.
    People without depression are satisfied with the normal level, because they have nothing to overcome. In short, depression is not caused by serotonin deficiency, but high levels of serotonin help to cope with it.

  5. When I was on antidepressants, they made me feel like I didn’t care. And that I didn’t care that I didn’t care. I didn’t care about how my apartment looked, how I looked. I didn’t care about anything. Sometimes I didn’t know what I was doing. I finally decided to go off when the doctor was going to go over the maximum amount. I reduced the drug I was on by titrating down the amount I was taking. When I got off the drug, it was like waking up. I started walking. Changed my diet. I realized I had been no different than someone who was an addict thinking that the way out of my problems was through a pill. I will never take another antidepressant.

  6. People can debate (comments above) the role of serotonin but are doing so in an evidence vacuum and without reference to underlying cause.

    The big elephant in the room is that depression is a symptom, not a disease. There are many pathologies, deficiencies, toxicities, stresses etc that can cause it, and THAT needs to be the diagnosis. Depression is therefore a bogus diagnosis: like ALL psychiatric diagnoses it lacks any objective defining measure. This is like diagnosing an achy head as a disease called “headache”, which tells the sufferer NOTHING.

    For instance, if you can’t pay your bills, you don’t need prozac, you need money. If your marriage is crap you need a divorce. If you have a depleted diet you will be low in B vitamins and that can and will manifest as depression etc. If you rely on stimulants you’ll be forever battling a state of comedown.

    Don’t get me started on gut flora, antibiotic use and other drug side-effects.

    One thing is sure, “SSRI deficiency” is unequivocally NOT the cause of depression.

  7. @Forem Lapsiwala. 100 percent agree, antidepressants do work. If they didn’t, they wouldn’t be prescribed

  8. @Allanor it all depends what we mean by “they work”. Lots of things can make you feel better, but without any relation to the cause of the problem. Many come with a significant downside. The more we can narrow our outcome measures, the more things we will find that “work”, but so what?

    But there is only one thing that can ever address the root cause of a problem – and that is addressing the root cause of the problem! EVEN SUPPOSING chemical imbalance really is THE unique disease process for all depression (which is simplistic to the point of ridiculous), there is still the question of WHY!!!

    “They work” is a fairly vacuous statement I’m afraid and advances our understanding not one jot.

  9. I think that depression could be a neurological disorder brought about by the loss of neurological stimulation from a degree a person is used to down to a lesser degree, coupled with the brain chemicals released when an individual believes that the return of such a degree and similarity of stimulation can or will be experienced anytime soon is unlikely if not impossible. But this is just a wild guess, probably crazy.

  10. Depressing experiences lead to depressed mood. Who knew?

    I’m glad that the truth about the “chemical imbalance” theory has finally gone mainstream. The truth is, there has never been even decent evidence that depressed people had low serotonin levels. The idea was convincingly disproven way back in the mid-80s. The main reason people believe this is pharmaceutical industry advertising, supported by the psychiatric industry.

    Antidepressants do seems to have a positive effect for some people, but that has also been massively overstated. See Irving Kirsch’s work.

    Maybe it’s time to go back and look at those “stressful events” that actually DO seem to have a high correlation with depression? But who can make enormous profits by actually helping people cope with and control their lives?

  11. I’m reading into these comments a bit of a false dichotomy between mind/experience and chemical imbalance, like it has to be one or the other.

    Think more broadly, people. The brain is an organ, it has certain needs. At medical school they tell us that basically means glucose and oxygen. Well, 2/10, must try harder.

    Everything medical is chemical – why? Because that is what the chemical industry decided when it took over the American Universities in 1919.

    You don’t have to look very far to find plenty of people who have broken out of depression. I’m one of them. A bit like or cancer, when you actually do beat it, nobody seems to want to ask you how. But they all have an opinion on it nevertheless.

    I’ll throw you a teaser. The performance of an organ depends on its environment, and that is a huge subject. But suffice to say the problems do not begin with the affected organ, they begin elsewhere. I could run a university course on this, but who would pay me?

  12. Correlation and causation are 2 different things.

  13. Saying that depression is simply a reflection of life issues/stress is a way-oversimplification; just as much as suggesting a lack of appropriate serotonin levels is the root cause. I, along with my identical twin brother were born premature; I was incubated for 3 weeks (being deprived of food compared to my brother led me to be 3.12lbs vs his 5.8lbs) while he was sent home. I firmly believe my depression has a physical cause, whether due to lack of brain development (I have learning difficulties) or not being held as much due to the incubation. From day one, my brother smiled in every picture while I didn’t. At age 5 I told my mom I wanted to kill myself. SAME nurture/environment, a bit different nature (for those 3 weeks). I have ALWAYS been depressed; my brother? Never. The jury is still out. If talk therapy, mindfulness exercise, etc. doesn’t work, yet an SSRI does (not to mention NDRIs and others not so much as mentioned) then who are we to deprive someone of that option? I have tried EVERY conceivable thing out there and I’ve spent way more than $500,000 over 35 years of my own money (basically all my extra income goes to find a treatment/solution) to no avail. Now I am looking at seeing if psilocybin or ayahuasca/dmt may help. For people who have never experienced depression (NOT sadness) over a long period of time, they have no clue of what they say, particularly with claims that depression is a choice, or that meditation, strict diet of x,y,z or Jesus is all you need, is grossly disrespectful, trivializing and just plain ignorant. I pray each day to find a treatment for myself and all others in the same boat. Also, depression (again, NOT sadness which people quickly conflate it with) is just as much a physical feeling as it is a mental/emotional one. It physically HURTS.

  14. The first comment by “David” sounds like a post paid for by BP.

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