No Meaningful Brain Differences in Depression

Researchers find that neuroimaging results are unable to distinguish between the brains of depressed people and healthy controls.


In a new study, researchers found that no brain imaging test has been able to identify a meaningful brain difference that can distinguish people with a diagnosis of major depressive disorder (MDD) from people without MDD. The researchers write:

“Healthy and depressive participants are remarkably similar on the group level and virtually indistinguishable on the single-subject level across a comprehensive set of neuroimaging modalities.”

Because of this, they write, all of the previous neuroimaging research has failed to provide any clinically relevant outcomes:

“We conclude that the phenomenological, descriptive case-control studies which have dominated the last two decades in psychiatric neuroimaging and genetics failed to identify substantial, clinically relevant biological differences between MDD patients and healthy controls,” they write.

The current study analyzed the existing brain imaging studies comparing patients with MDD with healthy control subjects. They describe their study as a comprehensive analysis, looking at all the various imaging modalities to see if they could find any existing brain difference. They also looked at the polygenic risk score (PRS), a complex measure of genetic risk.

They found that people with and without MDD overlapped on all the measures and that none of them could be used to identify individuals with the diagnosis.

“In this study, we show that healthy and depressed individuals are strikingly similar with regard to univariate neurobiological and genetic measures,” they write. “Even when considering the upper bound of the deviation in each modality, none could be considered informative from a personalized psychiatry perspective with both groups being nearly indistinguishable on a single-subject level.”

They add, “Overall, no modality explained more than 2% of the variance between healthy and depressive subjects.”

This number is contrasted with factors such as childhood abuse, trauma, and lack of social support, which—according to the researchers—explain up to 48 times more of the variance than neuroimaging and genetics.

The researchers explain that published neuroimaging studies do tend to have results that are technically statistically significant, and they are reported on as if this means that there is an identifiable brain difference between people with MDD and people without. But the focus on statistical significance obscures the fact that the effect size is tiny and clinically insignificant—and that these slight average differences between groups do not provide any predictive value for individuals.

“Even under ideal statistical conditions,” they write, the overlap between people with MDD and healthy controls “corresponds to classification accuracies between 53.5% and 55.4%”—meaning that this information allows for predictions that are barely better than chance (50%).

The researchers also analyzed whether focusing on only acute or chronic depression might yield better biological results—but they came up empty-handed: “This pattern remains virtually unchanged when considering only acutely or chronically depressed patients.”

The researchers don’t suggest that researchers stop looking for neurobiological differences, though, or focus on the known risks—like childhood maltreatment, trauma, and lack of social support—which have high predictive value. Instead, they encourage funding of even larger neurobiological studies and artificial intelligence-driven statistics like “digital phenotyping.”

They write:

“We urge researchers and funding agencies to go beyond univariate analyses and foster 1) the development of quantitative, theory-driven research as done, e.g., in computational psychiatry, 2) predictive multivariate methods with a clear focus on maximum predictive power and replicability, 3) research into novel measurement approaches, and 4) in-depth phenotyping including longitudinal assessment and digital phenotyping. Future studies will have to investigate whether this can improve clinical utility and theoretical relevance of neurobiological data in mental health.”

The study was posted before review on the open-access website arXiv and involved a team of 31 cross-disciplinary researchers, including neuroscientists, geneticists, and computer scientists. They were led by Nils Winter at the Institute for Translational Psychiatry, University of Münster, Germany.




Winter, N. R., Leenings, R., Ernsting, J., Sarink, K., Fisch, L., Emden, D., . . . & Hahn, T. (2021). More alike than different: Quantifying deviations of brain structure and function in major depressive disorder across neuroimaging modalities. Uploaded to arXiv on December 21, 2021. (Link)


  1. One would need to know more info about what they were measuring. We do know from other research that depression is correlated with decreased number of brain cells and decreased synaptic connections between them. This might not show up in general structure but in overall brain size. I’m not sure, but the article doesn’t provide enough detail to ascertain exactly what the researchers were looking at in this study.

    • Remember always that such studies are not always controlling for psychiatric drug use. We know at least in “schizophrenia” that brain shrinkage is causesd by the drugs themselves, and there is suggestive evidence that this happens with stimulants for “ADHD” as well. Any generalized measurements like brain volume are not valid if substance use, legal and illegal, is not accounted for.

      • I’m reading a book on neurogenesis. Various studies show that brain shrinkage, dell death, and/or decreased neurogenesis is correlated with toxins, inflammation, stress, inadequate sleep, key nutritional deficiencies, sedentary lifestyle, lack of intellectual activity, deprived environment, etc.

        One might note that most of these studies have nothing to do with depression. But, obviously, depression overlaps with many other health conditions and diseases. That is because depression is often more of a symptom than a cause. Interestingly, some anti-depressants increase neurogenesis.

        • It should be clear that any brain-affecting drug could cause brain shrinkage, based on your research. I’ve never found the “neurogenesis” explanation/claim for SSRIs to be particularly convincing. But you are very correct, depression is almost always a symptom of something else. In fact, I think it’s fair to say that “depression” is not the “cause” of anything. It’s an experience people have, which could mean a hundred different things. Calling it a ‘disorder’ is always euphemistic.

          • I don’t find it unbelievable that particular SSRIs might have specific benefits like neurogenesis. There is a small but significant percentage of people who apparently do experience improvements, for whatever reason. That isn’t to say they are necessarily overall beneficial.

            Many chemicals can cause results that are a mix of good and bad. Smoking a cigarette before taking a test will improve your results, but not many people are going to take up tobacco as a smart drug. Even natural substances in foods or made in the body can have detrimental effects at too high of levels or out of balance with other things.

            About this study, I still wonder what they were measuring and how. As mentioned, depression isn’t a single disorder. So, one wouldn’t expect to find a single pattern in the brain. But that isn’t to say patterns couldn’t be found. My suspicion is these researchers were simply looking at total averages and not at distinct patterns within sub-groups of depressives.

          • The difference I see in your analogy is that no one is promoting cigarette smoking as a “treatment” for “ADHD” or any “educational disability.” Drugs can be useful for many things. I’d be dead today without modern medicine. But it sounds like we’d both agree that just because a drugs is perceived as helpful in a particular situation for a particular person, it doesn’t mean that person was “ill” or that the drug “cured” or “treated” a condition.

            A shot of Southern Comfort definitely reduces my anxiety, but it’s hardly a medical treatment!

        • “Interestingly, some anti-depressants increase neurogenesis.”

          The measurements/tests used for that claim find the drugs cause increases in certain biological factors. However, those same biological factors are also caused by brain cell death. Claims about “anti-depressants” increasing neurogenesis are based on assuming the drugs cause it rather then cell death.
          Luckily, there are direct measurements and they show that “antidepressants” both in cell cultures and inside humans cause brain cell disfigurement and death.

          (scroll to the neuronal proliferation, death section)

          • That is a fair criticism. Anyway, it’s not as if I’m defending antidepressants or other psychiatric medications. But I’m simply pointing out that physiological results are often complex and messy. Some people claim to have benefits from antidepressants and I’m not willing to dismiss their experience, even as I’m wary of overprescription of pharmaceuticals.

            As for the paper, I noticed that it is stated that, “It would be extremely odd if antidepressants directly and concomitantly promoted both neurogenesis and neuronal apoptosis.” I’m not sure what is the basis of that claim. Consider that long-term fasting induces autophagy with simultaneous elimination of cells and growth of new cells. In three days of fasting, every cell in the immune system is replaced.

            One could negatively conclude that fasting kills off all of one’s immune cells, which is true; and yet it misses the point that this improves immune functioning with new immune cells. Fasting has a similar effect on muscle cells, and it’s true that too much fasting will cause muscle wasting, but then immediately after fasting the body kicks cell production into high gear. Similarly, some drugs and supplements, including from plants, can mimic fasting with this kind of dual effect on cells.

            So, cell death doesn’t by itself tell us that more cells are dying than being generated. I’m not conversant with the research in this area and I won’t pretend to know the evidence on both sides of the debate, as I’m not defending either side. I have no dog in that fight, as I don’t take antidepressants nor recommend them. One might think it would be relatively easy to determine this neurogenesis issue, though.

            Researchers could take a group of depressives on antidepressants. And test for decreases in depressive symptoms, such that it could be determined who responds well. Then, using brain scans on those high responders, measure their brain size over years or even decades to see if it grows or shrinks. That would determine if SSRIs are causing a net gain or a net loss of brain cells. The problem is the drug companies wouldn’t likely pay for such research and so funding would be hard to come by.

      • These studies also don’t presume “Major Depressive Disorder” to be the wastebasket diagnosis it actually is, so they unknowingly have heterogeneous groups of patients. It would be truly remarkable if they did find some Universal Clinical Truth through such diagnostic “methods”.

  2. “The researchers don’t suggest that researchers stop looking for neurobiological differences, though, or focus on the known risks—like childhood maltreatment, trauma, and lack of social support—which have high predictive value. Instead, they encourage funding of even larger neurobiological studies and artificial intelligence-driven statistics like ‘digital phenotyping.'”

    Well, when a country “is controlled by its system of credit. Our system of credit is concentrated. The growth of the nation, therefore, and all our activities are in the hands of a few men.” And when those “few men” want to destroy our nation, to bring about their NWO, and to cover up the Ponzi scheme that is their banking system, with a “Great Reset.”

    And to achieve this goal, these “few men” have literally been controlling all industries in our country with pedophilia blackmail schemes and child sex trafficking crimes, et al. While – in all deceptive and criminals manners possible – they have been stealing from the American people, via the taxation system, the housing crisis, et al.

    One industry that was instrumental to this “small group of dominant men” – way back in Nazi Germany, was the psychiatric industry. And in the US today, the psychiatric industry’s DSM “bible” billing, and systemic child abuse covering up partners – the psychological industry, the social worker, the Child Protective Service, and Foster care industries – are all controlled, and still begging for money, from this “small group of dominant men.” Not to mention, so are the mainstream religions, who have “partnered with” the “mental health” industries.

    I could give you a bunch of peer reviewed journal and other articles verifying my research, but I’ve already sited those articles many times before on this website. The reality is, as a society, we need to “turn over the” – globalist banksters’ – “money changers’ tables” again.

    But what we don’t need is more funding into the eugenics / genetics beliefs of the scientific fraud based “mental health” industries. For God sakes, we have already medically proven the iatrogenic etiology of the two most serious DSM “mental illnesses.” And love, and true justice, cures / prevents depression, not pharmaceuticals.

    Thank you as always, Peter, for your honest reporting.

  3. At first is seems a bit brave that these neuroimaging experts would call out earlier studies as clinically useless. However, when we see at the end that all they do is beg for more funding, perhaps this makes more sense. I hate to be cynical about these people but…

    They have had over 50 years now to follow up on work that indicates that irrational emotional responses come from the triggering of mental pictures, and to discover for themselves the role the spiritual being plays in creating and paying attention to its own mental pictures. They have instead chosen to speak and write as if this information never existed. I can no longer give them any tolerance for their ignorance. They should have figured it out by now; they obviously have other fish to fry.

    • In isn’t just cynicisms but censorship.
      If they flat out said “the brain disease cause of mental illness spread by psychiatry was always a false lie” they would have a hard –if not impossible– time getting their study published.
      When Peter Gotzsche tried to get a review/study on psychiatric drug withdrawal published medical journals wouldn’t do it unless in his write up he –falsely– proclaimed how the drugs were effective and safe.

      A head shaking result is that studies showing negative effects of drugs get filled with pro-drug assumptive statements and propaganda. This occurs all the time when a study finds that psych drug worsens outcomes, where the authors –without and even counter to the evidence– make assumptions about how the people off drugs must have some unknown factor causing better outcomes. Harrow’s “antipsychotic” study exemplifies this. His study showed that people with the most severe labels off the drugs had 50% better outcomes than those with the more mild labels on them. Yet the authors originally made assumptive statements how this didn’t mean the drugs worsened outcomes. In later years they retracted those statements.

  4. Yeah, let’s not waste our money on the things that have a 50 times greater correlation! Let’s spend more money researching stuff that is barely better than chance at distinguishing “depressives” from “normals.”

    You know what my approach was for distinguishing depressed individuals from non-depressed individuals? I asked them if they felt depressed! It was a remarkably accurate “marker.” People who say they are depressed are statistically FAR more likely to be depressed than those who say they feel fine!

  5. I can only think of one actual time in my life when I was possibly “depressed” and I wasn’t taking psychiatric drugs. I was about fourteen and the very people who forced us to get rid of our beloved dog were coming to visit. Other than that, any possible “depression” I had, I was at the very least taking the psychiatric drugs prescribed me. When my brain and body finally began to say “no” to all the years of taking these prescribed psychiatric drugs and I began nearly comatose and almost died, when I was still in the hospital and finally awake; they made me undergo a very noisy MRI session one night. After that MRI session, they claimed that my brain was “normal” and had no abnormalities. But after reviewing that situation and a few related medical encounters from that time period in my life; I am likely to consider strongly that I was being fed a “bill of goods” or was basically lied to and that no alleged medical professional wanted to admit the truth of how these drugs had damaged my brain, etc. I am not sure about all that “neurogenesis” stuff that benjamindavidsteele wrote about. I am no scientist; but in my personal opinion, I consider psychiatric drugs and even related drugs like psychedelic drugs and opiates to be more dangerous to the brain and body than almost anything else listed; though I think some of those “causes” may be very close as they may mimic what these drugs do; but that is my completely unscientific opinion. Thank you.

  6. Now this finding is interesting. As I have read about there being a debate between gender differences in the brain. And studies done by MRI’s show — well, there is such large variation between two different brains of the same gender that it’s not very easy to find significant gendered brain differences.

    And here we have the same finding with respect to the brains of depressed people and those who aren’t. “No significant differences” if you ask those who do brain MRI’s.

    I feel, though, as someone who studied math that the workings of the brain probably involves stuff that — well, it’s like a chaotic system like the weather. Where, as they say, a butterfly flapping its wings in Arizona could have so much of an impact so as to cause a whole storm to happen thousands of miles away.

    Maybe depression — and gender differences — are things that theoretically could be seen but they manifest themselves in ways that otherwise look so subtle if you are trying to see it in the electrical circuitry of the brain that it’s kind of like how, only after a lot of theoretical work was Einstein able to postulate the existence of black holes. And then figuring out how they exist theoretically, they were able to figure out complicated ways to prove they really existed. To infer they really existed.

    Now, in academia, they need to lobby donors for funds. And they need to go tell them “the expensive machine you buy us IS DEFINITELY going to yield clear cut scientific findings that you will be able to see right away. And when you publish your company’s annual report and want to boast to everyone of all the good you did with your funding, we will be able to tell you of definitive findings.”

    How can scientists go and tell a donor who helped them buy an MRI something like “honestly, we didn’t find anything meaningful or significant yet — just be patient. Who knows, you might be dead before we finally figure out the current problem we are working on.”

    In America, they are all too impatient.

    The Japanese are wise in comparison, and maybe we need to learn something from them. They will start projects at present that they do not expect to fully come to fruition until several generations down the road. For instance, in gardening, they will go put a boulder underneath a waterfall today, and it will slowly over the course of 100 years or so produce beautiful holes and ripples in the boulder, and then they will take it out and put it in some garden. They have beautiful gardens today with special waterfall sculpted boulders that were originally put in a waterfall by their ancestors over 100 years ago.

    • Is it really too much to ask an intelligent person after arriving at the conclusions that these people arrived at that they might be barking up the wrong tree? Is the possibility of spiritual existence really such a zero for them that no possible set of experiences could ever get them to consider it might be true?

      • I think a lot of folks have been convinced that it is “unscientific” or “mystical” or superstitious” to entertain any possibility of a spiritual existence beyond our bodies. It’s odd, because most people in the world appear to believe in such a spiritual existence continuing beyond our physical existence in our bodies, yet somehow this doesn’t seem to conflict with claims that ‘science’ does not include the possibility of spiritual existence. I’m personally of the opinion that scientifically, there is no way to rule in OR rule out such spirituality to a certainty. But that means science ought to remain open to the possibility. There are certainly bits of circumstantial evidence, such as the placebo effect and neurofeedback, that suggest there is something about our existence as beings of whatever nature that allows our mental processes to control what happens to the body. How that effect occurs, no one really knows. So discounting the potential that we are spiritual beings that transcend our earthly existence on “scientific” grounds seems ungrounded in factual evidence.

        • I think science can and must confront this subject if it ever intends to move humanity forward.

          We have many good approaches to detecting spiritual action, and particularly in addressing spiritual memory in all its various aspects. Courtney Brown has pioneered a science-based approach to remote viewing and many others have been working along similar lines in their own fields. At this point it is clearly a matter of academic snobbery to keep this subject closed to scientific inquiry.

          If scientists can play around with concepts like multiple universes, neutrinos and qubits, then it can darn well begin to deal with everlasting life and the question of ultimate causality.

  7. This isn’t a peer reviewed study, it’s only a pre-print. It’s pretty bad to have written an article on a pre-print given that it hasn’t been reviewed, recognised, or even looked at by any other scientists. For all we know at the moment, the results could be completely flawed. Not sure why the author of this article decided to write about it given that it’s commonly accepted that you wait to see if it survives peer review first. Pretty disappointing.

    Best to wait for the paper to actually get checked over by other independent scientists, through peer review, before you start claiming that an entire field is useless.

  8. This study is a pre-print and not a peer reviewed paper. This is what the site where it has been uploaded to says about reporting pre-prints

    “Important: e-prints posted on arXiv are not peer-reviewed by arXiv; they should not be relied upon without context to guide clinical practice or health-related behavior and should not be reported in news media as established information without consulting multiple experts in the field.”

  9. Anti-depressants, like all psychiatric drugs can be very misleading. The person who takes them may think they are feeling better, when they are actually damaging the brain. I think one of the reasons the person may think they are feeling better is just pure brainwashing by the psychiatrists and therapists. Therefore, it is probably much more than theoretically impossible to ever obtain any quantitative data. But then the subject is human beings, not how many rocks remain at the seashore after a hurricane. Thank you.

  10. This isn’t a peer reviewed study, it’s only a pre-print. This paper hasn’t been reviewed, recognised, or even looked at by any other scientists. For all we know at the moment, the results could be completely flawed. It’s commonly accepted that you wait to see if it survives peer review before writing a media article on it.

    Best to wait for the paper to actually get checked over by other independent scientists, through peer review, before you start claiming that an entire field is useless.

      • I agree and since psychiatry/psychology is a “fraudulent science” a peer review is definitely meaningless. In my silly opinion, it would be nearly impossible to control all the variables to actually make it a decent experiment that warrants genuine peer review. I think the best thing to do is read the anecdotal stories of those who have been prescribed anti-depressants, and how they adversely affected them, even causing complications and side effects, etc. greater than any alleged depression or whatever alleged condition in which they were prescribed. The moral of the story: “Don’t do antidepressants or any psychiatric drug for that matter.” Thank you.