Is depression due to low serotonin levels? A new umbrella study finds no evidence. Was there ever any?
The "serotonin theory of depression" has been around for many years, along with popular notions that depression is caused by a "chemical imbalance" in the brain. But does the science support them?
Unfortunately, all too many of us know the symptoms of depression: Sadness, hopelessness, inability to find pleasures, irritability, poor sleep, lack of energy, anxiety, feelings of worthlessness, suicidal thoughts and impulses, plus a host of ill-defined physical symptoms such as headaches and bodily aches and pains.
Even before the Covid pandemic began in early 2020, an estimated 8.4% of U.S.-based adults suffered from major depression. Once the pandemic began, according to research at Boston University, this figure jumped up to about one in three adults.
This three-fold increase in the depression toll in the U.S. population underscores what researchers and lay persons have known all along: There is a close relationship between what life throws at us and our moods, including our deeper psychological states. Adverse life events can involve severe trauma, but even more temporary setbacks in one’s life can be traumatic in a chronic, ongoing way.
But this is not how much of mainstream medicine, and its comrade-in-arms, the pharmaceutical industry, wants us to see depression, either more moderate forms or the severely debilitating version, Major Depressive Disorder. For decades now, mainstream psychiatry and drug companies have engaged in a logical leap: Because anti-depressants like Prozac, which supposedly have the effect of increasing serotonin levels in the brain, can relieve symptoms of severe depression in many cases, depression must therefore be caused by low serotonin levels.
As some have pointed out, this is akin to saying that headaches, because they are relieved by aspirin, are due to low levels of aspirin in the brain. And, despite popular notions and drug company literature pushing the serotonin theory of depression, researchers have repeatedly failed to come up with convincing evidence of it.
The latest contribution to this skeptical literature was published last month in the high-profile journal Molecular Psychiatry, one of the Nature group of scientific journals. Entitled “The serotonin theory of depression: a systematic umbrella review of the evidence” (and freely accessible, fortunately), based on work by a team led by University College London psychiatrist Joanna Moncrieff, the review of the scientific literature concludes:
The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations. Some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentration.
Moncrieff is a well-known, long-time critic of mainstream psychiatry and its reliance on drug regimens to treat mental disorders. So some might not find her findings surprising. And of course all scientific studies, many of which conflict with one another, should be open to criticism and evaluation. But the approach used—an umbrella review, which is basically a review of reviews, including meta-analyses—has recently become a powerful tool for getting to the bottom of complex issues in biomedicine. As the famed psychiatrist Paolo Fusar-Poli put it in a 2018 article on umbrella reviews, penned with his colleague Joaquim Radua:
Umbrella reviews are reviews of previously published systematic reviews or meta-analyses. Therefore, they represent one of the highest levels of evidence synthesis currently available, and are becoming increasingly influential in biomedical literature.
Chemical imbalances: What is the evidence?
But the findings of the Moncrieff team are also unsurprising for another reason: Contrary to popular notions that “chemical imbalances” in the brain are the leading explanation for depression and other mental disorders (including schizophrenia, see below) there has never been any convincing evidence for this theory. Indeed, as two researchers pointed out back in 2005, in a paper in PLoS Medicine titled “Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature,” the serotonin hypothesis is based much more on pharmaceutical industry promotional literature than on the scientific literature.
Indeed, as doubts about the scientific basis for the use of so-called selective serotonin uptake inhibitors (SSRIs) such as Prozac, Lexapro, Paxil, and Zoloft have mounted, some researchers have even questioned whether they should be prescribed for major depressive disorders. While many would not go this far, Moncrieff has long argued that anti-depressants actually create “abnormal brain states” rather than “cure” them.
But other researchers and clinicians have argued that anti-depressants, however they actually function, can in many cases help patients to elevate their moods enough to benefit from other forms of treatment, for example psychotherapy. (There is also some evidence for this argument in schizophrenia, which I have written about extensively in the past.)
How long such maintenance doses of these drugs should be maintained—and whether some patients should be told, as is often the case, that they must take them all their lives to alleviate alleged chemical imbalances—is still fiercely debated among clinicians and psychiatric researchers.
What about genes? And does the chemical imbalance notion make us feel better or worse?
A corollary to chemical imbalance theories of mental disorders is the assumption that genes make some individuals more susceptible to depression, schizophrenia, and other psychological maladies (see here and here for more on that subject.) But that assumption is not holding up very well, according to recent research. While large-scale genetic studies have suggested that genes are involved in susceptibility to depression in some way, the inability to identify any particular gene with a large or significant effect—similar to the situation so far with schizophrenia—makes the practical and clinical importance of such findings very unclear.
As Eric Turkheimer, a behavioral geneticist at the University of Virginia, put it to me in an article for Scientific American about the search for “schizophrenia genes,” large scale genetic studies show that “schizophrenia is so highly, radically polygenic that there may well be nothing to find, just a general unspecifiable genetic background.”
The same may be true for depression. And it might explain why researchers have been unable to come up with definitive evidence for brain abnormalities or other neuroimaging markers linked to depression (see, for example, here and here.)
Yet there is another aspect of the serotonin and chemical imbalance theories of depression that have received little media attention that I have seen. That concerns the evidence that these theories have a negative impact on patients suffering from depression. Research on that topic suggests that while thinking one’s depression is due to a chemical imbalance does not, as one might hope, reduce feelings of self-blame and guilt, it does increase feelings of pessimism and hopelessness about recovering from depression.
Of course, if the neurochemical theories of depression were correct, then patients should be educated about them no matter what. But if they are not?
On the other hand, a study with a group of volunteers employing educational materials that emphasized the “malleability” of gene effects and neurochemistry—in other words, that underscored that these factors are not determinative in causing depression—decreased feelings of pessimism and hopelessness in the study group, along with increased feelings of agency, the ability to take control over one’s life (see “Fixable or Fate? Perceptions of the Biology of Depression.”
The present and future of depression.
I want to emphasize that I am not advocating, nor do I think the science supports, the idea of throwing away one’s anti-depressant medication or refusing to take such drugs in the first place. I know from my own past experience, and that of many others I have talked to, that taking such medications can be an important first step out of the depths of depression, whether their effects are due to increased serotonin levels or they simply serve as placebos. In cases of severe depression, drugs are sometimes the only way to get functioning again enough to take the next steps in crawling out of the abyss.
But it is also the case that risk of depression is closely linked to negative life events and trauma, as we are so clearly seeing right now during this devastating Covid pandemic. Understanding the social, political, and economic contexts of our emotional and psychological states is just as important, if not more so, than understanding the neurochemistry of our brains.
Update August 1: One of the authors of the Moncrieff et al. paper, academic psychiatrist Mark Horowitz, sent me a link to a post responding to criticisms of the work. Readers might find it of interest.