A Popular Theory About Depression Wasn’t "Debunked" by a New Review

A new paper that reviews the evidence around the serotonin “chemical imbalance” theory of depression has caused an online storm, with figures from across psychiatry commenting on the study’s merits and limitations. In this article, we cut through the hype and take a look at what the paper has changed about our understanding of depression.

Psychiatry gave up on the “chemical imbalance” theory long ago

The review article, published by an international research team including first author Prof. Joanna Moncrieff, aimed to assess the available evidence for and against the serotonin theory of depression systematically. The team explain this theory near the start of their paper: “[The theory is] the idea that depression is the result of abnormalities in brain chemicals, particularly serotonin (5-hydroxytryptamine or 5-HT).” The theory has been around for decades, but their overarching conclusion is that it is not correct, given that there appears to be no link between measurable serotonin concentration and depression.

The reaction of many academics to this finding can be summed up, briefly, as “Obviously!” In comments to the UK-based Science Media Centre, Dr. Michael Bloomfield, consultant psychiatrist and head of the translational psychiatry research group at University College London (UCL), said, “The findings from this umbrella review are really unsurprising. Depression has lots of different symptoms and I don’t think I’ve met any serious scientists or psychiatrists who think that all causes of depression are caused by a simple chemical imbalance in serotonin.”

Prof. Phil Cowen, a professor of psychopharmacology at the University of Oxford, said, “No mental health professional would currently endorse the view that a complex heterogenous condition like depression stems from a deficiency in a single neurotransmitter.”

Prof. Allan Young, director of the Centre for Affective Disorders at King’s College London, said, “Most psychiatrists adhere to the biopsychosocial model with very few people subscribing to a simple “chemical imbalance” theory.”

While the review has made headlines for “debunking” the serotonin imbalance theory, the reaction from many researchers suggests that this idea, in fact, has not been treated seriously within the field itself for years.

Psychiatry forgot to tell the public that it gave up on the “chemical imbalance” theory long ago

If you read the above point and felt rather perplexed to discover that the chemical imbalance theory has actually been in the academic wastebin for some years, you are not alone. The review authors highlighted a study (n = 893) that found that 88.1% of respondents believed a “chemical imbalance” to be a cause of depression. This idea, the authors point out, was heavily pushed by drug companies aiming to sell serotonin-selective reuptake inhibitor (SSRI) compounds. Eli Lilly, for example, promoted their compound Prozac in 2008 with the following: “Many scientists believe that an imbalance in serotonin, one of these neurotransmitters, may be an important factor in the development and severity of depression. PROZAC may help to correct this imbalance by increasing the brain's own supply of serotonin.”

This attitude wasn’t just a marketing ploy embraced by an unwitting public – Northwestern University’s Dr. Christopher Lane highlighted in a commentary in Psychology Today a 2005 study that explored the disconnect between advertisements of SSRIs and the scientific evidence to support their use. Lane quotes Daniel Carlat, the editor of The Carlat Psychiatry Report, “I’ll often say something like the way Zoloft works, is, it increases the level of serotonin in your brain (or synapses, neurons) and, presumably, the reason you’re depressed or anxious is that you have some sort of a deficiency. And I say that [chuckles] not because I really believe it, because I know the evidence really isn’t there for us to understand the mechanism.”

Lane further highlights that another study, this time a survey of 237 psychology students, which found that 46% had heard a physician explain the chemical imbalance theory to them. While academia long ago dismissed the imbalance theory, that message appears not to have reached the public.

Whether SSRIs are effective or not isn’t in question

While the original review paper focuses mainly on the serotonin theory, an accompanying article by Moncrieff and her coauthor Mark Horowitz in The Conversation took a different tack, arguing that the evidence against the serotonin hypothesis also disproves the need for SSRIs full stop. “We conclude that it is impossible to say that taking SSRI antidepressants is worthwhile, or even completely safe,” they write. This conflation has been a particular source of frustration among commenting psychiatrists. “Many of us know that taking paracetamol can be helpful for headaches and I don’t think anyone believes that headaches are caused by not enough paracetamol in the brain,” writes Bloomfield. “There is consistent evidence that antidepressant medicines can be helpful in the treatment of depression and can be life-saving.” [Updated July 27, 2022]

Bloomfield's statement is backed up by a significant body of research. While a debate separately exists around the critical element of whether antidepressants are more helpful than placebo, Moncrieff and Horowitz’s review can’t add any evidence to the pile either way, although Moncrieff has previously authored peer-reviewed articles highly critical of a drug-based approach to treating mental health. “It is important to point out that this study did not in fact look into the effectiveness of antidepressants directly. Antidepressants with serotonergic activity were already being used effectively for patients with depression prior to the theory of serotonin changes of depression,” commented Dr. Livia de Picker, a postdoctoral researcher at the University of Antwerp.

Is depression even a single disease?

While Moncrieff’s review is focused on disproving the idea of a particular cause of depression, perhaps the focus of debate should instead be on the idea that depression is a single disease. “Today, it is largely accepted that depression is a heterogeneous disorder with potentially multiple underlying causes,” says Prof. Gitte Moos Knudsen of the Copenhagen University Hospital, Denmark. As we have reframed cancer as not one but many diseases, perhaps mental health disorders like depression should be rethought of as resulting from many different environmental and biological factors. Abandoning the sole serotoninergic focus of the “chemical imbalance” model is a necessary part of that shift in thinking, but more work will have to be done to reframe the public’s perception of the complex biology of depression. 

Correction 

This article previously attributed a quote to Prof. Allan Young. It has now been correctly attributed to Dr. Michael Bloomfield. [Updated July 27, 2022]