How Depressing!

For many of us there seems to be no lack of reasons to be depressed about the state of the world. Where to turn for relief? Psychiatrists often prescribe SSRIs—Selective serotonin reuptake inhibitors. Better living through chemistry—brain chemistry!

Today at TGP there’s an interesting post on the topic of SSRI use, and it seemed timely to me in a general way, since we’ve recently been discussing the role of drugs—whether prescribed or through self medication—in the context of mass shootings. It seems the science isn’t “settled”, to say the least:

A New Study Says Antidepressants Are Not The Answer to Depression

The post summarizes an article at Psychology Today, which you can access here. As you can see, Psychology Today pitches the new study (conducted by researchers at University College London) much more strongly:

A Decisive Blow to the Serotonin Hypothesis of Depression

An exhaustive new review debunks the “chemical imbalance” theory of depression.

KEY POINTS

• Surveys indicate that 85-90 percent of the public believes low serotonin or a chemical imbalance causes depression.

• One study found that among 237 psychology students interviewed, 46 percent had heard the chemical imbalance explanation from a physician.

• The serotonin hypothesis has been challenged repeatedly and found wanting, even as it remains popular and influential in everyday life.

• A comprehensive, well-powered, high-quality umbrella review now determines that the theory is “not empirically substantiated.”

It turns out that doubts about SSRI use and the underlying hypothesis are not new. I would guess that the popularity of the hypothesis coincides with the rise of belief—I use the word advisedly—in man as a purely material being. In the popular phrase, the pharmaceutical industry saw multi-billion dollar profit potential in them thar ills:

The poor standing of the hypothesis in the scientific literature, however, barely dented its afterlife in textbooks, across clinical and treatment settings, and on mental health apps and websites. Nor has it dispelled the continued use of the phrase as “shorthand” between doctors and patients and in everyday settings, including for quite different mental states and conditions.

The “Chemical Imbalance” Metaphor Takes Root

Revisiting the history of this controversy raises several still-relevant details. In December 2005, as advertising for SSRI antidepressants flooded American magazines, talk shows, and network TV, the result of multibillion-dollar campaigns pitched in this case directly to consumers, Florida-based professors and researchers Jeffrey Lacasse and Jonathan Leo asked pointedly in PLoS Medicine, “Are the claims made in SSRI advertising congruent with the scientific evidence?”

The answer in “Serotonin and Depression: A Disconnect Between the Advertisements and the Scientific Literature,” their well-researched article, was a resounding no. The resulting “incongruence,” they determined, was “remarkable and possibly unparalleled.”

Lacasse and Leo found repeated evidence that the U.S. Food and Drug Administration had approved the marketing of SSRIs with two phrases still heavily in the subjunctive—that depression “may be due to a serotonin deficiency” and that SSRI efficacy, “modestly” outcompeting placebo, was “presumed to be linked to potentiation of serotonergic activity.” However, the research itself could not identify the precise mechanism.

Could this be true? I turned to Wikipedia to discover the truth! What I read wasn’t reassuring (there’s much, much more at the link, including re side effects):

Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions.

Something like a psychological panacea?...

SSRIs are the most widely prescribed antidepressants in many countries. The efficacy of SSRIs in mild or moderate cases of depression has been disputed and may or may not be outweighed by side effects, especially in adolescent populations.

Back to Psychology Today, where we learn that the FDA indulges in or accepts “aspirational language”. That’s science-speak for, well …

The FDA had accepted aspirational language that the drugs “help to restore the brain’s chemical balance” and “bring serotonin levels closer to normal,” even though both claims were, and remain, scientifically meaningless.

“There is no such thing as a scientifically established correct ‘balance’ of serotonin,” Lacasse and Leo cautioned more than a decade ago, joining numerous other experts then and now. Additionally, both aspirational claims rest on a hypothesis that follow-up studies would end up contradicting repeatedly. In short, both the hypothesis and the expensive marketing that pushed it into American living rooms rested on a hedge: “Scientists believe that it could be linked with an imbalance of a chemical in the brain called serotonin.”

A Multibillion-Dollar Error

The hedge proved highly effective, even though, as David Healy explained in 2015 in “Serotonin and Depression,” in the BMJ, in practice, it entailed embracing or tacitly accepting “the marketing of a myth.” Through further oversimplification, a revised metaphor of a “chemical imbalance” took root as folk wisdom for multiple, dissimilar conditions listed in the DSM.

Returning to the controversy in “Antidepressants and the Chemical Imbalance Theory of Depression” (2015), Lacasse and Leo found that while the marketing had shifted emphasis from “correcting imbalances” to “‘adjusting’ or ‘affecting’ neurotransmitter levels,” leading psychiatrists were if anything, more wedded to the “chemical imbalance” metaphor than before.

Some had taken to the airwaves to say that it simplified communication with their patients. Daniel Carlat, the editor of The Carlat Psychiatry Report, explained on National Public Radio when asked what we know about psychiatric medication:

We don’t know how the medications actually work in the brain…. 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—I think I say that because patients want to know something. And they want to know that we as physicians have some basic understanding of what we’re doing when we’re prescribing medications. They certainly don’t want to know that a psychiatrist essentially has no idea how these medications work (Qtd. in Lacasse and Leo).

Oh. That’s reasonable—in a sorta way. If all you’re really looking for is reassurance, rather than actual knowledge.

The article goes into lots more detail, but I’ll skip to the concluding section that extensively quotes one of the authors of the study:

Legacy Effects of a Discredited Theory

“The popularity of the chemical imbalance idea of depression has coincided with a huge increase in the use of antidepressants,” note Moncrieff and coauthor Mark A. Horowitz in the study’s press release. “Prescriptions for antidepressants have sky-rocketed since the 1990s, ...”

The practical ramifications of the umbrella review are thus vast and consequential, involving millions of people across multiple countries because the findings are tied to a discredited theory that is still fueling mass prescribing on a global basis.

Moncrieff explained in the press release:

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 hypothetical and unproven abnormalities. In particular, the idea that antidepressants work in the same way as insulin for diabetes is completely misleading. 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.

Invited to extrapolate the review’s findings for Psychology Today, Moncrieff added:

Antidepressant use has reached epidemic proportions across the world and is still rising, especially among young people. Many people who take them suffer side effects and withdrawal problems that can be really severe and debilitating. A major driver of this situation is 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.

Still, it’s reassuring to know that this is an isolated instance, and that there are no other examples of widespread prescription of powerful pharmaceuticals with well established and serious side effects, based on discredited pretty-much-seat-of-the-pants hypotheses, aka WAGs. Right?