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The New Study on Serotonin and Depression Isn’t About Antidepressants

In the original TV ad for the antidepressant Zoloft, a gray cloud hovers over a sad blob, rain falling on the blob’s dejected expression. “You know when you feel the weight of sadness,” a voiceover says.

The commercial lists the symptoms of depression, and explains that “while the cause is unknown, depression may be related to an imbalance of natural chemicals between nerve cells in the brain. Zoloft works to correct this imbalance. You shouldn’t have to feel this way anymore.”

Screenshot from original Zoloft commercial.

Screenshot from original Zoloft commercial.

The chemical the ad is referring to is serotonin, a neurotransmitter that does many things in the brain and has long been theorized to have something to do with the symptoms of depression. The slightly more complex version of the story that ad is alluding to goes that depression is caused by a “chemical imbalance,” or low or abnormal levels of serotonin, and that taking an antidepressant, or selective serotonin reuptake inhibitor (SSRI), by changing serotonin levels in the brain, makes a person feel better.

In the face of this story, it’s easy to understand how a new paper in Nature Molecular Psychiatry this week seemed like a bombshell. In a systematic review of studies on serotonin levels in people with depression, it found no evidence that depressed people had lower serotonin levels or abnormal serotonin activity compared to non-depressed people.

But the serotonin story of depression was just that: a story. It was a hypothesis that turned into a simplistic representation of a guess about the underlying causes of depression and how to “fix” it. Researchers and clinicians, in their responses to the review, said this theory hasn’t been widely held by the mental health community for some time. Yet the paper, and the response to it, reveal the still-existing chasm between what mental health professionals say they know and what the general public understands about what causes depression, and how it’s treated.

Past that, though, there’s been a larger pushback to this paper that has little to do with serotonin levels not causing depression. Clinicians and researchers told Motherboard they were worried about the framing of the findings, which are being used to question the utility and efficacy of antidepressants—imperfect drugs that aren’t for everyone, but do help a substantial amount of people with their symptoms.

Media coverage has honed in on the review’s findings specifically as they relate to the use of antidepressants. The Daily Mail reported, “Today’s landmark findings call into question society’s ever-growing reliance on antidepressants like Prozac.” The Guardian’s subhed was, “Researchers question use of antidepressants, prescribed to one in six UK adults.” In a summary of the work for The Conversation, two of the paper’s authors wrote, “If antidepressants exert their effects as placebos, or by numbing emotions, then it is not clear that they do more good than harm.”

This is what the new paper is overwhelmingly receiving critical feedback on: taking its findings, and making leaps to comment on the efficacy or mechanisms of antidepressants—something not reviewed in the paper itself. Context is important here: the mental health ecosystem this paper was released into is one in which some mental health professionals are raising questions about the basic practices of mental health interventions—from diagnoses and medication to the basic way mental illness is conceived of.

This new review is valuable in that it reveals what the general public still thinks about depression and its causes, and where mental health professionals need to do better in communicating the complexity underpinning conditions like depression, as well as its treatments. But Lucy Foulkes, an academic psychologist and author of Losing Our Minds: What Mental Illness Really Is–and What It Isn’t, said that multiple issues are being conflated in the interpretation of this paper. There are two separate questions being raised. One is: Do depressed people have different levels of serotonin? The review suggests the answer is no. The second question is: Do SSRIs work to help some people with symptoms of depression?

“The second question isn’t addressed in the paper,” Foulkes said. “The danger is, it’s now being used to answer that question.”

The new review combined evidence from 17 systematic reviews and studies, with data from hundreds of thousands of people both with and without depression. It found that there was little credence to the idea that low serotonin activity or low amounts of serotonin are associated with depression.

Some of the immediate responses from other mental health professionals pointed out that the chemical imbalance theory has long been known not to be a simple way to explain the cause for depression. Alexander Harris, a psychiatrist and neuroscientist at Columbia University, told Motherboard that he can’t speak to what all clinicians know, but that “the standard of care among psychiatrists and the consensus among depression researchers is that low serotonin is not the sole cause of depression.”

Awais Aftab, a psychiatrist at Case Western Reserve University, agreed, saying that the findings don’t alter the current scientific understanding of what causes depression, “which we recognize to be complex, heterogenous, and multifactorial, nor does it have any bearing on contemporary guidelines and practice recommendations regarding the use of antidepressant medications, which are based on efficacy data from clinical trials and not the serotonin hypothesis.”

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Still, there can be a difference between what experts know and the general public knows. The authors of the new paper cited surveys that suggested that more than 80 percent of the general public think depression is definitively caused by a “chemical imbalance.” In response to questions from Motherboard, the paper’s first and senior authors, Joanna Moncreiff and Mark Horowitz, psychiatrists at University College London, said that the narrative that depression is caused by a chemical imbalance is still widespread. “Just last week in the UK a GP was on the BBC explaining that people with depression need antidepressants to treat their chemical imbalance,” they said.

They allowed that it may be true that academic psychiatrists “acknowledge that the links between brain chemistry and depression are more complex, but they have not sought to correct this misconception in the public’s minds.” In a paper from this year, Moncreiff and Horowitz found numerous references to the “serotonin theory” in “highly cited and influential academic literature” from 1990 up to 2010.

Moncreiff and Horowitz said that while many prominent psychiatrists have responded to their study saying the findings are not new, their responses should be “compared to the fascination and interest produced in the public,” with the study and media coverage of it being widely shared and read.

But the controversy around this paper lies beyond who knows or doesn’t know that the chemical imbalance theory is regarded as outdated. The paper received most of its criticism for the extrapolation of these findings onto the use or mechanism of antidepressants. Harris said that while he found the paper’s results wholly unsurprising, as he read on, he felt the framing of the article “demonized brain-based explanations of depression and the use of antidepressant medication to treat depression.”

Some of this came from the authors themselves, not the media. Moncreiff tweeted that the reason this research was important was directly tied to antidepressants. “This research is important because many people take antidepressants because they have been told they have a chemical imbalance. It may be difficult news, but people deserve to know there is no evidence to support this idea,” she wrote. “This underlines how we do not know what antidepressants are doing to the brain, [especially] in [the] long-term, and should be more wary of prescribing them.”

This review paper was not designed to probe the psychopharmacological mechanisms of antidepressants, nor their efficacy. Its focus was a narrow one: the relationship between depression and lowered serotonin concentration or activity. Aftab also found the most problematic part of the paper to be the implication that their findings lead to a reason to stop the clinical use of antidepressants, or that antidepressants must only work through placebo effect, or the numbing of emotions.

“It does not systematically review evidence related to neurobiology of depression, it does not systematically review the mechanisms by which antidepressants may produce therapeutic effects, and it does not systematically review clinically efficacy of antidepressant medications,” Aftab said.

In response, Moncreiff and Horowitz said that their paper is focused on the lack of evidence for low serotonin or low serotonin activity in depression, and that “it does not address the effectiveness of antidepressants in clinical trials.”

Still, they asserted that “Patients have been told by doctors that antidepressants ‘work by correcting an underlying chemical imbalance’, in the same way as ‘insulin treats diabetes.’ Our paper finds that this is not supported by evidence.” They asked, “If they are not rectifying an underlying chemical deficiency then this brings up the question of what they are actually doing?” Moncreiff and Horowitz suggested the placebo effect or the “emotional numbing” of antidepressants may explain why it helps some people overcome a low mood. “Some people might want to take drugs that numb emotions, but many would probably not,” they said.

There are many other hypotheses about how antidepressants may help with the symptoms of depression, like the idea that they enhance neuroplasticity, or interact with serotonergic activity in brain circuits that are involved in reward seeking and mood. In people who experience depression, there may not be something “wrong” or “imbalanced” in their brains, but an SSRI could still interact with these circuits, and in some people, improve mood in that way. There are many reviews that suggest that antidepressants are helpful in the treatment of depression for some people—beyond placebo effect.

The additional important context of understanding the reactions to these claims about antidepressants is that the authors are part of a community that are vocally skeptical of psychiatric medication in general, and sometimes called “critical psychiatry” or “anti-psychiatry.” These groups can raise important issues around the limitations of individualized interventions, ethics in psychiatry, and conceptual questions around diagnoses, while some more extreme proponents challenge the existence of what we call “mental illness” at all.

“A different team of researchers could’ve taken the same findings and discussed them differently, and the reception would’ve been very different,” Aftab said. “It so happens that this review was conducted by authors who take a skeptical view of the efficacy of antidepressants, are of the opinion that the harms of the medications outweigh any benefits, and are inclined to think that millions of people have been duped into taking antidepressants because of the chemical imbalance narrative. From such a vantage, this review comes as a bombshell, a decisive blow to the hypothesis that provided a rationale for the use of antidepressant medication.”

Moncreiff and Horowitz said that they thought it was “unfortunate that people use labels like ‘anti-psychiatry’ to sideline discussion of topics that are important to patient care and safety.”

“I don’t think it is ‘anti-psychiatry’ or stigmatizing to carefully evaluate and examine the effectiveness and safety and medications that are widely prescribed—it is our duty as responsible clinicians,” they said.

They told Motherboard that they hope their paper gives people more accurate information about their mental health and options for treatments. “Patients should not be told that their depression is caused by low serotonin or a chemical imbalance because this is not supported by evidence,” they said.

They added that “no one should stop their antidepressant abruptly. Doing so can cause withdrawal symptoms (which can sometimes be mistaken for a return of an underlying condition) which in some people can be severe and long-lasting. People should always talk to their doctor and stop their antidepressant gradually in order to minimize the risk of withdrawal effects.”

The impact that this paper had is proof less of a byproduct of an earth-shattering, novel statement made about the mechanisms of depression, and more a reflection of the beliefs most people still hold about what causes depression. For those in the general public surprised by the paper’s findings, it’s likely because they are still inundated with the idea that depression is caused by a “chemical imbalance.” This is important to be aware of. Mental health professionals have been complicit in perpetuating this myth, and at the very least, have not succeeded at correcting it.

“Mainstream medical and psychiatric organizations have made very little efforts to correct this widespread misunderstanding,” Aftab said. “The complacency of the psychiatric establishment should not be downplayed in my opinion and this scandal could’ve been avoided if they had been more proactive.”

As with many complex topics, we are being asked to contend with several truths at once. Antidepressants can cause side effects, they can be difficult to taper off of, and an over-focus on them as an intervention can de-prioritize non-pharmacological or social interventions. Also, sometimes they just don’t work. If depression was caused by low serotonin, and SSRIs only effect on the brain was to increase serotonin, then these drugs would have long been miracle cures for everyone who tried to take them. That’s not the case.

But just because antidepressants don’t work by altering the amount of one single neurotransmitter, doesn’t mean they’re not clinically useful or have effects beyond placebo, or that they don’t powerfully help some people with their depression symptoms.

We shouldn’t give up on understanding the mechanisms of depression, which could lead to even better interventions. In a recent paper in JAMA Psychiatry, Aftab argued that studying psychopharmacological mechanisms of mental health requires “explanatory pluralism,” or the ability to conceive of the interactions of multiple explanations for these conditions, not limited to biology, but also psychosocial influences—and how all these parts interact with one another.

The British statistician George E. P. Box wrote, “All models are wrong, some are useful.” In many cases, what helps people in the clinic today may lie outside of biology, and many psychiatrists do advocate for a stronger focus on the social forces that bring about distress—in part, because these interventions are actionable right now, before we gain a better grasp on the inner workings of the brain and how it relates to mood and behavior.

But clinicians should proceed with humility and transparency. “We have to acknowledge the uncertainty and the limits of what we know,” Aftab said. “Many patients who were told that antidepressants correct a chemical imbalance feel, with good justification, that they were deceived or lied to, and it is important for clinicians to avoid saying things, even if they are said with good intentions, that can later be perceived as being deceptive or misleading.”

The story of serotonin and depression ultimately reminds us how much of a story there is at all in our understanding of our mental experiences. This doesn’t mean distress is made up, or that there is no consistency or biological underpinning to mental illness. But there is a social and cultural packaging that goes along with it, that can become entrenched, extremely sticky, and, at times, contentious. It can also be confusing for those trying to navigate this thicket of meaning.

Jake Johnson, a philosopher of psychiatry, said that it can lead to people being “epistemically adrift” from having to navigate their life with both the uncertain experience of having a mental disorder, while facing “social stigma, expert disagreements, and cultural debates as to what disorders are and how to treat them,” he said. “People are epistemically adrift when they feel that they must take responsibility for their mental health but are at a loss as to what these conditions are, how best to treat them, or who to trust regarding mental health information.

Constantly confronting different models and explanations for what causes mental illness—or what it is at all—leads to different understandings of the moral and personal responsibility of having these conditions. “Papers like this have a complicated effect on people with depression in trying to navigate their conditions and self-understanding,” Johnson said. That needs to be recognized too.

It’s interesting to consider why the chemical imbalance myth has persisted, and if there are lessons to learn for the future of mental health communication. Johnson thinks it’s because it offered a simple explanation, a raft to cling to while drifting around in all the uncertainty. In a way, it’s similar to older explanatory models of health, like Galen’s humoral theory of medicine, which claimed that the balance of the four different bodily fluids—blood, phlegm, yellow bile, and black bile—must be maintained to prevent illness. Madness was caused by an imbalance of black bile.

The chemical imbalance myth is a prudent warning for new mental health interventions and theories to be wary of pushing overly simplistic biological explanations—which can be sticky, and take on lives of their own, far into the future, with unseen consequences.

“Depression remains a fairly uncertain condition, and people gravitate to whatever half-truths or inconclusive theories appear sensible to them,” Johnson said. “This paper may just add to public confusion regarding what depression is and what it isn’t. I fear the best chance we have for moving on from this model is for its replacement with another simplified and compelling theory for the causes of depression, but there is no promise that such a theory will be more accurate, helpful for treatment, or alleviate stigma.”

Follow Shayla Love on Twitter.

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