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Antidepressants Work by Increasing Serotonin, Right? Right? A New Study Throws Shade

Antidepressants work by boosting the feel-good brain chemical serotonin, said all of us ever—until new research screamed “Nuh-uh.” What’s it mean if you take these meds? Seven top psychiatrists explain.

Imagine your brain is Instagram. Then serotonin—a neurotransmitter that governs your mood—is the tech that allows one brain nerve cell to slip into another’s DMs.

These messages tell your body what to do. Serotonin, often dubbed the “feel good” chemical, is the transport mechanism that delivers the message—like, for instance, about how to regulate your emotions in a given moment.

When you’ve got no Wifi and you can’t access your DMs, you’re not super jazzed, right? Maybe frustrated, irritated, even sad? So goes the theory for serotonin. As the Cleveland Clinic puts it, “When serotonin is at normal levels, you feel more focused, emotionally stable, happier, and calmer.” 

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And until a review of 17 serotonin studies hit the news this summer, the collective we—the general public, the media, the pharmaceutical industry, and pretty much all hospital sites—proselytized the theory that low serotonin levels lead to depression.

In fact, we believed, it’s why the most prescribed antidepressants, called SSRIs (or selective serotonin reuptake inhibitors), worked: They prevented serotonin from being reabsorbed by the nerve cells, leaving more of the big S in your brain. In other words, antidepressants increase serotonin and, as a result, improve depression symptoms. As the Mayo Clinic put it, “SSRIs treat depression by increasing levels of serotonin in the brain.” 

So when this 17-study review, published in the journal Molecular Psychiatry, declared that research showed “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,” you can imagine the freaking, the wigging, the ranting, and the wringing of OCD-raw hands (ok, that was me) that occurred.

What’s more, the review also suggested that depression is unlikely caused by a chemical imbalance of any kind. In the study authors’ words, current data “has not produced convincing evidence of a biochemical basis to depression.”

Mental’s Instagram followers, many of whom take an SSRI, responded to this news with a range of emotions, from “whaaaa” to “I don’t care what they’re doing, they help me function” to “confused” to “I don’t think anyone knows how brains work.”

Well, do they? What do doctors, particularly psychiatrists—the ones prescribing SSRIs—have to say? Should we stop taking our pills? Stay the course? Switch to a different antidepressant? Cry? Swear? Blame ourselves, if not our brains, for the fact we have depression in the first place? 

Thankfully, seven top psychiatrists answered the barrage of questions—including do antidepressants increase serotonin or not? And we won’t let you spiral on this key point: No, depression is not your fault. Here are their detailed thoughts on what this study means to you.

Jerrold F. Rosenbaum, M.D.
Psychiatrist-in-Chief Emeritus and director, Center for the Neuroscience of Psychedelics, at Massachusetts General Hospital, and Stanley Cobb professor of psychiatry at Harvard Medical School

“So SSRIs don’t work in the way you [Amy] thought they work, but psychiatrists and neuroscientists have known for at least 20 years that just increasing the amount of serotonin in the brain doesn’t explain how antidepressants treat depression. Antidepressants initiate however they work  by changing the dynamics of serotonin transmission, but that doesn’t mean that depression is caused by low or high levels of serotonin in the brain.

“The monoamine hypothesis about serotonin and norepinephrine was formulated in the 50s, when the tricyclic antidepressant medications [which, like SSRIs, block the reuptake of neurotransmitters including serotonin] were discovered to treat depression. Even before newer hypothesis about mechanisms of action, researchers and clinicians observed that  it took two, four, six weeks or more for the drugs to work, and the interaction with the serotonin system occurred immediately once you start taking one of these medications. So SSRIs in the their binding to the serotonin reuptake transporter were only in effect initiating a cascade of neurochemical and structural events that, downstream, eventually allowed some  people to recover.

“The currently most influential hypothesis of how they work is they can increase  neuroplasticity—that is, increases in new synapses and other neuronal structures, influencing how neurons sprout and connect and maybe even influencing neurogenesis is parts of the brain. This increase in neuroplasticity is more consistent with the time course of events of when SSRIs start showing results.

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“This response that, Omg we’ve had this wrong all along, is simply wrong. If there is a basis for the public’s misunderstanding, one might point to some of the advertisement efforts in the past including marketing efforts meant to convey both that there was a biology behind the medication and that  the disease of depression[ isn’t the sufferer’s  fault. Describing the serotonin mechanism of action served the goal of marketing but also destigmatizing.

“Doctors never thought a depressed patient pulled up to the pump and poured in serotonin. Again, antidepressants were discovered because they worked, not because we knew why they worked. We don’t stop taking efficacious medications just because we don’t know in detail how they work. All antidepressant treatments, including exercise and ECT, increase neuroplasticity, so that seems to seems to be an essential feature for treatment efficacy.

“Neurons when you’re under stress, or depressed, look like tree branches in winter. But with neuroplastic changes, they look like tree branches in springtime, with buds and growth.  

“[As to whether it’s still true to say that if you’re depressed there’s a chemical imbalance in the brain], you still have a brain, and it gives rise to the mind and it’s a complicated organ made up of wiring, chemicals, and structures that communicate with each other, and it is a challenging organ to study. We can image it in detail, which shows quite vividly how different parts of the brain communicate and interact with each other and how the balance among those ‘networks’ seem related to different psychiatric states. 

“Neurotransmitters including serotonin clearly are involved in depression because neurotransmitters are essential to how neurons in the brain signal and communicate with each other. And it may be that in very specific parts of the brain increasing neurotransmitter activity, as with dopamine in Parkinson’s Disease, that this is in fact critical to disease expression.

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“If you don’t have enough dopamine transmission in certain brain regions, you’re likely to experience depression and Parkinson’s. The level of neurotransmitters in brain regions this can matter. There are probably hundreds of genes involved in the neurochemical pathways that influence the change from well-being to depression.

“One of dilemmas when taking about depression is that the DSM-5 definition of it is very limiting—the symptoms  of DSM-5 major depression don’t feature common symptoms like increased hostility, irritability, and rumination. The diagnostic criteria include 9 possible symptom but you can generate225 phenotypes that are different from each other. You can have two people who don’t have a single symptom in common and still meet the criteria. There are those with onset in childhood with depression, and others who don’t develop it until their 70s. Some with brief and recurrent symptoms and some with chronic unremitting symptoms. Some are influenced profoundly by external factors and some that seem completely autonomous. The DSM is useful for giving a name to a condition. It’s useful for billing. It’s useful to identify a population of people who have depressive emotional distress in common, but it is not an ideal tool tool to understand the biology of depression.

“Depression is heterogeneous. There are likely hundreds of genes associated with a risk profile, and it is unlikely that two people are alike. We talk about a goal of  precision psychiatry that can select treatment in accord with  your unique biology and life experience, but the reality for now is that the best treatments we have so far are nonspecific and work across different types of depression.

“Consider fever: It has a number of characteristic symptoms, like high temperature, pain and achiness, fatigue, sweating etc. If you said, ‘this patient has fever disorder, and I have this treatment for it—aspirin,’ you wouldn’t say fever is an aspirin deficiency disorder. Or an antibiotic may not work for one fever and yet be magical for another, and a broad spectrum antibiotic may work across a number of different causes of ‘fever disorder.’ So antidepressants are a bit broad-spectrum, but perhaps one day we will be able to be more precise and match our treatments to more specific knowledge of cause or biology. Some people do respond to one combination of treatments, some to another, and unfortunately some may not now match to a treatment that helps. If you haven’t responded to one treatment, you should not stop trying. The treatment is a journey, with many options from medications of varying mechanisms, devices, therapies and beyond.”

Julia R. Frew, M.D.
Assistant professor of psychiatry and vice chair of education, department of Psychiatry at the Geisel School of Medicine at Dartmouth Hitchcock Medical Center

Are you surprised by the findings? 
“This article is a systematic review, which means that it gathers together and examines evidence from other studies. The main finding of this review was that depression does not appear to be caused by low levels of serotonin in the brain. I am not really surprised by these findings, because this is not new information. While it is appealing to think of depression being ’caused’ by a shortage of the brain chemical serotonin, it has been clear for several decades that this is probably not the case. Depression is a complex illness with many different causes. While depression is associated with abnormalities in various brain circuits, this is not as simple as a shortage of serotonin. However, just because depression is not caused by a shortage of serotonin, this does not necessarily mean that serotonin reuptake inhibitors (SSRIs, a commonly used type of antidepressant) are not effective in treating depression in some people.”

The study authors seem to suggest there is not a chemical imbalance in the brain. Do you agree or disagree?
“The study authors specifically provide evidence that the ‘serotonin hypothesis’ of depression is likely not accurate, or in other words, that depression does not appear to be caused by a shortage of serotonin in the brain. This is not the same as saying that there is not a biological basis to depression, but rather that this basis is not as simple as having too much or too little of a specific brain chemical. Many studies have demonstrated changes in the brain and elsewhere in the body with depression, in some cases using brain imaging technology to look at brain function. However, this introduces a “chicken or egg” question—does abnormal brain function cause depression, or does the state of being depressed cause the brain to function abnormally. The answer is probably both. We know that depression is a complex illness or perhaps group of illnesses that has many different causes including genetics, life stress (especially early life trauma), and other factors such as hormonal changes or inflammation.”

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Do you believe that SSRIs still work to treat depression?
“Evidence suggests that SSRIs do help many individuals with depression. We think that SSRIs help to normalize the function of brain circuits in depression and other disorders, but the exact mechanism of this is unclear and is not as simple as just raising serotonin levels.”

Will you still recommend SSRIs for the treatment of depression and other mental health conditions? 
“Yes, I will still recommend SSRIs to my patients as one of the tools in the toolbox for treating depression and anxiety disorders. SSRIs clearly help some people with depression, but not everyone, unfortunately. About half of people with depression will have a treatment response to SSRIs, meaning that their symptoms improve meaningfully. However, only about a third of people reach a full remission of depression with an SSRI. For those who do not respond, options include trying a different medication or adding a second medication.

“Psychotherapy is also an important part of treatment for depression and anxiety disorders and can be used in conjunction with medications or on its own. Even some of the internet-based psychotherapy options can be very effective if seeing a therapist is not available or affordable. I also recommend attention to nutrition, sleep, exercise, and a mindfulness practice as part of everyone’s daily routine for mental well-being. For people with severe depression who have not responded to multiple medication trials as well as to psychotherapy, treatment can include electroconvulsive therapy, transcranial magnetic stimulation, or treatment with ketamine. Research is ongoing to develop new treatment options for depression and other psychiatric disorders, so we may have even more options in the future.”

Key takeaway from this study?
“The key takeaway for me is that the brain is an intricate organ that scientists are still working to understand and that depression is a complex illness that has many causes, both biological and psychological. In other words, depression is an illness of both the brain and of the mind, and is not as simple as a shortage of a single brain chemical like serotonin. That being said, SSRI medications are still a useful tool that help many people and can be considered as part of an overall treatment plan for depression and anxiety.”

Priyanka R. Amin, M.D.
Assistant professor of psychiatry at the University of Pittsburgh School of Medicine

Are you surprised by the findings?
“I was not surprised by the results, as this umbrella review was focused on one specific neurotransmitter that has been implicated for depression. It is important to understand that the review was not a research study testing a hypothesis. Umbrella reviews look at and synthesize what previously published systematic reviews and meta-analyses had found about research on a specific topic.

“This review looks at ‘the serotonin theory of depression,’ which may be the public’s perception of what causes depression—serotonin was suggested as part of the monoamine hypothesis of depression, which includes other monoamines, such as dopamine and norepinephrine, not just serotonin. It has been decades since the field has thought that depression was due to a chemical imbalance. Depression is likely caused or mediated by several factors and is a heterogeneous diagnosis.”

The study authors seem to suggest there is not a chemical imbalance in the brain. Do you agree or disagree?
“I do not think that the review can conclusively state this for a few reasons. First, trying to get accurate measures of serotonin in prior studies has been challenging, leading to the use of proxy measures. Second, serotonin is just one of the chemicals that has been proposed as causing depression. Regardless, I think viewing depression as a chemical imbalance in the brain is an oversimplification of the pathophysiology.” 

Do you believe that SSRIs still work to treat depression, just in some other way?
“I do believe that they work for many individuals with depression, given the body of research demonstrating their efficacy as well as our clinical experience.”

Key takeaway from the study?
“Given the public’s perception of this review, it is clear there is a gap between what our understanding of the pathophysiology of depression versus the general population’s perception of what causes depression.”

Monisha Vasa, M.D.
General/addiction psychiatrist; resident physician wellness consultant, UC Irvine department of family medicine and pediatrics; and physician and trainee wellness consultant, City of Hope National Medical Center
Are you surprised by the findings?
“Most psychiatrists, myself included, have not subscribed to the belief that depression is solely caused by a lack of serotonin in the brain for quite some time. As such, I was not surprised by these findings. Depression is a complex and multi-factorial disorder, and there is still much we have to learn and understand about the biological underpinnings.”
The study author says there is not a chemical imbalance in the brain because of these findings. Do you agree or disagree?
“This is an overly simplistic conclusion, in my view. The symptoms of depression are not solely caused by a lack of one neurotransmitter in the brain. That doesn’t mean that there aren’t differences in the brains of those who struggle with depression or anxiety, or that biological interventions may not help in ways other than simply elevating serotonin. For example, Tylenol can help a headache, even though headaches are not caused by a Tylenol deficiency.” 
Do you believe that SSRIs still work to treat depression, just in some other way?
“We use SSRIs because their efficacy has been demonstrated based on randomized, controlled clinical trials—not on the basis of the serotonin hypothesis of depression.  We still don’t fully understand the exact mechanism of how and why they work. One theory is that they enhance neuroplasticity within the brain.
“It is also important to note that, as psychiatrists, we consider a biopsychosocial model when understanding and treating depression. Medications may be one part of the biological approach. However, we also need to look at the big picture, including other biological factors such as substance use, underlying medical conditions, nutrition, sleep, and more. We also need to address psychological factors such as past or present trauma and loss, as well as social issues that could be impacting one’s mental health. A full understanding of an individual’s depression should include all of these factors and address them in a comprehensive treatment plan.”   
Will you still recommend SSRIs for the treatment of depression?
“Whether we recommend medications depends on a variety of factors, such as the severity of the depression, diagnosis, prior response to medication treatment, other medical conditions, and, of course, patient preference. We as psychiatrists share what we know and make recommendations based on our experience and training. But ultimately, we make decisions jointly and collaboratively with our patients regarding how to proceed with treatment.
“It is our job to share the risks, benefits, and alternatives of any intervention—including medications and therapy—and support patients in their decision-making. We want to answer any and all questions that a patient may have. We also want to address issues such as shame and stigma that often influence how patients feel about taking medication.
“In my experience, medications have been life-saving for many of my patients, and I will certainly continue to recommend them when appropriate—alongside other biological, psychological, and social interventions.”  
Key takeaway from this study?
“I think a key takeaway from this study is that many individuals in the general public may still believe that low serotonin is the sole cause of depression. We as psychiatrists need to know that. It is important that we continue to educate our patients, and the community at large, that depression and all mental health conditions are complex and multi-factorial. 
“Just because the low serotonin hypothesis doesn’t fully explain depression doesn’t mean there aren’t biological aspects that are still helped by medication. I would encourage all patients to share their concerns and questions with a mental health professional, and not make any rash or abrupt decisions about their current medication regimen based on this study.”

Jason Cafer, M.D.
Assistant professor of clinical psychiatry at the University of Missouri School of Medicine

Are you surprised by these findings?
“Psychiatrists have known for a long time that ‘chemical imbalance” was not technically accurate and an oversimplification. We knew what SSRIs did but were less certain of how they worked.

“Depression is more of a problem with the neurons and networks of neurons that interact with chemicals—neurotransmitters including serotonin. Chemicals can help depression, but that does not mean that chemicals (serotonin and other neurotransmitters) were necessarily out of balance.”

Do you believe that SSRIs still work to treat depression, just in some other way?
“In my book, Cafer’s Psychopharmacology: Visualize to Memory 270 Mascots, I describe how serotonergic antidepressants lead to changes in serotonin receptors, something that takes a few weeks. Antidepressants may also reduce brain inflammation.

“[I will still recommend SSRIs] for typical depression with anxious distress. SSRIs are the most effective medication for OCD. Many effective treatments for depression do not involve serotonin at all: bupropion (Wellbutrin), lithium, transcranial magnetic stimulation, electroconvulsive therapy, esketamine, etc. With depression of bipolar disorder, SSRIs are generally not helpful.”

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Key takeaway from this study?
“Pharmacologic treatment of depression is complicated and there is not a straightforward way to explain to patients how antidepressants work. I tell them that antidepressants help correct a brain imbalance (dysfunction) by affecting neurotransmitters (serotonin, dopamine, norepinephrine) and reducing brain inflammation. Psychotherapy and a healthy lifestyle can also correct depressive brain dysfunction.”

Lissa Garcia Segui, M.D.
Psychiatrist in Houston, Texas

“From my point of view, the [study] implies or suggests that mental health professionals have completely ignored the huge importance of therapy. Psychiatrists often have a bad reputation (some have earned it) for ‘pushing for meds.’ But after reading way too many reactions to the study on social media of people suggesting to ‘start using’ therapy rather than relying on antidepressants—as if antidepressants don’t work at all—I want to emphasize that therapy is a part of treatments that psychiatrists do use and recommend.

[Many people missed] the point of the study, which repeats what has been said for years: that the mechanism of action of SSRIs might still be unknown and might be other than actually being directly linked to serotonin. Some people reacted as if, Medication is not the solution and not necessary; let’s rely on therapy 100 percent. I feel it is important to defend both treatment options, as they both can give excellent results, especially when combined together—of course, evaluating each case individually.

“Personally, I don’t know what I would do without therapists. I would say that roughly 95 percent of my patients are referred for therapy to get to the root of the issue and make long-lasting changes in behavior, learn coping techniques, etc. Now, when meds are needed, they’re needed, period. Therapy can only do so much when depression has reached the point of not letting the person be functional. 

“Also, not every SSRI is for everyone; sadly, there’s no magic recipe to know which one will work for whom. Each body reacts differently, and that’s ok, let’s move to the next option until we find something that helps. Managing expectations of what meds can do for someone is the beginning. Meds won’t magically solve your problems. It’s a very slow process, but after we find the one that works, it does give positive results.

Sue Varma, M.D.
Psychiatrist in New York City
“[This study] is not going to change the way that I practice. SSRIs have been beneficial for so many people—we know that it works. Depression is multifactorial. We are learning more about the social determinants of mental illness, things like adverse childhood events, and the importance of taking a detailed history on trauma and understanding its role in mental illness and having it treated. There is the role of addiction in mental illness. We also know that we are going through a loneliness crisis that is affecting people’s mental health and well-being.

“There is also the role of nutrition, exercise, and health habits—not to mention finding meaningful activities. When we don’t have or experience a sense of purpose, it worsens our mental health. I have always said that depression is complex. I would never reduce depression to a chemical imbalance. Many physicians practice (at least I do) a 360 holistic approach to mental health and wellness.”

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