Treating depression takes much more than serotonin

Neurotransmitters can't tell the whole story, no matter what "serotonin culture" says.
serotonin molecule structure
"Serotonin’s association with happiness and depression recovery is so well known that the molecule has become lucrative." topteen/depositphotos

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Grace Huckins is a Ph.D. student in neuroscience and philosophy at Stanford University. She holds two master’s degrees, in neuroscience and gender studies, which she obtained from the University of Oxford with the support of a Rhodes Scholarship. She currently writes and produces a podcast for NeuWrite West, an online outlet dedicated to the communication of neuroscience, by neuroscientists, to a public audience. In the past, she has written extensively on arts and culture for The Harvard Crimson. She lives in San Francisco, California.

Antidepressants aren’t a perfect solution to depression. So why do we act like they are?

On the internet, in newspapers, and in casual conversation, the brain can sound like an amusement park: reward centers “light up,” dopamine “floods” our system, we experience an “adrenaline rush.” In this simple world, depression is no longer a mysterious, devastating specter: it’s nothing more than a shortage of serotonin, the brain’s “happy chemical.” Unfortunately for those who suffer from depression, however, the truth is not nearly as straightforward as the internet might lead us to believe.

Serotonin’s association with happiness and depression recovery is so well known that the molecule has become lucrative. On Etsy, one may browse nearly 2,000 serotonin-themed necklaces, earrings, and trinkets. In loving homage to TV chef extraordinaire Ina Garten, Reddit user /u/annybananny coined a slogan that has since circulated widely on social media: Much like tomato sauce or pie crust, “If you can’t make your own neurotransmitters, store-bought is fine.” The motto has since been plagiarized by dozens of opportunists looking to make a quick buck.

Undoubtedly, there’s value in a phrase that implicitly equates Prozac with artificial insulin. Just as diabetes is no more than the body’s inability to produce its own insulin, so too is depression a straightforward, explicable physical ailment. Dozens of studies have established that stigma worsens the severity of mental illness symptoms, so the belief that mental illness and physical illness are really no different might literally alleviate one’s depression.

There’s one glaring problem, however: there’s no evidence that a lack of serotonin causes depression. While this theory, termed the “monoamine hypothesis” of depression, has remained popular since it was first proposed in the 1960s, by the 1990s various strains of evidence had established that it was at best a gross oversimplification. And the idea that depression treatment is as simple as augmenting your meager supply of neurotransmitters might actually be harmful.

Serotonin and SSRIs: A deceptively simple story

To the credit of public science (or, perhaps, the pharmaceutical industry), the basic contours of “serotonin culture” hold water. The jewelry and wall decorations available online accurately represent the structure of serotonin, a small, organic molecule that the human body makes naturally from L-tryptophan, an amino acid found in numerous foods. It is one of many neurotransmitters, molecules that neurons use to communicate with one another over the gaps between them, called synapses. When one neuron releases serotonin into a synapse, the molecules drift across to the subsequent neuron, in which they can provoke a variety of responses.

Serotonin also almost certainly plays a role in most pharmacological treatment of depression. Lexapro, Prozac, and Zoloft are all selective serotonin reuptake inhibitors (SSRIs), which means they prevent neurons from clearing serotonin out of their synapses. The serotonin then lingers in the synapse, where it can exert more of an effect on the neuron that receives it. SSRIs aren’t themselves serotonin pills—they don’t contain neurotransmitters—but they do act to increase the influence of serotonin in the brain.

The efficacy of SSRIs and of their precursors, monoamine oxidase (MAO) inhibitors, motivates serotonin theory. In fact, the monoamine hypothesis first arose when physicians discovered by chance that MAO inhibitors, which were used to treat tuberculosis, also had a positive effect on patients’ moods. If drugs that increase serotonin in the synapses can alleviate the symptoms of depression, it stands to reason that those symptoms could be caused by a lack of serotonin.

Serotonin theory was a great hypothesis—but it didn’t hold up under scrutiny

Even today, the relief that antidepressants provide for the 13% of Americans who take them remains the strongest evidence in favor of serotonin theory. But even that evidence is not bulletproof; upon examining the data more closely, the walls of serotonin theory quickly begin to crumble.

The first major hole in serotonin theory is the timeline of SSRI effects. Whereas a depressed patient who begins SSRI treatment will have increased serotonin levels in their synapses within hours, SSRIs take four to six weeks to exert a measurable effect on symptoms. If depression is simply a lack of serotonin, one would expect such a therapy to provide much quicker results.

This is not to say that serotonin is meaningless. Given enough time, SSRIs absolutely do have a measurable impact on depression symptoms when compared to placebo. Unfortunately, and quite worryingly for a culture that views SSRIs as an emotional panacea, these effects are not as dramatic as one might hope. When a group of researchers obtained antidepressant drug trial data from the FDA under the Freedom of Information Act, they discovered that placebos were 80% as effective as antidepressants.

Here is where our serotonin culture gets particularly dicey: A depressed individual who begins SSRI treatment might expect that, with their serotonin levels returned to normal, their illness will at last be cured. But there is a 40% chance that the first SSRI they try won’t work for them at all. The search for the right treatment plan can be a lengthy and trying process, and it carries its own significant risks: there is evidence that SSRIs can actually increase suicidal ideation, particularly in younger patients.

Effective depression treatment is much more than a matter of serotonin

Even though serotonin theory may reduce the stigma surrounding depression, we need to start telling a more complex story if we want to help patients find effective treatment. Serotonin and depression are by no means unrelated, but scientists are still trying to work out how exactly that link works, and there is no simple or guaranteed cure for depression. Successful SSRI treatment can take months of trial and error, and those uncertain months are critical to finding the best possible pharmacological treatment.

Equally essential are the various non-pharmacological treatment options available to depressed patients. Talk therapies like CBT (cognitive behavioral therapy) are extremely effective; a significant body of work has shown that CBT works just as well as antidepressants, on average, and may even more effectively prevent remission. When used together, CBT and antidepressants are more effective than either is alone.

And one of the most successful treatments for mild and moderate depression is free, widely accessible, and multipurpose: exercise. Other pharmacological agents may even work better than SSRIs. Ketamine can almost immediately alleviate suicidal thoughts, and psychedelic drugs are showing promise as a potential treatment. Ignoring the full spectrum of treatment options in favor of a myopic focus on SSRIs could have a devastating human cost.

Just as physicians in the 1950s prescribed MAO inhibitors before they had formulated serotonin theory, today our portfolio of depression treatments far outpaces our understanding of the underlying causes and mechanisms. Though it may be decades until we have a working theory of depression that accommodates the current evidence, in the meantime, we can continue working on the ultimate goal of all such research: returning joy and hope to those who may have despaired of ever experiencing those emotions again.