The debate over how antidepressants work puts millions of people at risk

Almost 10 percent of all Americans experience symptoms of depression each year. Common forms of treatment include a combination of therapy and antidepressants. About 13 percent of Americans over the age of 18 took antidepressants between 2015 and 2018, according to the CDC. The most commonly prescribed form of these are called selective serotonin reuptake inhibitors (SSRIs), which are designed to alter the flow of serotonin in the brain.

I’m one of millions who take an SSRI – one called sertraline to treat the symptoms of anxiety, depression and OCD. Before speaking to a psychiatrist about taking this drug, I grappled with feelings of doom and anxiety arising on a whim, and dozens of intrusive thoughts and emotions every minute. Basically, it’s like your own heckler yelling at you all day. Taking the medication was immensely helpful for me, as it was for many others.

And that makes it all the stranger to realize that, like many other complex illnesses, researchers still don’t know exactly what causes depression and whether serotonin is a key culprit. In the 1960s, scientists accidentally discovered that certain drugs used as sedatives helped alleviate depression. Because these drugs acted on the serotonin system, it led to “a very simplistic notion that low levels of serotonin lead to depression,” Gerard Sanacora, a psychiatrist at Yale University and director of the Yale Depression Research Program, told The Daily Beast.

Most scientists today cling to the notion that there are many genetic, social, and biological factors that contribute to depression; and yet the idea of ​​a chemical or serotonin imbalance has gotten stuck in the popular zeitgeist. Thanks to its prominent placement in advertisements for drugs like Prozac in the late 1980s, it has largely stuck – even as psychiatric research was already changing its perspective.

This brings us to the current debate surrounding SSRIs. Most neuroscientists, psychiatrists, and clinicians who study and treat depression agree: antidepressants like SSRIs work just as well as cognitive therapies. With the right treatment, remission rates for depression can range from 5 to 50 percent. There’s no question that people like me are finding real relief thanks to these drugs.

But if depression isn’t quite as closely linked to serotonin levels as we once thought, then that raises the problem that we don’t really know how SSRIs work and why they may help some depressed people. There are several promising theories that suggest they play a role in mediating gut bacteria to help the brain grow new cells and need themselves to bring about larger and more complex physiological changes that go beyond the mere increase in serotonin levels. But none of these theories have been proven so far.

The ensuing discussion has turned into a rambling debate, pitting mainstream psychiatry against a minority of researchers who don’t believe antidepressants actually work.

Every few years a new spate of studies emerge from the shadows that purport to “debunk” the notion of the serotonin hypothesis. These studies suggest that depression is either a result of social factors or caused by traumatic experiences, and that antidepressants either don’t work, numb emotions, or actively cause harm. Instead of medication, they believe depression is better treated with therapy alone.

“The ensuing discussion has turned into a rambling debate, pitting mainstream psychiatry against a minority of researchers who don’t believe antidepressants actually work.”

The clashes between competing academics and researchers are just as intense and vicious as any other battle that takes place on the internet – with features Twitter feuds, comments for think tanks and news outlets themselves. The shady history of the pharmaceutical industry further fuels skepticism about the effectiveness of antidepressants. When clinical trials of antidepressants failed to confirm the results they were hoping for, drug companies essentially buried the evidence and skewed the record in favor of antidepressants — which has only increased distrust of these drugs and their manufacturers.

Adding fuel to the fire, a review study recently published in the journal Molecular Psychiatry re-evaluated decades of past data on serotonin levels in depression, found no evidence linking the two, and offered this as evidence that SSRIs do not work or only work by blunting emotions. This conclusion was criticized by many psychiatrists and clinicians—the study didn’t even analyze whether antidepressants work—but with the support of the study’s authors, right-wing media spread the message anyway.

“If there are benefits, I would say they are due to this emotion-numbing effect, and otherwise the evidence shows these very small differences between the drugs and the placebo,” said Joanna Moncrieff, a psychiatrist at University College London who led the study study, said The Daily Beast. “Antidepressants are drugs that change the normal state of your brain, so it’s generally not a good idea [that] long term.”

Moncrieff himself is an influential figure in so-called “critical psychiatry”. The Critical Psychiatry Network, of which Moncrieff is co-chair, describes the movement on its website: “It challenges claims about the nature and causes of mental disorders and the effects of psychiatric interventions.” Researchers associated with this movement oppose the use of drugs in mental illness and have even promoted COVID-19 conspiracies.

If depression is caused by the interplay of stressful events and biology, as some within the Critical Psychiatry Network argue, Sanacora doesn’t follow why this means antidepressants don’t work. “I just don’t follow logic,” he said.

Four other experts who spoke to The Daily Beast strongly dismissed Moncrieff’s findings, noting that her and her team’s work roughly conflates two hypotheses under the serotonin theory. There is the fairly well-known chemical imbalance hypothesis which suggests that a lack of serotonin neurotransmitter in the body leads to depression. But according to Roger McIntyre, professor of psychiatry and pharmacology at the University of Toronto, “The notion of brain chemical imbalance has never been proposed as a coherent, comprehensive, evidence-based proposition.”

Instead, the dominant serotonin hypothesis that psychiatry takes seriously, and which McIntrye and others argue is supported by evidence, is that dysregulation of the body’s entire serotonin system contributes to clinical depression. These include problems with the amount of receptors available for serotonin to bind to, problems with the way cells fire, and numerous other disruptions at the biomolecular level. They argue that Moncrieff is wrong in making the grand claim that there is no evidence of serotonin’s involvement in depression.

“The notion of chemical imbalances in your brain has never been put forward as a coherent, comprehensive, evidence-based proposal.”

— Roger McIntyre, University of Toronto

Additionally, ignorance of a drug’s mechanism is not sufficient reason to discourage its use if it has been shown to help people. “We’re very confident that SSRIs work for depression,” Tyler Randall Black, a child and adolescent psychiatrist at Children’s Hospital of British Columbia, told The Daily Beast. “There’s tons of evidence showing us they work, but not why they work.” McIntrye pointed out that we don’t even fully know how Tylenol works — despite it being one of the most commonly used pain relievers around world is. Tylenol also affects the brain in unexpected ways — while it numbs social or psychological pain, it’s no reason to take it off the market.

Denigrating these drugs can have unintended consequences, as therapy is often unavailable, making SSRIs the only accessible option. “The demand for mental health care far exceeds the available access,” Sanacora said, adding that many Americans have to wait months to see a good cognitive-behavioural therapist. In addition, making an abrupt decision to stop taking SSRIs can be dangerous: one in five patients experience flu-like symptoms, insomnia, imbalance, and other symptoms that can last for a year.

While the psychiatrists who spoke to The Daily Beast emphasized that the serotonin hypothesis is a way to simply explain a complex disorder like depression, they emphasized that over time it has led to disadvantages. A history of “chemical imbalance” has negatively impacted patient decision-making and self-image,” Awais Aftaib, a psychiatrist at Case Western Reserve University in Cleveland, Ohio, told the Daily Beast.

“The demand for mental health care far exceeds the available access.”

— Gerard Sanacora, Yale University

Phil Cowen, a psychopharmacologist at the University of Oxford in the UK, told The Daily Beast that socioeconomic status is a contributing factor to depression, leading those in the critical psychiatric field to believe that it “constrains doctors and industry gives power over patients”. Ironically, it ignores the millions of “experienced” people who have been helped by antidepressants.

Still, the million-dollar question remains: how do SSRIs work? Aftaib explained that a new leading hypothesis is that they promote the formation of new neurons and new connections between neurons in the brain. The hippocampus, a seahorse-shaped region of the brain important for memory and learning, shrinks and loses neurons when depression hits. SSRIs appear to stimulate the production of neural stem cells, which integrate into the hippocampus to restore its function and structure. Other studies suggest that SSRIs help the brain rewire the connections that cause the clinical symptoms associated with depression.

He also added that SSRIs may work through different mechanisms in different people, so treatments may need to be tailored more on a case-by-case basis.

And more specific, individualized treatments might require psychiatrists to be more honest with their patients about what we do and don’t know about these drugs, rather than providing an oversimplified (and downright inaccurate) explanation.

Black is already trying this with his patients: “I’m saying we know for sure that it affects serotonin, but we don’t know how that affects your brain, and we don’t know that you’re lacking in serotonin to begin with.” He has found that these open discussions about what we know about therapy and medication will pay off in the long run, and many of his patients will still choose to take the antidepressant to find out what works best for them. The debate over how antidepressants work puts millions of people at risk


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