In 2006, a new study on antidepressants was making headlines with its promising results: Two-thirds of participants who tried various antidepressants recovered from their depression symptoms within less than a year. The findings seemed to offer hope to the tens of millions of Americans who suffer from depression.

But Henry Edmund "Ed" Pigott, then a psychologist in private practice, wasn't buying it. After further exploring the study — a major National Institutes of Health trial that enrolled 4,000 patients — he was convinced that the researchers’ methods greatly inflated their results, almost doubling them. In other words, the drugs may work, but not for as many people as the study suggested.

Related

“Once I got started on it, it was like, ‘Okay, this really needs to be exposed,’” said Pigott, who is now retired. His suspicion sparked a two-decade quest to obtain a review or retraction from the authors of the NIH study, whose work had received $35 million of federal funding. In 2023, Pigott and colleagues published a reanalysis of the NIH data in BMJ Open, finding that the original study's remission rates were roughly half of what was reported.

Pigott isn’t against antidepressants wholesale — he said he just wants patients to understand the complete risks and benefits. And many experts and clinicians stress that antidepressants are lifesaving medications. David Matuskey, a psychiatrist and associate professor at Yale University, described them as vital tools to help patients in desperate need: “Is it a perfect tool? No, but it's an important one.”

The drugs are now widely prescribed in the United States. Around 13 percent of American adults regularly take an antidepressant, according to 2020 data, the most common of which are SSRIs — selective serotonin reuptake inhibitors — so called because they work to raise overall levels of serotonin, a neurotransmitter, in the brain.

Still, questions remain on how exactly antidepressants lift the symptoms of depression, which may include persistent feelings of hopelessness, low energy, and suicidal thoughts. In recent years, the drugs have also been criticized for potential side effects, such as loss of libido and dizziness, while some patients experience withdrawal effects when they stop taking them.

Among the most vocals critics has been Robert F. Kennedy Jr., who has made numerous statements about the overprescription of antidepressants, particularly among children. Advocates now worry that Kennedy’s influence as secretary of the U.S. Department of Health and Human Services could limit patients’ access to SSRIs. In an executive order signed in February, President Donald J. Trump established the Make America Healthy Again Commission, which would, among other directives, “assess the prevalence of and threat posed by the prescription of selective serotonin reuptake inhibitors,” alongside mood stabilizers and other drugs.

“These are not benign drugs. They have potential for benefit and harm. You gotta weigh out those risks.”

The American Psychiatric Association, National Network of Depression Centers, and other organizations shot back: The safety and efficacy of antidepressants had been clearly established through decades of rigorous study, they wrote. They further expressed concern that the MAHA Commission unfairly “casts doubt on this research.”

But other researchers concede that some measure of doubt, or at least uncertainty, has dogged SSRIs for decades — not just in terms of their potential benefits and side effects, but even their basic mechanism of action. Rifaat El-Mallakh, who leads the Mood Disorders Research Program at the University of Louisville Depression Center, said that while many clinicians believe that antidepressants help their patients, “nobody has ever been satisfied with how effective they are.”

To Pigott, that means more and better research is needed — at long last.

“These are not benign drugs. They have potential for benefit and harm,” Pigott said. “You gotta weigh out those risks.”

Until the 1950s, few pharmaceutical options were available to treat depression. At the time, the psychoanalytical theories of Freud and others emphasizing the role of the unconscious mind were dominant, but some clinicians were developing medical categorizations of mental conditions, and procedures like electroconvulsive therapy and lobotomy pointed towards somatic remedies — those focused on the physical body rather than psychology or emotions.

The early drugs were discovered somewhat by accident. One drug, iproniazid, was being used to treat tuberculosis when doctors realized that it helped improve patients’ mood. It was prescribed off-label as an antidepressant for just a few years before researchers realized that it could severely damage the liver.

More pharmacological discoveries followed, including the first tricyclic antidepressants — drugs that reduce the absorption of neurotransmitters called catecholamines. But adverse effects ranged from blurred vision and dry mouth to more serious outcomes. Adults could fatally overdose if they took a two-week supply at once, said Siegfried Kasper, a professor emeritus of psychiatry at the Medical University of Vienna, Austria. If a child found their parents’ medicine and took a single day’s dose, they could die.

Why, after nearly 40 years in existence and with wide support among psychiatrists, are the benefits and risks, the effectiveness, and even the mechanism of function of SSRIs still so hotly debated?

As doctors were beginning to prescribe these drugs to patients in the 1960s, two views on brain biochemistry came together to offer new models for depression. One was the brainchild of Joseph J. Schildkraut, a researcher from Brooklyn who spent most of his career at Harvard University and the Massachusetts Mental Health Center. Schildkraut had initially planned to become a psychoanalyst but completed training just as tricyclic antidepressants came into use. He began to explore the role of pharmacology in treating depression, and in 1965 published a seminal paper positing that depression arose due to low levels of certain neurochemicals, highlighting the role of one, norepinephrine. According to a psychiatrist and historian of the field, David Healy, Schildkraut’s paper “defined the psychopharmacological era.”

Around the same time, a psychiatrist called Alec Coppen was working in the United Kingdom. He was a less charismatic figure, according to Kasper, who was a young researcher at the time. “Alec Coppen did not communicate that well,” he said. “He was a smart guy, but Schildkraut was an excellent communicator.” Coppen was interested in mood disorders and studied the effect of lithium on major depression and bipolar disorder, and the role of serotonin imbalance as a cause of depression. His 1967 paper, titled “The Biochemistry of Affective Disorders,” reviewed studies of reserpine, iproniazid, and other recently discovered drugs, and proposed that low levels of a different neurotransmitter, serotonin, could underlie depressive illness.

That idea took hold in the pharmaceutical industry, which set out to find a pill that could address the chemical imbalance.

It took another 20 years for one to be brought to the U.S. market: the first SSRI, Prozac. Psychiatrists were enthusiastic. Patients could tolerate higher doses than earlier drugs; a fatal overdose was a much smaller risk. SSRIs had other more minor side effects, but at the time, Kasper said, their arrival was “a big revolution.” (Other SSRIs have since become available, including Zoloft, Paxil, Celexa, and Lexapro.)

David T. Wong, who helped develop Prozac at the drug company Eli Lilly, described the profound effect of that development in a co-authored account published in Nature Reviews: “Numerous lives have been saved from suicide by the widespread use of these drugs, as well as many relationships restored and careers saved.”

Wong and his colleagues explained that the idea of needing to boost serotonin helped reduce the stigma surrounding depression. “Having an underlying biological rationale for a treatment — that is,........

© Salon