A Brief History of Antidepressants

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Puzant Apkarian / First Light / Corbis

Antidepressant drugs are as controversial as they are popular. And, boy, are they popular. As many as 1 in 10 Americans is on some form of antidepressant medication. Now a new study suggests that while the drugs benefit severely depressed people, they have a "nonexistent to negligible" impact on patients with milder, run-of-the-mill blues. The study, in the Journal of the American Medical Association, analyzed previously published data from trials of the popular drug Paxil and its older generic cousin, imipramine. Some doctors hope the findings will help tone down the popular image of antidepressant pills as magic bullets.

Researchers discovered the first antidepressants purely by chance in the 1950s. Seeking a treatment for schizophrenia, scientists at the Munsterlingen asylum in Switzerland found that a drug that tweaked the balance of the brain's neurotransmitters — the chemicals that control mood, pain and other sensations — sent patients into bouts of euphoria. For schizophrenics, of course, that only made their condition worse. But researchers soon realized it made their pill perfect for patients with depression. On first trying it in 1955, some patients found themselves newly sociable and energetic and called the drug a "miracle cure." The drug, called imipramine and marketed as Tofranil in 1958, was quickly followed by dozens of rivals — known as tricyclics for their three-ring chemical structure — as drug companies rushed to take advantage of a burgeoning market.

The drugs provided relief to 60% to 80% of patients, but they also caused serious side effects, including sluggishness, weight gain and occasionally death from overdose. The ground was ripe for a better pill, and it wasn't long before scientists produced a new, highly targeted class of antidepressants, led by Prozac, which hit the U.S. market in 1987, followed by Zoloft in 1991 and Paxil in 1992. Instead of blanketing a broad range of brain chemicals, the drugs — known as selective serotonin reuptake inhibitors (SSRIs) — zeroed in on one: serotonin, a critical compound that ferries signals between nerve cells. SSRIs provided relief for the same percentage of patients as their predecessors did but were easier to prescribe without risking overdose and had fewer side effects.

The drugs were a massive success. In 1987 analysts predicted Prozac could earn its parent, Eli Lilly & Co., up to $175 million a year by 1990. It blew past that target in 1989, earning $350 million — more than had been spent annually on all antidepressants put together just two years previously. By 1990, Prozac was the country's most prescribed antidepressant, with 650,000 scrips written or renewed each month. Annual sales soon topped $1 billion.

But the very idea of a drug so powerful and transformative inevitably had its naysayers. Critics complained Prozac and its siblings were prescribed too liberally and were still unproven. Some previously sound patients reported turning violent or fantasizing about killing themselves after starting the drug and used a "Prozac defense" in court. Others appeared on talk shows calling themselves "Prozac survivors." (Despite anecdotal evidence linking antidepressants to violent behavior, scientists have reached no conclusive answer as to whether the drugs are to blame.)

Nevertheless, sales stayed strong. By 1993, Prozac had been taken by some 10 million people around the globe. In contrast to the obscure antidepressants of generations past, Newsweek noted in 1994, "Prozac has attained the familiarity of Kleenex and the social status of spring water." Depression had begun to shake its stigma.

At the same time, hints that the drugs could make anyone — not just depressed people — feel better raised tantalizing (and troubling) questions about the future of mood-bending drugs. If Prozac gives you an up even when you're not down, why wouldn't you want to take it? Dr. Peter Kramer of Brown University asked that question in his best-selling 1993 book, Listening to Prozac. A drug that makes patients feel "better than well," he suggested, might give rise to a new era of "cosmetic psychopharmacology," in which reshaping your personality would be as easy as highlighting your hair.

We may not be there (yet), but the drugs have taken flight and soared far beyond the depressed patients for whom they were initially approved. Doctors have prescribed them to everyone from pensioners to preteens for everything from PMS to fear of public speaking. Prozac is used even in veterinary medicine, for dogs that seem down in the dumps.

More worrying than concerns about overprescription, however, are the implications of a study in the January issue of the Archives of General Psychiatry that found that half of depressed Americans don't get the treatment they need. On that score, experts say, prospective patients ought not to be scared off by the skepticism over antidepressants and should consult their doctors to find a course of treatment. In the nearly two decades since he published Listening to Prozac, Kramer notes, the standards of care have risen and the options have increased. "If people are doing badly," he tells TIME, "there are lots of good resources. They ought to turn to them."