However, starting in the 1990s, researchers began to understand that depression was much more complicated and that serotonin played only a nominal role. For one thing, S.S.R.I.s increase serotonin levels immediately, but it takes several weeks before people start to feel better. Studies also started to emerge showing that another brain system played a role: People with depression consistently have less volume in an area called the hippocampus that’s important for regulating mood.

The current prevailing theory, Dr. Hellerstein said, is that chronic stress can cause the loss of connections — called synapses — between cells in the hippocampus and other parts of the brain, potentially leading to depression. Antidepressants are now thought to work at least in part by helping the brain form new connections between cells. Researchers aren’t exactly sure how increasing serotonin with an S.S.R.I. causes these synapses to regrow. One possibility is that the medications also increase levels of other brain chemicals, called growth factors, that help those connections form and spread.

A paper published earlier this year made headlines for presenting several decades’ worth of evidence that people with depression don’t have less serotonin than people who are not depressed. To most psychiatrists, the paper didn’t reveal anything new, and it didn’t mean antidepressants aren’t effective (a widely held misinterpretation of the paper). Instead it revealed a fundamental disconnect between how the public viewed depression and how the experts thought about it.

“To me, that is an old theory for depression,” said Dr. Daniel Iosifescu, a professor of psychiatry at N.Y.U. Langone Health. “That was already invalidated 20 years ago, so we’re just essentially putting the nail in the coffin, so to speak.”

Alternative treatments for depression have emerged that attempt to help the brain create new connections more efficiently — most notably ketamine and psychedelic therapy (which is not approved by the Food and Drug Administration). These interventions appear to be about as effective as antidepressants, improving depression scores in roughly 60 percent of the people who try them. More significant is that they are able to treat some of the people who don’t respond to the traditional medications. The drugs are seen as riskier and more invasive than antidepressants, though, so are meant to be used as a last resort, not a first-line treatment, Dr. Sanacora said.

Some psychiatrists have also started to recommend nonpharmaceutical treatments to help people with depression. Dr. Hellerstein said that when he evaluates a new patient, he now pays more attention to habits, such as sleep, diet and exercise, and would often recommend behavioral changes, therapy or meditation before medication. There’s research suggesting that exercise also may help new connections grow in the brain, and in some studies exercise has been shown to be as effective as antidepressants at treating depression. Meditation has been found to help with feelings of stress and anxiety, and there’s a clear connection between sleep deprivation and anxiety in the brain.

“You’re making, I think, a more holistic assessment of that person’s way of living than maybe you did in the late 1980s,” Dr. Hellerstein said.