Antidepressants Don’t Work the Way Many People Think

The most commonly prescribed medications for depression are somewhat effective — but not because they correct a “chemical imbalance.”


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Over the course of the Covid-19 pandemic, rates of depression and anxiety

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, and many Americans turned to antidepressant medication to help them cope. Even before the emergence of Covid,

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was taking an antidepressant drug. According to one estimate, that number

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during 2020. Zoloft is now the

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in the United States.

Given this, you might assume that the question of how — and how well — these drugs work has been clearly answered. And yet

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have challenged their efficacy and actions in the brain. Some researchers even say the medications are barely better than a placebo and ask whether they warrant such widespread use.

For psychiatrists, this debate is nothing new. Dr. David Hellerstein, a professor of clinical psychiatry at the Columbia University Irving Medical Center, said the question comes in many iterations but boils down to: Do antidepressants work?

“I think they do,” he said. “The best clinical trials and meta-analyses, most of them indicate that there’s some medication effect. I would say it’s less than we would like it to be.”

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, trial, which was conducted by the National Institute of Mental Health during the early 2000s. The clinical trial tested multiple antidepressants on nearly 3,000 people with depression, starting everyone on an S.S.R.I. If people didn’t respond to the S.S.R.I. after 12 weeks, they moved on to either another type of S.S.R.I. or a different class of antidepressants. Those include Effexor, a serotonin and norepinephrine reuptake inhibitor, or S.N.R.I., which boosts serotonin and norepinephrine levels; and Wellbutrin, which works similarly on norepinephrine and dopamine.

The trial continued in this way until people who weren’t responding to the medications had tried four different antidepressants. By the end of the study, half of the participants had significantly improved after using either the first or second medication, and nearly 70 percent of people had become symptom-free by the fourth antidepressant.
“If you look at the STAR*D, better than 60 percent of those patients actually had a very good response after going through those various levels of treatment,” said Dr. Gerard Sanacora, a professor of psychiatry at the Yale School of Medicine. “But it really did make people aware of the fact that these are not miracle treatments. There’s still a lot of people that are suffering despite having these treatments out there.”

One critique of the STAR*D trial is that it didn’t compare the medications against a placebo. Other research has shown that much of the benefit antidepressants provide comes not from their chemical effects in the brain but from a placebo effect. In

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, antidepressants helped people improve 9.6 points on a depression scale, while people taking a placebo improved 7.8 points, meaning that 80 percent of the benefit people experienced could be attributed to a placebo effect. Subsequent

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that combined multiple trials assessing the efficacy of several types of antidepressants have found that people are about

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more likely to improve on a drug than on a placebo.

To Dr. Sanacora, what matters more than the source of the improvement — whether it’s the pharmacological action of the medication or the placebo effect, which he prefers to call the “nonspecific response” — is that patients got better after taking the drug. He points out that when you take an antidepressant, you benefit from both the drug’s chemical effects on the brain and the placebo (or nonspecific) effects, such as the daily reminder that you are doing something to help your mental health. But if you don’t take the medication, you don’t benefit at all.

“I worry that patients who are really struggling, especially now, when rates of depression are higher than ever, are going to hear this and get the idea that these drugs don’t work,” he said, referring to some of the skeptics’ claims. “That’s not true. They do work.”

Predicting who will improve on antidepressants and who won’t is virtually impossible. Attempts to use genetic screening to forecast a person’s potential treatment response haven’t panned out. Those tests provide information on how efficiently the body metabolizes the drug, but Dr. Sanacora said that is most useful for assessing adverse reactions, not effectiveness.

“I think it’s been oversold by some people that you could do a genetic test and it’s going to tell you which drug you’re going to respond to,” he said. “That has never been the case.”

How do these drugs work?

Experts initially thought that depression must be caused by low levels of neurotransmitters in the brain, in part because the first antidepressant drug —

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— increased circulating amounts of the chemicals. Further research suggested that serotonin played an especially important role in mood. This so-called “chemical imbalance” theory gained a foothold in the cultural psyche and was

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for the medications.

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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

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in an area called the hippocampus that’s important for regulating mood.

The

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, 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

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, called growth factors, that help those connections form and spread.

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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.”

What alternatives to antidepressants are available?

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

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, improving depression scores in roughly 60 percent of the people who try them. More significant is that they are

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some of the people

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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

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, and in some studies exercise has been shown to be

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at treating depression. Meditation has been found to help with

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, and there’s a clear connection between

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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.

Finding the best solution for your depression, whether that’s an S.S.R.I., another antidepressant or a behavioral intervention, can take a lot of trial and error, but it’s important to remember that you do have options. And while psychiatrists acknowledge that S.S.R.I.s and other antidepressants are imperfect — and they hope a better drug will come along eventually — for the time being, they’re the best medications currently available.

“I wouldn’t write these older antidepressants completely off and say we should get rid of them,” Dr. Iosifescu said. “They do seem to work for a good number of patients.”

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