Every year, millions of people start taking a drug with therapeutic effects that can’t be fully explained, for a condition that can’t be objectively diagnosed with a laboratory test. Selective serotonin reuptake inhibitors, or SSRIs, are among the most prescribed medications in the world. Yet, even after decades of use, scientists are still untangling the biological changes that SSRIs trigger in the brain and body.

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“We fundamentally don’t know how they work,” says Maurizio Fava, a psychiatrist at Massachusetts General Hospital in Boston.

That uncertainty collided with politics earlier this year when, speaking at a wellness summit focused on mental health, US Secretary of Health Robert F. Kennedy Jr argued that the drugs are greatly overused and have withdrawal risks that are on a par with heroin. His claims prompted an outcry from some scientists and clinicians, who warned that Kennedy had overstated the concern, potentially scaring people away from life-saving treatment. But others said he had identified a real problem, even if clumsily. “This is a major public-health issue,” says Mark Horowitz, a psychiatrist at Adelaide University in Australia. “I hope the messenger’s controversialness doesn’t kill the message.”

The divide reflects how much remains unresolved with regards to SSRIs. Researchers are still piecing together a complicated picture of the drugs’ therapeutic actions, involving neural circuits and their connecting synapses, gene expression, inflammation, stress hormones and psychological expectation. None yet offers a complete explanation. And the chain of biological changes that ultimately relieves symptoms can look very different from one person to the next. “There’s not one route to depression,” says Catherine Harmer, a cognitive neuroscientist at the University of Oxford, UK.

But many scientists say the field is entering a more revealing era, as new tools begin to connect symptoms to biological processes. “We’re at an inflection point,” says Mark Rapaport, a psychiatrist at Stanford University in California and president of the American Psychiatric Association. He likens it to cancer research in the 1990s, when advances in molecular biology and basic science were leading to the development of the first targeted therapies.

Even many people who are critical of Kennedy’s claims acknowledge that SSRI withdrawal can be a substantial issue for some people. With an estimated one in six adults in the United States taking an antidepressant, even a small proportion experiencing serious problems while discontinuing the drugs amounts to a large public-health concern. “It’s a real phenomenon,” says Fava.

Before scientists can explain fully why withdrawal symptoms occur — or how best to prevent or treat them — they need to finish answering more basic questions: what is happening in the brain when someone is depressed? And what, exactly, are SSRIs doing to change it?

A difficult diagnosis

There is no standard blood test for depression. No genetic screen or brain scan can confirm a diagnosis. Instead, clinicians rely on what people report and how they are functioning in aspects such as sleep, appetite, mood and interest in daily life. “It’s entirely subjective,” says Manish Jha, a neuroscientist at the University of Texas Southwestern Medical Center in Dallas.

“The diagnosis of depression is problem number one,” says Eric Nestler, a neuroscientist and psychiatrist at the Icahn School of Medicine at Mount Sinai in New York City. Finding appropriate treatments has been difficult as a result.

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The first modern antidepressants were discovered mostly by accident. In the 1950s, physicians began noticing that drugs developed to treat tuberculosis seemed to lift people’s moods. Working backwards, scientists found that these drugs increased the availability of monoamine neurotransmitters, including serotonin and noradrenaline, chemical messengers that affect mood. This led to the earliest antidepressants, monoamine oxidase inhibitors, which prevent those neurotransmitters from being broken down. Around the same time, scientists discovered tricyclic antidepressants, which increased monoamine-neurotransmitter signalling through a different mechanism: blocking the reuptake of serotonin and noradrenaline. Both drugs were effective but blunt, causing side effects throughout the body.

So, drug developers sought a safer alternative that specifically targeted the serotonin system. Fluoxetine — commonly known by the brand name Prozac — was approved in the United States in 1987.

Its success helped to cement a clinical narrative: depression was caused by too little serotonin; an SSRI could correct that imbalance. But the science has never neatly fitted that story. In experiments that lowered serotonin production by depleting tryptophan — the raw material the body uses to make serotonin — most healthy participants didn’t become depressed¹. But many people who responded well to antidepressants, including SSRIs, relapsed under similar conditions². The findings suggested serotonin was unlikely to be the root cause of depression, even if it remained central to how the drugs work.

Over the following decades, more SSRIs and related drugs expanded the prescriber’s toolkit. As they came off-patent and became cheaper, and as the health-care system grew strained, the threshold for prescribing them dropped. SSRIs are now among the most prescribed treatments for depression and anxiety. More than 100 million prescriptions for sertraline, escitalopram and fluoxetine were filled in 2024 in the United States.

“Practitioners are trying to find the easiest, maybe fastest solution,” says Giovanni Ostuzzi, a psychiatrist at the University of Verona in Italy. “This increases their tendency to prescribe SSRIs.”

Beyond the serotonin hypothesis

At a basic level, SSRIs do exactly what the name suggests. When neurons release serotonin, a transporter normally draws much of it back into the cell. SSRIs block that transporter, leaving more serotonin available in the synapses between neurons. The bump in serotonin signalling is rapid. But substantial symptom relief can take weeks, sometimes months.

Scientists’ understanding of what happens in that time remains fragmented and incomplete. Chronic stress has long been considered a contributor to depression. It can dysregulate stress-response systems involving cortisol and noradrenaline, as well as the body’s balance between pro-inflammatory and anti-inflammatory factors, says Ostuzzi. These changes might, in turn, weaken neural connections and atrophy parts of the brain, such as the hippocampus and amygdala, he says.

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One possible way in which antidepressants counter these effects is by promoting neuroplasticity — the brain’s capacity to remodel its connections. By altering gene expression, and enhancing growth-promoting and protective factors in the brain, says Ostuzzi, “antidepressants might reverse the effects of prolonged stress”.

Among the most studied biological players in depression is brain-derived neurotrophic factor, or BDNF, a molecule involved in the growth and remodelling of neural connections. People with major depressive disorder have, on average, lower levels of BDNF in their blood than do healthy people. Over time, some antidepressants seem to increase production and signalling of BDNF. “It’s changes like that, downstream, that are actually helping with depressed mood,” says Anita Clayton, a psychiatrist at the University of Virginia in Charlottesville. “It’s not treating a [serotonin] deficiency per se. It’s just changes in the circuits and the connections.”

Another clue comes from the order in which changes emerge after people start SSRI treatment. “People begin to exhibit improvements even before they appreciate those improvements exist,” says Nestler. “Oftentimes a family member or friend notices them doing better.”

Harmer has investigated a potential reason for this. Depression often involves a bias towards negative information. Her work suggests that antidepressants can quickly yet subtly shift how people process emotional information, well before they consciously feel better. A person might be more likely to notice a smile from someone on the street, or to register praise, even when mixed with criticism.

SSRIs seem to soften that negative bias — and gradually tip the balance towards the positive — in part by altering activity in the amygdala and related brain circuits. Over time, those small perceptual shifts might change how a person engages with the world. “Your mood is a product of how you’re processing that information,” says Harmer.

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Gerard Sanacora, a psychiatrist at Yale University in New Haven, Connecticut, points to another layer: expectation. A 2022 meta-analysis³ of more than 200 randomized, placebo-controlled trials found that the median improvement for people taking SSRIs was about ten points on a standard depression scale and seven points for those assigned to the placebo.

The drug effect was real, but placebo and indirect effects probably contributed too. Sanacora compares it with the act of taking a blood-pressure pill every morning: it also becomes a reminder to take the stairs and to manage stress.

The physiological and psychological pathways might overlap. “If you’re seeing more positive things and you’re more engaged in your environment,” says Harmer, “that in itself can stimulate this plasticity effect in your brain.”

The seemingly modest improvements over placebo lead some to question whether SSRIs work at all. But averages can obscure how some people improve substantially, whereas others experience little benefit. “Every meta-analysis shows a difference from placebo,” says Sameer Jauhar, a psychiatrist at Imperial College London. “But they’re no panacea.”

Understanding risks

SSRIs are generally considered to be safe for long-term use, although not without side effects — from emotional blunting to stomach troubles and sexual dysfunction.