Antidepressants don’t work by correcting serotonin levels; understand

The most commonly prescribed drugs to fight depression are somewhat effective – but not because they correct a “chemical imbalance”

Rates of depression and anxiety have skyrocketed throughout the Covid pandemic, and many Americans have turned to antidepressant medications. Even before the emergence of Covid, one in eight American adults was taking an antidepressant. That number would have risen 18.6% in 2020, according to one estimate. Today Zoloft (sertraline) is the 12th most prescribed drug in the United States.

In view of this, we could assume that the question of how and how well these drugs work has already been unequivocally answered. However, recent scientific articles dispute the effectiveness of antidepressants and their action on the brain. Some researchers go so far as to say that the drugs are barely better than a placebo and question whether their widespread use is justified.

This discussion is not new to psychiatrists. David Hellerstein, a professor of clinical psychiatry at Columbia University’s Irving Medical Center, said there are many versions of the question, but it all boils down to a simple question: Do antidepressants work?

“I think they work, yes,” he said. “Most of the best clinical trials and meta-analyses indicate that there is some drug effect. I would say the effect is less than we would like it to be.”

That answer may not be very reassuring to the tens of millions of Americans who take an antidepressant. But for the psychiatrists who prescribe these drugs, the reality is that while they are imperfect, they actually help most people who take them.

If you already take an antidepressant or are thinking about taking one, here’s what you need to know about how they work and how their effectiveness is measured.

What do we know about the effectiveness of antidepressants?

The most prescribed antidepressants are SSRIs (selective serotonin reuptake inhibitors). These include Prozac, Zoloft and Celexa. These drugs stop neurons from sucking up the neurotransmitter serotonin, allowing more of this chemical to move around the brain.

Other antidepressants raise circulating levels of different brain chemicals, such as norepinephrine and dopamine, in addition to serotonin. But these carry more side effects, which is why psychiatrists often start by prescribing an SSRI for people with depression.

The largest study of antidepressants to date was the Sequenced Treatment Alternatives to Relieve Depression, or STAR*D trial, conducted in the early 2000s by the National Institute of Mental Health.

The clinical trial tested several antidepressants with nearly 3,000 people with depression. All participants started by taking an SSRI. If after 12 weeks people did not respond to the SSRI, they were switched to another type of SSRI or a different class of antidepressant.

The trial went on like this until people who weren’t responding to the drugs had tried four different antidepressants. By the end of the study, half of the participants had shown significant improvement after using their first or second medication, and nearly 70% of people were symptom-free by the time they reached their fourth antidepressant.

“Looking at STAR*D, more than 60% of patients actually had a very good response after going through those different levels of treatment,” said Gerard Sanacora, professor of psychiatry at the Yale School of Medicine.

“But it really made people aware that antidepressants are not miracle treatments. There are still a lot of people suffering despite the availability of these treatments.”

One criticism leveled at the STAR*D trial is that it did not compare the drugs to a placebo. Other research has indicated that much of the benefit provided by antidepressants comes not from their chemical effects on the brain, but from a placebo effect.

In another study, antidepressants helped people improve by 9.6 points on a depression scale, while people who took a placebo improved by 7.8 points — that is, 80% of the benefit people felt could be attributed to an effect. placebo.

Subsequent meta-analyses that combined multiple trials that evaluated the effectiveness of various types of antidepressants concluded that people are about 25% more likely to improve by taking a drug than taking a placebo.

For Sanacora, more important than the source of the improvement — whether it’s the pharmacological action of the drug or the placebo effect, which he prefers to call the “nonspecific response” — is the fact that patients have improved after taking the drug.

He points out that when you take an antidepressant, you benefit as much from the drug’s chemical effects on the brain as you do from the placebo effects, such as reminding yourself daily that you are doing something concrete to benefit your mental health. But if you don’t take the medicine, you won’t have any benefit.

“I’m afraid that patients who are really suffering, especially now when depression rates are higher than ever, hear about it and start to think these drugs don’t work,” he said, alluding to some of the ideas propagated by skeptics. “Not true. They do work.”

It is virtually impossible to predict who will or will not get better by taking antidepressants. Attempts made to use genetic screening to predict a person’s potential response to treatment have failed. The tests provide information about how efficiently the body metabolizes the drug, but for Sanacora, this is more useful for evaluating adverse reactions, not its effectiveness.

“I think some people have taken the argument too far that you can do a genetic test and it will tell you which drug you’re going to react well to,” he said. “That was never true.”

How do antidepressants work?

Initially, experts thought that depression must be caused by low levels of neutronmitters in the brain, in part because the first antidepressant drug — discovered accidentally in the 1950s — increased the amounts of chemicals circulating in the brain.

Additional research has shown that serotonin plays an especially important role in mood. This so-called “chemical imbalance” theory gained traction in the cultural psyche and was promoted by drug advertisements.

But from the 1990s onwards, researchers began to understand that depression is much more complex than that and that the role played by serotonin is only secondary. For starters, SSRIs raise serotonin levels right away, but it takes people several weeks to start feeling better.

Studies have begun to emerge indicating that another brain system plays a role: People with depression almost always have less volume in an area called the hippocampus, which is important in regulating mood.

The prevailing theory today, 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 believed to work at least in part by helping the brain form new connections between cells.

Researchers aren’t sure how raising serotonin with an SSRI causes these synapses to grow again. One possibility is that the drugs also raise levels of other brain chemicals called growth factors, which help these connections form and spread.

A scientific paper published this year drew attention for presenting several decades of evidence that people with depression have no less serotonin than people who are not depressed. For most psychiatrists, the article did not reveal anything new and does not mean that antidepressants are not effective (a misconception advocated in the article). Instead, the study revealed a fundamental disparity between how the public views depression and how experts view it.

“To me, this is an old theory of depression,” said Daniel Iosifescu, a professor of psychiatry at NYU Langone Health. “It was already invalidated 20 years ago. Basically, we are reinforcing what was already known.”

What alternatives are available to antidepressants?

Alternative treatments for depression are emerging that seek to help the brain make new connections more effectively. Notable among them are ketamine and psychedelic drug (which is not approved by the US food and drug regulatory agency). These interventions appear to be more or less as effective as antidepressants, improving the level of depression of people who experience them by about 60%.

Most significantly, they work with some of the people who do not respond to traditional medicines. But these drugs are seen as more invasive and riskier than antidepressants, so they should be used as a last resort, not a first treatment option, Sanacora said.

Some psychiatrists are starting to recommend non-pharmaceutical treatments to help people with depression. Hellerstein said that when evaluating a new patient, he now pays more attention to the person’s habits, such as their sleep, eating and exercise, and often recommends behavioral changes, therapy or meditation before drug treatment.

There is research suggesting that physical exercise may also help the formation of new connections in the brain, and in some studies exercise has been shown to be as effective as antidepressants in treating depression. Medication has been found to help with feelings of stress and anxiety, and there is a clear brain link between sleep deprivation and anxiety.

“I think we now do a more holistic assessment of a person’s way of life than we did in the late 1980s,” Hellerstein said.

Finding the best solution for your depression, whether it’s an SSRI, another antidepressant, or a behavioral intervention, can involve a lot of trial and error, but it’s important to remember that you have options. And while psychiatrists recognize that SSRIs and other antidepressants are flawed — and hope that a better drug will one day come along — for now they are the best drug options available.

“I wouldn’t totally rule out these older antidepressants or say we should get rid of them,” Iosifescu said. “They seem to work well with a good number of patients.”

Translation by Clara Allain