The Nuance

You’ve probably heard that mental health disorders, including depression, are caused by chemical imbalances in a person’s brain. You’ve probably also heard that antidepressant drugs work by correcting these chemical imbalances.

None of this appears to be true.

The so-called “chemical imbalance theory” of mental illness, though once widely embraced by psychiatrists, is not backed up by solid science and is now increasingly and openly questioned by experts.

“None of the biological theories about the causal role of brain chemistry in depression have been supported by evidence,” says Michelle Newman, PhD, a professor of psychology and director of the Laboratory for Anxiety and Depression Research at the Pennsylvania State University.

While antidepressants can alter the brain’s neurochemical activity, exactly how these alterations help people with depression, anxiety, or other mental health problems — or even if they help — is now a topic of heated debate within the field of psychology.

The truth is that despite decades of research into SSRIs and other commonly prescribed antidepressants, psychiatrists can’t really tell you how they work. This is one reason why some experts are calling for a reconsideration of how we use these drugs.

The United States is awash in prescription antidepressants.

Even before the pandemic, which has undoubtedly worsened the country’s collective mental health and increased its use of psychiatric drugs, the Centers for Disease Control and Prevention estimated that roughly 1 in 8 Americans ages twelve and older was taking an antidepressant. The use of these drugs has risen more than 400% since the early 1990s, and a quarter of users stay on these medications for 10 years or longer.

‘I do not know of any identifiable group of patients for whom antidepressants are clearly warranted.’

Considering that tens of millions of Americans — many of them teens — are on these substances, you would hope that the evidence supporting their benefits would be rock solid. It’s not.

A new study in the journal PLOS ONE looked at the long-term use of antidepressants among people with major depressive disorder. Like other similar research efforts, it found that nearly all of the therapeutic benefits occurred during the first three months of use. It also found that people who took antidepressants for years tended to fare no better than people with major depression who never took them at all.

Even those initial benefits may not be attributable to the drugs themselves.

Some experts have argued that the early improvements associated with antidepressants can be explained by placebo effects (which can be very powerful).

Irving Kirsch, PhD, is associate director of the Program in Placebo Studies at Harvard Medical School. Kirsch has uncovered unpublished data from drug company clinical trials that show many of these drugs fail to outperform placebos. “I do not know of any identifiable group of patients for whom antidepressants are clearly warranted,” Kirsch told me.

Other researchers have concluded that antidepressants are not only ineffective but also dangerous.

A 2012 review in the journal Frontiers in Psychology found that antidepressants can cause neuronal damage and developmental problems. Among the elderly, these drugs have been linked to an increased risk for bleeding, stroke, and death. “Our review supports the conclusion that antidepressants generally do more harm than good,” its authors wrote. More research has found that antidepressants may be associated with increased suicide risks among young people.

‘Mental health experts should be steering people toward therapy and away from drugs.’

Of course, not all the work on antidepressants is negative.

“While SSRIs have small effect sizes compared to placebo, they do work very well in a subset of people,” says Clark Roberts, a doctoral researcher at the University of Cambridge in the U.K.

Roberts has published a research summary on the action of selective serotonin reuptake inhibitors (SSRIs) and other antidepressants. Some of this research shows that antidepressants may increase brain neuroplasticity in ways that create an opportunity for new and helpful patterns of thinking, perhaps especially when these drugs are combined with psychotherapy.

“A common view in psychiatry now is that many disorders are characterized by rigid and inflexible states or beliefs about the world or the self,” Clark says. Antidepressants (as well as other depression treatments, such as psychedelics) may help dislodge people from these inflexible states, thereby creating a window for helpful change.

This “increased brain plasticity” narrative, and the idea that antidepressants can push people out of some kind of cognitive rut, is an increasingly popular justification for the use of these drugs. However, Roberts says that any plasticity enhancements could be a “double-edged sword.”

For example, while someone taking these drugs in the context of psychotherapy could experience an enhanced benefit, it’s also possible that taking these drugs without proper therapeutic support could leave someone in worse shape than before. “Hypothetically, you could go from good to bad or bad to worse depending on the environmental feedback, which serotonin seems to amplify,” he explains.

Moreover, even this plasticity hypothesis is controversial. Roberts says there is contradictory evidence that suggests antidepressants blunt emotional responses, which again could have both positive and negative effects.

“It’s funny that people outside of psychiatry imagine there to be much of a consensus on almost anything regarding the specific psychological mechanisms of common antidepressants,” he says.

That consensus doesn’t exist.

It is very difficult to square the widespread use of antidepressants with the peer-reviewed research on their effects.

Unless you wander back to work published in the 1990s or early 2000s, almost all of the recent observational studies or meta-analyses are either critical or ambivalent on the subject of their usefulness.

While many people experience relief from their symptoms once they start on these drugs — and this is clearly one of the main reasons that antidepressants continue to be prescribed — this benefit seems to be driven in large part by patient expectations (e.g., placebo effects). The research to date also indicates that most of this benefit could be accomplished by psychotherapy alone, and that adding drugs to the mix does not lead to improved outcomes.

Finally, and remarkably, there is no well-established protocol to help people safely get off these drugs without adverse effects, which can be severe. Once you start on these medications, it’s very difficult to stop.

Considering the complexity of the human brain, it’s tough to read the antidepressant research without concluding that we’re monkeying around with something we don’t understand. The word “hubris” comes to mind. Until science has a much stronger grasp of the mechanisms of action and long-term effects of antidepressants, Penn State’s Newman says that people should rely on safer, non-pharmacological forms of treatment.

“Mental health experts should be steering people toward therapy and away from drugs,” she says.