For years, people have been told their sadness was the result of a chemical imbalance—a fixable flaw—like how insulin helps people with Type 1 diabetes.
The “chemical imbalance” theory has shaped mainstream treatment for depression, fueling widespread prescriptions of antidepressants. Yet, psychiatrist and former U.S. Food and Drug Administration (FDA) medical officer Dr. Josef Witt-Doerring said the theory, popularized in the 1950s, has never been proven and lacks scientific backing.
In a recent episode of American Thought Leaders, Witt-Doerring told host Jan Jekielek that relying on the chemical imbalance narrative can lead to overmedication, often with worse—not better—outcomes for patients, and that the way antidepressants are prescribed needs reform.
Origins of the Chemical Imbalance Theory
The chemical imbalance theory first emerged with doctors’ amazement that a tuberculosis drug called iproniazid seemed to energize and lift patients’ moods. Psychiatrists soon tested the drug on people with depression and saw similar improvements.
Iproniazid worked by preventing the breakdown of neurotransmitters—chemical messengers such as serotonin, norepinephrine, and dopamine—thereby increasing their levels. Researchers theorized, based on their observations, that depression must be caused by a shortage of these chemicals in the brain.
The idea revolutionized psychiatry, offering a biological explanation for emotional suffering and paving the way for widespread prescription of antidepressants. For decades, the chemical imbalance theory dominated both medical practice and public perception.
However, once accepted as a medical fact, the theory has begun to crumble.
“A lot of people think that they [antidepressants] work in that they are fixing this imbalance; they are restoring them to a normal state,” Witt-Doerring said. However, growing evidence disputes this.
For instance, a 2022 systematic review published in Molecular Psychiatry found no consistent evidence that low levels of serotonin cause depression. Additional clinical studies have likewise failed to identify reliable differences in neurotransmitter levels between people with and without depression.
“There is no way to differentiate patients who are depressed from those who are not depressed using any objective markers,” he added. “That’s why when you go and see a psychiatrist or a family medicine doctor, they’re not doing blood tests, they’re not scanning your brain—they’re essentially just doing a checklist.”
What Antidepressants Do
Witt-Doerring said that antidepressants don’t correct an underlying defect but instead create a predictable drug effect. For the most common class—selective serotonin reuptake inhibitors (SSRIs)—the effect is often one of emotional blunting or numbing.
SSRIs boost the amount of serotonin in your brain. Serotonin is a chemical that helps manage your mood and emotions. Normally, once serotonin delivers its message, it is taken back into the brain cell that released it. SSRIs slow down that process, so more serotonin stays active between brain cells for a little longer.
Having more serotonin can help even out your mood and ease feelings of anxiety or sadness. However, it can also make emotions feel somewhat flat—you might notice less excitement or joy, as well as less distress—sometimes referred to as emotional numbing or blunting.
For some patients, the dulling of emotional extremes can be therapeutic. For others, it suppresses emotions that need to be processed, leaving underlying issues unresolved.
“If you are in a state where you’re having a lot of anxiety, and you take a drug and it kind of constricts that, it sort of numbs that out, you’re going to feel better,” he said. “And if you’re highly suicidal, you might even say the medication saved your life.”
Hidden Risks of Long-Term Antidepressant Use
Relief derived from antidepressants can come at a cost. Over time, the body adapts to the medication’s effects.
“People become tolerant to them,” Witt-Doerring said, explaining that the drug starts to wear off, doses are increased, and “eventually you’re maxed out—still struggling with the same issues that led you to seek help in the first place.”
To compensate, other medications—mood stabilizers, sleep aids—may be added, a practice known as polypharmacy. However, stacking drugs can also mask, rather than resolve, the underlying problem.
“And this is why you hear that some people are on four, five, six medications,” he said.
When medications lose effectiveness, the body has simply adapted, yet patients are often told they have treatment-resistant depression and are prescribed more drugs—continuing the cycle. The more medications a person takes, the higher the chance of unpleasant or dangerous side effects—and it can become harder to tell which drug is causing which reaction.
