TThat chemical imbalance theory of depression is well and truly dead. The article by Joanna Moncrief and colleagues, who have long criticized the effectiveness of antidepressants, has resonated. The paper summarizes other summaries that show there is no evidence to support the idea that depression is caused by a disruption of the brain’s serotonin system.
They’ve done us a favor by collecting evidence that speaks volumes even if we don’t know it.
And the death of the chemical imbalance theory has nothing to do with the efficacy or effectiveness of antidepressants that affect the serotonin system. These drugs were not developed on this basis. In fact, on the contrary, the chemical imbalance theory is based on an emerging understanding of how antidepressants work.
How did the theory of “chemical imbalance” appear?
The first two antidepressant drugs discovered in the 1950s were found to have positive effects on mood as side effects of their expected functions. Iproniazid was developed to treat tuberculosis, and imipramine was developed as an antihistamine.
We now know that ipronizide is a monoamine oxidase inhibitor—it blocks an enzyme that breaks down serotonin and similar brain chemicals. But we didn’t know this when its antidepressant effects were discovered in 1952.
Imipramine is a tricyclic antidepressant and, among other effects, it blocks the reuptake of serotonin after release, allowing it to remain in the brain longer.
A simple hypothesis then arose: if both classes of antidepressants were shown to increase serotonin levels in the brain, then depression must be caused by low levels of serotonin.
Scientists have shown this in patients with depression, and found serotonin and its metabolites and precursors in blood, cerebrospinal fluid, etc. showed that it is low.
But these studies, as we know them, suffered from many studies of their era, leading to the so-called “replication crisis.” Studies used small samples, reported their results selectively, and often did not report them at all if they failed to demonstrate a hypothesis. In short, the findings were unreliable, and since then large studies and meta-analyses (summarizing many smaller studies) have clearly shown that the hypothesis is not supported.
What is the relationship between the theory and antidepressants?
A fine line has been drawn for pharmaceutical companies to communicate the efficacy of their drugs. Depression is caused by a “chemical imbalance” that can be corrected with antidepressants.
This coincided with the development of a new class of antidepressants, selective serotonin reuptake inhibitors, which, as their name suggests, were more selective than tricyclic antidepressants in targeting serotonin reuptake as their mechanism of action.
These drugs—then called Prozac, Zoloft, and Cipramil—became blockbusters and are still widely used today (albeit under different names since their patents expired).
Few psychiatrists who understood the nuances of brain function believed in the chemical imbalance theory. They never had to see the SSRIs work, and the serotonin function changed a few hours after taking the drug, but the depression didn’t improve for four weeks.
But many medical professionals who have little understanding of the neurochemistry of depression were and are happy to repeat this message to their patients. It was a powerful message and a popular dream. I heard it repeated many times.
Are antidepressants effective?
While the new paper by Moncrief and colleagues says nothing new, it does us all a favor by repeating what has been clear for some time: there is no evidence to support the chemical imbalance theory. Their statement was fueled by the media attention the article received.
However, most of the commentary extrapolates from the study findings and downplays the effectiveness of antidepressants, including by the authors themselves.
This shows a misunderstanding of how medical science works. Medicine is pragmatic. It is often determined that a treatment is working well before it is understood how it works.
Many commonly used drugs were used for decades before we understood their mechanisms of action: from aspirin to morphine to penicillin. Knowing that they worked motivated us to determine how they worked; and this knowledge has led to new treatments.
The evidence that SSRIs are effective for depression convinces most reasonable counselors. They are not effective for many people with depression, as I have written before, but they are more effective than placebo treatments.
Critics argue that the magnitude of the difference between drugs and placebos does not warrant their use. This is a matter of opinion. And many people report significant benefits, although some people do not report any harm.
How do antidepressants work?
In fact, we still don’t know how or why antidepressants work. The brain is a complex organ. We do not have a clear idea of how general anesthetics work. However, few people would consider doing a serious operation on this basis and refuse anesthesia.
In the same vein, when considering whether an antidepressant might be an option for someone with depression, it is not insignificant that its mechanism of action is not fully understood.
So let’s put the chemical imbalance theory aside. We must continue our efforts to understand the nature of depression while we search for better treatments.
Diet, exercise, and sleep are effective for many people with depression. Psychotherapy can also be very helpful. However, many people struggle with depression despite trying these things, and for them we need to continue our efforts to find better treatments.