The chemical imbalance theory of depression is dead, but that doesn’t mean antidepressants don’t work

The chemical imbalance theory of depression is well and truly dead. A paper by Joanna Moncrieff and her colleagues, long-time reviews of the effectiveness of antidepressants, caused a sensation. The paper provides a summary of other summaries that confirm that there is no evidence to support the idea that depression is caused by a disruption in the brain’s serotonergic system.

They did us a favor by putting together the evidence that says as much, even though we already knew it was.

But the death of the chemical imbalance theory has no bearing on the effectiveness of antidepressants that affect the serotonergic system. These drugs were not developed on this premise. In fact, quite the opposite is true – the chemical imbalance theory was based on an emerging understanding of how antidepressants work.



Read more: Depression probably isn’t caused by a chemical imbalance in the brain – new study


How did the “chemical imbalance” theory begin?

The first two antidepressant drugs, both discovered in the 1950s, were observed to have positive effects on mood as side effects of their intended functions. Iproniazid was developed as a treatment for tuberculosis and imipramine as an antihistamine.

We now know that ipronizaid is a monoamine oxidase inhibitor – it shuts down the enzyme that breaks down serotonin and similar brain chemicals. But we didn’t know that when its antidepressant effects were first observed in 1952.

Imipramine is a tricyclic antidepressant and, among other effects, it blocks the reuptake of serotonin after it is secreted, also allowing more to remain in the brain.

The mechanism of action of antidepressants came before the chemical imbalance theory, not the other way around.
Shane/Unsplash

A simple hypothesis then presented itself: if both classes of antidepressants have been shown to increase serotonin levels in the brain, then the depression must be caused by low serotonin levels.

The researchers set out to demonstrate this in patients suffering from depression, showing that serotonin and its metabolites and precursors were lower in the some bloodin the cerebrospinal fluidetc

But these studies suffered from what we know now that plagued many studies of their time, leading to the so-called “replication crisis”. Studies used small sample sizes, reported their results selectively, and, if they failed to demonstrate the hypothesis, were often not reported at all. In short, the results were unreliable, and since then larger studies and meta-analyses (which summarized the many smaller studies) have clearly shown that the hypothesis is not supported.



Read more: Explained: what is depression?


What is the link between the theory and antidepressants?

Meanwhile, pharmaceutical companies have spotted a clear line to communicate the effectiveness of their drugs. The depression was caused by a “chemical imbalance” that could be corrected by antidepressants.

This coincided with the development of a new class of antidepressants, selective serotonin reuptake inhibitors (SSRIs), which, as their name suggests, were more selective than tricyclic antidepressants in targeting serotonin reuptake. serotonin as a mechanism of action.

These drugs – then known as Prozac, Zoloft and Cipramil – became blockbusters and remain widely used today (albeit with a variety of names since their patents expired).

Few psychiatrists familiar with the nuances of brain function believed in the chemical imbalance theory. It never matched how they could see the SSRIs working, with serotonin function changing within hours of taking the drug, but the depression didn’t improve for about four weeks.

But there were, and still are, many medical practitioners with a less sophisticated understanding of depression and neurochemistry who were happy to repeat this message to their patients. It was an effective message that took root in the popular imagination. I heard it repeated several times.

Pills in the shape of happy and sad faces
SSRIs don’t work for everyone.
Shutterstock

So, are antidepressants effective?

The new paper by Moncrieff and colleagues, while saying nothing new, does us all a favor by reiterating the message that has been clear for some time: there is no evidence to support the chemical imbalance theory. Their message was amplified by the extensive media coverage the article received.

But much of the commentary extrapolated from the study’s findings to suggest it undermines the effectiveness of antidepressants — including by the authors themselves.

This shows a misunderstanding of how medical science works. Medicine is pragmatic. Medicine has often established that a treatment works well before it has 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 gave the impetus to establish how they worked; and this knowledge has generated new treatments.

The proof for SSRIs are effective for depression convinces most reasonable evaluators. They are not effective for as many people with depression as we might hope, as I have writing before, but they are, on the whole, more effective than placebo treatments.

Critics suggest that the magnitude of the difference between the drugs and the placebo is not large enough to justify their use. It’s a matter of opinion. And many people report very significant benefits, even if some people report none, or even cause harm.



Read more: What causes depression? What we know, don’t know and suspect


If it’s not a chemical imbalance, how do antidepressants work?

In truth, we still don’t really know how or why antidepressants work. The brain is a complex organ. We still don’t have a clear idea on how general anesthesia work. But few people would refuse anesthesia when considering serious surgery on this basis.

Along the same lines, when considering whether an antidepressant might be an option for someone with depression, it doesn’t matter that its mechanism of action is not fully understood.

So let’s put aside the theory of chemical imbalance. We must continue our efforts to understand the nature of depression, while continuing to seek better treatments.

Dieting, exercising, and sleeping are effective for many people with depression. Psychotherapy can also be very helpful. But many people struggle with depression despite their trials, and it is for them that we must continue our efforts to find better treatments.

Sharon D. Cole