TThe chemical imbalance theory of depression is well and truly dead. The article by Joanna Moncrieff and colleagues, longtime critics of the effectiveness of antidepressants, caused a stir. The article provides a summary of other summaries confirming that there is no evidence to support the idea that depression is caused by a disorder of the brain’s serotonin system.
They have done us a favor by confirming the evidence that says this, even though we knew it to be so.
But the death of the chemical imbalance theory has no bearing on whether antidepressants that affect the serotonin system are effective. These drugs were not developed based on this assumption. In fact, the opposite is true – the chemical imbalance theory was based on a new understanding of how antidepressants were shown to work.
How did the “chemical imbalance” theory begin?
The first two antidepressants, both discovered in the 1950s, were observed to have positive effects on mood as side effects of their expected functions. Iproniazid was developed as a treatment for tuberculosis and imipramine as an antihistamine.
We now know that ipronizide is a monoamine oxidase inhibitor – it stops the enzyme that breaks down serotonin and similar chemicals in the brain. 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 has been excreted, allowing more to remain in the brain.
Then a simple hypothesis emerged: if both classes of antidepressants were shown to increase serotonin levels in the brain, then depression must be caused by low serotonin levels.
The researchers decided to prove this in depressed patients and showed that serotonin and its metabolites and precursors were lower in the blood, in the cerebrospinal fluid, and so on.
However, these studies suffered from what we now know plagued many studies of their era, leading to the so-called “replication crisis”. Studies used small sample sizes, selectively reported their results, and often did not report at all if the hypothesis failed to be proven. In short, the findings were unreliable, and since then larger studies and meta-analyses (which have summarized many smaller studies) have clearly shown that the hypothesis was not supported.
What is the connection between the theory and antidepressants?
Meanwhile, drug companies have drawn a clear line on how to communicate the effectiveness of their drugs. Depression was caused by a “chemical imbalance” that could 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 a mechanism of action.
These drugs—then known as Prozac, Zoloft, and Cipramil—became blockbusters and are still widely used today (albeit under different names after their patents expired).
Few psychiatrists with an understanding of the nuances of brain function believed in the chemical imbalance theory. It never fit how they could see that SSRIs worked, serotonin function changed hours after taking the drug, but depression showed no improvement for about four weeks.
But there were and are many doctors 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 caught the popular imagination. I’ve heard it repeated many times.
So are antidepressants effective?
The new paper by Moncrieff and colleagues, while not saying anything new, does us all a favor by repeating a 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 attention the article received.
But much of the commentary extrapolated from the study’s findings to suggest that it undermines the effectiveness of antidepressants — including the authors themselves.
This shows a misunderstanding of how medical science works. Medicine is pragmatic. Often the treatment was shown to be working well before she understood how it was working.
Many commonly used drugs were used for decades before we understood their mechanisms of action: from aspirin to morphine to penicillin. Knowing that they work provided the impetus for finding out how they work; and this knowledge created new treatments.
The evidence for the efficacy of SSRIs in depression is convincing to most reasonable evaluators. They are not effective for as many people with depression as we might hope, as I have written before, but overall they are more effective than placebo treatments.
Critics suggest that the magnitude of the difference between drugs and placebo is not large enough to justify their use. That’s a matter of opinion. And many people report significant benefits, although some people report none or even harm.
How do antidepressants work?
In fact, we still don’t know how and why antidepressants work. The brain is a complex organ. We still don’t have a clear idea of how general anesthetics work. But few people would refuse anesthetic when considering serious surgery on this basis.
In the same vein, when considering whether an antidepressant might be an option for someone with depression, it is of little importance that its mechanism of action is not fully understood.
So let’s put the chemical imbalance theory to bed. We should continue our efforts to understand the nature of depression while searching for better treatments.
Diet, exercise and sleep are effective for many people with depression. Psychotherapy can also be very helpful. But many people struggle with depression despite trying these things, and it is for them that we must continue our efforts to find better treatments.
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