TThe chemical imbalance theory of depression is really dead. The research paper by Joanna Moncrieff and her colleagues, long-standing critics of antidepressants’ effectiveness, has caused quite a stir. The paper provides a summary of other summaries confirming the lack of evidence to support the idea that depression is caused by a disturbance in the brain’s serotonin system.
They’ve done us a favor by backing up the evidence that says the same thing, even if we know that’s the case.
But the death of the chemical imbalance theory has no effect on whether or not antidepressants that affect the serotonin system are effective. These drugs were not developed on this basis. In fact, quite the opposite is true – the chemical imbalance theory has been based on an emerging understanding of how antidepressants display work.
How did the “chemical imbalance” theory begin?
The first two types of antidepressant drugs, which were discovered in the 1950s, were noted to have positive effects on mood as side effects of their hoped-for 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 stops the enzyme that breaks down serotonin and similar chemicals in the brain. But we didn’t know this when its antidepressant effects were first noticed in 1952.
Imipramine is a tricyclic antidepressant that, among other effects, blocks the uptake of serotonin after it has been released, which also allows it to remain in the brain.
Then I made a simple hypothesis: If both classes of antidepressants are shown to increase serotonin levels in the brain, then the depression must be caused by low serotonin levels.
The researchers set out to prove this in patients with depression, showing that serotonin and its metabolites and precursors were lower in the blood, in the cerebrospinal fluid, etc.
But these studies suffered from what we now know plagued many studies of their time, resulting in the so-called “replication crisis”. Studies have used small sample sizes, selectively report their results, and if they fail to prove the hypothesis, they are often not reported at all. In summary, the results were unreliable, and since then the larger studies and meta-analyses (which summarized many smaller studies) have made it clear that the hypothesis is not supported.
What is the link between theory and antidepressants?
Meanwhile, drug companies have set a clear line for communicating the effectiveness of their drugs. The cause of the depression was a “chemical imbalance” that could be corrected with antidepressants.
This coincided with the development of a new class of antidepressants, the 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 known as Prozac, Zoloft, and Cipramil—became a blockbuster, and are still widely used today (albeit under various names since their patents expired).
Few psychiatrists who understand the nuances of brain function believe the chemical imbalance theory. It never fit the way they could see the action of the SSRIs, with serotonin function changing hours after taking the drug, but the depression didn’t show improvement for about four weeks.
But there were, and still are, many medical practitioners with a less complex understanding of depression and its neurochemistry, and they were happy to repeat this message to their patients. It was a touching message and entrenched in the popular imagination. I’ve heard it repeated many times.
Are antidepressants effective?
The new paper by Moncrieff and colleagues, while it says nothing 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 intense media attention the article received.
But many comments extrapolated from the study results to suggest that they undermine the effectiveness of antidepressants – including by the authors themselves.
This indicates a misunderstanding of how medical science works. Medicine is practical. He has often proven that a treatment works well before he understands how it works.
Many commonly used drugs were in use for decades before we understood their mechanisms of action: from aspirin to morphine to penicillin. The knowledge that they worked provided the motivation to determine how they worked; This knowledge generated new treatments.
Evidence for the effectiveness of SSRIs for depression is compelling to most rational residents. It’s not as effective for as many depressed people as we’d hope, as I wrote before, but it’s generally more effective than placebos.
Critics suggest that the size of the difference between the drugs and a placebo is not large enough to justify their use. This is a matter of opinion. And many people report significant benefits, even if some people don’t report anything, or even cause harm.
How do antidepressants work?
In fact, we still don’t really know how and why antidepressants work. The brain is a complex organ. We still don’t have a clear idea of how general anesthesia works. But few people refuse anesthesia when considering serious surgery on this basis.
By the same token, when considering whether an antidepressant might be an option for someone with depression, it is not a consequence that its mechanism of action is not fully understood.
So let’s put the chemical imbalance theory to bed. We must continue our efforts to understand the nature of depression as we continue to search for better treatments.
Diet, exercise, and sleep are effective for many people with depression. Psychotherapy can also be very helpful. But many people suffer from depression despite experiencing these things, and for their sake we need to continue our efforts to find better treatments.