The Chemical Imbalance Theory of Depression Is Dead — But That Doesn’t Mean Antidepressants Don’t Work | Christopher Davey for the talk

TThe chemical imbalance theory of depression is really dead. An article by Joanna Moncrieff and colleagues, who have long been critics of the effectiveness of antidepressants, made a splash. The article summarizes other abstracts that confirm that there is no evidence to support the idea that depression is caused by a disruption of the brain’s serotonin system.

They did us a favor by collecting the evidence that says so much, even if we knew it was the case.

But the death of the chemical imbalance theory does not affect the effectiveness of antidepressants that affect the serotonin system. These drugs were not developed on this basis. In fact, the opposite is true — the chemical imbalance theory was based on an emerging understanding of how antidepressants have been shown to work.

How did the theory of ‘chemical imbalance’ come about?

The first two antidepressants, both discovered in the 1950s, were found to have positive effects on mood as side effects of their hoped-for functions. Iproniazide was developed as a treatment for tubercolosis 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 brain chemicals. But we didn’t know this when the antidepressant effects were first observed in 1952.

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

Then a simple hypothesis arose: If both classes of antidepressants were shown to increase serotonin levels in the brain, then depression must be caused by low serotonin levels.

Researchers wanted to demonstrate this in patients with depression, showing that serotonin and its metabolites and precursors were lower in the blood, in the cerebrospinal fluid, and so on.

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

What is the connection between the theory and antidepressants?

Meanwhile, pharmaceutical companies saw a clear line to communicate the effectiveness of their drugs. Depression was caused by a “chemical imbalance” that could be corrected by 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 the tricyclic antidepressants in targeting serotonin reuptake as their mechanism of action.

These drugs — then known as Prozac, Zoloft, and Cipramil — became blockbusters and are still widely used today (albeit with different names since their patents expired).

Few psychiatrists with an understanding of the nuances of brain function believed in the chemical imbalance theory. It never matched the way they could see SSRIs working, with serotonin function changing hours after taking the medication, but depression showing no improvement for about four weeks.

But there were and are many physicians with a less advanced understanding of depression and neurochemistry who were eager to repeat this message to their patients. It was an effective message, and one that caught the popular imagination. I’ve heard it repeated many times.

So are antidepressants effective?

While the new paper by Moncrieff and colleagues doesn’t say anything new, it pleases us all by repeating the message that has been clear for some time: There is no evidence to support the chemical imbalance theory. Their message has been reinforced by the extensive media coverage the article has received.

But much of the commentary has been 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. Often a treatment is established to work well before understanding how it works.

Many common drugs were used for decades before we understood their mechanism of action: from aspirin to morphine to penicillin. Knowing that they worked was the impetus for establishing how they worked; and this knowledge generated new treatments.

The evidence that SSRIs are effective for depression is compelling to most reasonable raters. They’re not effective for as many people with depression as we’d hope, as I’ve written before, but they’re generally more effective than placebo treatments.

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

How do antidepressants work?

In reality, 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 about how general anesthetics work. Few people would refuse an anesthetic if they were considering serious surgery on the basis of this.

In a similar vein, when considering whether an antidepressant might be an option for someone with depression, it is of little 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.

Attention to diet, exercise and sleep is 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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