The Times Australia
The Times World News

.
The Times Real Estate

.

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

  • Written by Christopher Davey, Head of the Department of Psychiatry, The University of Melbourne
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[1] by Joanna Moncrieff and colleagues, long-time critics[2] of the effectiveness of antidepressants, has caused a splash. The paper provides a summary of other summaries that confirm there is no evidence to support the idea that depression is caused by disturbance of the brain’s serotonin system.

They have done us a favour by corralling the evidence that says as much, even if we already knew this to be the case.

But the death of the chemical imbalance theory has no bearing on whether antidepressants that affect the serotonin system are effective. These medications weren’t developed on this premise. In fact quite the opposite is true – the chemical imbalance theory was based on an emerging understanding of how antidepressants were shown to work.

Read more: Depression is probably not caused by a chemical imbalance in the brain – new study[3]

How did the ‘chemical inbalance’ theory start?

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

We know now that ipronizaid is a monoamine oxidase inhibitor[4] – it stops the enzyme that breaks down serotonin and similar brain chemicals. But we didn’t know this when its antidepressant effects were first observed in 1952.

Imipramine is a tricyclic antidepressant[5] and, among other effects, it blocks the reuptake of serotonin after it has been secreted, also allowing more to stay in the brain.

Woman on floor with dog
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 were shown to increase brain levels of serotonin, then depression must be caused by low levels of serotonin.

Researchers set out to demonstrate this in patients with depression, showing that serotonin and its metabolites and precursors were lower in the blood[6], in the cerebrospinal fluid[7], and so on.

But these studies suffered from what we now know plagued many studies of their era, leading to the so-called “replication crisis[8]”. Studies used small sample sizes, selectively reported their results, and if they failed to demonstrate the hypothesis, were often not reported at all. In short, the findings were unreliable, and since then larger studies and meta-analyses (which summarised the many smaller studies), made it clear the hypothesis wasn’t supported.

Read more: Explainer: what is depression?[9]

What’s the link between the theory and antidepressants?

In the meantime, pharmaceutical companies spotted a clear line to communicate the effectiveness of their medications. 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 (SSRIs), 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 remain widely used today (albeit with a variety of names since expiration of their patents).

Few psychiatrists with an understanding of the nuance of brain function believed the chemical imbalance theory. It never fitted with the way they could see that SSRIs worked, with serotonin function changing hours after taking the medication, but depression not showing improvement for about four weeks.

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

Pills in 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 not saying anything new, does us all a favour by reiterating the message that has been clear for some time: there is no evidence to support the chemical imbalance theory. Their message has been amplified by the extensive media attention the article has received.

But much of the commentary has extrapolated from the study’s finding to suggest it undermines the effectiveness of antidepressants – including by the authors[10] 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 medicines were used for decades before we understood their mechanisms of action: from aspirin to morphine to penicillin. Knowing they worked provided the impetus for establishing how they worked; and this knowledge generated new treatments.

The evidence for SSRIs being effective[11] for depression is convincing to most reasonable assessors. They are not effective for as many people with depression as we might hope, as I have written[12] before, but they are, overall, more effective than placebo treatments.

Critics suggest the magnitude of the difference between the medications and placebo isn’t great enough to warrant their use. That is a matter of opinion. And many people report very significant benefits, even as some people report none, or even that they have caused harm.

Read more: What causes depression? What we know, don’t know and suspect[13]

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 about how general anaesthetics work[14]. But few people would refuse an anaesthetic when contemplating serious surgery on this basis.

In the same vein, when contemplating whether an antidepressant might be an option for someone with depression, it is of little consequence that its mechanism of action is incompletely understood.

So let’s put the chemical imbalance theory to bed. We should continue our efforts to understand the nature of depression, while we keep searching for better treatments.

Attending to diet, exercise, and sleep is effective for many people with depression. Psychotherapy can be very helpful too. But many people struggle with depression despite trying these things, and it is for them that we need to keep up our efforts to find better treatments.

References

  1. ^ paper (www.nature.com)
  2. ^ long-time critics (www.ucl.ac.uk)
  3. ^ Depression is probably not caused by a chemical imbalance in the brain – new study (theconversation.com)
  4. ^ monoamine oxidase inhibitor (www.mayoclinic.org)
  5. ^ tricyclic antidepressant (www.mayoclinic.org)
  6. ^ blood (pubmed.ncbi.nlm.nih.gov)
  7. ^ cerebrospinal fluid (pubmed.ncbi.nlm.nih.gov)
  8. ^ replication crisis (www.vox.com)
  9. ^ Explainer: what is depression? (theconversation.com)
  10. ^ authors (theconversation.com)
  11. ^ SSRIs being effective (www.thelancet.com)
  12. ^ written (www.mja.com.au)
  13. ^ What causes depression? What we know, don’t know and suspect (theconversation.com)
  14. ^ general anaesthetics work (www.sciencealert.com)

Read more https://theconversation.com/the-chemical-imbalance-theory-of-depression-is-dead-but-that-doesnt-mean-antidepressants-dont-work-187769

The Times Features

Why Regional Small Businesses in Bendigo Deserve Better Access to Finance in 2025

In the heart of regional Victoria, Bendigo has long stood as a beacon of innovation, resilience and community spirit. As we step further into 2025, the importance of nurturing sm...

Is It Time for a Deep Cleaning? Signs You Shouldn’t Ignore

Most people know they should visit the dentist for a regular check-up and cleaning every six months. But sometimes, a standard cleaning isn’t enough. When plaque and tartar build...

The Hidden Meaning Behind Popular Engagement Ring Cuts

When it comes to engagement rings, the cut of the diamond is not just about aesthetics. Each shape carries its own symbolism and significance, making it an important decision for...

Annual Health Exams in the Office: How They Can Reduce Sick Days and Healthcare Costs

Regular health check-ups, especially annual health exams in the office, can significantly impact the overall well-being of your workforce. A proactive approach to employee health...

Best Deals on Home Furniture Online

Key Highlights Discover the best deals on high-quality outdoor furniture online. Transform your outdoor space into a stylish and comfortable oasis. Explore a wide range of d...

Discover the Best Women's Jumpers for Every Season

Key Highlights Explore lightweight jumpers for spring and summer, ensuring breathability and ease. Wrap up warm with cozy wool jumpers for the chilly autumn and winter season...

Times Magazine

The Essential Guide to Transforming Office Spaces for Maximum Efficiency

Why Office Fitouts MatterA well-designed office can make all the difference in productivity, employee satisfaction, and client impressions. Businesses of all sizes are investing in updated office spaces to create environments that foster collaborat...

The A/B Testing Revolution: How AI Optimized Landing Pages Without Human Input

A/B testing was always integral to the web-based marketing world. Was there a button that converted better? Marketing could pit one against the other and see which option worked better. This was always through human observation, and over time, as d...

Using Countdown Timers in Email: Do They Really Increase Conversions?

In a world that's always on, where marketers are attempting to entice a subscriber and get them to convert on the same screen with one email, the power of urgency is sometimes the essential element needed. One of the most popular ways to create urg...

Types of Software Consultants

In today's technology-driven world, businesses often seek the expertise of software consultants to navigate complex software needs. There are several types of software consultants, including solution architects, project managers, and user experienc...

CWU Assistive Tech Hub is Changing Lives: Win a Free Rollator Walker This Easter!

🌟 Mobility. Independence. Community. All in One. This Easter, the CWU Assistive Tech Hub is pleased to support the Banyule community by giving away a rollator walker. The giveaway will take place during the Macleod Village Easter Egg Hunt & Ma...

"Eternal Nurture" by Cara Barilla: A Timeless Collection of Wisdom and Healing

Renowned Sydney-born author and educator Cara Barilla has released her latest book, Eternal Nurture, a profound collection of inspirational quotes designed to support mindfulness, emotional healing, and personal growth. With a deep commitment to ...

LayBy Shopping