The new theory around depression

The idea that some antidepressants corrected a chemical imbalance in the brain is being revisited

Second-grade teacher Melissa Shugg teaches a lesson at Paw Paw Elementary School about thoughts, feelings and actions on December 2, 2021, in a school in, Michigan, US. Shugg is one of many teachers at the school who've been trained to teach a social-emotional curriculum created at the University of Michigan called TRAILS.  Research suggests TRAILS lessons for at-risk kids can reduce depression and improve coping skills. AP
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Occasionally a research article helps change the way we view things. This happened last month when University College London psychiatrists Prof Joanna Moncrieff and Dr Mark Horowitz published an article on depression in Molecular Psychiatry. Their study, a systematic umbrella review, was a comprehensive look at past research exploring the chemical (serotonin) imbalance theory of depression. Their conclusion was, for many, a bombshell: depression is probably not caused by a serotonin imbalance in the brain.

The media quickly picked up this work, with the study receiving coverage from 269 news outlets worldwide. Additionally, the story became the day's most-read article in several prestigious publications. More than 6,000 unique users on Twitter commented and retweeted the article to about 17 million followers. Out of 21 million journal articles on record, this study is already among the top 500 most shared scientific papers ever.

This widespread interest can be pegged to the fact that depression has become one of the biggest health concerns of our age. In 2017, the UN health agency declared depression "the leading cause of disability worldwide", affecting an estimated 300 million people. The other primary reason for the interest and the outrage is that this research fundamentally challenges the scientific foundation of the drugs we use to treat depression. Today the most frequently prescribed antidepressants are based on the idea that they correct a chemical imbalance in the brain, specifically low or inactive serotonin levels.

The serotonin theory has caused many people to rethink depression

This serotonin theory of depression goes back to the 1960s. However, it wasn't until the early 1990s that it took off, with help from the pharmaceutical industry. In 1987, Eli Lilly, a multinational pharmaceutical company, was granted permission to market a drug called fluoxetine, better known by its brand name, Prozac.

This new drug was based on the serotonin theory, the notion that low serotonin levels caused depression, an imbalance that the new wonder drug claimed it could fix. The narrative was seductive in its simplicity, an easy-to-swallow capsule that could reset faulty serotonin levels, thereby vanquishing depression.

In less than a decade, Prozac sales accounted for about a quarter of Eli Lilly's $10 billion annual revenue. By 2001, Eli Lilly's patent for fluoxetine had expired. An event that opened the door for other serotonin-targeting antidepressants, known as selective serotonin re-uptake inhibitors (SSRIs), to enter the rapidly expanding market. Alongside Prozac, today's SSRIs include names such as Zoloft, Celexa, Paxil and more.

However, this latest review, the most comprehensive to date, is essentially a kill-shot to the serotonin theory. The idea that low levels of serotonin cause depression – the rationale for SSRI antidepressants – is just not supported by scientific research evidence.

For example, the review found that studies looking at serotonin levels in blood and brain fluid reported no differences between those with and without depression. Similarly, extensive genetic studies exploring genes associated with serotonin (the serotonin transporter gene) reported no differences in the frequency of gene versions between healthy controls and people experiencing depression. Furthermore, experimental studies that intentionally depleted/reduced the serotonin levels of healthy people generally failed to induce/cause depression.

This review has vast implications and raises important questions. For example, if depression is not caused by a serotonin imbalance, what is the cause? And what exactly are these antidepressants doing; how and why do they work? Such questions must be answered if mental health professionals continue prescribing SSRIs. We can no longer tell people: "You have a chemical imbalance, and this pill will fix it." To continue parroting this old (unsupported) theory as though it were a near fact is ethically dubious, undermining the principles of transparency and honesty in patient communications.

Undoubtedly, many people are helped by antidepressants – they do work but don't seem to work in the way previously proposed. Therefore, discontinuing such medication is ill-advised without first consulting a physician. It is also worth considering that new biochemical theories will emerge. Some of these may eventually shed light on the mechanisms (how they work) of today's antidepressants.

Alongside this biochemical focus on antidepressant medication, however, we also need a social focus, working towards developing antidepressant families, antidepressant communities and antidepressant societies. Experiencing stressful life events, such as victimisation, economic insecurity and social exclusion is strongly associated with the development of depression. As the saying goes, prevention is better than cure. A statement published in a UN report in 2017 echoes this sentiment, calling member states to "shift their mental health investments” from focusing on “chemical imbalances” to tackling “power imbalances” and “inequalities”.

Minimising inequality, injustice and victimisation experiences will go a long way to reduce the current rate of depression. Hand-in-hand with such initiatives, we might also focus on helping people enhance their stress resilience. Interventions such as mindfulness-based stress reduction and mindfulness-based cognitive therapy have been proved to be effective, helping people prevent stress from spiralling out of control and morphing into something more malignant, such as a depressive episode.

The massive coverage received by Prof Moncrieff and Dr Horowitz's article reflects a growing public concern about depression and mental health in general. Their review of the serotonin theory has caused many people to rethink depression. Hopefully, this rethink will give rise to new ideas about causation, treatment and, most importantly, prevention.

Published: August 08, 2022, 9:00 AM