Depression is not a 'Chemical Imbalance' in your brain.

Reviewing the research that debunks the Serotonin model of depression.

For decades, the idea that depression stems from a ‘chemical imbalance’ in the brain has dominated public and clinical understanding. The idea that low serotonin levels cause depression gave rise to a multi-billion-dollar industry centred on selective serotonin reuptake inhibitors (SSRIs), a class of antidepressants designed to increase serotonin levels.

Throughout university I was prescribed three different types of SSRIs. None of them worked.

If you’ve had a similar experience, this article might help put that into context for you.

La Melancolie by Louis-Jean-François Lagrenee (1785)
Source: collections.louvre.fr

In July of 2022 a landmark review was published in Molecular Psychiatry which has cast serious doubt on this long-standing assumption. As always, i’ll try to keep it simple:

The origins of the Serotonin Hypothesis

The serotonin hypothesis took root in the 1960s when researchers observed that drugs altering serotonin levels seemed to impact mood. A tidy, compelling narrative:

Low serotonin = depression.

Raise serotonin levels = alleviate depression.

From its inception, the hypothesis was speculative.

What the review found:

The Molecular Psychiatry review, (led by Professor Joanna Moncrieff of University College London) analysed decades of research into serotonin and its relationship to depression. They reported:

1. No evidence of low serotonin in depression
   Studies comparing serotonin levels in depressed and non-depressed individuals consistently found no significant differences. This included analyses of serotonin in blood plasma, cerebrospinal fluid, and brain tissue.

2. Genetics offers no clear answers
   Researchers have also looked at whether genetic variations in serotonin-related genes might predispose individuals to depression. The review found no robust evidence linking specific serotonin-related genes to an increased risk of depression.

3. Serotonin receptors and transporters are also inconclusive
   Studies on serotonin receptors and transporters (the molecular machinery involved in serotonin signaling) also failed to show any consistent abnormalities in people with depression.

4. There’s a placebo effect in antidepressants
   Many antidepressant trials reveal that a significant portion of their efficacy may be due to placebo effects. Patients often improve simply because they expect to, rather than because of the drug’s chemical action on serotonin.

Why does this all matter?

The serotonin hypothesis has deeply shaped how we think about depression. That some people are just born with this ‘chemical imbalance’. It has influenced treatment strategies, public perceptions, and even the way people who suffer from depression understand their own experiences.

From my personal experience as someone who has been depressed, being told I have a chemical imbalance in my brain is both comforting (because we can fix it) and disempowering (I will always need fixing).

It’s especially disempowering when what we use to fix it doesn’t actually fix it. I felt like there was something severely wrong with me because even the highest doses of SSRIs didn’t work.

Depression isn’t about being sad all the time, for me it felt more like ‘nothingness’. A hollow, emotionless void where nothing mattered, and I didn’t care what happened to me. That indifference led to risky behaviour because if nothing matters, why should I? It wasn’t about wanting harm, it was about not caring at all.

And then, when the medications that are supposed to help don’t seem to work, it amplifies that emptiness. It feels hopeless, like this numb, unchanging state is permanent. You wonder what the point is if this is all there will ever be. It’s the absence of connection, purpose, and even yourself.

Coincidentally, I look back on the times when I was clinically depressed. And surprise surprise- it coincided with experiencing intimate partner violence and other traumatic events. Had my doctors (and my university curriculum) communicated the complexity of depression, I might have been quicker to make more positive decisions - like leaving an abusive relationship (not that it’s that easy), or quit my PhD sooner (In one study of 3,659 PhD students-researchers found that 32% are at risk of developing common psychiatric disorders, particularly depression compared to the general population/educated employees/higher education students).

I also sometimes experience suicidal thoughts in the week before my period, and have done even during years where I haven’t been depressed. (Hi PMDD)

Depression is a multifaceted condition influenced by biological, psychological, and social factors. If we simplify it to a serotonin deficiency, then we ‘re gravely overlooking the complexity of the human mind and the varied causes of emotional suffering.

Currently, I would say I’m not depressed at all. I’m in a loving relationship, I enjoy my work and find meaning in it, I have supportive friendships and family relationships, I eat well, I move my body every day.

However, i’ve seen people close to me battle consistent bouts of depression, especially when they’re without medication. So that begs the question:

Do antidepressants still work?

The review does not suggest that antidepressants are ineffective. For some people, SSRIs work, but their mechanism of action is likely more complicated than just ‘fixing’ serotonin levels.

Some researchers believe SSRIs might work by enhancing neuroplasticity, allowing the brain to adapt and recover from stress. Others point to their impact on emotional regulation, which can help people navigate difficult periods in their lives.

The review, however, does challenge the narrative that SSRIs address the ‘root cause’ of depression. For many patients antidepressants alleviate symptoms without necessarily addressing underlying issues like trauma, chronic stress, or social isolation.

Understanding depression

So if depression isn’t a chemical imbalance, what is it? It’s not simple… It likely arises from an interplay of factors, including:

• Stress and trauma. Particularly early life adversity and chronic stress are strongly linked to depression.

• Biological vulnerabilities. Other biological factors aside from serotonin might play a role, like inflammation or hormonal imbalances.

• Psychosocial factors. Loneliness, financial instability, and lack of purpose contribute to poor mental health.

So we need a bit more of a holistic approach.. therapy, lifestyle changes, social support, and, when necessary, medication. Maybe even a change in direction of how we medicate, but more on psychedelics in the next article :)

The dangers of oversimplification

The chemical imbalance theory persists in the cultural vernacular because it’s easy to communicate, because it’s been repeated cojuntless times, and because it’s reassuring to know we have ‘the solution’.

However, it’s misleading. When, like me, you don’t respond to SSRIs, you may feel like you’re broken beyond repair because your ‘chemical imbalance’ isn’t fixed.

In the worst of cases you’ll feel like there’s no hope.

If we have the solution and it doesn’t work for you, that might divert your attention from making changes in your life that could help.

As a society, focusing solely on serotonin can divert attention from broader social issues like poverty, inequality, and lack of mental health resources that significantly impact mental well-being on a larger scale.

Sorrow by Paul Cezanne (1869) Source: Wikiart

What next?

We need to re evaluate of how we approach and treat depression. We n

→ Researchers must expand their focus to include more holistic models of mental health

→ Clinicians need to communicate the complexity of depression to their patients, and provide more compassionate care.

Most importantly,

→ We should all continue to challenge simplistic narratives that reduce mental health to biology alone.

(A great first step is to send or discuss this article with people in your inner circle).

There’s also a case for new approaches to treatment, like with psychedelics for example. I’ll get to that in the next article. Stay tuned!

Lots of Love,
Anne-Sophie