What we can and cannot conclude from the “Death of the Chemical Imbalance Theory”

Aug 18, 2022 - Florian Kleinau

We all have some knowledge about what antidepressant drugs are. When asked how they work, most of us would reply along the lines of “they restore the balance of chemicals in the brain”. But is this true?

What is the Chemical Imbalance Theory?

We all have some knowledge about what antidepressant drugs are. When asked how they work, most of us would probably reply along the lines of “they restore the balance of chemicals in the brain”. Is this true? The hypothesis under which antidepressant drugs like Prozac and other so-called Selective Serotonin Reuptake Inhibitors (SSRIs) are used is that they influence the uptake of Serotonin in the synapses of the brain. Serotonin is a neurotransmitter that is involved in the regulation of mood, sleep, and digestion. It is mainly produced in the Raphe nucleus of the brain but most prevalent in the gut, not the brain. Antidepressant drugs are thought to increase the levels of serotonin in the synapses thereby positively influencing symptoms of depression.

The theory behind this mechanism is called “chemical imbalance theory”. The idea is that depression is the result of abnormalities in the brain’s serotonin levels – in specific, that low levels of serotonin cause depression. Since the inception of this theory, it has received much criticism – nonetheless 80% of the public would agree that the cause of depression is an imbalance in the brain’s chemical composition3.

Chemical imbalance theory has gained much attention in the media of late, such as this article by Christopher Davey in The Guardian and The Conversation.  We take this as an opportunity to take a closer look at the chemical imbalance theory and ask our team of clinical experts for their opinion on the implications on the reality of clinical practice.

Why has the Chemical Imbalance Theory Recently come under scrutiny?

Earlier this year Joanna Moncrieff and colleagues published findings of a systematic meta-analysis of studies on the topic of serotonin levels and symptoms of depression.   In their paper, Moncrieff and colleagues conducted a systematic meta-analysis of previous meta-analyses that reviewed most of the studies on the topic of serotonin levels and symptoms of depression. In his write-up on the scientific article, Davey concludes:

while not saying anything new, [the new paper] does us all a favor by reiterating the message that has been clear for some time: there is no evidence to support the chemical imbalance theory.1

However, he – alongside Moncrieff and colleagues – emphasizes that this does not mean we can conclude antidepressants don’t work. In fact, as Davey concludes:

In truth, we still don’t really know how or why antidepressants work1.

This seems to be the most important conclusion. Although the researchers present sufficient evidence that depression is likely not caused by a chemical imbalance in the brain (1) we still know that antidepressant drugs influence a patient’s mood.

What are the Clinical Implications of the “Death of the Chemical Imbalance Theory”?

Where does this leave us? Certainly, we can say that more research is needed to understand the underpinnings of depressions. But what about the implications for clinical practice? If the chemical imbalance theory can be “put to bed” as Davey concludes from Moncrieff and colleagues’ analysis, how is the clinical reality affected? Neuroscientist Yuki Mizutani-Tiebel, who works with neurocare, weighs in on the topic: 

Psychiatric diseases are special. If you have cancer, you know which cells you need to remove to cure it. If you have a broken bone, you know which bone to fix. But psychiatric diseases do not have a consensus yet on where the symptoms come from. Especially depression is one of the most difficult ones as it is quite a “vague” symptom. Most likely, the causes are in various dysfunctions and combinations of those.

It seems the clinical reality, therefore, needs to be grounded in personalization, analysis, and multi-modal treatment approaches. Antidepressants may help some patients become better, but they cannot be the only, nor a generalizable treatment approach. Referring to a study on monotherapy conducted by Stone and colleagues4 Ms. Mizutani-Tiebel says:

The most important take home message in my opinion from this paper is that 85% patients show improvement in symptom anyways without antidepressant. We just need to help them accelerate their natural will of being healthy by any method which suits the individual (much easier said than done), and for some cases antidepressant may help.

It seems that tailoring treatments to the patient's individual needs and preferences is central. The modern clinic has to offer patients different therapy approaches that can be tested and applied based on personal characteristics.  There are now more patients interested in alternative and viable treatments for depression which are becoming more prominent. Neurostimulation techniques are in this space, such as Transcranial Magnetic Stimulation, or "TMS" therapy.

The wide interest in the topic of chemical imbalance theory has attracted reflects an attitude neurocare’s clinicians have seen for a while: Patients are asking for more options than the one-size-fits-all approach antidepressants have offered.

While precise knowledge of the underlying mechanisms of depression and other mental health disorders remains up for debate and research – we see that clinical outcomes are driven by personalization.


  1. Davey. C., (2022). The chemical imbalance theory of depression is dead – but that doesn’t mean antidepressants don’t work. https://www.theguardian.com/commentisfree/2022/aug/03/the-chemical-imbalance-theory-of-depression-is-dead-but-that-doesnt-mean-antidepressants-dont-work
  2. Moncrieff, J., Cooper, R. E., Stockmann, T., Amendola, S., Hengartner, M. P., & Horowitz, M. A. (2022). The serotonin theory of depression: a systematic umbrella review of the evidence. Molecular Psychiatry, 1-14.
  3. Pilkington, P. D., Reavley, N. J., & Jorm, A. F. (2013). The Australian public’s beliefs about the causes of depression: Associated factors and changes over 16 years. Journal of Affective Disorders, 150(2), 356-362.
  4. Response to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration: individual participant data analysis | The BMJ



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