The latest depression debate – serotonin deficiency or inflammatory disorder?

New research connects the dots and reviews serotonin’s role in the development of depression and whether lower levels of serotonin are in fact associated with the disorder in the first place.

By Neil Bridgeman
Aug 17, 2022 • 8 min read

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20% of people in their lifetime will suffer from Major Depressive Disorder (MDD) and it is often characterised by emotional dysregulation, motivational decline, cognitive impairment, and a comprehensive list of physiological symptoms which make it a challenging disorder to manage. 

Selective serotonin reuptake inhibitors (SSRIs) are one of the most common first line antidepressant medications (ADM) prescribed to those presenting with MDD and function by reducing the reabsorption of serotonin. 

While the efficacy of ADM has been asserted across many individual studies, at least half of patients on ADM will be non-responsive to their effect, and for those who are responsive, the effect is primarily symptom suppression versus curative. 

Understandably, it was only a matter of time before someone attempted to connect the dots and review the most current research on serotonin, its role in the development of MDD, and whether lower levels of serotonin were in fact associated with MDD in the first place.

“Selective serotonin reuptake inhibitors (SSRIs) are one of the most common first line antidepressant medications”

In medical research there is a hierarchy that underpins what is deemed to be of highest quality research. At the very top is what’s termed an ‘Umbrella Review’. It assesses and analyses all the data and findings from other high quality research papers called systematic reviews and meta-analyses. This is exactly what was published recently in the peer review Journal of Molecular Psychiatry and the findings were…enlightening to say the least. 

The authors conclude that there is “…no convincing evidence that depression is associated with, or caused by, lower serotonin concentrations or activity”. Their analysis revealed:

  • Lower levels of plasma serotonin in those taking antidepressants – one would expect these to be higher if indeed antidepressants inhibit serotonin reuptake
  • No difference in serotonin receptor activity between those with MDD and healthy controls – those with MDD would theoretically have reduced receptor activity than healthy controls
  • A possible reduction in serotonin transporter proteins – in MDD, it would be more likely that this should be increased, not reduced

So if the association between MDD and serotonin depletion is looking tenuous, what’s at play with MDD?

“There is a growing body of evidence that points to MDD as a neuroinflammatory disorder”

There is a growing body of evidence that views MDD as a neuroinflammatory disorder – the result of an interconnected cascade that impacts not only neurotransmitter production (including serotonin), but also activates neurotoxic pathways, reduces the brains ability to grow and repair itself and dysregulates our response to stress.

Multiple systematic reviews and meta-analyses conducted indicate elevated levels of pro-inflammatory cytokines (chemical messengers that initiate inflammatory pathways) in those diagnosed with MDD versus control groups. In fact, there was a 46% higher odds of inflammation in those with MDD vs healthy controls. 

Current research asserts that pro-inflammatory cytokines like C-Reactive Protein and Interleukin-6 up-regulate an enzyme called indoleamine 2,3dioxygenase (aka IDO) to redirect tryptophan (a common protein) down the neurotoxic pathway to produce Quinolinic Acid. Quinolinic Acid acts at a synaptic level in our brains inducing synaptic damage and subsequent sickness-like behaviours that in a less fast-paced and demanding world, force us to stop, rest, revive and repair ourselves.

Makes sense, right? Traumatic life event – slow down, rest, take time to recuperate. But now, in today’s rat-race paced life, we rarely allow ourselves the opportunity to do this. We (try) often to push through and this is where things get understandably tough for a lot of people.

“There was a 46% higher odds of inflammation in those with MDD vs healthy controls”

The point? That there is no quick fix with depression. In truth, it needs to be approached from a number of angles, because the evidence clearly states that it isn’t simply serotonin deficiency. What’s often needed is a combination of cognitive behaviour or talking therapies, nutrition and lifestyle interventions, appropriate medication and/or supplementation as well as supportive social networks. Depression isn’t a get-well quick disorder; unfortunately it takes time and multiple modalities to manage it in the long-term.

This is where what we eat and lifestyle can make a big difference in supporting those suffering with depression. To read more on how diet and lifestyle modifications can support mood disorders like MDD, click here.

If you feel things are off, fill out the PHQ-9 questionnaire – an internationally standardised set of questions that give you a score on mild, moderate or acute depression and/or anxiety – you can find it on the NHS website. And of course, if you are struggling or at crisis point, CALM and Samaritans offer invaluable helplines – call them if you need to.


DeRubeis, R. Siegle, G. & Hollon, S., et al., (2008) ‘Cognitive therapy versus medication for depression: treatment outcomes and neural mechanisms’ National Revue of Neuroscience, 9 (10), pp. 788-96 

Ferguson J. (2001) ‘SSRI Antidepressant Medications: Adverse Effects and Tolerability’ Primary Care Companion to the Journal of Clinical Psychiatry, 3 (1), pp. 22–27 

Malhi, G & Mann, J. (2018) ‘Depression’ The Lancet, 392 (10161), pp. 2299-2312

Ménard, C. Hodes, G. Russo, S., et al., (2016) ‘Pathogenesis of depression: Insights from human and rodent studies’ Neuroscience, 3 (321), pp. 138-162 

Moncrieff, J., Cooper, R. E., Stockmann, T. et al. (2022) ‘The serotonin theory of depression: a systematic umbrella review of the evidence’ Molecular Psychiatry, May, pp. 1–14. 

Osimo, E. Baxter, L. Lewis, G., et al., (2019) ‘Prevalence of low-grade inflammation in depression: A systematic review and meta-Analysis of CRP levels’ Psychological Medicine, 49 (12), pp. 1958–1970 

Ogyu, K. Kubo, K. Noda, Y., et al., (2018) ‘Kynurenine pathway in depression: A systematic review and meta-analysis’ Neuroscience and Biobehavioral Reviews, 90 (March), pp. 16–25 

Pariante, C. & Miller, A. (2001) ‘Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment’ Biological Psychiatry, 49 (5), pp. 391–404

Skorobogatov, K. De Picker, L. Verkerk, R., et al., (2021) ’Brain Versus Blood: A Systematic Review on the Concordance Between Peripheral and Central Kynurenine Pathway Measures in Psychiatric Disorders’ Frontiers In Immunology, Vol 12 

DISCLAIMER: The information provided on this website is for informational purposes only and should not be used for diagnosis. It is not intended as a substitute for advice from your GP or other qualified health practitioner.

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