Inflammation and Depression: The Hidden Biological Driver Behind Low Mood

Author: Rohan Smith | Functional Medicine Practitioner | Adelaide, SA

Quick Answer

Depression and anxiety are often treated as purely psychological or “chemical imbalance” conditions, but growing evidence suggests that chronic, low-grade inflammation may play a significant biological role. Inflammatory immune signals known as cytokines can influence neurotransmitter production, stress hormones, sleep regulation, and brain energy metabolism. Elevated inflammatory markers—such as C-reactive protein (CRP), interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNF-α)—have been consistently associated with depressive symptoms and reduced response to standard antidepressant medications (1–4).

Inflammation may be driven by multiple underlying factors, including gut dysfunction, nutrient deficiencies, chronic stress, metabolic imbalance, and immune activation. This helps explain why some people experience persistent depression, brain fog, or anxiety despite therapy or medication. Identifying and addressing these biological contributors through targeted testing may support more personalised and comprehensive mental health care (5–8).

The Core Concept: How Inflammation Affects Mood

The traditional “chemical imbalance” model of depression focuses on neurotransmitters such as serotonin and dopamine. While neurotransmitters remain important, this model alone does not fully explain many clinical patterns. Research increasingly supports the cytokine theory of depression, which proposes that immune signalling molecules influence brain function and emotional regulation.

Pro-inflammatory cytokines may:

• Reduce serotonin synthesis by diverting tryptophan metabolism
• Alter dopamine signalling involved in motivation and reward
• Disrupt sleep–wake cycles and increase fatigue
• Increase activation of the stress (HPA) axis

Together, these effects may contribute to low mood, anhedonia, anxiety, cognitive impairment, and reduced treatment responsiveness (2,3,6).

Symptoms That May Suggest Inflammatory Drivers

Inflammation-associated depression often presents with physical symptoms alongside mood changes. Common features include:

• Persistent fatigue or a “heavy body” sensation
• Brain fog and reduced mental clarity
• Muscle aches, headaches, or unexplained pain
• Digestive symptoms such as bloating or bowel irregularity

These symptoms may reflect ongoing immune–nervous system interaction rather than isolated psychological distress (4,7). This overlap is also commonly seen in people experiencing chronic fatigue and post-viral syndromes.

Nutrient Deficiencies That Can Mimic or Worsen Depression

Several micronutrient deficiencies are associated with depressive symptoms and impaired neurotransmitter function:

• Vitamin B12 and folate – involved in methylation and monoamine neurotransmitter synthesis (9,10), with further discussion in our overview of methylation and mental health
• Vitamin D – influences immune regulation and neuroinflammatory signalling (11)
• Omega-3 fatty acids (EPA/DHA) – structural components of neuronal membranes with anti-inflammatory properties (12)
• Magnesium – supports stress regulation and excitatory–inhibitory balance in the nervous system (13)

Because symptoms of deficiency can closely overlap with psychiatric diagnoses, assessment is generally more informative than empirical supplementation.

The Gut–Brain–Inflammation Axis

Approximately 70% of immune tissue is located within the gastrointestinal tract. Disruption of the gut barrier, microbial imbalance (dysbiosis), and intestinal inflammation may allow immune-active molecules to enter systemic circulation, contributing to neuroinflammation (5,14). This bidirectional communication pathway is known as the gut–brain axis.

Gut dysfunction has been associated with:

• Increased inflammatory signalling to the brain
• Altered vagal nerve communication
• Changes in microbially derived neurotransmitter metabolites

This relationship may help explain why digestive symptoms frequently co-occur with mood disorders.

Functional Testing to Identify Root Causes

Rather than relying solely on symptom-based assessment, functional and integrative approaches may include targeted investigation of biological contributors:

• Inflammatory markers (CRP, ESR)
• Nutrient status (B12, folate, vitamin D, magnesium, zinc, omega-3 index)
• Gut health testing for inflammation and dysbiosis
• Stress and thyroid markers where clinically indicated

These assessments aim to clarify physiological patterns that may interact with mood regulation (6–8) and are commonly used within a functional medicine mental health framework.

When to Consider an Inflammation-Focused Approach

Exploring inflammatory drivers may be appropriate when depression or anxiety:

• Responds poorly to antidepressant therapy
• Is accompanied by fatigue, pain, or digestive symptoms
• Fluctuates with illness, stress, or metabolic health

Next Steps

Addressing inflammation does not replace psychological or medical care. Instead, it may complement conventional approaches by supporting immune balance, nutrient sufficiency, and gut health as part of an integrated mental health strategy.

Key Insights

• Inflammation is increasingly recognised as a biological contributor to depression
• Immune signalling can influence neurotransmitters, sleep, and stress pathways
• Nutrient status and gut health may amplify inflammatory burden
• Testing can help personalise treatment strategies

A More Integrated Perspective

If you are based in Adelaide and experiencing ongoing depression or anxiety despite standard care, a functional medicine assessment may help explore underlying biological contributors. Individualised testing and interpretation can support a more targeted, whole-body approach to mental health care.

1. Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006.
2. Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016.
3. Felger JC, Lotrich FE. Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications. Neuroscience. 2013.
4. Valkanova V, Ebmeier KP, Allan CL. CRP, IL-6 and depression: a systematic review and meta-analysis. J Affect Disord. 2013.
5. Maes M et al. The gut–brain barrier in major depression. Neuro Endocrinol Lett. 2008.
6. Haroon E, Raison CL, Miller AH. Psychoneuroimmunology meets neuropsychopharmacology. Neuropsychopharmacology. 2012.
7. Dantzer R et al. Inflammation-associated depression. Nat Rev Neurosci. 2008.
8. Kiecolt-Glaser JK et al. Depression, inflammation, and health. Brain Behav Immun. 2015.
9. Coppen A, Bolander-Gouaille C. Treatment of depression: time to consider folic acid and vitamin B12. J Psychopharmacol. 2005.
10. Almeida OP et al. B-vitamin deficiencies and depression. Am J Psychiatry. 2015.
11. Anglin RE et al. Vitamin D deficiency and depression. Br J Psychiatry. 2013.
12. Grosso G et al. Role of omega-3 fatty acids in the treatment of depressive disorders. Int J Mol Sci. 2014.
13. Tarleton EK et al. Role of magnesium supplementation in depression. PLoS One. 2017.
14. Clapp M et al. Gut microbiota’s role in mood disorders. Front Psychiatry. 2017.
15. Rogers GB et al. From gut dysbiosis to altered brain function. Gut Microbes. 2016.