Neuroinflammation and Depression – A Simplified Guide

Depression has significant heritability, yet from an evolutionary perspective, it is maladaptive and presents significant survival and reproductive disadvantages. Allelic variants that enhance the risk of depression are common in the human genome and persist even in the face of Darwinian fitness. 

The PATHOS-D hypothesis proposes that modern humans have a bias towards inflammation because it was beneficial to our ancestors. [Miller and Raison, 2016]

There is an important relationship between mammals and micro-organisms that has driven human evolution: 

• Until recently, 30% of all deaths occurred before the age of 5 years, and this was mainly due to infectious diseases (e.g. pneumonia, tuberculosis, and diarrhoea) 
• An inflammatory response enhances survival and reproduction in a highly pathogenic environment. 
• Evolution, therefore, favoured our ancestors, whose immune system responded vigorously to acute stress on the basis that for many stressful situations, there was the chance of being wounded and acquiring an infection. 

In addition, genes associated with depressive symptoms were advantageous to our ancestors because they were implicated in social behaviours that promoted host survival [Slavich and Irwin, 2014]:

Depressive symptoms promoted survival from an evolutionary perspective:

• Anhedonia promoted a host’s defence by allowing better energy conversation, which could then be used for fighting an infection and healing wounds. 
• The hypervigilance present in anxiety protected an individual from further pathogenic exposure. 
• Social isolation reduced the risk that an individual will spread the infection to family members. 

However, there is an increased prevalence of immune dysregulation in the form of autoimmune, allergic and inflammatory diseases in today’s modern way of life. [Raison et al., 2010] 

Improvement of sanitary practices has reduced the microdiversity of commensal and symbiotic microbial cells present in the human microbiome: 

• Non-lethal micro-organisms and parasites in the gut, skin, nasal and oral cavities suppress immunological effector cells through the induction of interleukin-10 (IL-10) and transforming growth factor-β (TGFβ) [Raison et al., 2010], [Rook et al., 2015]
  
• These cytokines activate macrophages, T_reg cells and regulatory B cells that maintain homeostasis and prevent autoimmune responses. 
• Without this regulatory input, humans can find themselves in a condition of exacerbated inflammatory bias. 

Exacerbated inflammatory bias in the context of genetic susceptibility to depression and increased environmental stresses would account for the increased co-morbidity of depression and autoimmune, allergic and inflammatory disorders. 

As well as both genetic and environmental factors, depressive symptoms are frequently associated with inflammatory diseases.

Most notably, there is an increase in chemokines and inflammatory cytokines in Major Depressive Disorder (MDD) patients, impacting disease duration and the severity of mood episodes. [Miller et al., 2009]

• Psychological stress induces peripheral monocytes to infiltrate the brain and alter behaviour [Wohleb et al., 2013], [Ataka et al., 2013], [Wohleb et al., 2015]
• Inflammatory mediators affect glutamate uptake by microglia and astrocytes [Dantzer and Walker, 2014]
• Inflammatory processes up-regulate the synaptic reuptake of monoamines and reduce monoamine synthesis. [Miller and Raison, 2016]

Stress, HPA Axis and Depression: 

• Stress affects the hypothalamus-pituitary-adrenal axis (HPA), closely related to both inflammation and depression. Chronic stress responses are known to be associated with depression and inflammatory disorders.
• Overall, there is a shift in peripheral inflammatory processes that profoundly affect mood and behaviour.

Gut Microbiome:

• The dysregulated peripheral immune response in patients with depression may also result from changes at the microbiome level.
• Patients with depression exhibit significant changes in the relative abundance of Firmicutes, Actinobacteria, and Bacteroidetes compared to healthy individuals. A recent study also showed that patients with depression are deficient in several species of gut bacteria (Coprococcus and Dialister).
• Coprococcus is associated with dopamine pathway activity and produces butyrate, which is anti-inflammatory. In addition, Coprococcus is positively associated with measures of quality of life. [Valles-Colomer et al., 2019]

Read a detailed review on the Gut microbiome and depression. 

Also, see a previous PsychScene Hub review: Gut-Brain Axis and Mental Health.

Role of Inflammasomes

• Inflammasomes are intracellular protein complexes in myeloid cells in response to physiological and pathogenic stimuli. Although they are an integral part of the innate immune system, overt inflammasome activation is a significant driver of autoimmune and inflammatory disorders.
• During an inflammatory response, the innate immune response detects molecular patterns (pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs)) with pattern recognition receptors (PRRs). [Martinon  et al.,2002]

• Activated T and B cells, peripheral cytokines can pass through the BBB under certain circumstances. They can then activate microglia and astrocytes, triggering off a neuroinflammatory response.

• In the CNS, PRRs are commonly expressed on microglia, astrocytes and neurons as membrane-bound Toll-like receptors (TLRs) or in the cytoplasm as Nod-like receptors (NLRs). [Kigerl et al., 2012]

• Activation of NLRs involves the assembly of inflammasomes and the activation of caspase enzymes to cleave precursor forms of pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18) into their active forms. [Singhal et al., 2014]
• NLR subtypes in the CNS include NLRP1, NLRP2 and NLRP3, which are found in neurons, astrocytes, and microglial cells, respectively.
• NLRP3 activation and IL-1β/IL-18 secretion activate the kynurenine pathway, which is associated with neuroinflammation and the pathogenesis of MDD. [Najjar et al., 2013]

At present, clinical data is scarce:

• One study showed that in comparison to non-depressed subjects, MDD patients had increased expression levels of NLRP3 mRNA, which correlated with increased NLRP3 protein levels in blood mononuclear cells. [Alcocer-Gómez et al., 2014]
• Post-mortem analysis has revealed that patients with bipolar disorder had higher levels of NLRP3 in the frontal cortex, which is suggestive of its involvement in mood regulation. [Kim et al., 2016]

Neurotransmitter systems

Neuroimaging studies have shown cytokine-induced brain changes consistent with the evolutionary advantages previously described.

Cytokine targets in the CNS involve:

• Pro-inflammatory cytokines such as interferon-I and -II, IL-1β, and tumour necrosis factor (TNF) can reduce the availability of serotonin, dopamine and norepinephrine by increasing the expression and function of the presynaptic reuptake transporters for these monoamines.
• Reduction in dopamine release in the basal ganglia is associated with anhedonia and reduced motor activity and thus promoting social avoidance and energy conservation. [Eisenberger, et al, 2010], [Capuron, et al 2012]
• Activation of circuits in the dorsal anterior cingulate cortex and amygdala is associated with arousal, anxiety, and alarm, thus promoting hypervigilance and protection against infection. [Harrison NA, et al], [Slavich et al., 2010]

Furthermore, IL-1β and TNF can also decrease relevant monoamine precursors by:

• Activating the enzyme indoleamine 2,3-dioxygenase breaks down tryptophan (precursor to serotonin) into kynurenine.
• Activated microglial cells convert kynurenine into quinolinic acid, which binds to NMDA receptors (glutamate receptors).
• In the presence of a cytokine-induced reduction of astrocytic glutamate reuptake and stimulation of astrocyte glutamate. release, this results in excessive glutamate
• Glutamate is an excitatory amino acid neurotransmitter that in excess causes excitotoxicity and reduces brain-derived neurotrophic factor (BDNF).
• Increased inflammation (CRP >3 mg/L) is also associated with increased basal ganglia glutamate (compared with patients with a CRP <1 mg /L), which correlated with anhedonia and decreased psychomotor speed. [Haroon et al., 2015]
• Through inflammation, reduction in BDNF levels, particularly in the hippocampus, can fundamentally affect neurogenesis and thus affect learning and memory. [Marin & Kipnis, 2013]
• There is also a close relationship between insulin resistance, a known feature in depression and inflammation.  [Oxenkrug, 2013]

Inflammation and its Relationship with Serotonin and Glutamate:

Inflammation and its Relationship with Dopamine: 

Not all patients with major depressive disorder (MDD) exhibit increased inflammation.

Increased inflammatory markers have been associated with atypical symptoms of depression and with suicidal MDD.

Different inflammatory profiles are associated with different subtypes of depression [Beurel et al., 2020]

• Pro-inflammatory states: Non-melancholic patients
• Reduced pro-inflammatory cytokine production: Melancholic patients
• TNF: Associated with atypical features and chronicity
• IL-6: Possible “state indicator for acute exacerbation” in melancholic patients
• Higher levels of IL-6:  Chronicity of depression and higher severity of depression at follow-up
• CRP and TNF:  Greater symptom severity in MDD. Elevated CRP in late-life depression. [Su et al., 2016]
• Low-grade inflammation: Associated with treatment-resistant depression and poor treatment response to antidepressants.
• Neurofilament light chain (NfL) and N-terminal propeptide of type 1 procollagen (P1NP) are linked to inflammation, and their levels correlate with symptom severity and cognitive decline in mood disorder patients. [Bai et al., 2023]

A scoping review examined the effects of inflammatory markers on MDD with the following findings: [Paganin & Signorini, 2024]

IL-1β:

• Elevated in depression, detected in blood, cerebrospinal fluid, and brain tissues.
• Affects neurotransmitters and activates other neuroinflammatory pathways.
• Plays a key role in the pathogenesis of depression.

IL-6:

• Strong indicator of depressive severity, especially anhedonia and low motivation.
• High levels linked with depressive symptoms, particularly in those with high BMI.
• Associated with CRP, correlating with symptoms like sadness, loss of interest and difficulty concentrating.
• Serves as an indicator of depressive presence but also suggests potential resistance to standard antidepressant therapies.

CRP:

• Elevated CRP levels exacerbate the depressive effects associated with IL-6 and TNF-α
• High levels predict an increased risk of depressive symptoms, notably impacting appetite and concentration.
• Strongly associated with systemic inflammation in depression.
• High plasma CRP, TNF, and soluble IL-6 receptors in CSF correlate with severe symptoms like anhedonia.
• High serum CRP levels correlate with cortical thinning in key brain regions involved in mood and cognitive regulation, including the left superior frontal lobe, left insula, and left superior temporal lobe.

TNF-α:

• Elevated in MDD with obesity, associated with poor cognitive function (e.g., slower processing speed, working memory issues).
• Linked to fatigue in depressive symptoms, showing a direct impact on physical aspects of depression.
• When elevated alongside CRP, TNF-α is associated with a greater severity of depression.
• Relevance varies, with some studies finding no association with depressive symptoms when compared to CRP and IL-6.

Other Pro-Inflammatory Markers:

• IL-17, IL-21, and IL-23 levels are often elevated, and IL-35 is reduced in MDD patients, indicating a pro-inflammatory state.
• Increased IL-12 and IL-4 are associated with depression severity, highlighting a link between immune response and depression pathology.

Age, particularly in individuals over 50, plays a significant role in amplifying the relationship between cytokine levels, such as IL-6 and CRP, and the severity of depressive symptoms.

This effect is often linked to age-related systemic inflammation, known as ‘inflammaging,‘ compounded by immune changes accumulated through chronic stress over the lifespan.

Research indicates that inflammation may serve as a pivotal risk factor for both the development and recurrence of major depressive disorder (MDD) in older adults, highlighting the importance of personalised treatment strategies that account for age. Further longitudinal and interventional studies that focus on age as a central variable are essential. [Zainal et al., 2021]

Furthermore, trauma is also closely associated with inflammation and depression. The co-occurrence of MDD and inflammation is present in individuals with a history of childhood adversity but not in those without the latter.

Individuals with exposure to Childhood sexual abuse and trauma are at risk of Chronic fatigue syndrome and fibromyalgia, which have strong inflammatory underpinnings.

Read more on the Neurobiology of PTSD and Complex PTSD.

Evidence increasingly supports a link between elevated cytokine levels and the severity of depressive disorders, particularly within treatment-resistant populations, highlighting the potential utility of anti-inflammatory therapies in the management of treatment-resistant depression.

The current data suggests only a subgroup of patients would receive any meaningful benefit: those who show increased peripheral inflammation (e.g. individuals with medical conditions including osteoarthritis and psoriasis).

However, in patients with depression who do not show elevated peripheral levels of inflammation, anti-inflammatory treatments may impair placebo responses that contribute to the effectiveness of all known antidepressant modalities. [Kohler et al., 2014], [Raison CL et al., 2014]

Infliximab: 

• Infliximab, a TNF-neutralising antibody, only benefits a sub-population of treatment-resistant MDD patients with elevated levels of inflammation (CRP >5 mg/L) [Raison et al., 2013] or patients with a history of childhood trauma. [McIntyre et al., 2019]
• Infliximab, however, did not significantly reduce depressive symptoms in bipolar depressed patients. [McIntyre et al., 2019]

Depression and inflammation exist in a bi-directional relationship.

A subset of patients with MDD has inflammation underpinning the pathogenesis of the illness.

Despite the associations between inflammation and major depressive disorder (MDD), the complexity of this relationship necessitates caution when interpreting peripheral inflammatory biomarkers as indicators of neuroinflammation. [Paganin & Signorini, 2024]

Methodological inconsistencies and confounding factors further complicate establishing direct correlations between peripheral and central cytokine levels. Thus, advancing measurement techniques and integrating psychosocial and environmental variables remain essential to deepening our understanding of MDD and enhancing therapeutic approaches.

With an increased understanding of the complex nature of the brain-immune interaction, there is the possibility of discovering anti-inflammatory agents with antidepressant properties. Targeting inflammation in depression may help develop effective antidepressant treatments that go beyond the current neurotransmitter hypothesis of antidepressants.

Research is, however, in the early stages, and many questions remain unanswered.

Learn more:

Cytokines and Inflammation By Professor Michael Berk

Oxidative and Inflammatory Biomarkers As Targets For Novel Therapies – Prof Michael Berk