Neuroinflammation and Depression – A Simplified Guide
A novel and emerging framework describes the involvement of neuroinflammation and the immune system in the pathophysiology of depression.
The PATHOS-D hypothesis states that depressive symptoms are components of the immune system that promote pathogen defence. [Raison and Miller, 2013]
We recommend this article is read in combination with the following articles to get a comprehensive overview of neuroinflammation in psychiatry and its relevance to clinical practice.
- Chronic Fatigue Syndrome | Myalgic Encephalomyelitis – Neurobiology | Diagnosis | Management
- The Neuropsychiatry of Long COVID and Post-Acute COVID-19 Syndrome: A Review
- Psychiatric and Neuropsychiatric Manifestations of COVID 19 – SARS-CoV-2 and the Brain
- The Neuropsychiatry of Fibromyalgia – Etiology and Management
INFLAMMATION AND DEPRESSION - EVOLUTIONARY PERSPECTIVE
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 old, 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]:
Exposure to threats activated a Conserved transcriptional response to adversity (CTRA) that involved up-regulation of pro-inflammatory immune response genes, which combat extracellular pathogens and wound-related bacterial infections, and down-regulation of antiviral immune response genes, which target intracellular pathogens such as viruses. This redeployment of the leukocyte basal transcriptome is adaptive in the context of actual physical threat because it enhances wound healing and recovery from injury and infection. The CTRA can also be activated by modern-day social, symbolic, anticipated, and imagined threats, however, leading to increased risk for several inflammation-related conditions, including depression.
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 G et al., 2015]
- These cytokines activate macrophages, Treg 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.
NEUROINFLAMMATION AND DEPRESSION - PATHOGENESIS
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 A et al., 2009]
- Psychological stress induces peripheral monocytes to infiltrate the brain and alter behaviour [Wohleb E et al., 2013], [Ataka K et al., 2013], [Wohleb E 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.
- 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]
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:
INFLAMMATION AND CLINICAL FEATURES OF DEPRESSION
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.
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.
TARGETING THE IMMUNE SYSTEM INFLAMMATORY PATHWAYS
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 O, et al. 2014], [Raison CL, et al, 2014]
- 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].
COX-2 inhibitors (Celecoxib):
- Celecoxib, when administered concurrently with either reboxetine, a selective noradrenaline reuptake inhibitor, or the SSRI antidepressant fluoxetine, enhanced the release of noradrenaline and dopamine, and serotonin, respectively.
- This could explain the synergistic effect of COX 2 inhibitors on the therapeutic effects of antidepressants. [Muller, 2006], [Johansson et al, 2012]
- Minocycline is an antibiotic that reduces the release of proinflammatory cytokines from activated microglia.
- Minocycline has an anti-inflammatory profile and experimental evidence of antidepressant-like effects.
Antidepressants and Anti-inflammatory effects:
SSRIs and SNRIs decrease neuroinflammation through multiple mechanisms: [Dionisie et al., 2021]
- Reduction of blood or tissue cytokines (IL-1β, IL-6, and TNF)
- Regulating complex inflammatory pathways: nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), inflammasomes, Toll-like receptor 4 (TLR4) and peroxisome proliferator-activated receptor-gamma (PPARγ).
- SSRIs modulate astrocytes reducing astrocyte dysfunction.
- Fluvoxamine (SSRI) has shown benefits in the treatment of Covid-19 via immune modulation and anti-inflammatory effects mediated by sigma (σ-1) receptor (S1R) agonism. [Read more in the article on neuropsychiatric of covid]
Read more about the mechanisms of SSRIs beyond the serotonergic hypothesis.
The largest meta-analysis of 45 studies representing 1517 MDD patients revealed that antidepressant treatment significantly decreases peripheral levels of IL-6, TNF, IL-10, and CCL2, but these were not associated with treatment response. [Köhler et al., 2018]
Combination therapy of Bupropion and SSRI was associated with a greater reduction of treatment severity in individuals with elevated baseline levels of IL-17A at baseline. IL-17 putatively disrupts the blood-brain barrier and affects dopamine synthesis, whereas dopamine has been shown to decrease Th17 cell-mediated immune response. [Jha et al., 2017]
In another study, patients with low levels of CRP (<1 mg/L) showed greater improvement with Escitalopram than nortriptyline. However, improvement was greater with nortriptyline than with Escitalopram for patients with higher CRP levels. [Uher et al., 2014].
A recent meta-analysis comprised of 36 randomized controlled trials (RCTs) including data from 10,000 patients found that the following showed antidepressant efficacy: [Köhler-Forsberg et al., 2019]
- Monotherapy and add-on NSAID therapy
- Cytokine-inhibitor monotherapy
- Statin add-on therapy
- Glucocorticoid add-on therapy
- Minocycline (microglia inhibitor) add-on and monotherapy
The authors reported an increased risk for infections, and all studies showed a high risk of bias.
Diet and Exercise:
- Both diet and exercise show antidepressant effects, with anti-inflammatory effects being with one of the postulated mechanisms.
Effect of the Mediterranean Diet On Depression By Prof Michael Berk
Effect of Diet and Lifestyle Changes in Depression By Prof Michael Berk
Depression and inflammation exist in a bi-directional relationship.
A subset of patients with MDD has inflammation underpinning the pathogenesis of the illness.
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.
Cytokines and Inflammation By Professor Michael Berk
Oxidative and Inflammatory Biomarkers As Targets For Novel Therapies – Prof Michael Berk
Köhler CA, Freitas TH, Stubbs B, Maes M, Solmi M, Veronese N, de Andrade NQ, Morris G, Fernandes BS, Brunoni AR, Herrmann N, Raison CL, Miller BJ, Lanctôt KL, Carvalho AF. Peripheral Alterations in Cytokine and Chemokine Levels After Antidepressant Drug Treatment for Major Depressive Disorder: Systematic Review and Meta-Analysis. Mol Neurobiol. 2018 May;55(5):4195-4206.