2 Neuroscience2.8 Modulators, hormones and inflammatory responses

2.8.4 Inflammation and immune responses in psychiatric illness

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Written by Resident Doctor Committee · Published

Cytokines

Cytokines are cell-signalling proteins. They act on the brain through endothelial, vagal, glial and endocrine routes.

Group

Cytokines

Pro-inflammatory

Interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), tumour necrosis factor alpha (TNF alpha)

Anti-inflammatory

IL-4, IL-10 and transforming growth factor beta 1 (TGF-beta1)

  • A cytokine's effect depends on timing, receptors and concentration.

Effects on the brain

  • Sickness behaviour is fatigue, withdrawal, altered sleep, appetite loss and poor concentration, and it does not need a leaky blood-brain barrier.

  • Temporary sickness behaviour is not depression, but it can become maladaptive if it persists.

  • Inflammation diverts more tryptophan into kynurenine metabolism: microglia make excitotoxic quinolinic acid, while astrocytes make kynurenic acid, which dampens glutamate signalling.

  • Stress and inflammation reinforce each other, because cytokines activate the hypothalamic-pituitary-adrenal axis and stress may reduce glucocorticoid sensitivity.

Follow tryptophan away from serotonin into kynurenine, which then splits into kynurenic acid, the astrocyte product that dampens glutamate signalling, and quinolinic acid, the excitotoxic microglial product. Inflammation diverts more tryptophan down this route. Edwinophilus21, CC BY-SA 3.0, via Wikimedia Commons

Inflammatory markers in depression

Marker

Finding

IL-6

Most consistently raised against healthy controls, with the clearest two-way prospective link; raised childhood and adult levels predict later episodes

C-reactive protein

Acute-phase protein the liver makes in response to IL-6; modestly raised; predicts poorer response to selective serotonin reuptake inhibitors; conventional threshold 3 mg/L

TNF alpha

Least consistent findings

  • About a quarter to a third of depressed samples show raised markers, often alongside obesity, smoking, adversity or treatment resistance.

  • Group differences overlap too much to diagnose an individual, and reverse causation is possible.

  • Interferon treatment can precipitate depression.

  • Anti-inflammatory trials show small, heterogeneous effects, mostly in inflammatory subgroups.

  • Autoimmunity, such as NMDA receptor antibody encephalitis, produces a defined syndrome rather than a generic rise in markers.

Revision material for the MRCPsych examinations. Not clinical guidance, and not for use in patient care.