In search of biomarkers for mood disorders

Novel biomarkers for mood disorders will enable early diagnosis and inform the development of new treatments. They include immunological, oxidative and nitrosative stress biomarkers for depression; cytokines, and oxidative stress markers for clinical staging of bipolar disorder. Experts provided thought-provoking presentations on progress in these areas at EPA 2019.

Immunological biomarkers for depression1

Depression is associated with a permanent state of pathological proinflammatory readiness

The immune system of people with depression is in a permanent state of pathological proinflammatory readiness, said Professor Piotr Galecki, Medical University of Lodz, Poland, resulting in increased:

  • proinflammatory cytokines; such as tumour necrosis factor-alpha (TNF-α), interleukin (IL) 1β and IL-6, and interferon-gamma (IFN-ɣ)
  • positive acute phase proteins — mainly C-reactive protein, acid α1-glycoprotein, α-chymotrypsin, haptoglobin, α1-macroglobulin, 2-macroglbulin α
  • complement components C3 and C4 induced by increased prostaglandin (PG) E2
  • neopterin (inflammatory index)
  • T cell CD4/CD8 index

On the other hand, the acute phase proteins (albumin and transferrin), IL-10 and IL-12 are decreased.

Enzymes involved in the inflammatory process, including manganese superoxide dismutase, myeloperoxidase and inducible nitric oxide synthase contribute to the pathophysiology of recurrent depressive disorders, added Professor Galecki. These enzymes also produce free radicals and damage proteins, fatty acids and cellular DNA.

Oxidative and nitrosative stress biomarkers for depression2

Pro-oxidative processes are also involved in the pathophysiology of depression, Professor Galecki said, resulting in:

  • increased lipid peroxidation and reactive oxygen species (ROS) — superoxide, hydrogen peroxide and reactive nitrogen species
  • decreased antioxidant enzyme (dismutase, catalase, peroxidase, reductase) activity

Further biomarker abnormalities in the pro- and anti-oxidant equilibrium in depression include:

  • decreased total glutathione, uric acid, ascorbic acid, and glutathione peroxidase
  • increased malondialdehyde (MDA), 8-hydroxy-deoxyguanosine, nitrite and nitrate
  • high free radical generation

Activation of the kynurenine pathway leads to tryptophan depletion

A proposed pathophysiological mechanism for the development of depression, explained Professor Galecki, is through the induction of:

  • indoleamine 2,3-dioxygenase (IDO) by IFN-ɣ, PGE2, IL-6 and IL-1β; and
  • tryptophan 2,3-dioxygenase (TDO) in response to psychological stress, glucocorticoids or tryptophan

Both IDO and TDO activate the kynurenine pathway leading to tryptophan depletion.3

Biomarkers for staging bipolar disorder 

Allostasis leads to the accumulation of negative consequences over time

Bipolar disorder (BPD) exemplifies allostatic load, said Professor Marcin Siwek, Jagiellonian University Medical College, Krakow, Poland. Allostasis is the ability of the body to restore and maintain a new balance in response to pathogenetic factors so the organism stays alive though negative consequences accumulate over time,4 he explained. The associated manifestations are oxidative; and nitrosative stress, inflammation, neurodegeneration and neurotoxicity are causal or the effects.

Staging of BPD is an integrated model to detail the clinical and biological progression of BPD5, and suggests a gradual progression towards more severe treatment-resistant, disabling disease resulting from the accumulation of pathophysiological processes, said Professor Siwek.

Increased TBARS are associated with depression in stages 1 and 2, and remission in stages 3 and 4

Professor Siwek highlighted the large number of biomarkers linked to oxidative stress including thiobarbituric acid reactive substances (TBARS).6 He noted that an increase in TBARS is the most frequently observed and most intensified phenomenon reflecting oxidative stress in BPD. Current insights on the changes in biomarkers with different stages of BPD include:

  • an increase in TBARS associated with depression in stages 1 and 2, but associated with remission in stages 3 and 4
  • normalization of TBARS associated with remission in stages 1 and 2
  • decreased zinc associated with depression in stages 3 and 4

In the future, integration of data may lead to the creation of a battery of clinically useful biomarkers for BPD, concluded Professor Siwek, and he also emphasized the need to link immunological, neuropsychological, neuroimaging and genetic biomarkers.

For further reading on biomarkers in psychiatry, please see https://progress.im/en/content/biomarkers-future-diagnosis-psychiatry

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.

References
  1. Miller A, Raison C. Nat Rev Immunol. 2016;16(1):22–34.
  2. Maes M, et al. Prog Neuropsychopharmacol Biol Psych. 2011;35(3):676–92.
  3. Maes M, et al. Prog Neuropsychopharmacol Biol Psych. 2011;35(3):702–21.
  4. Vieta E, et al. Eur Psych. 2013;28(1):21–9.
  5. Kapczinski F, et al. Expert Rev Neurother. 2009;9(7):957–66.
  6. Siwek M, et al. Pharmacol Rep. 2013;65:1558–71.
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