New Frontiers in Depression

Depression is a terrible disease, according to the WHO approximately 350 million people from all ages has to live with it, it is the leading cause of disability worldwide and in severe cases it leads to suicide.

Despite the advances in the field and the availability of a range of antidepressants, still a number of patients have refractory depression, this can partly be explained due to our lack of a complete understanding of this disease, however new research into brain-immune communication could be the key we were missing.

We have all experienced the torment caused by an infection, we feel terrible, everything aches and hurts us, we are cranky, downhearted, we’re never hungry and we are really sleepy, but why do we feel like this? And what does it has to do with depression?

When something activates our immune system, like an infection, as a part of the response a group of glycoproteins called cytokines are released, these affect all of the cells around them in different ways, they can increase the activity of other immune cells to increase their capacity to phagocytize and destroy harmful agents, they can also prepare other cells to endure damage, secrete hormones and now we know they also change the way our brain works.

So to alter brain function cytokines must reach it first, but as we have reviewed in prior posts the blood-brain barrier is a problem for anything in the periphery that might need to do something in the brain, so to surpass this cytokines have 4 main routes to reach the brain:

  1. Citokines activate the vagus nerve, which sends the signal through the solitary tract nucleus in the medulla oblongata, modifying the activity of this area.
  2. The circumventricular organs (area postrema, subfornical organ, organum vasculosum laminae terminalis, choroid plexus) lack a traditional blood-brain barrier, allowing them to sense citokines and respond releasing cytokines to the brain.
  3. The blood-brain barrier has specialized transporters to some cytokines, which allows them to pass a certain quantity.
  4. A number of brain venules present a large number of macrophages and endothelial cells which upon cytokine activation secrete an other transmitter called prostaglandin E towards the brain.

This signals allow the brain to create an image of the immune’s system activity so it generates an adequate response, all of the manifestations that ensue are calles sickness behavior, that includes a heightened pain perception, fatigue, hypersomnia, lack of appetite, irritability and of great importance anhedonia, anxiety and depression.

When Smith in the 90s saw these manifestations, he proposed the “macrophage theory of depression”, he also found that depressed patients had an increased level of inflammatory markers (acute phase proteins) along with an increase in the hypothalamus-hypophysis-adrenal gland axis.

Other experiments supported this view, for example patients that received IL-2 or INF α, inflammatory mediators used in the treatment of hepatitis C and melanoma, developed major depressive disorder, the pretreatment with an antidepressant like paroxetine prevented the depressive effect of these mediators.

The mechanism through which inflammation generates the sickness behavior is still elusive, however a number of mechanisms seem to play a role. When macrophages in the periphery, or microglial cells in the brain are activated with cytokines they avidly take tryptophan and metabolize it to a compound named kynurenine, this process has 2 important outcomes, firstly there is a tryptophan depletion and since it is serotonin’s precursor this important neurotransmitter is also depleted, on the other hand kynurenine by itself can block the activity or release of other neurotransmitters like glutamate and dopamine.

Other proposed mechanisms are the hypothalamus-hypophysis-adrenal hyperactivity with the consequent excess of CRH and glucocorticoids, which are known to cause depression and even psicosis.

Inflammation can also inactivate tetrahydrobipterin, an essential cofactor in the synthesis of serotonin, melatonin, dopamine, noradrenaline and nitric oxide.

The discoveries in this field of the neurosciences has important repercussions, for example in the treatment of depression that is refractory to current therapy, for example in patients with depression accompanied with high inflammatory markers in blood, the addition of aspirin or a COX 2 inhibitor like celecoxib can lead to an important recovery, the use of antibodies that block cytokines has also shown promise, drugs like etanercept can also help alleviate depression in a subset of patients.

The research in neuro-immune interactions has shown a lot of promise in a number of pathologies and depression could be next, offering hope to patients with severe refractory depression, and maybe later even diseases like anxiety, schizophrenia and autism, that we will cover in further articles.

 

OMS depresión: http://www.who.int/mediacentre/factsheets/fs369/en/

Dantzer, R., Connor, J. C. O., Freund, G. G., Johnson, R. W., & Kelley, K. W. (2010). NIH Public Access, 9(1), 46–56. http://doi.org/10.1038/nrn2297.From

Smith RS. The macrophage theory of depression. Med Hypotheses 1991;35:298–306. [PubMed: 1943879]

Berk, M., Dean, O., Drexhage, H., McNeil, J. J., Moylan, S., O’Neil, A., … Maes, M. (2013). Aspirin: a review of its neurobiological properties and therapeutic potential for mental illness. BMC Medicine, 11(1), 74. http://doi.org/10.1186/1741-7015-11-74

Muller N, et al. The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry 2006;11:680–684. [PubMed: 16491133]

Tyring S, et al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet 2006;367:29–35. [PubMed: 16399150]

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