Effects of anti-inflammatory drugs on the expression of tryptophan-metabolism genes by human macrophages, 2018, Freeman et al

[Andy]

Abstract
Several lines of evidence link macrophage activation and inflammation with (monoaminergic) nervous systems in the etiology of depression. IFN treatment is associated with depressive symptoms, whereas anti-TNFα therapies elicit positive mood.

This study describes the actions of 2 monoaminergic antidepressants (escitalopram, nortriptyline) and 3 anti-inflammatory drugs (indomethacin, prednisolone, and anti-TNFα antibody) on the response of human monocyte-derived macrophages (MDMs) from 6 individuals to LPS or IFN-α. Expression profiling revealed robust changes in the MDM transcriptome (3294 genes at P < 0.001) following LPS challenge, whereas a more limited subset of genes (499) responded to IFNα. Contrary to published reports, administered at nontoxic doses, neither monoaminergic antidepressant significantly modulated the transcriptional response to either inflammatory challenge.

Each anti-inflammatory drug had a distinct impact on the expression of inflammatory cytokines and on the profile of inducible gene expression—notably on the regulation of enzymes involved in metabolism of tryptophan. Inter alia, the effect of anti-TNFα antibody confirmed a predicted autocrine stimulatory loop in human macrophages. The transcriptional changes were predictive of tryptophan availability and kynurenine synthesis, as analyzed by targeted metabolomic studies on cellular supernatants.

We suggest that inflammatory processes in the brain or periphery could impact on depression by altering the availability of tryptophan for serotonin synthesis and/or by increasing production of neurotoxic kynurenine.

Open access at https://www.researchgate.net/public...ptophan-metabolism_genes_by_human_macrophages

 

[Woolie]

Interesting. However, the explanation may be way simpler than this.

If you look carefully at the research suggesting a link between inflammation and depression, you notice that only a subset of people with depression have evidence of inflammation, and only a subset respond to anti-inflammatory interventions. That subset are unusual in other ways too - on self-report measures of depression, they score particularly highly on "physiological" items (I feel tired all the time, I have difficulty concentrating, I have difficulty sleeping). And interventions that involve anti-inflammatory drugs tend to alter responses to these items specifically.

Also, although there's been some studies showing that placing people on interferon can lead to increased scores on self-report measures of depression, the majority of people on interferon score highly mostly on the physiological items. There is only a subset of people that reach clinical levels of depression and that tends to be those who have previously had a depressive episode.

My conclusion: inflammation is probably not linked with depression in the way we normally understand it, its probably associated with some other set of problems that look a bit similar, especially on self-report measures.

Sound familiar?

We need to sort out what depression is before we can start talking about what causes it. To me, it seems like it is a collection of pretty different conditions with different aetiologies.

(Edited to explain myself better)

 

[WillowJ]

We need to sort out what depression is before we can start talking about what causes it.

Would it be fair to say that depression is a symptom that means a variety of things, some of which are experienced by healthy people, some of which may be secondary to various other conditions, and one or more which is a disease in its own right?