Depression and Inflammation

Now that I know what inflammation is and have given you my personal view of depression, I can talk about depression as an inflammatory disease.  Most specifically, the article “So depression is an inflammatory disease, but where does the inflammation come from?” from BiomedCentral Medicine.  I’ll do some additional research as warranted, but mostly I want to talk about this article.  Prepare for deep dive.

Background: We now know that depression is associated with a chronic, low-grade inflammatory response and activation of cell-mediated immunity, as well as activation of the compensatory anti-inflammatory reflex system. It is similarly accompanied by increased oxidative and nitrosative stress (O&NS), which contribute to neuroprogression in the disorder. The obvious question this poses is ‘what is the source of this chronic low-grade inflammation?’

Translation:

  • As I painstakingly established last week, inflammation means a chronic dilation of blood vessels allowing more stuff to leak into tissue.
  • cell-mediated immunity involves producing new white blood cells in response to a specific antigen, as opposed to producing new antibodies in response to a specific antigen, or non-specific immunity that is not a response to anything in particular (example: skin).
  • Almost every system in your body is moderated by a complex series of signals that can aid or inhibit one another.  Rather than just produce less of an activator to reduce a reaction, your body instead introduces an inhibitor.   Having high levels of both activators and inhibitors has similar primary effects to having low levels of both, but can be either cause weird secondary effects or be a symptom of something weird going on.  It’s also plain more stressful, just like keeping yourself steady against a strong wind is harder than standing still.  “[A]ctivation of the compensatory anti-inflammatory reflex system” implies that depressed people are falling in the “high levels of both” category.
  • In the course of the day, your body naturally produces many types of molecules.  Some of those molecules contain oxygen, or nitrogen and oxygen, and a net negative charge.  These are the home wreckers of the molecular neighborhood, luring parts of other molecules to dump their other halves and bond with them instead.  This is a problem if that other molecule is doing something important, like being the blueprint for every other protein in your body.  The damage these homewreckers cause is called oxidative stress.  Your body has ways to contain it, but not perfectly.  Oxidative/nitrosative stress can arise either from producing too many of the reactive molecules, or from a deficiency in the post-processors.
  • Fun fact: we don’t know if Nitric Oxide is a pro- or anti-inflammatory messenger.  It looks the answer may be “anti- under normal circumstances, pro- under times of stress”, which implies but doesn’t prove that it’s primary effects are anti-inflammatory, but the containment mechanisms break down under stress and cause a lot of damage.

Discussion: This review explores the role of inflammation and oxidative and nitrosative stress as possible mediators of known environmental risk factors in depression, and discusses potential implications of these findings. A range of
factors appear to increase the risk for the development of depression, and seem to be associated with systemic inflammation; these include psychosocial stressors, poor diet, physical inactivity, obesity, smoking, altered gut permeability, atopy, dental cares, sleep and vitamin D deficiency.

Translation:

  • Two very common bad things seem to have a lot in common.  I think there’s a lot of merit to their hypothesis, but this venn diagram does not impress me.

Summary: The identification of known sources of inflammation provides support for inflammation as a mediating pathway to both risk and neuroprogression in depression. Critically, most of these factors are plastic, and potentially amenable to therapeutic and preventative interventions. Most, but not all, of the above mentioned sources of inflammation may play a role in other psychiatric disorders, such as bipolar disorder, schizophrenia, autism and post-traumatic stress disorder

Translation:

  • If we are right, this suggests several really easy ways to treat, cure and prevent depression, and potentially other psychiatric issues.

Oh wow, apparently you can induce depression-like symptoms by activating the immune system, either by triggering it with a toxin or just injecting some cytokines (a broad class of messenger, many of which signal the immune or inflammatory system) directly.  SSRIs (the most common class of anti-depressants) decrease production of proinflammatory cytokines,* and a return of symptoms is often associated with the loss of these effects.

The authors then go on to cover in detail various things you already knew were bad or good for you (Sleep- good.  Chronic stress- bad).  The research isn’t at the stage where it’s generating novel recommendations yet.  Which is not a criticism, it’s an impressive set of basic science work and it takes time to translate that into practice.If you are deeply interested in the biochemistry I encourage you to check it out, but I have no more to add.

*SSRI stands for selective serotonin reuptake inhibitor.  Because serotonin is a neurotransmitter, we originally assumed SSRIs treated depression by making serotonin more available.  Except serotonin levels change within hours of taking an SSRI, but the anti-depressant effects takes weeks to show up (unless you’re bipolar, in which case they can trigger a manic phase almost immediately).