Recently there has been increasing interest in the relationship between depression and chronic overactivity of the body’s biological defense system – inflammation.
When we have an infection, or an injury, or almost any other kind of illness, the body activates a series of processes designed to respond to the threat.
Unfortunately, the inflammation system, especially if it is turned on chronically, has many negative effects on the body itself.
Inflammation plays a major role in a number of chronic medical diseases, such as heart disease, rheumatoid disease, etcetera.
Now there is evidence that some people with depression may also have an over-active inflammation system. These people appear to be less likely to respond to traditional antidepressants.
Causes of Treatment Resistance
We know that a number of factors are associated with less likelihood of responding to antidepressants, these include childhood mistreatment or adversity, the presence of a chronic medical illness, obesity, and having certain 
additional psychiatric disorders (anxiety, personality disorder, perhaps bipolar). It turns out that most of these factors are also associated with increased inflammation.
How might an overactive inflammation system affect response to treatment of depression?
There are a number of ways that inflammation affects systems that are essential to treatment response. These can be broken down into three categories.
Glutamate Effects
Inflammation increases activity of glutamate neurotransmission. Glutamate is one of the main stimulatory neurotransmitters – when it is released by one neuron (or brain cell) it stimulates activity in the next neuron. However, excessive activation of the glutamate system is associated with toxic effects on the brain (as happens with seizures, or after a stroke).
It was recently discovered that ketamine (an anesthetic agent that blocks some of glutamate’s effects) has remarkable short-term positive effects on depression. Some people with chronic treatment resistant depression snap out of their depression briefly after just one treatment with ketamine.
Brain Growth Effects
Many of the longer term beneficial effects of antidepressants are associated with increases in the release of factors that stimulate the growth of neurons (brain cells). For example, depression is associated with a reduction in brain levels of Brain-Derived Neurotrophic Factor (BDNF) which is a key chemical that support brain cell health. Treatment of depression with anti-depressants results in a return to normal levels of BDNF.
Inflammation causes a reduction of BDNF, and blocks the brain’s ability to create neural stem cells (cells that may be able to replace lost brain cells).
Effects on Monoamine Neurotransmitters
Monamine neurotransmitters (serotonin, norepinephrine, dopamine) are the primary first target of antidepressants. Almost all antidepressants increase the release of these neurotransmitters.
Inflammation can reduce activity of monoamine systems by interfering with the production of monoamine neurotransmitters directly and by increasing activity of the reuptake proteins in brain cells. Think of reuptake as a system that vacuums up monoamines – thus reducing their level in the brain – most antidepressants block reuptake, and inflammation increases reuptake.
Implications
At this point we don’t know for sure how much of a role inflammation plays in chronic treatment resistant depression. What we know is that many things that predict poor response to antidepressants are associated with inflammation,and inflammation itself can negatively affect many brain functions that are necessary in order to respond to treatment.
But what to do about this?
If you are a neuroscientist, you might want to consider looking at the possibility that medications that block inflammation could help in treating some people with depression (those who don’t respond adequately to an antidepressant or who have some of the marker suggesting chronic inflammation – such as a high C-Reactive Protein or CRP).
For now it doesn’t make sense to take these medications. Inflammation plays important beneficial roles as well as harmful ones in the brain.
On the other hand, there is one treatment for depression that can have dramatic beneficial effects on excessive inflammation – exercise.
It has been hard to find a big positive effect of exercise on depression, although a recent comprehensive analysis of the literature by the Cochrane Review group suggests that there is a benefit.
Perhaps the reason for this is that exercise is not essential to treatment response for everyone who is depressed. It may be only those with inflammation who respond the best to exercise.
This may help clinicians as well. For many people exercise may not be an essential intervention, but for those with chronic depression and risk factors for chronic inflammation, it may make sense to really focus on increasing aerobic exercise (perhaps adding a trainer to the treatment team?).
For More Information
A somewhat technical but very informative review of this area is in an article in Psychiatric Times by Charles Raison et al (“Inflammation and Treatment Resistance in Major Depression: The Perfect Storm”).