Some neurological research is beginning to show that inflammation and dysfunctional reward processing may play a large role in depression. It is estimated that antidepressants don’t work for about a third of the people taking them, and these new theories may explain why.
In this post I tie some theories together and suggest my own ideas about the causes of treatment resistant depression. This is what I’ve gathered from some readings, but should not be taken for fact. Rather than viewing treatment resistant depressed individuals as too “broken” or “messed up” for proper treatment, I want to suggest the view of treatment resistant depression as reinforced sickness behavior, completely outside of serotonin or norepinephrine. Sickness behavior is the lethargy, sleep disturbance, hyper vigilance, social avoidance, and anhedonia we may experience when we’re sick or injured. It’s why we want to lay on the couch and not talk to anyone when we have a cold, or why injured athletes may experience depression. But why do our bodies react this way?
First, there are biological processes (e.g. cytokines) that cause inflammation when our bodies are attacked by a pathogen. There are biological processes that result in the experience of sickness behavior. Seems like common sense. Here it gets more interesting. It is theorized that the processes leading to sickness behavior have resulted from natural selection. For example, in the past our sick and injured ancestors who developed a lack of motivation to socialize and a lack of interest or pleasure in normal activities were more likely to conserve energy and use that energy to recover faster. Because they were more vulnerable in a sick or injured state, hyper vigilance would have also increased survival as well. If this theory is correct, it would make sense why depression and anxiety are so often co-morbid. It also makes sense why women are more likely to experience depression and anxiety than men, because evolutionarily women showing sickness behavior when sick or injured may be more likely to survive longer and reproduce more.
With this way of thinking, it makes sense that people whose biology allowed them to experience sickness behavior passed on genes that made their descendants more likely to experience sickness behavior. Maybe, just maybe, this is the depression gene. It’s possible that when someone is sick or injured and experiences inflammation, that tendency to show sickness behavior becomes activated, stronger for some than for others. With inflammation leading to sickness behavior, and sickness behavior a theorized equivalent of depression, understanding inflammation is essential.
In regard to inflammation, there are biological and environmental factors that affect it. Let’s look at the lifestyle factors. Diet can be a huge contributor to inflammation. Sugar and saturated fat lead to inflammation and disease. Too much can lead to obesity, which increases insulin resistance and fat cells, worsening the situation. Inactivity leads to inflammation as well. Today, chemicals pollute our air and food. Most people live a high stress lifestyle with little sleep. Men and women experience physical and emotional trauma, both mild and severe. These factors, along with disease and infection, all promote inflammation. Most are intertwined with each other, where if we have one unhealthy lifestyle factor it will likely impact another (e.g. inactivity impacts sleep which impacts diet and stress, etc.) With so many of these factors combined, that could add up. These factors also impact hormones which can further impact mood and brain chemistry.
Ok, so if depression is sickness behavior and sickness behavior evolved to help us survive, why is it so prevalent, chronic, and debilitating today? While there may be factors like the reduction of natural anti-inflammatories, a newer theory suggests this behavior becomes reinforced. Lets take injury related depression for example. Let’s say we have two athletes who are both injured, unable to play, and experience subsequent depression and anxiety. One athlete recovers from the injury, their depression lifts, and they are able to get back into the game. The other athlete, however, recovers from the injury, but the depression persists on and even impacts their career as an athlete. Why is one athlete resilient to depression and the other not?
There are various answers to that question – theories mostly. It could be that one had positive coping skills and social support to combat the sickness behavior of anxiety, social avoidance, and lack of pleasure. If the other didn’t, they may have engaged in negative coping skills like drinking and social isolation. These things would then increase sleep disturbance, anxiety, and inactivity, thereby increasing inflammation, thereby reinforcing sickness behavior.
Another theory involves what is called the disappointment circuit. Typically, when we experience rewards, dopamine is released in the brain and makes us feel good. When we are expecting to be rewarded, but are not, dopamine is suppressed. This is the disappointment circuit, and if it is powerful enough it can inhibit the reward circuit, further suppressing dopamine, encouraging anhedonia, decreasing motivation, and leading to further social avoidance and negative coping skills. This can then lead to further negative lifestyle factors, increasing inflammation, increasing sickness behavior, strengthening this disappointment circuit.
Here’s where it gets really interesting, because it is not just being sick that leads to this sickness behavior. If you remember from above, trauma and stress also lead to inflammation, and also suppress dopamine release thereby reinforcing the disappointment circuit. In fact divorce, death of a loved one, loss of a job, neglect, etc. all seem to support this view of the disappointment circuit. In this way, inflammation, sickness behavior, and the disappointment circuit may all be interconnected. Traditional therapy of antidepressants, CBT, DBT, and positive coping skills aim to reduce the impact of sickness behaviors, but in treatment resistant individuals they do not work to treat depression because they do not break the cycle.
I suggest that proper treatment of depression does more than mask the symptoms. It should intervene with harmful lifestyle factors, promote anti-inflammatories, reduce sickness behaviors, suppress the disappointment circuit (ketamine may have potential to do this), and reinforce positive lifestyle changes, emotional expression and regulation, and experience of pleasure and gratitude in order to fully override the years of reinforced depression.
So much interesting research has come out (I suggest researching GABA and glutamate in depression and reward systems). The evidence is still new and uncertain, but this seems like a common sense explanation for depression to me.