In a recent Pint of Science event Professor Carmine Pariante from King’s College London talked about the link between mood disorders like clinical depression and the immune system. The main question he addressed in his presentation was how inflammation and depression are related to each other and why it is necessary to diagnose and treat both in order to help patients. His talk stayed with me for quite a while and made me ponder: how much do we actually know about the connection between the depressed mind and the body?
Mood disorder: symptoms without a cause?
In the early history of psychiatric treatment the term mental disorder (or rather neurosis, neurasthenia or hysteria in the Freud era) was usually applied to all syndromes with no apparent organic reason; a convenient category that covered a wide range of phenomenons observed in patients that were not physiologically explainable. In the meantime this view has changed and the notion that mental disorders are a “disease of the mind” with no underlying organic causes or effects has become obsolete. The advent of new technological achievements and progress in the field of neuroscience have allowed spectacular insights into changes in the brain during mental disorders. For instance, numerous studies show altered neurotransmitter expression in several brain regions in people with mood disorders or related conditions (1).
Decreased overall brain activity, which can be monitored by looking at glucose metabolism, is also a common finding in depressed people (2). In other words, their brains temporarily loose functionality or processing power. To “see things from a different perspective” literally becomes an impossible endeavour for the depressed mind, in the same way as taking the initiative to change the situation is now beyond the individual’s capacity.
Most studies so far have focussed on immediate effects on the brain during depression. Although many patients also complain about physical symptoms, such as frequent headaches, back pain, muscle aches, joint pain or digestive problems, in most cases underlying organic reasons cannot be identified. Still, this poses an interesting question: how is the body affected by the depressed mind? Is it affected at all?
The depressed mind in an inflamed body.
If we look at the symptoms described, one thought immediately comes to mind: they could all be caused by low-grade smouldering inflammation. And indeed an increased level in inflammatory markers has been reported as a frequent companion of depression already in the 1980s (3).
Scientists found evidence that high levels of cytokines and inflammatory factors are present in the blood of clinically depressed patients, serious signs of chronic inflammation (4). This increase in inflammation is sometimes also found in patients who are not yet depressed and has been implicated as a risk predictor (5). Conversely, some anti-inflammatory drugs have been shown to successfully treat depressive disorders, an effect that was certainly not on the list of medical indications at the time of the first drug approval. Likewise, some anti-depressants exhibit an anti-inflammatory effect.
What comes first: inflammation or depression?
So where is the connection between all of this? Is depression causing inflammation or vice versa? And more importantly: why is this happening? According to Professor Pariante one answer might be found in our distant past: for the versatile hunter in prehistoric times it made a lot of sense to be forced to lie down and rest after a period of acute stress and injury. Depression – or rather a period of deceleration and weariness – was the body’s plea to allow complete physical regeneration.
But the evolutionary benefit has long been lost: our modern world is one of chronic stress and sensory overload (without physical damage hopefully) where long periods of rest and idleness are not tolerated anymore. Today depression, at least when it develops into the severe clinical variant, is a debilitating disease and, if left untreated, comes with a high mortality rate.
But let’s leave the speculations about evolutionary reasons aside for a moment. If we assume that inflammation comes first, is it actually physically possible that it affects the brain? How do immune system and brain communicate? While there are specialised immune cells such as microglia in the brain, they cannot leave it or recruit immune cells from other parts of the body. The brain is protected by a blood-brain barrier and cannot be entered by pathogens, immune cells or even large molecules (which makes it different to deliver certain drugs into the brain). However, inflammatory factors, also called cytokines, that the immune cells use to communicate can be transported along the nerves, penetrate the barrier and activate neurons and other cells in the brain. In this way, inflammation can have a direct effect on the nervous system. There are also inflammatory and autoimmune diseases such as meningitis or multiple sclerosis in which the blood brain barrier gets disrupted and leaves the brain vulnerable to external influences.
The finding that certain people with high initial levels of inflammatory factors later develop depression would argue that the immune system paves the way. We should not forget, though, that many people who suffer from depression in their lives can trace it back to a single or multiple traumatic events in their past. A number of clinical studies have been done to examine the biological response to childhood trauma, for example (7). They find higher levels of stress hormones and an over-activation of the immune system; when these people are exposed to stressful situations later in life they typically respond with higher levels of stress hormones than people with no history of trauma (6). Children with a history of maltreatment who are currently depressed also show higher levels of the inflammatory marker C-reactive protein (4).
Stress causes an instant response.
Taken together these results imply a simple cascade: the body’s innate and a bit old-fashioned response to stress is to activate it’s immune system in anticipation of invading microorganisms like bacteria or viruses (it’s still not fully adapted to modern challenges like horrible bosses, lawyers or party-animal neighbours). This leads to a release of inflammatory cytokines which access the brain, induce the production of stress hormones and trigger changes in neurotransmitter metabolism (serotonin, dopamine etc) that eventually lead to depression if the stressful event is repeated often enough (4).
Does this explain everything? Of course not, it wouldn’t be science if there were no questions left. For example: does it work the other way round? Can depression cause inflammation?
Interestingly, Dr Fulvio D’Acquisto mentioned in his Pint of Science talk that Multiple Sclerosis patients (an inflammatory disease where the immune system starts to attack the patient’s nervous system) show signs of depression long before the disease can be diagnosed. I admit, this is controversial and could indicate that there already is low-grade inflammation before it develops into full-blown MS. But what about people who are pre-disposed to depression because of genetically inherited factors; where it “runs in the family”? Are they always inflamed as well? We don’t know the answer yet and this side of the story is much less investigated. What we do know is that inflammation and depression often seem to be associated, as if one thing cannot occur without the other.
What does this mean for therapy?
In addition to the immediate effect on the long-suffering individual and a higher suicide risk, there is also an alarming societal aspect of depression: when individuals develop clinical depression and cannot be treated properly they will pass it on to their children. Recent studies done by the Pariante group find high levels of the cytokines interleukin 1 and 6 in (currently healthy) children of severely depressed parents.
His advice to people suffering from depression would be to get their inflammatory markers checked. If there is a correlation, chances are high that successful treatment might be achieved by an anti-inflammatory drug and not necessarily by an anti-depressant, which only targets the neurotransmitter imbalance but ignores the rest of the symptoms. Starting to self-medicate with aspirin is not recommended, however, due to the adverse effects of non-steroidal anti-inflammatory drugs upon long-term use.
Want the scientific details? Here are the references:
- Reviewed in Werner et al. Classical Neurotransmitters and Neuropeptides Involved in Major Depression: a Review. 2010.
- Ketter et al. Functional brain imaging, limbic function, and affective disorders. 1996.
- Lieb et al. Elevated levels of prostaglandin e2 and thromboxane B2 in depression. 1983.
- Danese et al. Elevated Inflammation Levels in Depressed Adults With a History of Childhood Maltreatment. 2008; Raison et al. Cytokines sing the blues: inflammation and the pathogenesis of depression. 2006.
- reviewed here
- Heim et al. The link between childhood trauma and depression: insights from HPA axis studies in humans. 2008.
- Jonathan Hill. Childhood trauma and depression. 2003.