THE INFLAMMATORY PROCESS EXPLAINED
How can inflammation, the body’s physical response to injury and infection, possibly lead to depression? To understand the inflammatory process, it’s necessary to understand the role of a few key players in our immune system: macrophages, cytokines and lymphocytes.
Macrophages fire up when the body encounters a foreign invader. They break down substances such as bacteria and dish them up to the lymphocytes to target and destroy them. The macrophages also produce proteins called cytokines, which have either proor anti-inflammatory effects (and, confusingly, sometimes both). It’s a group of pro-inflammatory cytokines – interleukin 1, tumour necrosis factor (Tnf)-alpha and interleukin 6 – that has excited the interest of scientists investigating the links between inflammation and depression.
Typically, these cytokines are used as signals to turn on some later aspects of the immune system, and their production tends to increase when we need them, and reduce when we don’t.
Here’s where some fascinating animal studies come in. Rats injected with infectious bacteria tend to withdraw from social contact, move less, and have disturbed sleep and eating behaviour – symptoms commonly seen in depression. But you don’t need to infect a rat with the actual bacteria to see this sort of sickness behaviour: injecting a rat with cytokines alone will produce the same effect, suggesting it’s not the germ itself that makes the animal sick, but the immune response to it.
Research has also shown that if a bacterial toxin is injected into the rat, the toxin itself won’t get into the brain – the blood–brain barrier will prevent that – but the inflammatory signals from the response to the toxin will.
The brain’s macrophages, known as microglial cells, pick up those signals and start producing cytokines, which in turn damage nerve cells in surrounding tissue. The result, says Edward Bullmore in The Inflamed Mind, is that nerve cells die or shrink, and the supply of neurotransmitters such as serotonin (which are produced in the brain as well as the gut) is disrupted. “Not only can angry microglial cells kill nerve cells in their immediate neighbourhood, they can also block the regenerative process that would form new nerve cells in their place.”
The fact that the cytokines change the way neurons make and release serotonin may also explain why people who are inflamed respond less well to traditional SSRI antidepressants, which prolong the amount of time serotonin stays in the synapse (the communication junction between neurons). “When inflammation reduces the amount of serotonin released into the synapses, it is effectively pulling in the opposite direction to SSRIS.”
ANTI-TNF drugs have been used in rheumatoid arthritis since the late 1990s, and Bullmore’s book notes the experiences of doctors and nurses treating patients with the early infusions of one drug, infliximab (Remicade).
“They knew the patient would feel better and be full of gratitude almost immediately. It was so predictable that it had a nickname. They called it the Remicade high. It’s exactly what you’d expect if cytokines caused depression: that anti- cytokines should be anti- depressant; that a shot of anti-tnf should make people with inflamed minds feel high.”
The point was also proved in reverse, when patients with hepatitis B being treated with interferon, an inflammatory cytokine to boost the immune response to the hepatitis virus, became depressive. “This is not a side effect, but a sign that the treatment is having its intended effect of stimulating an inflammatory response. This happens to people who were not depressed immediately before the interferon injection. Their experience provides some of the clearest evidence in humans that an inflammatory stimulus can cause depression.”
C-reactive proteins and proinflammatory cytokines are all present at higher levels in people who have depression than in people who don’t. They’re also higher in other disorders such as obesity, diabetes and cardiovascular disease. But while they are markedly higher in conditions such as blood poisoning, they’re only mildly to moderately raised in people with depression.
Of course, it’s not just infection and injury that spark an inflammatory response, but also stress, poverty and adverse childhood experiences.
Left: an illustration of a tumour necrosis factor (Tnf)-alpha, a proinflammatory protein that’s thought to be linked to depression.