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What’s the point of Depression?

Let me first clarify this video’s title. When I say “What is the point of depression?,” I don’t mean to say what is the point of people choosing to be depressed - in the case of depression, certain physiological changes leave the mental state out of that person’s control.

What I mean to say is: We know that certain genes are associated with depression. So what is the point of these genes sticking around? Could they have some evolutionary benefit? For example, if people inherit two faulty copies of the gene for haemoglobin, then they’ll unfortunately develop sickle-cell disease, a condition in which the red blood cells are abnormally shaped.

However, having just one copy of this faulty gene provides resistance to malaria. This gene prevents the infection from taking hold after someone has been exposed to the pathogen. Sickle cell disease can shorten people’s lifespan to as little as 40 years, but that’s a decent tradeoff for not dying in a just a year or even a few weeks or days with malaria.

So, Is there some sort of tradeoff like this taking place in the people who have the genes associated with depression? To understand this, let’s look at not how we’ve lived, but how we’ve died.

Thanks to advances in science and medicine, death from a variety of causes has been drastically reduced, and now the two main causes of death in middle and upper income economies are heart disease and stroke.

Though, we’ve only reached this level of progress relatively recently. It wasn’t until 1876 that for the first time, a specific bacterium was linked with a specific disease - this marked the golden age of bacteriology, thanks to Robert Koch.

The idea that many diseases were caused by microorganisms - “the germ theory of disease,” arose in 1546, but even as late as the 1860’s, the prevailing idea was that bad air or bad smells caused diseases like cholera or the black death.

This is why plague doctors wore a bird looking mask with aromatic herbs in it to counter the “evil” smells of the plague. Unfortunately, what brought these life threatening diseases was human progress - agriculture provided humans with enough food to drastically increase the population, but it also increased the number of infectious diseases.

Pathogens that had once been exclusive to animals made their way over to humans thanks to domestication. Cattle brought tuberculosis and smallpox and pigs and ducks brought influenzas. Permanent settlements and the conversion of forests to farmlands created warm water-holes which were just right for mosquitoes to multiply and spread malaria.

If we go way back into the paleolithic era, where we lived as nomadic hunter-gatherers in small, mobile units - infectious diseases similar to smallpox, measles, the flu and the like were probably virtually unknown.

The microorganisms responsible for these kind of diseases rely on high population densities to thrive. There is evidence that respiratory infections, gut infections and gastrointestinal pathogens were threats to hunter-gatherers survival, but most people were likely to die of trauma.

That is, once a hunter gatherer was wounded through an act of violence or an accident, even if he escaped the situation alive, he would now have to worry about bacterial infection of his wounds.

But with a strong enough immune system, the body’s inflammatory sickness response could sometimes be enough to get rid of these kinds of organisms and keep the person alive. So what does all this have to do with depression?

Well, consider this: as is explained in this 2013 Molecular Psychiatry paper, 8 of the top 10 genes associated with depression also have some sort of immune or inflammatory function. Which suggests that the consequence of the body being able to better fight against pathogens or infections happens to lead to a higher risk for depression.

This concept is extensively explored in Charles Raison and Vladimir Maletic’s 640 page book titled “The New Mind-Body Science of Depression.” To clarify though, this isn’t quite like the case of having protection against malaria at the cost of getting sickle cell disease.

The genes associated with depression provide defense against infections, but the depression is not just an unfortunate consequence, depression itself would have actually helped deal with infections. This might sound a little far fetched, but for now take a moment and think about how you felt the last time you were sick.

If you’ve had the flu before: You may have experienced a change in appetite and sleep patterns, you probably had much lower energy levels, maybe were more irritable, didn’t have as much interest in daily activities and you probably weren’t up for going out and meeting new people.

It’s not a perfect match, but behavior and mentality during sickness looks a lot like depression. Flu symptoms of feeling crappy, lethargic, and having a fever are not the effects of the influenza virus itself but your body’s response to it. So then, could depression be the result of the body thinking it has an infection?

Evidence for this is the surprising fact that depressed people have lower levels of iron, and they have a higher body temperatures. Higher body temperature provides resistance to both viral and bacterial pathogens, which is why we get fevers when we’re sick. But what does having low iron have to do with an infection?

Well, Iron is essential for the survival of nearly all infectious microorganisms, so one immune strategy of the body is to deplete its own iron stores to deprive these microorganisms of their precious iron.

In fact, it’s been found that if you supplement people with iron while they have an infection, they are more likely to have worse health outcomes or even die from that infection. Now, infections can cause depressive symptoms, but doesn’t mean the cause of most depressions nowadays is an actual infection.

Rather, something may be triggering the body to think it has an infection, so it starts to act like it has an infection. And, Inflammation seems to be this trigger. Studies have found that people with depression have higher biomarkers for inflammation by up to 50%, and the risk of major depression increased as biomarkers for inflammation increased.

In one study, when people were injected with inflammation inducing substances, they experienced an acute increase in depressive symptoms like anxiety, feelings of social disconnection and anhedonia - the inability to feel pleasure. If you type in the phrase “Lipopolysaccharide-induced depression” into pubmed, you’ll get almost 200 results.

It is well known that giving lipopolysaccharide to various types of animals will reliably produce behavior that looks like depression and anxiety. Lipopolysaccharide powerfully stimulates the release of inflammatory cytokines.

It’s also well known that obesity is associated with depression, and the higher your body mass index, the higher your risk for depression. Then, body mass index has also been shown to correlate with more inflammation; This is in part because fat tissue can produce inflammatory cytokines.

And, A paper in the journal “Biological Psychology” suggests that the underlying link between metabolic syndrome and depressive symptoms is inflammation. In fact, many of the known risk factors for depression also increase inflammation: Now, At this point, you might be thinking: “Hold on.

If depression has an inflammatory cause, why is it that people get depressed after some mentally traumatizing or stressful life event?” Well, psychological stress is actually a trigger inflammation.

Work by Steven Maier’s group at the University of Colorado found that mice, when stressed with social isolation, secrete an increased amount of a particular inflammatory cytokine. These mice also develop cognitive difficulties and changes in brain chemicals similar to the changes seen in Major Depressive Disorder.

I don’t know if the blood of prison inmates in solitary confinement has ever been checked for inflammatory cytokines before, but we do know how people’s bodies react to another type of social stress thanks to something called the Trier Social Stress test.

This is a test where subjects are put in front of some very stone faced interviewers and asked to give a monologue on something like pitching themselves for a new job. The interviewers are instructed to make no facial reactions during the presentation, and make no comments.

If the subject finishes their speech too early, the interviewer will simply say “You have more time, please continue.” After that they have to count backwards from 1,022 in steps of 13 “..983?” and if they mess up they have to restart. “…No, one thousand and twenty two.”

Having to sit through this kind of social pressure has been shown to cause a 2 to 4-fold increase in the stress hormone cortisol. And, This social stress test also increases increases plasma concentrations of inflammatory cytokines. So what would be the point of increasing inflammation when you are experiencing stress?

Well, one explanation is that violence in hunter gatherer times was a lot more rampant than it is now. So, back then, when interacting with new people, acting in the wrong way might result in you getting attacked.

Then, if you got of there without dying, you’d want your immune system to turn on inflammation beforehand so it can be ready to fight against the pathogens that could infect your potential wounds.

And, not just social stress, other things that would cause you to get stressed out very likely meant you were in danger of getting wounded. So we know that inflammation can induce depressed mood, anhedonia, fatigue, and social avoidance.

It can also cause sleep disturbances like insomnia or hypersomnia - excessive sleeping. This behavior / emotional state sounds very similar to depression. Now we’re back to our original question, but we can make it a little clearer: If inflammation signals to the body that it needs to prepare to fight off an infection, what is the point of the inflammation also inducing depression?

Let’s look at some ideas for why these symptoms could actually have an evolutionary benefit in defending against pathogens: The reason for the lethargy is that limited metabolic resources can be preserved and used for the energy expensive processes of fighting off pathogens with immune activation and fever generation.

Then there’s sleep disturbances: Hypersomnia- excessive sleeping, would be a part of this energy conservation strategy, but depressed people can also have insomnia which is more the case when you are exposed to inflammation chronically- that is, for a long time.

Getting more sleep, and more slow wave sleep in particular, would be a good strategy initially to regenerate the body and defend against the perceived infection, but it’s not a good long term strategy.

What happens with chronic inflammation is that it makes people more vigilant: you get more anxious, agitated, irritable and develop insomnia. This still makes sense from an evolutionary context.

While it’s not a good mental state to be in, being excessively vigilant would have helped you to avoid predators and environmental dangers - which was especially important considering increased inflammation means health is already compromised.

Then, there’s the symptom of social withdrawal: Since prehistoric humans lived in small groups of genetically related people, social withdrawal would prevent you from infecting your peers and endangering your gene pool.

Many studies have found that even subtle indications of infection in others causes people to understandably react with disgust and even shunning the infected person. Nowadays, social status has many enjoyable perks, but for a hunter gatherer, being shunned and losing the cooperation of their tribe could mean death.

So, having the sense to not stick around and infect everybody else could help preserve your social status. Then, social withdrawal and being less outgoing may have helped sick people survive because it would limit a sick person’s contact with strangers who potentially carried dangerous foreign pathogens that the sick person would have had reduced immunity to. Depression is a very complex disease - what I’ve presented here of course doesn’t address every type or instance of depression.

However it does provide some useful context for understanding depression. In Robert Whitaker’s book “Anatomy of an Epidemic,” he describes the case of Melissa, who at age 16 was diagnosed with depression and told that she would need drugs the rest of her life. At that point, she received a prescription for Zoloft.

Things went well but after a while Zoloft quit working. Melissa said that the high dose of Paxil that came after that made her feel “like a zombie.” Her early adult life became a series of experiments with psychiatric medications.

Her depression followed her throughout college and while she graduated and had a promising beginning to her career, she ended up on Social Security Disability. What if at age 16 Melissa’s healthcare professional approached depression as an inflammatory disease rather than a “chemical imbalance”?

You may have heard about exercise being as effective or more effective than some antidepressants. There are a couple different mechanisms through which exercise can help depression, but exercise also has anti-inflammatory effects.

And In one study, people were injected with the inflammatory cytokine interferon alpha that normally induces depressive symptoms, but they were also given the anti inflammatory omega-3 fatty acid EPA (which is found in fish oil), and they didn’t experience the expected depressive symptoms. Thanks to the widespread use of vegetable oils, people nowadays are getting far too many omega-6 inflammatory fatty acids and not enough omega-3 anti inflammatory fatty acids.

Other ways to keep inflammation low are probably unsurprising: get enough sleep, keep a healthy weight, don’t spike your blood sugar, and cut out refined carbohydrates and sugar, cut out processed vegetable oils, trans fats and artificial sweeteners.

The information presented in Charles Raison and Vladimir Maletic’s book “The New Mind-Body Science of Depression,” and other sources provide a new and intriguing way of thinking about depression.

Rather than depression being a disorder that arises due to a so-called chemical imbalance in the brain, depression could be the body’s response to chronic inflammation. Equipped with this way of thinking about depression, hopefully people can take more safe and effective approaches to treating depression.