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[​R​], 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.[​R​] 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.[​R​] 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.[​R​] 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,[​R​, ​R2​] 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.[​R​]

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.[​R​] 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.[​R​]

That 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, 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.[​R​] 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.[​R​,​R2​] 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.[​R​, ​R2​] In one study, people were
injected with inflammation inducing substances. These people experienced
an acute increase in depressive symptoms like anxiety, feelings of social
disconnection and anhedonia - the inability to feel pleasure.[​R​]

In fact, as Dr. Charles Raison explains: “​inflammatory molecules, or

anything that activates them, are among the most potent inducers of
depression known to science.”

One method of treatment for people with the hepatitis C virus infection is to
enhance immune function by giving these patients the inflammatory
cytokine​ interferon-alpha (IFN-α)- this was almost a miracle cure for the
hepatitis infection. But, people have to take it for weeks or months at a
time, and thanks to its potent inflammatory effect, it can induce clinical
depression. The rates for this have been reported to range from 20 percent
to as high as 82 percent of the time.[​R​, R2​, R3, Raison, Maletic - pg 80]

If you type in the phrase “Lipopolysaccharide-induced depression” into

pubmed, you’ll get almost 200 results. It is well known that giving
lipopolysaccharide (LPS) to various types of animals will reliably produce
behavior that looks like depression and anxiety. LPS powerfully stimulates
the release of inflammatory cytokines ​(especially TNF, IL-1, and IL-6)​.

It’s also well known that obesity is associated with depression, and the
higher your body mass index, the higher your risk for depression.[​R​] Then,
body mass index has also been shown to correlate with more inflammation;
This is in part because fat tissue can produce inflammatory cytokines.[​R​] ​A
paper​ in the journal “Biological Psychology” suggests that the underlying
link between metabolic syndrome and depressive symptoms is
inflammation.[​R​]

In fact, many of the known risk factors for depression also increase
inflammation:
-Medical illness
-Sedentary lifestyle
-Smoking and second-hand smoke exposure
-Obesity
-Air pollution
-Diminished sleep
-Social isolation
-Psychosocial stress
-Low socioeconomic status
-Change of seasons (e.g., winter in those with seasonal affective disorder)
-Diet (e.g., low ratio of omega-3 to omega-6 fatty acids, high-fructose
sugars)

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 ​(IL-1β)​.
These mice also develop cognitive difficulties and changes in brain
chemicals similar to the changes seen in Major Depressive Disorder.[​R​]

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 and if they mess up they have
to restart.

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.[​R​] And, This social
stress test also increases ​increases plasma concentrations of inflammatory
cytokines, especially one called IL-6.[​R​,​R2​] 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.

Luckily, nowadays, you can rest assured that you’ll be leaving a job
interview without any bloody gashes, but our bodies still react as though
that may be a possibility.

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.[​R​] 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.[​R​] Raising the
body temperature is an energy expensive process.[​R​]

Then there’s ​sleep disturbances​: Hypersomnia- excessive sleeping,

would be a part of this energy conservation strategy, but depressed people
can also have ​in​somnia​ 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. [​R​] ​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. This is opposed to pathogens
present in the person’s home group that they would have developed some
adaptive immunity to​.[​R​, R
​ aison, Maletic - Pg 474] An example of strangers
bringing dangerous foreign pathogens over was the European contact with
Native Americans where the novel diseases killed an estimated ​90%​ of
Native Americans.

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 and hopefully treating
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. In a meeting with Whitaker, Melissa said “I do
wonder what might have happened if [at age sixteen] I could have just
talked to someone and they could have helped me learn … to be a healthy
person. [Instead of helping me] with my eating problems, and my diet and
exercise … it was you have this problem with your neurotransmitters, and
so here, take this pill Zoloft and when that didn’t work, it was take this pill
Prozac, and when that didn’t work, it was take this pill Effexor… I am so
tired of pills.”
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.[​R​] There are a couple different mechanisms
through which exercise can help depression, but exercise also has
anti-inflammatory effects.[​R​]

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.[​R​]
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. [​R​,​R2​,​R3​,​R4​,​R5​]

Antidepressants are a touchy subject because they have really saved the
lives of some people, but there’s also strong evidence that suggests that
people become dependent on the drugs and the chance for relapse into
depression is far higher than if someone went without antidepressant
treatment. These are both points made in Robert Whitaker’s book. In the
case of Melissa, That initial prescription of Zoloft may have saved her life
because what alerted her doctor to her depression was a suicide attempt.
But, maybe Melissa could have been able to wean off the drugs if her
healthcare professional had her make some anti inflammatory lifestyle
changes.
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.