Sometime around 1907, well before the modern randomized
clinical trial was routine, American psychiatrist Henry Cotton began removing
decaying teeth from his patients in hopes of curing their mental disorders. If
that did not work, he moved on to more invasive excisions: tonsils, testicles,
ovaries and, in some cases, colons.
Cotton was the newly appointed director of the New Jersey
State Hospital for the Insane and was acting on a theory proposed by
influential Johns Hopkins psychiatrist Adolf Meyer, under whom Cotton had
studied, that psychiatric illness is the result of chronic infection. Meyer's
idea was based on observations that patients with high fevers sometimes
experience delusions and hallucinations.
Cotton ran with the idea, scalpel in hand.
In 1921, he published a well-received book on the theory
called The Defective Delinquent and Insane: the Relation of Focal Infections to
Their Causation, Treatment and Prevention. A few years later, The New York
Times wrote, "eminent physicians and surgeons testified that the New
Jersey State Hospital for the Insane was the most progressive institution in
the world for the care of the insane, and that the newer method of treating the
insane by the removal of focal infection placed the institution in a unique position
with respect to hospitals for the mentally ill." Eventually Cotton opened
a hugely successful private practice, catering to the infected molars of
Trenton, N.J., high society.
Following his death in 1933, interest in Cotton's cures
waned. His mortality rates hovered at a troubling 45 percent, and in all likelihood,
his treatments did not work. Though his rogue surgeries were dreadfully
misguided and disfiguring, a growing body of research suggests that there might
be something to his belief that infection — and with it inflammation — is
involved in some forms of mental illness.
Symptoms of Mental
and Physical Illness Can Overlap
Late last year, Turhan Canli, an associate professor of
psychology and radiology at Stony Brook University, published a paper in the
journal Biology of Mood and Anxiety Disorders asserting that depression should
be thought of as an infectious disease. "Depressed patients act physically
sick," says Canli. "They're tired, they lose their appetite, and they
don't want to get out of bed." He notes that while Western medicine
practitioners tend to focus on the psychological symptoms of depression, in
many non-Western cultures, patients who would qualify for a depression
diagnosis report primarily physical symptoms, in part because of the
stigmatization of mental illness.
"The idea that depression is caused simply by
changes in serotonin is not panning out. We need to think about other possible
causes and treatments for psychiatric disorders," says Canli.
His assertion that depression results from infection
might seem far-fetched, or at least premature, but there are some data to
bolster his claim.
Harkening back to Adolf Meyer's early 20th century
theory, Canli notes how certain infections of the brain — perhaps most notably
Toxoplasma gondii — can result in emotional disturbances that mimic psychiatric
conditions. He also notes that numerous pathogens have been associated with
mental illnesses, including Borna disease virus, Epstein-Barr and certain
strains of herpes, including varicella zoster, the virus that causes chickenpox
and shingles.
Toxoplasma gondii, a parasitic protozoan, afflicts cats
and other mammals. Acute toxoplasmosis produces flu-like symptoms and has been
linked to behavioral changes in humans.
Infection with the T. gondii strain of bacteria can cause
rats to become fearless around cats, a natural predator for these animals. And,
one of the recent studies of 2012 suggested people who owned cats had a higher
risk of suicide, as their pets could make them vulnerable to a Toxoplasma
gondii (T. gondii) infection.
A Danish study published in JAMA Psychiatry in 2013
looked at the medical records of over 3 million people and found that any
history of hospitalization for infection was associated with a 62 percent
increased risk of later developing a mood disorder, including depression and
bipolar disorder.
Canli believes that pathogens acting directly on the
brain may result in psychiatric symptoms, but also that autoimmune activity —
or the body's immune system attacking itself — triggered by infection may also
contribute. The Danish study also reported that a past history of an autoimmune
disorder increases the risk of a future mood disorder by 45 percent.
The new study was headed by Michael Eriksen Benros, PhD,
a senior researcher at the National Centre for Register-based Research at
Aarhus University, Denmark. The study was based on medical data from 3.56
million Danes. Around 90,000 of these have had either a depression or bipolar
disorder.
”Unlike anywhere else in the world, in Denmark we have
the opportunity to follow the medical history of the entire population by
combining hospital records with psychiatric records,” says Benros.
Infectious agents
affect mood and behavior
There's some literature on intestinal bacteria and
probiotics. We have more than 1,000 strains of bacteria in our intestines, and
it turns out that you need those to digest food. They may also play a role in
our emotional states, so that people who have experienced negative emotions
report improved mood when placed on a probiotic. These people may experience a
reduction in depressive symptoms and anxious symptoms. So, that is just one
example of bacteria playing a role in mood.
Some work on animals goes deeper into the potential
mechanisms. There are mice that were bred to have no intestinal bacteria -- so
these are germ-free, super clean mice. When you take them into a laboratory
setting where you stress them out, they show a very strong stress response. But,
when you then put them on a diet of common intestinal bacteria, their stress
response normalizes. So, there is a possibility that these bacteria that we
have in our guts may not only help us digest our food, but may also play a role
in our emotional well-being. You could flip that upside down and say, well there
is good bacteria, but maybe there is also bad bacteria that instead of lifting
your mood could depress your mood...
There was one epidemiological study that looked at the
prevalence of a particular parasite across 20 different European countries, and
they correlated that with suicide rates, and they found a significant positive
correlation. Now, we all know from any introductory science course that
correlation is not causation, so we do not know what the deal is with that, but
there is a correlation there. It is also correlated with higher levels of
self-reported neuroticism as a personality trait...
Antibodies Provide
a Clue
The idea that there could be a relationship between the
immune system and brain disease is not new. Autoantibodies were reported in
schizophrenia patients in the 1930s. Subsequent work has detected antibodies to
various neurotransmitter receptors in the brains of psychiatric patients, while
a number of brain disorders, including multiple sclerosis, are known to involve
abnormal immune system activity. Researchers at the University of Virginia
recently identified a previously undiscovered network of vessels directly
connecting the brain with the immune system; the authors concluded that an
interplay between the two could significantly contribute to certain neurological
and psychiatric conditions.
Both infection and autoimmune activity result in
inflammation, our body's response to harmful stimuli, which in part involves a
surge in immune system activity. And, it's thought by many in the psychiatric
research community that inflammation is somehow involved in depression and
perhaps other mental illnesses.
Multiple studies have linked depression with elevated
markers of inflammation, including two analyses from 2010 and 2012 that
collectively reviewed data from 53 studies, as well as several postmortem
studies. A large body of related research confirms that autoimmune and
inflammatory activity in the brain is linked with psychiatric symptoms.
Still, for the most part the research so far finds
associations but does not prove cause and effect between inflammation and
mental health issues. The apparent links could be a matter of chance, or there
might be some other factor that has not been identified.
Dr. Roger McIntyre, a professor of psychiatry and
pharmacology at the University of Toronto, tells Shots that he believes an
upset in the "immune-inflammatory system" is at the core of mental
illness and that psychiatric disorders might be an unfortunate cost of our
powerful immune defenses. "Throughout evolution our enemy up until
vaccines and antibiotics were developed was infection," he says. "Our
immune system evolved to fight infections so we could survive and pass our
genes to the next generation. However, our immune-inflammatory system doesn't
distinguish between what's provoking it." McIntyre explains how stressors
of any kind — physical or sexual abuse, sleep deprivation, grief — can activate
our immune alarms. "For reasons other than fighting infection, our
immune-inflammatory response can stay activated for weeks, months or years and
result in collateral damage," he says.
Unlike Canli, McIntyre implicates inflammation in
general, not exclusively inflammation caused by infection or direct effects of
infection itself, as a major contributor to mental maladies. "It's
unlikely that most people with a mental illness have it as a result of
infection," he says, "but it would be reasonable to hypothesize that
a subpopulation of people with depression or bipolar disorder or schizophrenia
ended up that way because an infection activated their immune-inflammatory
system." McIntyre says that infection, particularly in the womb, could
work in concert with genetics, psychosocial factors and our diet and microbiome
to influence immune and inflammatory activity and, in turn, our risk of
psychiatric disease.
Trying Drugs against
Inflammation for Mental Illness
The idea that inflammation — whether stirred up by
infection or by other factors — contributes to or causes mental illness comes
with caveats, at least in terms of potential treatments. Trials testing
anti-inflammatory drugs have been overall mixed or underwhelming.
A recent meta-analysis reported that supplementing SSRIs
like Prozac with regular low-dose aspirin use is associated with a reduced risk
of depression, and ibuprofen supplementation is linked with lower chances of
obtaining psychiatric care. However, concomitant treatment with SSRIs and
diclofenac or celecoxib — two other anti-inflammatories often used to treat
arthritis — was associated with increased risk of needing hospital care due to
psychiatric symptoms.
A 2013 study explored the antidepressant potential of
Remicade, a drug used in rheumatoid arthritis. Overall, three infusions of the
medication were found to be no more effective than a placebo, but patients
whose blood had higher levels of an inflammatory marker called C-reactive
protein did experience modest benefit.
"The truth of the matter is that there is probably a
subset of people who get depressed in response to inflammation," says lead
author Dr. Charles Raison, a psychiatry professor at the University of Arizona.
"Maybe their bodies generate more inflammation, or maybe they're more
sensitive to it."
How infection and other causes of inflammation and overly
aggressive immune activity may contribute to depression and other mental
illnesses — and whether or not it's actually depression driving the
inflammation — is still being investigated, and likely will be for some time.
But plenty of leading psychiatrists agree that the search for alternative
pathologic explanations and treatments for psychiatric disorders could help
jump-start the field.
"I'm not convinced that anti-inflammatory strategies
are going to turn out to be the most powerful treatments around," cautions
Raison. "But I think if we really want to understand depression, we
definitely have to understand how the immune system talks to the brain. I just
don't think we've identified immune-based or anti-inflammatory treatments yet
that are going to have big effects in depression."
But the University of Toronto's McIntyre has a slightly
brighter outlook. "Is depression due to infection, or is it due to
something else?" he asks. "The answer is yes and yes. The bottom line
is inflammation appears to contribute to depression, and we have interventions
to address this."
McIntyre notes that while the science of psychiatry has a
long way to go, and that these interventions have not been proved effective,
numerous approaches with minimal side effects exist that appear to be generally
anti-inflammatory, including exercise, meditation and healthy sleep habits.
He also finds promise in the work of his colleague:
"Like most cases in medicine, Charles Raison showed that anti-inflammatory
approaches may benefit some people with depression, but not everybody. If you
try on your friend's eyeglasses, chances are they won't help your vision very
much."
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