[INTRO ♪] A century ago, the idea that pharmaceuticals
could treat mental illness was considered fringe science—now, it’s
fundamental psychiatry. That shift happened when effective drugs for
conditions like schizophrenia and depression were found
in the 1950s—by accident. Basically, some unexpected side effects in
anesthesia boosters and antibiotics gave birth to the entire field
of psychopharmacology: the study of how drugs affect mood and behavior. Which means we have some serendipitous side
effects to thank for everything from Abilify to Zoloft. You’d think drug development would begin
with doctors studying an illness, figuring out what’s going wrong, then looking
for compounds that might fix it. Instead, things often happen in reverse— unexpected side effects pop up when drugs
are being tested for one thing—and sometimes, those prove
more interesting. This was especially true a few decades ago
in the early days of psychiatry, when loose regulations made it easier to test
drugs on people. For example, the antipsychotic chlorpromazine was first investigated as an antihistamine: a drug that reduces immune reactions, including allergies. Antihistamines also tend to have sedative
effects, so in 1952, French surgeon Henri Laborit thought
that he could combine it with anesthesia to induce a kind of ‘artificial
hibernation’ which would prevent patients from going into
shock during surgery. Instead he noticed that it made them calm
and disinterested without putting them to sleep like other antihistamines. Based on his observations, he convinced psychiatrists
at a military hospital to try it on patients exhibiting psychosis: a break from reality that’s a common symptom of certain mental disorders, like schizophrenia. The calming effects on the first patient, a 24 year old man named Jacques, were immediate. 20 days later, he was able to leave the hospital and “resume normal life”—something basically
unheard of at the time. Over the next few years, the drug spread across
the world, helping thousands of mentally ill patients
leave institutions. But it wasn’t until over a decade later
that researchers discovered how it works: by blocking receptors for the
compound dopamine, one of the brain’s most important neurotransmitters
sending signals between neurons. Chlorpromazine is not a cure-all for all people
with schizophrenia, but it led to further research on the role
of dopamine in psychosis and eventually the development of newer meds like aripiprazole, better known as Abilify. And it’s credited for beginning the cultural
shift in psychiatric science towards understanding the chemical basis of
disorders. Prior to chlorpromazine, the focus was on
electrical activity in the brain—which is why shock therapy
was so popular. So this discovery paved the way for research
on all kinds of drugs for mental disorders. And that includes the first antidepressant, which was also discovered through unexpected
side effects. At the time, doctors in New Jersey were trying
to find new antimicrobials to fight tuberculosis. So they were tinkering with hydrazine, a rocket fuel that is the precursor to some drugs, because they were able to obtain it cheaply after
World War II ended. Because what else are you going to do with
all that extra fuel, I guess? They kept trying slightly modified versions
on volunteer patients with chronic TB, and in 1952, they realized one variant—iproniazid— had an entertaining side effect: improved
mood. Patients were described as literally “dancing
in the halls tho’ there were holes in their lungs”. These euphoric effects were seen as a bad
thing by the drug developers— but New York psychiatrist Nathan Kline thought
otherwise. He was looking for something that would lift
depressive states; basically, to do the opposite of a drug like
chlorpromazine. So when he saw the energy iproniazid gave
mice and people alike, he begged the Jersey company to let him test it. He and two of his colleagues led the first
small psychiatric trial, published in 1958, finding significant improvement in 70 percent of their 17 depressed patients. Soon it was all the rage, and for a few years, it became the go-to antidepressant. Doctors actually already knew what it did
from studies on its use as a treatment for tuberculosis. In 1952, researchers found that it inhibits
an enzyme called monoamine oxidase or MAO. What they didn’t realize then is that MAO
breaks down neurotransmitters like serotonin which are involved in regulating
mood. So when you block MAO in the brain, levels
of serotonin go up— lifting people’s spirits. Iproniazid’s use was short lived. In 1961, the drug was withdrawn because of
toxic effects on the liver. But its popularity and effectiveness helped
change the negative attitude many psychiatrists had towards the idea of
treating mental illness chemically. And it wasn’t the only serendipitous antidepressant
discovery in the late 1950s. Following on the success of that first drug
we talked about, Swiss psychiatrist Roland Kuhn was trying
to find the next antihistamine-based antipsychotic when he discovered the tricyclic antidepressant
imipramine. It has three rings in its chemical structure—hence
tricyclic. Since it’s somewhat similar to chlorpromazine
in shape, Kuhn and the pharmaceutical company he was
working with thought it might also treat psychosis. But when Kuhn gave it to his psychotic patients, it did not calm them—if anything, it made
them manic. It was only really helpful in his schizophrenic
patients who had severe depressive symptoms. Based on these observations, he tested the
new drug on roughly 100 patients with depression, publishing his subjective
summary of the results in 1957. His findings were so promising that the tricyclic
antidepressant quickly gained popularity. Studies done in the 1960s showed that, like
iproniazid, it also increases the level of serotonin-based
signaling in the brain, but without inhibiting MAO. Instead, it prevents neurons from sucking
serotonin back up after they release it, leaving more floating
around. MAO inhibitors and tricyclic antidepressants
are still sometimes prescribed, but not as commonly, since they have unwelcome
side effects. But even though they’re less used now, they
formed the rationale for research into other drugs that could increase
serotonin levels in the brain. That includes the blockbuster antidepressants
on the market today: selective serotonin reuptake inhibitors like
sertraline—also known as Zoloft— which work a lot like tricyclic antidepressants
but with fewer side effects. Thanks in large part to all of these discoveries, more than 60 different psychiatric drugs were
available by the end of the 1970s, including 22 calming drugs following on the
heels of chlorpromazine and 15 antidepressants inspired by imipramine. And in general, they were foundational to
our understanding of the neurobiology of mental illness. So now, pharmaceutical companies and scientists
can go about psychiatric drug discovery in the way that
you would expect: by building chemical compounds that hone in on parts of our bodies that are off balance. Which means more people with mental illnesses have reason to dance in the halls—and are
leading happier, healthier lives. Thanks for watching this episode of SciShow
Psych! If you would like to learn more about how antidepressants work, we have an episode on the science behind them. [OUTRO ♪]
