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The brain is incredibly complex and things just go wrong sometimes, but scientists have managed to create effective medications... with the help of a few happy accidents.

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[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 ♪].