It was when he became a father that Michael Briggs resolved to somehow bring his ulcerative colitis under control.
He was determined to avoid what many people with the disease end up needing – having part or all of their large intestine removed.
A trained scientist, manager of a physics lab at the University of New Hampshire, he began reading medical research papers, looking for anything that might help him.
He knew there wouldn’t be just one single cure, just as he knew there was not one single cause behind this inflammatory bowel disease (IBD), which causes gut pain, bleeding and diarrhea. He had already been on a drug called Remicade (infliximab) for more than five years. This blocks the action of an inflammatory protein called tumor necrosis factor alpha (TNF alpha) in order to stop the immune system from attacking the colon wall.
The problem is that drugs like this can have significant side-effects, such as leaving patients more prone to infections and, in rare cases, cancer.
Another problem, Briggs tells me, is that the drugs stop working as people’s immune systems develop antibodies against them.
Briggs knew he couldn’t stay on infliximab for ever and he was tired of dealing with the cycle of flare-up and remission with his disease. Seeking a way to heal following a nasty flare-up during the summer of 2013, he sifted through more than 150 papers on anti-inflammatory supplements, diet and TNF blockers.
Eventually, he stumbled upon research suggesting that an antidepressant called bupropion had an effect on Crohn’s disease, another type of IBD where the immune system attacks the lining of the gut. Studies on mice had shown that instead of blocking the action of inflammatory proteins, bupropion appeared to lower the production of those proteins in the first place.
Briggs decided to give it a try.
It’s not unusual for a drug to be prescribed for a disease it hasn’t been officially approved to treat. It’s certainly not illegal; it’s not even that difficult.
Doctors all over the world are allowed to prescribe drugs off-label, and antidepressants are used for several conditions and diseases beyond depression, including migraines, hot flashes, attention deficit hyperactivity disorder (ADHD) and disorders of the digestive system.
Off-label use means that more potentially effective treatments have a chance of becoming available in medical practice. But it also means that the drugs haven’t been tested in clinical trials or received approval from regulatory agencies for these other uses.
The potential downside, in the case of antidepressants, is that doctors won’t know about possible risks when these drugs are used by people who are not depressed.
Bupropion has been around for more than 30 years, however, and has a pretty good track record for safety. Even so, aside from a few assertive patients like Briggs, very few people know bupropion might have a double life as an IBD drug.
Within two weeks of starting bupropion, Briggs was bleeding far less and had experienced almost no side-effects. Gradually, all his bleeding stopped. After using bupropion to get his disease under control, he added a variety of anti-inflammatory supplements and changes in diet to keep his ulcerative colitis from flaring up again.
He believes he has succeeded in creating a functional cure for his disease – he’s remained in remission since starting his ‘protocol’ in 2013.
He’s written about his research and experiences to help spread the word to others with colitis. And like any good researcher, he declares his interests: “In research papers, it is typical for the author to disclose any vested interests that might bias their views. In that vein, I want to clarify that I have a vested interest, which is that I hope to never crap blood again.”
I have to declare an interest, too: I also have colitis, and I followed Briggs’s lead after he shared his protocol.
I first asked my gastroenterologist about trying bupropion, but he waved it off as a mental health matter. (Briggs says it’s typical for patients to get bupropion from primary care physicians rather than specialists.)
My psychiatrist was justifiably cautious. I was already taking a different type of antidepressant for anxiety and sleep problems, so she wasn’t sure about giving me a drug that could cause insomnia. But since I could quickly get off bupropion if its side-effects were intolerable, she was willing to give it a try.
Bupropion wasn’t a miracle cure for me, but after taking it, I didn’t have to go to the bathroom as many times each day. As for side-effects, I didn’t have insomnia, but did feel jittery the first week of taking it.
As Briggs had predicted, those side-effects quickly subsided. He estimates that, of the people with IBD who have contacted him about bupropion, 80% have had complete success, while the remaining 20% saw improvement.
It seems surprising that antidepressants should work on other diseases, but perhaps it’s time to stop thinking of these drugs as ‘antidepressants’ and admit that they are not one-trick ponies, but jacks of all trades.
Antidepressants can all help relieve depression, but they do this in many different ways, acting on different chemical messengers in the brain and nervous system. Those same neurotransmitters have roles in controlling what happens in other organs and systems, so it’s no wonder that antidepressants have other effects. Some are unwanted, which we call side-effects, and others are useful, which may be why almost a third of antidepressant prescriptions are off-label.
But the very nature of how we regulate and produce drugs means there are many obstacles to understanding everything that a drug might be capable of. And that means patients could be missing out on potentially beneficial treatments.
A little bit of luck
The research that persuaded Briggs to try bupropion was published by an unorthodox Vermont psychiatrist named Richard Kast.
In 1999, Kast had started treating a woman with Crohn’s disease for depression. When he switched the woman from fluoxetine, an antidepressant that increases serotonin availability, to bupropion, something entirely unexpected occurred. Her Crohn’s went into remission.
It was remarkable because, despite the powerful anti-inflammatories she was taking, she had had chronic abdominal pain, blood in her stool and frequent bouts of diarrhea until she started bupropion.
Kast increased her dose of bupropion and her Crohn’s symptoms decreased further, to the point where she had normal bowel movements once a day and no pain. On occasions when she stopped taking bupropion, the blood and abdominal pain returned until she started taking the drug again.
In 2001, Kast and neuroscientist Eric Altschuler wrote the case up for a scientific journal, alongside another case they’d found of a middle-aged man who had suffered from Crohn’s for 20 years but went into remission when he started taking bupropion. They followed this up with a couple more papers exploring the mechanisms behind how bupropion might work to treat IBD.
It sounded promising, but they didn’t think they could drum up the interest or funds to do clinical trials.
Science is littered with these kinds of stories. Case studies offer intriguing results, there are small studies with mice that seem promising, but then it fizzles out.
To truly vet a treatment, it must undergo multiple phases of randomized, double-blinded clinical trials of hundreds of patients, which can cost millions of dollars. With a drug like bupropion, one that’s already been through trials for one indication, and which might not be particularly profitable any more, there isn’t much incentive for pharmaceutical companies to invest in additional large clinical trials.
For Jenna Wong, a researcher at McGill University in Montreal who studies off-label use of antidepressants, the future doesn’t necessarily lie in dragging old drugs through the regulatory approval process again. Instead, she thinks doctors need to get better at tracking drug indications in the first place.
In many places around the world, a prescription for an antidepressant doesn’t list whether it’s actually used for depression or not. France is one of the few countries to set up a system of evaluating drug indications by requiring drug companies to track off-label use.
There, companies have a three-year window to evaluate unlicensed use of their drugs and attain additional licensing. But setting up a similar system large-scale would be difficult.
It’s not that off-label use is bad, says Wong, it’s just when doctors find these extra uses, they should be able to back that up with plenty of evidence. “When I talk to a lot of physicians, they didn’t know certain uses were not approved,” she explains. Often they also don’t know which uses are based on sufficient evidence. “The off-label uses without evidence, that’s what we’re concerned about.”
Picking your poison
The story of how doctors discover new uses for antidepressants is usually the same, according to Jeffrey Jackson, professor of internal medicine at the Medical College of Wisconsin.
Patients report to their doctors that more than just their depression has improved after taking a drug. This has happened in cases of people with dyspepsia, irritable bowel syndrome, chronic pelvic pain, chronic prostatitis, fibromyalgia, headaches and more.
A few antidepressants do have multiple indications, meaning they are approved for purposes besides mental health.
Duloxetine (Cymbalta) has indications for mental health disorders and also nerve pain such as fibromyalgia, and even osteoarthritis. But the complexities of how patients respond to pain mean that one drug or treatment doesn’t work for everyone. So other antidepressants are also often used off-label to treat pain.
Some people assume antidepressants will have a profound effect on their mood, or will drug them up. Others, who may have suffered from pain for many years, can be defensive if doctors suggest an antidepressant – they don’t want to be told the pain is all in their head. Jackson assures them their personality won’t change: “I will say, ‘Listen, everything in the universe is in your head, pain is perceived in your brain.’”
Indeed, a growing body of evidence suggests that one of the more effective treatments for pain is cognitive behavioural therapy (CBT) – changing the way people think about pain to change the way it feels. Jackson’s argument to persuade patients is that antidepressants can work directly on their physical symptoms, but it will also help the depression that comes with physical misery.
He not expecting to cure disease. “But if I can make [people] more functional and feel better, that’s a win.”
Houston, we have an opportunity
Richard Kast, who studied bupropion for Crohn’s, continues to seek new uses for old drugs. His quest has taken him to research areas well beyond behavioral science – as well as IBD, he’s delved into treatments for brain cancer, often through off-label use of antidepressants.
There is a growing movement to repurpose old drugs, he says, but it’s still not a common practice. “The normal thing is to get a bazillion dollars from some drug company or some funding agency and then explore new molecules.”
Instead, Kast likens his work to the scene in Apollo 13 where engineers try to figure out how to fix the space shuttle by using the ordinary objects found within it.
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Researchers have this box of approved drugs, he explains: “That’s what we have to work with. Now what can we see in the pile of drugs, what is there that we can potentially use to do what we want?”
Just because a drug has been labeled an antidepressant, he adds, that doesn’t mean it can’t help treat other conditions. And they are so often used off-label that the label ‘antidepressant’ may now be a complete misnomer.
“That’s a name we use, but they’re not really ‘antidepressants’,” he says. “They block a certain neurotransmitter pump.” Whatever we call it – a serotonin agent, clog for neurotransmitter pumps, something entirely different – “the drug is doing what it’s supposed to do in the brain.”
He offers an example of how antidepressants might help supplement cancer treatment: the antidepressant mirtazapine can dramatically increase appetite in people with cancer, and prevent the appetite suppression associated with the disease treatment. But like many insights from off-label prescribing, the idea remains intriguing and, for the moment, obscure.
“No one is going to fund research like the kind I do,” says a resigned Kast. “It’s not what people expect. It’s not what you’re supposed to do.”
Copyright 2015 The Wellcome Trust. Some rights reserved.