Despite the dozens of prescription drugs on the market for treating depression, up to half of depressed people can’t find relief.
That’s an enormous market opportunity: millions of people who need daily treatment for a chronic condition. But after years of expensive failures trying to develop new antidepressants from scratch, many companies have largely lost interest.
“A lot of big pharma companies have exited the area,” Robert Alexander, clinical head of the neuroscience and pain research unit at Pfizer, told BuzzFeed News. Pfizer is still in depression research, but it has shifted to looking at specific symptoms, rather than the whole disorder.
“It’s too difficult, too failure-prone," Alexander said. "The failure tends to occur late in development, so that means a lot of money has already been spent before you realize the drug doesn’t have potential.”
Which explains why, over the past few years, many of the experimental antidepressants have been so...weird. Small and medium-sized companies are trying out an unexpected bunch of old drugs: the abortion pill, the active ingredient in Robitussin, an anesthetic, and even Botox.
“It’s kind of led to a garage industry approach to these common disorders,” Peter Kramer, a professor of psychiatry and human behavior at Brown University, told BuzzFeed News. "You have lots of little areas of interest that are legitimate clinical areas of inquiry, and everybody gets a shot.”
Several market forces have pushed big pharma out of the game. Developing a drug from scratch costs as much as $2 billion. There’s a lot of competition from drugs already on the market, many in generic form, and the placebo effect makes it tricky to prove that a new antidepressant actually works.
“For most manufacturers to spend that kind of money to enter a crowded marketplace, where there are many inexpensive, generically available drugs, it’s just not worth the expense,” Kenneth Kaitin, professor and director of the Tufts Center for the Study of Drug Development, told BuzzFeed News.
It makes a lot more sense for pharma companies to look at drugs they already know do something useful (and that the FDA has already approved as safe), to see if they could have a second life. A new use for an old drug just might nab a company the exclusive right to market their drug for depression, or even an extension on a patent that’s about to run out.
“The idea of repurposing old drugs for new indications, that’s not an uncommon biotech strategy,” Alexander, of Pfizer, said. It doesn’t require a lot of investment, he said, “if you have a good idea.”
The most famous example of this rummage sale approach is ketamine, an anesthetic often used for surgery and as a sedative. A number of studies have found that it rapidly relieves many patients of their depression, especially the desire to commit suicide. Many doctors already prescribe the drug “off-label” to people with depression.
But pharmaceutical companies can’t patent ketamine, limiting their incentive to put it through the clinical trials required for FDA approval. Instead, they’ve been looking for chemical cousins that might affect the same biological systems while still leaving them room for a profit.
Enter dextromethorphan, a popular over-the-counter cough suppressant used in Robitussin and NyQuil. Like ketamine and some street drugs like PCP, dextromethorphan blocks a protein in the brain called the NMDA receptor. Teens have known for decades that high doses of “DXM” can get you high, causing distorted perceptions and even hallucinations (as shown by the popularity of “Robo-tripping” posts on drug message boards).
Avanir, a pharma company based in Aliso Viejo, California, combined the cough suppressant with quinidine, a drug that slows the body’s breakdown of dextromethorphan so it sticks around in the blood longer. The resulting prescription drug, Nuedexta, was approved by the FDA in 2010 for the uncontrollable laughing and crying that sometimes accompanies a brain injury or disease.
But there are way more people with depression than there are people who laugh or cry uncontrollably — and Avanir has its eye on the market. The drug is currently in the middle stage of drug trials, “phase 2,” for treating depression.
Buprenorphine, a long-acting opioid that doesn’t lead to a big high, has been prescribed to heroin addicts for years to help wean them off the drug. Addicts often reported an improved mood when on buprenorphine, leading to small clinical trials in the 1990s showing that it could effectively improve symptoms in some people with depression who didn’t respond to other drugs.
In the last few years, the Irish company Alkermes has combined a low dose of buprenorphine with another chemical that further reduces the potential for euphoria (and overdose). Unfortunately, when tested on people with depression, the drug failed to beat a placebo, leading to a 36% drop in the company’s stock price. Alkermes has one last trial planned for the drug.
Another disappointment came from mifepristone, better known as the “abortion pill.” It terminates pregnancy by blocking the hormone progesterone. But researchers noticed that at high doses, mifepristone also blocks the stress hormone cortisol, which likely plays a role in depression. In the mid-2000s, Corcept, based in Menlo Park, California, tested the drug on people with depression, but those trials failed. The company tried another round of testing, but stopped that in 2014 after lackluster early results.
One of the most promising new treatments is also, perhaps, the strangest. Botox first entered the depression arena when physician Eric Finzi, now an assistant professor of psychiatry at George Washington University, began researching the connection between facial expressions and emotions.
The idea that smiling can make you happy and frowning can make you sad has been around for decades; many behavioral therapists recommend their anxious and depressed patients try “half-smiling” for a few minutes to boost mood.
So Finzi, then a dermatological surgeon, got the money together to test the theory that paralyzing the muscles between the brow, which wrinkle when a person frowns, would help treat depression. The team injected some patients with saline and others with Botox, a neurotoxin that, when injected, causes localized paralysis of muscles.
A recent analysis combining that trial with several others found that people with depression who got the toxin were eight times more likely to feel better than those who were injected with saline alone, and nearly five times more likely to have their depression disappear completely. Based on Finzi’s results, Botox’s maker, the Irish company Allergan, is conducting its own trials, hoping for FDA approval.
Given what scientists know — and don’t know — about what biological pathways cause depression, it makes sense that companies would try so many different angles to treat the disorder. Finzi, for instance, told BuzzFeed News that researchers may very well discover that depression is several different illnesses with overlapping symptoms.
“Any way we can possibly get information to the brain to tell it, ‘Hey, you should feel happier,’ is a potential way to treat it,” Finzi said.