Why It’s So Hard to Develop a New Drug for Depression

Depression is still mystifying to researchers

InIn a March 2019 study, researchers at Johns Hopkins Medicine reported that they had identified and tested a new compound for depression that may work differently from all other depression drugs on the market.

As part of the study, researchers put mice in a cage with a bigger and more aggressive mouse for 10 minutes a day. The smaller mice were bullied and started to isolate themselves by hanging out in an empty corner of their cage. These “depressed” mice were then given daily doses of a new compound called JHU-083, which succeeded in bringing back the rodents’ sociable personas.

The study, published in the journal Neuropsychopharmacology, suggests that the drug may lower signs of depression in mice by targeting immune cells and tamping down on inflammation in the brain that may be interfering with important brain connections. The results are compelling, but very early. And as history suggests, developing a truly new drug for mental illness is no easy task, as the brain is one of the most mystery-laden areas of medicine.

WWhile drug development is a complex and lengthy process by default, the discovery of new medications for depression is especially fraught. The brain is a highly complicated organ and scientists still don’t fully understand the various causes of depression and how to treat them.

But the stakes are high: Over 17 million Americans have diagnosed depression and about a third of people with depression do not respond well to currently available antidepressants. Until recently, there were very few alternatives. Earlier this year two new antidepressants were approved: a ketamine-based nasal spray for treatment-resistant depression, and a drug for women with postpartum depression. Before that, the last major breakthrough in depression treatment was the release of Prozac over 30 years ago.

While the small study from Johns Hopkins suggested their new compound might work for depression, the researchers are currently tasked with attempting to understand how it works. “There are aspects of it we still don’t understand,” says Atsushi Kamiya, associate professor of psychiatry at Johns Hopkins and one of the authors of the study. For example, does the compound work similarly in humans? Will it have side effects?

“There are 20 to 30 things that antidepressants are known to do. There is some debate about which of those are most relevant to the treatment of depression.”

These are not simple questions. Clinical studies show that antidepressants are effective for many if not most people with depression, but it is not completely clear how they work. Most of the classic antidepressants, including Prozac and Zoloft, target a group of neurotransmitters — chemicals that work as messengers between neurons — called the monoamines. A simple hypothesis is that antidepressants increase these neurotransmitters (namely the chemicals serotonin and norepinephrine) in a person’s brain, improving mood.

But the fact that these drugs impact neurotransmitters does not mean that is definitely how they work for depression. One of the central mysteries about antidepressants is why it takes weeks or even months for a person’s symptoms to improve, even though the drugs impact their neurotransmitter levels within hours of taking them. “There are 20 to 30 things that antidepressants are known to do,” says Steven Dubovsky, professor and chair of the department of psychiatry at the University at Buffalo, SUNY. “There is some debate about which of those are most relevant to the treatment of depression.”

The unanswered questions are not just about how antidepressants work, but also about what exactly goes on inside a depressed brain. Most of the theories to explain what depression is have emerged from watching what changes happen to the brain when someone takes antidepressants or drugs like ketamine. But even then, there’s so much to observe, and it’s hard for scientists to know what changes are most important. To complicate things further, these tweaks can be different from person to person.

“There are multiple changes, including in the way neurons in the brain work and how those neurons interact with each other in networks,” says Dubovsky. “You can’t explain something as complex as depression by a change in just one chemical in the brain.”

Another challenge for antidepressant development is finding good animal models to test drug compounds. For the JHU-083 study at Johns Hopkins, for example, researchers bullied laboratory mice into acting less social and motivated. These behaviors are often present in depressed humans, says Kamiya, but do not occur exclusively in people with depression.

“In general, we cannot categorically mimic psychiatric symptoms in mice,” Kamiya says, though they are one of the best animal models available. “We have no way to characterize or detect depression in animals. Any type of higher brain function is impossible to be measured in animal models.”

If scientists are able to get an experimental drug through animal trials and tested in humans, new challenges await. Since virtually all studies of new antidepressants are sponsored by pharmaceutical companies, it is of the companies’ interest to choose people that are more likely to respond, says Dubovsky, which means the list of exclusion criteria is long. “They can’t be chronically depressed, can’t have any other psychiatric problem, can’t use any substances,” he says. Not only those people are hard to find, but they don’t always represent the real-life patients, he says. It’s not often clear just how well a given drug will work for a group of people until it’s on the market.

Another issue with clinical trials is that it is hard to prove that the experimental drugs perform better than placebo, simply because those studies are known to have a large placebo response. Research at Harvard Medical School has found that depressed people given dummy pills improved almost as much as people getting real drugs. A possible explanation is that a sense of hopelessness is one of the main characteristics of depression. As the researchers put it, it’s possible that the mere promise of an effective treatment helps to alleviate depression.

BBut promise only goes so far, and amid these challenges, research groups throughout the U.S. continue to push forward. The approval of two new depression drugs in 2019 offered motivation.

In the early 2000s, scientists at Yale University identified the antidepressant potential of ketamine, an old anesthetic also used as a party drug called “Special K.” The most impressive attribute of ketamine is how fast it acts, being able to revert symptoms of depression in a matter of hours. (One person quoted in the Guardian described its effect like a spring breeze that had blown through her head and cleaned out all the detritus accumulated over the years.)

But ketamine can also lead to inconvenient side effects such as bad hallucinations, nausea, high blood pressure, and it has an addictive potential, which is why it is used only experimentally to treat depression. Meanwhile, it has inspired the development of numerous new compounds, including the recently approved nasal spray drug, the work by the Johns Hopkins team, and more.

The Johns Hopkins scientists are continuing to experiment with JHU-083 in mice to better understand how the compound might work. Kamiya’s laboratory is also extending its research to other potential targets that, like JHU-083, also affect inflammation in the brain, in an effort to discover even more drug candidates to treat depression.

Whether these early studies result in new drugs for depression remains to be seen. But for the millions of Americans with depression, the progress is a long time coming.

Science and health journalist with a special interest in evidence-based medicine and epidemics. Columbia Journalism School alumna. mari.lenharo@gmail.com.

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