Pharma companies are exploring a crop of new depression treatments, and one of them could become the first new blockbuster drug in 30 years (AGN)

Depression is the leading cause of disability worldwide, and it can kill. While not the sole cause of suicide, depression is often a contributing factor. And while suicide rates have climbed for nearly 20 years, not a single new drug for depression has emerged.

Imagine coming to the emergency room “with pain so bad that you can’t think,” said Cristina Cusin, a psychiatrist at Massachusetts General Hospital and an assistant professor at Harvard University, and having the doctors give you a drug that takes five weeks to work and has a 40% to 50% chance of not working at all.

For a person who’s suicidal that’s “currently the best we can do,” Cusin told Business Insider.

Most treatments for depression and suicidal thinking are limited to a narrow class of drugs known as selective serotonin reuptake inhibitors, or SSRIs, which includes popular drugs like Prozac and Lexapro. While they can help some people, failure rates hover around 50%.

So researchers are on the hunt for better options.

While some scientists pursue drugs inspired by ketamine, others are looking hopefully at psychedelics like psilocybin (the active ingredient in “magic mushrooms”). Still others are studying opioid-like drugs and metabolites of key hormones involved in mood regulation like progesterone.

Ketamine is inspiring novel drugs for some of the hardest-to-treat forms of depression and suicidal thinking

A widely used anesthetic that’s also known as a party drug, ketamine, was shown to have benefits as a rapid-fire antidepressant nearly a decade ago. Early studies suggested ketamine could help people who failed to respond to existing medications or were suicidal.

The authors of one paper called ketamine “the most important discovery in half a century.”

As opposed to existing antidepressants, ketamine acts on a brain mechanism that scientists have only recently begun to explore. Homing in on this channel appears to provide relief from depression that’s better, arrives faster, and works in far more people than current drugs.

After a lack of new drugs for depression spurred scientists to go back to the drawing board, pharmaceutical companies like Allergan and Johnson & Johnson are now in hot pursuit of several new blockbuster depression drugs that take after ketamine.

Allergan’s injectable drug, rapastinel, is in the last phase of clinical trials and has received a key FDA designation designed to speed it through the approval process. The company is also working on an oral-tablet version of rapastinel, but that drug is in an earlier phase of research. Johnson & Johnson presented promising research on its nasal spray drug, esketamine, in May and told Business Insider that it expected to file for FDA approval this year. A third company, VistaGen, is studying a drug that’s similar in function to Allergan’s but in pill formulation. It expects to see results from an earlier phase of research next year.

Applying the brakes on the brain could help treat conditions like postpartum depression

Sage Therapeutics’s treatment, brexanolone, acts on GABA, one of the neurotransmitters in the brain. The idea is that by modulating GABA, it may help to treat depression by applying a brake to slow down parts of the brain that could be getting overexcited. To start, Sage is in front of the FDA for approval to treat postpartum depression.

In two late-stage, phase-three clinical trials of more than 200 women, researchers found that women who received the injected therapy had a decrease in depressive symptoms over a 30-day compared to the women who were on the placebo control. The FDA is expected to review the drug by December.

Beyond that, Sage said on Tuesday that it was launching a phase-three trial evaluating the drug in the treatment of major depressive disorder that it would then bring to the FDA for approval as well.

Existing drugs “don’t do fantastic jobs of treating people who suffer,” Al Robichaud, the chief scientific officer of Sage Therapeutics, told Business Insider. “We believe we have the opportunity to it better.”

The way opioids work in the brain could lead to new treatments for depression

At the same time the opioid crisis has been raging in the US, researchers have been looking into whether aspects of the medications could be useful in treating depression. That’s the case with a compound from Alkermes, known as ALKS 5461. The drug is being developed to treat major depressive disorder by modulating the opioid system in the brain by combining buprenorphine — a drug often used to treat pain as well as opioid addiction — and samidorphan.

Unlike a traditional opioid, however, the drug doesn’t produce a feeling of euphoria when taken, Alkermes CEO Richard Pops said. “If you’re addicted to opioids and you take 5461, you’ll go into withdrawal because it’s functionally different,” he said.

The drug is in front of the FDA for review, with a decision expected by January.

A compound in hallucinogenic mushrooms shows promise for depression that develops later in life

Last year, researchers studying psilocybin, the main psychoactive ingredient in hallucinogenic mushrooms, likened its quick effects on cancer patients with anxiety and depression to a “surgical intervention” for the mental illness.

Brain-scan studies suggest that depression ramps up the activity in brain circuits linked with negative emotions and weakens the activity in circuits linked with positive ones. Psilocybin appears to restore balance to that system.

With that in mind, a company called Compass Pathways, which is backed by influential entrepreneur Peter Thiel, has plans to start its own clinical trials of mushrooms for depression later this year.

That said, no one has yet presented clinical-trial data for a drug formula using psilocybin to the FDA; the compound is still a Schedule 1 substance with “no recognized medical use,” according to the Drug Enforcement Administration — a designation that continues to make it difficult to study. That means an FDA-approved psilocybin drug is years away, at best.

But some researchers still have high hopes that a psilocybin-inspired drug will be approved within a decade. David Nutt, director of the neuropsychopharmacology unit at Imperial College London, told Business Insider last year that he believed psilocybin would become an “accepted treatment” for depression before 2027.

If you or someone you know is struggling with depression or has had thoughts of harming themselves or taking their own life, get help. The National Suicide Prevention Lifeline (1-800-273-8255) provides free, 24/7, confidential support for people in distress, as well as best practices for professionals and resources to aid in prevention and crisis situations.