When Armin Szegedi was working as a psychiatrist in Berlin, he felt as if he were running a lengthy experiment on his depressed patients.
After prescribing them an antidepressant, he'd wait up to a month to hear if the drugs were working, Szegedi, who's now a vice president of clinical development at Allergan, told Business Insider. Then he'd prepare for bad news, since only about one out of every three of his patients responded to the medications.
The rest of them clearly needed something else â but he had nothing to give.
"The frustrating thing is that all the approved antidepressants are remarkably similar," Szegedi said. "But you never know which patient will be treated best by which drug."
For the first time in decades, Szegedi thinks a better option is within reach: a drug inspired by ketamine.
A widely used anesthetic that is also known as a party drug, ketamine is now emerging as a rapid-fire antidepressant. Early studies suggest that it could help people who've failed to respond to existing medications and those who are suicidal.
Cristina Cusin, a psychiatrist at Massachusetts General Hospital and an assistant professor at Harvard University, is one of the leading researchers studying ketamine. Although Cusin said the drug needs more research, she told Business Insider that it "absolutely has potential."
Pharmaceutical companies including Allergan and Johnson & Johnson are in hot pursuit of a new blockbuster depression drug that takes after ketamine, which 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 is better, arrives faster, and works in far more people than existing drugs.
Ketamine may reveal what depression really does to the brain
Unsplash / jesse orricoDepression is one of the world's leading causes of death. Our current treatments, which take roughly five weeks to begin to take effect, may not work well in up to 80% of the people who get them.
Most existing antidepressants, from Abilify to Zoloft, work by plugging up the places where our brain takes up serotonin, a chemical messenger that plays a key role in mood. The result is more free-floating serotonin and, in some people, relief from a dark curtain of depressive symptoms.
The new drugs being developed by Allergan and Johnson & Johnson, as well as one from San Francisco-based drug company VistaGen, capitalize on a different mechanism in the brain â the system that's engaged by ketamine.
"When we say this is a new generation of drugs, we mean it. This drug is fundamentally different from all the other antidepressants that have been approved so far," Shawn Singh, VistaGen's CEO, told Business Insider.
Ketamine affects key switches in the brain called NMDA receptors. Like serotonin receptors, those for NMDA play an important role in our mood and help keep our emotions in check. But NMDA receptors also keep our brain's synapses â the delicate branches that serve as the ecosystem for our thoughts â flexible and resilient.
Potentially because of depression's damaging effects on these brain switches, it appears to cause our synaptic branches to shrivel up and in some cases even to die. Scientists think existing antidepressants send help to those branches indirectly over time by way of serotonin. Ketamine, by contrast, delivers its aid directly to the source, plugging up NMDA receptors like a cork in a bottle and nipping depressive symptoms within hours.
A 2012 study published in the journal Science analyzed ketamine's rapid ability to reduce depressive symptoms in people who'd failed to respond to other drugs. The authors called ketamine "the most important discovery in half a century." Five years later, researchers concluded in a study in the American Journal of Psychiatry that the drug's antidepressant effects appeared to last at least a month.
Turning a 'party drug' into a blockbuster medication
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Today, roughly 50 to 100 clinics across the US offer ketamine off-label for depression. It's administered through an IV drip, a roughly 45-minute process that has to be done in a clinical setting.
Because ketamine is not FDA-approved to treat depression, most patients pay for it out of pocket. It isn't cheap, typically costing between $400 to $1,000 per infusion. (Some clinics recommend patients do up to 10 sessions for the best results.)
Another issue with ketamine in its current form is that it's a dissociative drug, so can induce powerful feelings of confusion, dizzy spells, and the sensation of being separated from one's own body.
Experts like Cusin worry those effects could lead patients to either react negatively to the experience and not want to repeat it, or react positively and want to repeatedly use, potentially leading to a drug-use disorder.
Those concerns may be relevant to Johnson & Johnson's work, since the company's formulation of the depression drug is a nasal spray with a chemical mirror image of ketamine.
The drugs being developed by Allergan and VistaGen, on the other hand, are inspired by ketamine but appear to produce fewer negative side effects. That's thanks to a slightly more sophisticated way of working on the brain's NMDA receptor.
Instead of plugging the receptor up like a cork in a bottle as ketamine does, Allergan's and VistaGen's drugs merely restrict its flow of activity.
Allergan is currently testing a shot formulation of its drug, Rapastinel, which would take 10 to 30 seconds to administer. VistaGen is pursuing an oral tablet version of its drug, currently known only as AV-101.
"We're essentially going for a kinder and gentler version of ketamine without the requirement for an IV and without the nasty side effects," Singh said of VistaGen's approach.
The path ahead for ketamine-inspired depression drugs
All of the new drugs being developed have shown promise for rapidly decreasing the symptoms of depression in patients enrolled in clinical trials.
The most promising results have come from Allergan's Rapastinel and VistaGen's AV-101.
"We now have these larger studies that confirm what we hoped â that we have a rapid antidepressant with good safety and little or no abuse potential," Szegedi said.
The US Food and Drug Administration appears to agree: Rapastinel has twice been granted Breakthrough Therapy designation, a distinction designed to expedite vital new drugs through the development process. AV-101 was recently placed on the agency's Fast Track list of new treatments for serious conditions that have an unmet medical need.
Johnson & Johnson researchers are expected to present the results of the next stage of their research to the American Psychiatric Association in May but have not yet presented their findings to the FDA.
"To offer people who are depressed a treatment that could potentially help them within hours, is well tolerated, and has hopefully no significant abuse liability â that sounds to me like what I always wanted when I was treating my patients," Szegedi said.
