Is ketamine’s contentious therapeutic potential worth the risk?

However, as noted in the first part​ of this two-part piece, a study by Stanford University found that it may achieve this by activating opioid mechanisms in the brain, which has made moving forward with clinical trials all the more complex. One of the drugs in on-going clinical trials is AV-101.

Not quite the same: AV-101​

AV-101 is a drug that does not have any form of ketamine or esketamine within it but works mechanistically the same. Developed by VistaGen, it is currently in three clinical trials. Two Phase II studies in patients with major depressive disorder who have had inadequate response to prior treatments, and one Phase Ib trial is testing the engagement of AV-101 on NMDA receptor functioning related to suicidality.

Unlike IV-ketamine or INDD esketamine, AV-101 is orally-administered and does not have to be used in a clinical setting. According to Shawn Singh, CEO of VistaGen, “It’s different in that it’s orally available, which is really critical for something to have success on a long term basis. It needs to be, especially in this area [psychiatrics] something suitable for at home use – not requiring people to go into a clinic.”​

According to Singh, AV-101 is not metabolized by the liver the way most orally administered drugs are. “AV-101 is metabolized in the kidney, so it gets up to the blood-brain barrier and once it’s across, it becomes something else.” ​

Both esketamine and AV-101 are delivered to the brain quickly and work on receptors at a faster rate without having to be built up in the bloodstream over weeks, such as in the action of selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors.

A key difference between esketamine and AV-101 is the way in which they reach the brain. AV-101 is metabolized through the kidney and esketamine bypasses the first pass metabolism.

AV-101 also works on the N-methyl-D-aspartate (NDMA) receptor differently. According to Singh, “Ketamine goes to the NDMA receptor and there’s a channel, the ion channel, which is totally blocked by ketamine, like a cork in a bottle, and as a result of that ketamine blockade, you get the psychological side effects that are often problematic for patients.” ​

He continued, “AV-101 doesn’t block that channel, instead it locks onto an outside corner of the receptor and modulates or downregulates the activity of that receptor to generate the anti-depressant effects without those psychological side effects – those don’t happen because we’re not blocking the channel like Ketamine does.”​

VistaGen created the ketamine-like drug because, according to Singh, it’s unclear if ketamine can be used on a long-term basis due to concerns regarding safety or convenience.

Singh said that the effects of ketamine wear off eventually and when those effects wear off the possibility of suicidal ideation or severe depression symptoms can return. “Maybe AV-101 takes a better role following ketamine. I think that IV Ketamine would work best right out of the gate but you have to maintain that benefit in a safe way, in a fragile patient population,”​ said Singh.

Stanford and the opioid system ​

As we mentioned in part one researchers at Stanford published a study​ in the American Journal of Psychiatry that stated ketamine worked on the opioid system of the brain.

Alan Schatzberg, one of the researchers on the study told us, “Basically, ketamine does block NMDA receptors and that’s been concluded. The problem with that mechanism of action is that other receptors than just NMDA antagonists are affected. And that has always kind of troubled me, and ketamine itself has always been known to have some weak opioid properties and we’ve argued that one ought to have be very careful that ketamine is not acting through the opioid mechanism.”​

“I think the data pretty clearly indicates, from my perspective, that it is acting not so much through the NMDA receptors to give anti-depressant effects but, in fact, [it is acting] like an opioid and opioids are well-known to improve mood,”​ he concluded.

The research conducted at Stanford was a randomized double-blind crossover trial conducted with participants living with treatment-resistant depression. The study dosed participants with naltrexone, an opioid blocker, or a placebo prior to ketamine treatment. Twelve participants completed both conditions in randomized order.

The research showed that through the administration of an opioid inhibitor in combination use with ketamine, ketamine did not present the anti-depressant effects it usually does.

However, some researchers outside of Stanford made the comment that naltrexone acts on mood negating the study’s findings.

Nolan Williams, another researcher at Stanford, replied to this argument by telling us, “There is no acute mood detrition with naltrexone. In 200 controlled studies, in patients with depression chronically given naltrexone produced an anti-depressive effect, it’s a weak one but it’s statistically significant at the six-week stage in people with opiate dependence and alcohol dependence.”​

Greg Pacino of Janssen, where the esketamine study is being conducted, told us in response to the Stanford study, “Based on published scientific findings with ketamine and esketamine, as well as on our internal esketamine data, at antidepressant doses neither ketamine nor esketamine would sufficiently occupy opiate receptors to exert a clear functional effect on these receptors.”​

Pacino also said that esketamine is thought to help restore the connection between brain cells through the study of glutamate receptor modulation.

Are atypical drugs a real possibility in the future of mental illness drug development? Clinical trials are ongoing, as are drug formulation and delivery studies, but what seems to be steadfast is the possibility of finding a solution for those suffering from severe mental illness.