A new study led by scientists at Yale University has described the promising early-stage results of a new drug designed to mimic the rapid antidepressant effects of ketamine, but without that drug's dissociative psychoactive qualities. The experimental drug is currently in early phases of human testing.

While a great deal of attention has recently been circling the extraordinarily speedy antidepressant qualities of ketamine, the drug is not an ideal candidate to become a widely administered medicine. Ketamine, originally developed in the 1950s as an anesthetic, is a powerful psychoactive drug that, when administered in effective doses results in a strong acute psychedelic experience, that for some, can be confronting and disturbing.

So, while it may be an effective antidepressant, it needs to be administered in controlled environments with medical oversight. Even the recently approved ketamine-inspired nasal spray was only allowed by the FDA in clinical scenarios. In its complete form, ketamine could never be a take-home antidepressant pill.

Scientists have been working in recent years to home in on exactly how ketamine works on the brain to exert its antidepressant effects, and possibly find new molecules that can mimc the beneficial qualities of the drug without the negative side effects. A newly developed experimental drug called NV-5138 is one of the more promising new antidepressant agents to come out of this recent work.

"Recent research has raised the possibility that a new drug, such as NV-5138, could be developed that is rapid-acting but also more efficacious and safer than current formulations of ketamine," says Ron Duman, senior author on the new study.

One of the actions of ketamine that is suspected to be key to its ability to rapidly exert an antidepressant effect is the way it activates a metabolic pathway in the brain dubbed mTORC1. Subjects with major depression notably display reduced mTORC1 activity, and researchers have been working to find a way to spur signaling along that brain pathway.

NV-5138 has been developed to very specifically activate mTORC1 pathways while avoiding the broader neural stimulation associated with ketamine's negative side effects. The latest published study describes the experimental drug's effects on several mouse models, showing rapid antidepressant behavioral responses alongside speedy penetration of the blood-brain barrier.

As well as displaying behavioral improvements, the new study revealed the drug increased synaptic activity and growth of dendritic spines in regions of the brain associated with mood. These actions resemble results from recent studies into how ketamine could be generating its antidepressant effects, and why these effects seemingly last for weeks or even months past single doses.

NV-5138 is currently in the midst of its first human phase of testing. Navitor Pharmaceuticals, the company developing the drug, suggests the first wave of human results should be expected later in 2019, offering an indication as to how safe and effective this new antidepressant will be in people.

The new study was published in The Journal of Clinical Investigation.

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