With NIH BRAINS award, Assistant Professor Cody Wenthur is using a vaccine approach to develop safer and more effective antidepressants from ketamine 

By Arushi Gupta

Major depressive disorder is the most common disorder in the United States, affecting nearly 15 percent of the population. In the world, major depression affects 300 million people.

Cody Wenthur, assistant professor in the University of Wisconsin–Madison School of Pharmacy’s Pharmacy Practice Division, was recently awarded a $2.3 million R01 grant, the oldest and most prestigious funding mechanism of the National Institutes of Health, to lay the groundwork for more effective treatments for the millions of people living with the disorder.

The award is supported by the National Institute of Mental Health’s Biobehavioral Research Awards for Innovative New Scientists (BRAINS) mechanism, which is only awarded to about seven “exceptional and outstanding scientists in the formative years of their career” each year. As part of this award, Wenthur will gain access to a network of mentors from across the country who are world experts in his field to further advance his research, as well as recognition and featured presentations at national research symposia focused on mental health research.

The grant will go through till 2025, which will be five crucial years for the Wenthur Lab, he says.

“This grant is fundamental and central to what we want to accomplish and it represents an investment in our philosophy and our core ideas,” Wenthur says.

One of the major areas of focus for the Wenthur Lab is understanding the interactions between the immune and central nervous systems to develop therapeutics for addiction and psychiatric illnesses, including a vaccine-based approach for treating opioid use disorder.

“This grant is fundamental and central to what we want to accomplish and it represents an investment in our philosophy and our core ideas.”
—Cody Wenthur

With the BRAINS award, Wenthur and his team will be using an incremental vaccination approach method to understand the mechanism of action of ketamine — which is increasingly being explored as a treatment for severe depression — and its metabolites to create a more effective therapeutic.

This breakthrough could alter the lives of millions of people with psychiatric disorders.

Addressing depression

“I’ve always been interested in how small molecules can profoundly alter brain function and human behavior. One of the most interesting areas in this regard is neuroplasticity,” he says.

The study of neuroplasticity, or the ability of the brain to restructure itself, is another main focus in the Wenthur Lab. Wenthur says that the strength of neuronal connections in the brain, which give the body signals and tell it what to do, change over time. These changes manifest in effects on memory and patterns of behavior, potentially including behaviors relevant to symptoms of depression and substance use disorders.

“Ketamine is a neuroplastic molecule that changes behavior over periods of days to weeks,” Wenthur says, even hours after it is no longer present in the body. His search for a therapeutic for depression is based on the idea that the one-time administration of ketamine, or other psychoactive molecules like psilocybin, can result in rapid and long-term changes in the structure of the brain.

“Despite its effectiveness, the dissociative and psychoactive effects caused by ketamine administration have resulted in a need for a strictly limited access and use protocol, which drastically limits the pool of individuals receiving this medication,” says Zhen Zheng, a postdoctoral research associate in the Wenthur Lab.

Dissecting small molecule effects

Although ketamine has proven effective, the mechanism of ketamine as an antidepressant remains controversial.

One theory is that ketamine’s blockade NMDA receptors — a protein that plays an important role in memory function and synaptic plasticity — is the direct mechanism supporting ketamine’s therapeutic effects. Another theory argues that hydroxynorketamine, which is a major metabolite of ketamine, is the actual relevant species and is acting through a pathway alternative to that of ketamine.

This is why Zheng is developing a hapten — a small molecule that triggers the production of antibodies, like a vaccine — against ketamine, and a structurally distinct hapten against hydroxynorketamine.

Wenthur is using the haptens as the key tools in the DISSECTIV approach, which is a method he developed as a way to use selective antibodies to take apart a complex small molecule mixture to see which molecules cause which effects.

In this case, Wenthur will be using the haptens to suppress the effects of ketamine itself and separately suppress the effects of the metabolite hydroxynorketamine.

“If we can take apart this mixture and figure out which molecules are causing the positive effects and which are causing the dissociative psychotic effects, the two could be independently isolated. You could potentially have a much more accessible therapeutic for a broader range of patients,” he says.

Their results are promising so far.

“In animal models, we’ve found that our vaccine can successfully block the effects of ketamine in a dose-dependent manner,” says Zheng. “This indicates we might be able to generate ketamine antibodies which can bind ketamine and block it from entering the central neural system.”

Throughout the experiments, the Wenthur Lab will be building up a database of information about the molecules and what they do in isolation and in combination.

“We have information about what doses of ketamine and hydroxynorketamine independently have antidepressant activity, as well as pharmacokinetic data on when these molecules enter the brain after administration,” he says. “We can answer questions about the onset, the time of metabolism, and how that relates to when molecules are likely to be present on their own versus periods where they will be co-present.”

Capturing neuronal changes

After the haptens are created and proven effective, the Wenthur Lab will be moving on to a second stage of data collection that involves using advanced microscopy techniques to capture images of a full brain structure.

First, he will clarify the brains of animal models and label activated neurons for ketamine, hydroxynorketamine, or both. Using light sheet microscopy, Wenthur and Zheng will be able to trace the intricate circuits that will be activated in the neuronal ensembles.

“We should be able to see a wiring diagram of what’s getting turned on for either one set of receptors, the other set, or both at the same time,” Wenthur says.

“Millions of additional individuals with psychiatric disorders would stand to benefit from ketamine-relevant therapeutics.”
—Zhen Zheng

With the identified neuronal ensembles, the genetically modified animals will be used to tag the neurons that will be activated and then chemically ablate them with a molecule that will seek out and kill the tagged neurons.

He mentions this is useful because he can run them through a behavioral paradigm in the presence of the drug.

For the first pass, they will do what they normally do, and the neurons will be labelled. For the second pass, however, he will examine whether the drug has lost its ability to affect change after the activated neurons have been killed.

This step is crucial, and should there be a behavioral change, the results would be groundbreaking: the activation of the neurons from each independent drug (or a mixture) can be causally related to behavioral change, paving the way for an improved therapeutic.

“By understanding the mechanism of action for ketamine, we might be able to give out new psychiatric therapeutics that mimic ketamine’s beneficial properties while avoiding its substantial adverse risks,” says Zheng. “In this way, millions of additional individuals with psychiatric disorders would stand to benefit from ketamine-relevant therapeutics.”