On the frontiers of psychiatry

Physician-scientists aim to reduce the impact of mental illness on society

By Jim Dryden

Matt Miller
The Taylor Family Institute, a collection of several member research laboratories, is studying the potential therapeutic value of natural and synthetic neurosteroids, which act on brain receptors to affect cognitive and emotional functions.

Up to one-third of the 16 million Americans with clinical depression don’t get relief from antidepressant drugs. As a result, they endure continuing sadness, problems with sleep, and often, difficulty concentrating, so that reading a book or functioning at work is problematic. Some even contemplate and attempt suicide. And the impact extends to family and friends.

For doctors treating patients with depression and other psychiatric disorders, the reality is that many of the therapeutic drugs at their disposal have major limitations — both in terms of effectiveness and potential adverse side effects. Not only that, but the last new class of antidepressant drugs, selective serotonin reuptake inhibitors (SSRIs) such as Paxil, Zoloft, Lexapro and Prozac, hit the market 30 years ago.

At Washington University’s Taylor Family Institute for Innovative Psychiatric Research, investigators are looking for new solutions. Their ultimate goal: Reduce suffering and diminish the impact of psychiatric illnesses on society.

Institute investigators are exploring receptors in the brain to identify new targets for therapy, developing potential drug candidates, and partnering with industry to speed progress. The institute is on the verge of helping get two investigational antidepressant drugs to the market, and there could be other promising compounds in the pipeline, too.

Private funding = fast progress

The institute was created in 2012 through private funding from the university’s Leading Together campaign. Its founding mission: to provide flexible funding to foster and streamline efforts in basic research, clinical research and drug development as scientists work across disciplines to uncover new ways to treat psychiatric illness. Members of the institute collaborate among several departments, including psychiatry, anesthesiology, developmental biology, radiology and neurology.

Matt Miller
Steven J. Mennerick, PhD, prepares to use a collection of technology — including a microscope and amplifiers — to measure the tiny electrical impulses between brain cells. The equipment helps him assess how the electrical conversations of neurons are influenced by therapeutic drugs.

“The institute really was founded on the premise that we need flexible funding to support pipelines of research development, rather than focusing on individual projects in specific departments,” said Steven J. Mennerick, PhD, a professor of psychiatry and of neuroscience and the institute’s scientific director. “Government grants tend to be very specific, so to take a project to the next step, you need another grant, and then another. But with flexible funding through the institute, we can partner — quickly — with people who have expertise in other areas of science or drug development, and we can make progress faster than is possible with traditional grants.”

Their work starts with understanding the genetics and biology of psychiatric illness, as well as the brain circuits involved. Then, when basic science reveals a potential new therapeutic approach, institute investigators can get their findings into the hands of collaborators in private industry very quickly, especially through the institute’s close relationship with Massachusetts-based biopharmaceutical company Sage Therapeutics.

“I have received notes from people around the country who have been impacted by mental illness. They now have a sense of hope; someone is paying attention. I want many people to pay attention, because I think awareness promotes momentum.”

— Andrew C. Taylor, Life Trustee; Chair, Leading Together campaign
Andrew C. and Barbara Taylor, and the family’s Crawford Taylor Foundation, made major commitments to establish and enhance the Taylor Family Institute for Innovative Psychiatric Research.

A new treatment target

Much of the focus at the institute today is directed toward a class of compounds called neurosteroids — chemicals that occur naturally in the brain and are involved in brain networks used for cognition, emotion and motivation. Disruptions in neurosteroid levels can contribute to mood disorders such as depression, anxiety disorders, schizophrenia, alcoholism, sleep disorders, chronic pain, epilepsy and neurodegenerative illnesses such as Alzheimer’s disease.

Current evidence suggests that stress and disorders such as depression affect neurosteroid production in the brain, so institute scientists believe that replacing or enhancing these depleted steroids may alleviate that stress response to make the brain function more normally.

Although the institute only has been around for a handful of years, some of its members have been studying natural and synthetic neurosteroids for several decades. That work began in 1993, when Douglas F. Covey, PhD, then a professor of molecular biology and pharmacology, and Charles F. Zorumski, MD, then an associate professor of psychiatry, were part of a Program Project Grant from the National Institutes of Health (NIH) to study neurosteroids for their anesthetic effects. Their process: Covey’s lab synthesized neurosteroid molecules, and Zorumski tested them in brain cells.

Advances in treating mental illnessTaylor Family Institute investigators are setting their sights on a new set of therapeutic targets in the brain. Their goal: Develop drugs that engage these new targets and better address depression and other mental illnesses.
THEN – Target serotonin receptors

Administer selective serotonin reuptake inhibitors (SSRIs) and tricyclic drugs, which increase brain levels of serotonin and promote feelings of well-being.


PROS
– Existing SSRIs and tricyclics are effective for many people.


CONS
– Drugs can have undesirable side effects. Up to one-third of patients are not helped by these drugs.

NOW – Target GABA and glutamate receptors

Generate and test compounds that augment the action of gamma-aminobutyric acid (GABA), which calms key brain cells, and glutamate, which excites key brain cells. Seek ways to balance their activities to achieve well-being.

 

PROS – The prevalence of, and variations in, GABA and glutamate receptors may facilitate targeting specific receptor classes for more effective therapies.


CONS
– The landscape is complex and not thoroughly understood. Defining a “normal” balance may be difficult.

“In those early days, we mostly were trying to learn about whether these molecules had anesthetic effects, and if so, how they might work,” said Covey, a professor of developmental biology, of anesthesiology and of psychiatry. They discovered that neurosteroids weren’t working through serotonin receptors the way SSRIs did. Instead, many were influencing gamma-aminobutyric acid (GABA) receptors, the same neuronal receptors affected by anesthetics.

Fast-forward about 20 years. By the spring of 2012, Covey had made hundreds of synthetic neurosteroids, some of which seemed to have the potential to alleviate symptoms of depression. And Zorumski, now the Samuel B. Guze Professor, head of the Department of Psychiatry and professor of neuroscience, believed that after years of making and testing neurosteroids, they had a good handle on how the molecules interacted with two types of receptors in the brain: GABA receptors and excitatory glutamate receptors. They could, he thought, be on the verge of identifying neurosteroids to alleviate depression and other psychiatric disorders.

“Some of these neuroactive steroids were potent anesthetics, but we believed others were going to prove to be useful for treating several psychiatric disorders,” Covey said.

But at just about that time, a letter arrived from NIH announcing that the program project group was about to lose its funding.

Within a day or two of receiving the bad news, Zorumski started drafting a new white paper, attempting to explain the importance and potential impact of the project he’d been involved in for two decades.

“It was written around the time that Doug Covey and I were just starting to interact with Sage Therapeutics, and it was built around the idea that we could take neurosteroids — as well as the synthetic molecules that had been developed here at Washington University — and turn them into therapies,” he said. “We weren’t entirely sure what these molecules actually would treat, but epilepsy was a clear target, so was insomnia, and so was postpartum depression.”

The proposals in the white paper eventually received funding, and the Taylor Family Institute for Innovative Psychiatric Research was born.

Matt Miller
Douglas F. Covey, PhD, left, Charles F. Zorumski, MD, and colleagues have spent decades conducting groundbreaking research on the therapeutic potential of neurosteroids.

On the verge

The results are impressive.

“We’re literally only about six years from when the institute was created, and there already could be new drugs coming to market just several months from now,” said Zorumski, now the director of the institute.

Sage is seeking Food and Drug Administration approval of two neurosteroids that it developed based on Washington University research: an IV drug called brexanalone to treat postpartum depression, and an oral drug known as Sage 217 for clinical depression in men and women.

During the Taylor Institute’s first half decade of existence, its scientists have published more than 60 scientific papers. They have continued to prepare new compounds to enlarge the original set of over 700 compounds, and multiple U.S. and foreign patents are pending. In collaboration, investigators at Taylor Institute and Sage are discovering and applying ways to optimize these neurosteroids for therapeutic use in humans.

Covey, who has patented many of the molecules developed in his lab, served for a time as a partner at Sage, and Zorumski serves on the company’s scientific advisory board. As a result, much care has been taken to avoid conflicts of interest, so a good deal of the clinical testing of neurosteroid molecules has occurred at other centers.

But other clinical research is underway at the institute. For example, institute researchers have been involved in clinical testing of anesthetic drugs, such as ketamine and nitrous oxide, as treatments for depression. Their common goal, one way or another, is to find new ways to provide relief to the many individuals, families and friends living with the effects of psychiatric illnesses.

“The success of the Taylor Family Institute demonstrates the critical impact of private philanthropy on Washington University’s efforts to improve human health,” said David H. Perlmutter, MD, executive vice chancellor for medical affairs and the George and Carol Bauer Dean at the School of Medicine. “The investment to launch the institute was instrumental in helping our scientists make discoveries that hold great promise for ameliorating the burden of mental illness, and their continued support will bolster our ability to work on the therapeutic frontiers of psychiatry.”

Published in the Winter 2018/2019 issue