NIH Funds Scripps Research-Novartis Collaboration To Target New Treatments for Depression and Nicotine Addiction

By Jason Socrates Bardi

A group of researchers from The Scripps Research Institute and Novartis Pharma AG have been awarded a $3.45 million grant to collaborate on the design of new ways to treat depression and nicotine addiction.

The grant, titled "Development of GABAB compounds for depression and smoking," was funded jointly by two of the agencies within the National Institutes of Heath, the National Institute of Mental Health (NIMH), which contributed 80 percent, and the National Institute on Drug Abuse (NIDA), which contributed 20 percent.

"We are very excited about this opportunity," says Athina Markou, who is associate professor at Scripps Research and the director of the overall collaborative project. "It will allow us to focus on drug discovery for depression and nicotine dependence in a way that neither Scripps nor Novartis could accomplish on their own."

Issuing collaborative grants jointly to academic research institutes and pharmaceutical companies is a strategy that other NIH institutes, such as the National Cancer Institute and the National Institute for Allergy and Infectious Diseases, have used successfully and one that the NIH is encouraging, according to the recent NIH Roadmap. The Scripps Research–Novartis Pharma AG grant was made through a new funding mechanism called the "National Cooperative Drug Discovery Group for the Treatment of Mood Disorders or Nicotine Addiction" and marks the first time the neurosciences institutes (NIMH and NIDA) have funded a public-private partnership in drug discovery.

Depression and Suicide

A widespread medical problem, depression is an often debilitating psychiatric condition marked by persistent feelings of sadness or hopelessness, inactivity, changes to sleep and eating patterns, and suicidal tendencies. Doctors as far back as Hippocrates recognized the problems of depression and have sought ways to treat it.

NIMH estimates that, in any given year, about one out of every ten American adults suffers some form of major depression, and the World Health Organization estimates the annual cost of depression in the United States exceeds $43.7 billion. About two percent of all Americans will use antidepressants at some point in their lives.

One of the core symptoms of serious depression is suicidal tendencies. In 2000, according to the National Center for Injury Prevention and Control (NCIPC), 29,350 Americans committed suicide, making it the eleventh leading cause of death in the United States that year. In fact, in 2000, many more people died from suicide than homicide.

Depression is defined by a number of symptoms that have been well recognized and described by doctors for years, and doctors can diagnose and treat depression in patients based on these symptoms. But the disease is highly variable and manifests itself differently from person to person. On the neurobiological level, the disease is not well understood. Are genes being turned on and off to fuel depression? Are neurons rewiring? Are neurons secreting more or less of neurotransmitters at particular brain sites? Which sites? We simply do not know.

Today there are a number of drugs for treating for depression, but they are not a panacea. Treatment characteristically takes six to eight weeks to kick in, and as many as a third of patients do not respond to any antidepressant. New ways to treat depression are needed. Given the risk of suicide for patients beginning medication, a quick-acting compound for the treatment of depression would be a great boon.

"That would be an absolutely major advance and would save many lives," says Paul Herrling, who is head of Corporate Research at Novartis International and who has many years of experience with drug discovery and academia-industry collaborations.

GABA and Depression

The grant is based on evidence that there are mechanisms of depression that have not yet been targeted by therapeutics. This system revolves around a neurotransmitter called gamma-aminobutyric acid (GABA) and the cell receptors to which it binds.

GABA is one of the major inhibitory neurotransmitters in the brain—a chemical that carries a signal from one neuron to another. GABA is released by certain neurons into a synapse or gap between two neurons, and it diffuses across this gap and binds to GABA receptors on the adjacent neuron.

The TSRI and Novartis teams will be looking at the role of GABA in depression and will be exploring the hypothesis that increasing GABA transmission will have a beneficial effect on depression.

Novartis has developed some compounds that enhance GABA neurotransmission, and Markou and her colleagues at Scripps Research will be testing them, hoping to identify one or more that have a measurable effect on depression.

The work will be split between Novartis and Scripps Research, and will involve frequent interaction, visits to each other's sites, and joint publications. Novartis will conduct the molecular biology studies of the GABA receptor system, the medicinal chemistry of GABA positive modulators, and the traditional aspects of drug discovery and design. Scripps Research will focus on behaviorally testing the compounds Novartis produces. The behavioral testing will be conducted in existing models of depression and nicotine dependence, and both the Novartis and the Scripps Research teams will also focus on developing new behavioral models of depression. New models of depression are desperately needed in this field, and the NIMH, recognizing the limitations of the current models, has encouraged the development of a new model by making it an explicit goal.

The Novartis portion of the grant will be led by John Cryan at Novartis Pharma AG. Cryan will lead the behavioral pharmacology work at Novartis, and Klemens Kaupmann and Wolfgang Froestl, two other scientists at Novartis Pharma AG in Basel, will build on their respective experience in GABAB receptor pharmacology and medicinal chemistry to focus on this receptor as a therapeutic target in nicotine dependence. Finally, Graeme Bilbe, head of the Disease Area Neuroscience at Novartis Pharma AG, will be a collaborator on this grant on the Novartis site, and will advise the team on drug discovery issues.

"I am thrilled that we will be able to work with such an outstanding and experienced multidisciplinary team of Novartis researchers," says Markou. "And I am also very grateful that Dr. Bilbe has agreed to assist us with this project. His support and input will be very valuable."

Nicotine and GABA Another goal of the grant is to look at the connection between cigarette smoking and depression, which could shed light on what makes nicotine so addictive, and how these same sorts of compounds could be used to treat nicotine addiction.

Smoking is a major health problem in the United States, and, according to the U.S. Centers for Disease Control and Prevention, hundreds of thousands of Americans die each year from smoking-related lung cancer, ischemic heart disease, and chronic airway obstruction.

Markou has been working for several years in the area of drug dependence and withdrawal and has found evidence of depression-like states in withdrawal from amphetamines and from nicotine. In other words, those who are trying to quit smoking often experience depression—sometimes severe—and tobacco use may be higher among people suffering from depression because they are using it to self-medicate depressive symptoms.

"Fifty percent of depressed people smoke, versus thirty percent in the general population," says Markou.

This observation is bolstered by clinical evidence that treating people for depression during smoking cessation can help them quit smoking. In fact, one type of antidepressant is approved by the U.S. Food and Drug Administration (FDA) for use in smoking cessation—the only non-nicotine based therapy for smoking cessation approved by the FDA.

There is also strong evidence in the scientific literature that GABA is involved in nicotine addiction, just as it is in depression. If you increase GABA transmission, then the rewarding effects of nicotine decrease. For instance, if scientists block the enzyme that breaks down GABA, resulting in more GABA around in the synapse, or if they activate GABA receptors through the administration of agonist drugs, nicotine self-administration decreases.

An increase of GABA may lead to a general blocking of some of the positive effects of nicotine, like the accumulation of dopamine in the nucleus accumbens—one of the so-called pleasure centers of the brain.

While the grant is focused primarily on depression, it is also funding research on nicotine dependence. The TSRI scientists will conduct experiments to determine whether the compounds Novartis produces block the reinforcing aspects of nicotine use and/or reduce the negative aspects of nicotine withdrawal that may have phenomenological and neurobiological similarities with symptoms of depression.

Towards Further Collaborations

The recently funded grant is an experiment of sorts itself.

It is designed to foster a collaborative approach aimed at developing new medicines to treat depression by bringing together scientists in an academic research institute such as Scripps Research with their counterparts in industrial pharmaceutical laboratories such as those at Novartis Pharma AG.

The grant is the first of its kind for NIDA and NIMH, and may become a free-standing program if this sort of collaboration proves to be a good model for stimulating drug discovery at the National Institutes of Health.

The idea is part of the National Institutes of Health's new roadmap to create these sorts of public–private partnerships and collaborations, combining the strengths of academic laboratories with those of pharmaceutical companies.

The idea behind a collaborative grant between an academic research institute, such as Scripps Research, and a pharmaceutical company, like Novartis Pharma AG, is that it could speed up the identification of new and high-risk targets for drug development—in this particular case, a new class of drugs for treating depression that would hopefully act differently than the traditional tricyclics or selective serotonin reuptake inhibitors.

In general, the idea of this sort of collaboration between academic laboratories and pharmaceutical companies is that if a drug candidate shows promise, then a pharmaceutical company collaborator might devote resources towards getting them into trials much sooner than they otherwise would. The hope is that this will bring promising lead compounds into clinical testing more rapidly.

One of the benefits of the grant is that it is designed so that certain molecules that are developed as part of the grant, but which are not pursued further as drug candidates, will be placed in the public sector where they can serve as starting points for further basic research and drug discovery in the scientific community at large.

Part of the National Institutes of Health's roadmap calls for the creation of a library of small molecules available to public sector biomedical researchers. These could be used as chemical probes to study cellular pathways in greater depth, providing new ways to explore the functions of major components of the cell in health and disease and accelerating the development of promising new drugs, especially for rare diseases.

Markou and the scientists at Scripps Research will test the compounds that Novartis generates for efficacy in several behavioral pharmacology models of depression.

Another public benefit will be that this research may generate new models of depression. Markou has been working for several years in this area and is hoping to validate new models as part of her work on the grant.

"I'm happy to say that our many years of interaction with Scripps have led us to the state where we can do this collaboration," says Herrling. "This is a perfect collaboration."





"We are very excited about this opportunity," says Athina Markou, who is associate professor at Scripps Research and director of the collaborative project. Photo by Jason S. Bardi.




















Depression, Nicotine dependence, and GABA. Click to enlarge