Hope is Real: The UCLA Depression Grand Challenge

December 16, 2015

Depression ruins lives, destroys families and kills nearly a million people a year worldwide. Some say the problem is too intractable to address. Not so, say UCLA scientists, who have launched a historic effort to tackle and treat the world’s largest health problem.


Nelson Freimer, Michelle Craske and Larry Zipursky. Photos by David Black.

Disease, epidemic, condition — whatever you want to call it, either you’ve suffered from depression or you know someone who has.

In the U.S., 1 out of every 5 people will be diagnosed with depression at some point in their lives. At UCLA, about 20 percent of the students on campus consult student health services about anxiety and depression.

People who are depressed are not just sad. They are unable to do the simplest things, like get out of bed or go to the office.

Michelle Craske, professor of psychology, psychiatry and biobehavioral sciences and director of the Anxiety and Depression Research Center at UCLA, says, “I think of depression as having two main components: A high level of negative effect — sadness, guilt. Another area present for many is that they cannot look forward to and savor positive events.”

But this disease doesn’t only diminish quality of life. It kills.

Psychiatric Genetics

Jonathan Flint discusses his research into the causes and treatments of anxiety and depression.

Every year, 30,000 people in the U.S. and 1 million people worldwide commit suicide, almost always because of depression. That’s more than the number of people who die from car accidents or homicide. Moreover, depression either increases the risk or worsens the outcome for millions of people suffering from the other deadly diseases that afflict us, including cancer and heart disease. There are also connections to conditions such as migraines and sleep deprivation.

The more stressful and competitive society becomes, the more vulnerable we are to anxiety and depression, notes Peter Whybrow, best-selling author and director of the Semel Institute for Neuroscience and Human Behavior at UCLA.

And yet we don’t really know what causes depression in its many forms. The treatments we have work only about half the time.

Confounding the problem, many people still don’t even think of depression as a real disease.

“Depression devastates families, but the reason there hasn’t been more conversation about it is that there is a stigma attached to depression, even more than something like schizophrenia,” explains Nelson Freimer, Maggie G. Gilbert Professor of Psychiatry and Biobehavioral Sciences and associate director of the Semel Institute for Neuroscience and Human Behavior. “People who have schizophrenia are obviously disturbed. Depression often isn’t visible. There’s this idea that people who have depression are not really sick, they’re just not trying hard enough or they can snap out of it. Therefore, a lot of people with depression don’t talk about it. And as a society, we don’t talk about it for the same reason.”

Given all that, it’s not surprising that the World Health Organization estimates that by 2030, depression will be the leading cause of disease burden on the planet. If things remain the way they are, the scourge of depression is only going to get worse.

Fortunately, things are not going to remain the way they are.

Think Grand

In October, UCLA announced the launch of the Depression Grand Challenge (DGC), by far the largest and most ambitious effort ever undertaken to understand and treat this devastating disease. The DGC unites more than 100 UCLA faculty in 25 departments, from neuroscience and medicine to computer science and psychology. The DGC is led by Freimer, and its high-powered executive committee includes Craske; S. Lawrence Zipursky, distinguished professor of biological chemistry, director of the Neuroscience Theme in the David Geffen School of Medicine at UCLA and chair of UCLA Neuroscience, a committee that coordinates neuroscience research initiatives across the campus; and Jonathan Flint, a renowned depression researcher and psychiatric geneticist who has left Oxford University to join UCLA.


The Depression Grand Challenge is the second in a series of ambitious research projects united under the UCLA Grand Challenges program umbrella. The first, Sustainable LA, takes on the problem of meeting the city’s pressing need for energy and water independence while enhancing ecosystem health. UCLA Chancellor Gene Block calls the two Challenges “a new way of conducting research to solve the biggest problems of our society” and “the biggest, most collaborative and potentially most transformative efforts UCLA has undertaken to date.”

They have to be. These are huge problems that affect everybody. They demand equally impressive responses that involve everyone.

“Three years ago, 30 UCLA faculty from different areas of neuroscience got together to discuss this,” recalls Zipursky about the origins of the DGC, “and we were captivated by this idea of going after big problems. … We’re not waiting to deliver help to patients until we have the ‘cure.’ We’re doing genetic work. Basic science work. Clinical work. And we’re dealing with the economic aspects, the stigma aspects. We don’t typically look at problems that way in academia.”

Adds Whybrow, a member of the DGC Leadership Council, “The Grand Challenge is so important because it’s not just a study of biology and it’s not just a study of culture or economics. It’s a study of everything. It’s the first time that any university has tried to take on the continuum of depression, to say we need to know about the biology, we need to know more about the stressful environment. We need to know how they connect together. We need to know what factor age plays in depression. What role do hormones play? Why is it that some people manage to navigate these things much more easily than others?”

Strength in Numbers

The centerpiece of this massive, multi-element project is a genetic study of 100,000 patients, the largest in history for a single disorder. It will include people without depression, some at risk for it and some who already are clinically depressed. They will be chosen from the vast University of California (UC) system, including students, faculty, staff and patients enrolled in the UC health care system. Project participants will undergo a complete DNA sequencing and be treated and monitored for 10-15 years in an effort to illuminate both the genetic and the environmental causes of depression.

The study will be co-led by Freimer and Flint, who spearheaded the largest genetic study of depression to date, in which the genomes of 12,000 severely depressed Han Chinese women were sequenced. Unlike in China, where investigators went to great lengths to ensure that the subjects were remarkably homogenous, the UCLA study will provide the extraordinary diversity that is a hallmark of life in L.A.

“What’s made this possible is the idea that depression isn’t intractable,” says Flint. “[But] someone has to take responsibility for setting it up [for study]. A sample of this size is immensely ambitious, and it will rewrite some of the ground rules of how we do the science. It makes us focus very clearly on what is expected of us. We are part of the community, too. This is stakeholder science. And I have enormous respect for UCLA for taking this on.”

A set of rigorously reviewed two-year demonstration projects, funded with early investment from the UCLA David Geffen School of Medicine, will begin in the late summer or early fall of 2016. These will establish feasibility and mitigate risks for the study, and also produce high-impact early scientific results. Already, seven demonstration projects are under way, focusing on such aspects of depression as measuring mood disorder risk and the shared mechanisms of depression and migraines.


It typically takes anywhere from three to six weeks for most anti-depressive medicines to have a noticeable effect. But some treatments work more rapidly. One demo project will study biomarkers of these fast-acting treatments for major depression. They include methods for treating the disease such as ketamine, sleep deprivation and electroconvulsive shock therapy (ECT).

The latter changed the life of author, social worker and mental health activist Kitty Dukakis, wife of former presidential candidate, Massachusetts governor and, since 1991, UCLA Luskin School of Public Affairs fellow Michael Dukakis. She wrote about her experience with ECT treatments in her 2006 book Shock: The Healing Power of Electroconvulsive Therapy.

“It saved my life,” Dukakis says. “I’m very concerned that there is too much emphasis placed on medication and talk therapy. Many times they don’t work. They didn’t with me. The stigma [about ECT] is still out there. But every day I get calls from people here and in Europe about ECT.”

Another major element of the DGC is the creation of an Innovation Treatment Center to develop new and more effective ways to treat depression and to implement cutting-edge diagnostic and treatment approaches. Independent companies are already reaching out to collaborate with DGC researchers to harness emerging technology such as virtual reality to explore new behavioral treatments for depression. The project also will pursue discoveries in neuroscience to help us understand the brain’s role in depressive disorders and to develop ways to dismantle the stigma of depression.

The DGC will be supported by a robust social media campaign, soliciting support for the effort on social networks. Turning the negative perception of “being blue” into a positive message of hope, the campaign is connected via the hashtag #blueforhope.

Much attention is paid to the thirst for knowledge as a motivation for academics. The Depression Grand Challenge offers that in abundance. But there’s much more at play — the prospect of alleviating suffering and bringing hope to millions, perhaps hundreds of millions, of people.

“Most scholars in the university will tell you that their work is aimed at understanding what it means to be a human being,” says Kelsey Martin, interim dean of the David Geffen School of Medicine at UCLA and co-chair of the DGC’s Leadership Council. “What it means to build a civilization. Live in a society. Understand depression. It is a noble quest for those reasons.”

“We may not be able to entirely eliminate the burden of depression,” concludes Freimer. “It’s part of the human condition. Our goal, as with other aspects of the human condition, is to make depression manageable. So it doesn’t cause people to lose their jobs. It doesn’t cause people to lose their families. And it doesn’t cause people to commit suicide. The opposite of depression isn’t being happy. The opposite of depression is being well.”