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The End of Darkness

  The End of Darkness: UCLA's Depression Grand Challenge

By Lyndon Stambler • Illustrations by Jean-Manuel Duvivier

UCLA’s Depression Grand Challenge unites dozens of UCLA scientists and scholars with public and private stakeholders around a common goal: cutting the burden of depression in half by 2050 and eliminating it by the end of the century.

Robin Williams, who demonstrated a remarkable facility in his professional life to conjure the runs of hyperactivity and the creative twists of pressured thinking that psychiatrists associate with mania, consistently protested that his antics were merely a performance and not reflective of inner turmoil. Yes, Williams confessed, at times he did suffer sadness and, true, he had fallen victim to alcohol and cocaine abuse, but never had he experienced “clinical” depression. For me, as a psychiatrist, these protestations come as no surprise. We each strive for a coherent image of ourselves in the world, constructing as best we can a singular self from an amalgam of inherited biology and experience. Williams, as a young student at the Juilliard School, discovered early his fast wit and mercurial ability for mimicry. These skills were quickly woven into who he was to become as an extraordinarily talented and funny entertainer. Thus, for Williams to distance his talents as apart from an emotional self that might be aberrant, even dangerous, was an idea impossible for him to embrace. His denial of any disturbed mood state is a reminder that disabilities of mind and brain are both similar and distinct from other illnesses. When illness invades the body, it is perturbing to the mind. But when illness invades the brain, it simultaneously invades the mind, disturbing the pith of who we are and calling into question the subjective integrity of the self.

A Mood Apart: Depression, Mania, and Other Afflictions of the Self (Basic Books, 2015), by Peter C. Whybrow, MD

When Oscar-winning comedian Robin Williams hanged himself, at the age of 63, in his Tiburon, California, home on August 11, 2014, many wondered why someone who seemed so upbeat would take his own life. His autopsy disclosed he was taking antidepressants and a medication to treat Parkinson’s disease, and that he had Lewy body dementia. Although Williams never publicly acknowledged his struggles with depression, his death briefly opened a dialog about an illness that strikes rich and poor, young and old with equal vengeance.

Brandon, 30, a former community college student, was not famous when he sought treatment for depression at UCLA in October 2014. Since childhood, he felt isolated. As an adult, he couldn’t find a job or a romantic partner. He left his home once a week to buy groceries and spent the rest of his time sleeping and watching TV. Like Williams, Brandon was suicidal. But he worked with a psychotherapist and gradually broke his isolation, taking walks around the block, visiting a neighbor and a friend. He used cognitive-behavioral therapy to defuse his negative self-talk. Today, Brandon leaves his home at least once a day and no longer is suicidal.

Brandon and Williams are just two of the 350-million people worldwide who, at any given time, struggle with depression. Less than half seek treatment, and of those who do, only half obtain substantial benefit. Moreover, depression is the single most common cause of disability worldwide, and it is the strongest risk factor for suicide, which in 2010, according to the Institute for Health Metrics and Evaluation, accounted for more deaths than war, natural disasters and murder combined. In dollars-and-cents terms, depression has a devastating worldwide economic impact, including some $116 billion in medical and long-term care costs in the U.S. alone in 2010, and this doesn’t take into account the lost productivity of affected individuals or the impact on their families and communities.
UCLA is trying to do something about that. The UCLA Depression Grand Challenge aims to cut the burden of depression in half by 2050 and eliminate it by 2099.

It indeed is a grand challenge. But Nelson B. Freimer, MD, Maggie G. Gilbert Professor of Psychiatry and Biobehavioral Sciences and director of the Center for Neurobehavioral Genetics in the Jane and Terry Semel Institute for Neuroscience and Human Behavior at UCLA, believes it is an attainable goal. He leads an interdisciplinary team that, over the next 10-to-15 years, hopes to understand the biological risks and life events that can trigger depression. They will do this by sequencing the genomes of 100,000 people in the UCLA Health network to identify genes responsible for depression; using innovative techniques to screen, monitor and treat those people; conducting cutting-edge clinical and basic-science research to unmask the secrets about depression and develop effective treatments; and encouraging conversations about depression.

The Depression Grand Challenge is one of two current UCLA Grand Challenges, an ambitious campus-wide initiative to address some of society’s greatest problems through cross-campus research collaborations with shared goals. The other Grand Challenge, Sustainable LA, is focused on transitioning Los Angeles to 100-percent renewable energy and locally sourced water by 2050. Both are integral parts of the $4.2-billion UCLA Centennial Campaign. The Depression Grand Challenge seeks to attract hundreds of millions of dollars in funding, correcting the imbalance in support for depression research compared to that for illnesses such as cancer and heart disease.

“We don’t understand depression well; that’s one of the reasons we need the Depression Grand Challenge,” Dr. Freimer says. “Our main hypothesis is that people who have a genetic vulnerability are at increased risk, and certain kinds of stressful events increase the risk of depression. But there also are people with a genetic predisposition who will have depression that seems to come out of the blue, with no obvious stressor.”

Many people think of depression as sadness, but that’s not quite accurate. “Depression is a profound state of sadness that extends usually for weeks, often for months,” Dr. Freimer says. “It involves a host of associated symptoms: difficulty with sleep, eating and concentration; low energy; and feelings of very poor self-worth. In its most severe form, people feel life isn’t worth living and will have suicidal thoughts and will often attempt and frequently complete suicide. It doesn’t just occur on its own. It frequently occurs with, and complicates, other common diseases. It worsens the risk and the course of heart disease, cancer, stroke and Parkinson’s disease. It has a magnifying effect.”

In his recently republished classic, A Mood Apart, Peter C. Whybrow, MD, director of the Semel Institute, calls depressive illnesses “malignant and deadly diseases.” They upend everyday behavior — waking, eating, sleeping, assessing the emotions of others. “Depression reflects something that you lose rather than something that is gained,” Dr. Whybrow says. “Depression is a loss of these simple and well-oiled integrated functions that we take for granted every day.”

  The End of Darkness: UCLA's Depression Grand Challenge  

THE GREEKS AND ROMANS BELIEVED that imbalances in humours, or biles, were responsible for depression. Melancholia, the most severe form of depression, comes from the words melaina chole, or “black bile.” Shakespeare and his contemporaries wrote about it. A famous 17th-century book published in Britain was called The Anatomy of Melancholy. Abraham Lincoln and Winston Churchill were among leaders who suffered from depression.

Depression is likely not a single disorder but rather refers to many different disorders, each with similar symptoms. Researchers theorize that clusters of genes may increase a person’s vulnerability or, conversely, enhance resilience. There could be hundreds, even thousands, of genes involved. In schizophrenia, for example, 108 loci have been identified.

The Depression Grand Challenge will seek to identify genetic contributions for each component of the syndrome of depression, from sleep abnormalities to anhedonia, the inability to experience pleasure. Identifying such phenotypes could lead to effective treatments. As Dr. Whybrow puts it, “In order to attack something like depression, you have to dissect it.” The Depression Grand Challenge genetic study will be co-led by psychiatric geneticists Dr. Freimer and Jonathan Flint, MD, who conducted the largest genetic study of depression to date, while teaching at Oxford University. Dr. Flint and his colleagues sequenced the genomes of 10,000 severely depressed Han Chinese women. His study, published in Nature in July 2015, identified two loci for major depressive disorder. “It tells you this disease is genetically tractable,” says Dr. Flint, who has joined the Depression Grand Challenge leadership team and assumes a position as professor in the UCLA Departments of Psychiatry and Biobehavioral Sciences and Human Genetics.

Dr. Flint’s research in China will benefit the Depression Grand Challenge. For example, people once thought it would be too difficult to study a population as large as 10,000 people, but his work demonstrates it is possible. At UCLA, Dr. Flint doesn’t plan to sequence 100,000 people all at once, but rather start with 10,000-to-15,000 of the most severely depressed people, study them in a focused manner and then branch out. He expects there to be both similarities and differences with the severely depressed women he recruited at hospitals in 30 Chinese cities. “The molecular basis should be similar,” Dr. Flint says. “It makes no sense to say that the biology would be different depending on whether you’re born in Beijing or L.A.”

After he completed the China study, Dr. Flint knew the next step would be to study a larger heterogeneous population. Steven Hyman, MD, director of the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, supports that notion in an article in the November 2014 issue of Nature, “Depression Needs Large Human-Genetics Studies.” Dr. Hyman notes that depression is difficult to study for many reasons, including the diversity of symptoms and variable age of onset. “Amid these traps, one clue to molecular mechanisms of depression has long beckoned: genetic analysis,” Dr. Hyman wrote, asserting that it will require data from 100,000 people. Luckily, the cost of sequencing genomes has declined significantly since the Human Genome Project ended in 2001. But sequencing 100,000 people still will be expensive. The Depression Grand Challenge plans to raise the money through philanthropy, including individuals, foundations, corporations and crowd funding.

Settling into his new office in UCLA’s Gonda (Goldschmied) Neuroscience & Genetics Research Center, Dr. Flint praises UCLA’s effort to address the issue of depression on such a broad scale: “This is a major health problem, ignored by most of the world, which UCLA is going to make a major contribution to changing. How could I not come?”

THE QUEST FOR A UCLA GRAND CHALLENGE related to the brain originated in August 2012, when Michelle Popowitz, assistant vice chancellor for research and executive director of UCLA Grand Challenges, and Jill Sweitzer, co-director, asked professors of biological chemistry Kelsey C. Martin, MD, PhD, who now is interim dean of the David Geffen School of Medicine at UCLA, and S. Lawrence Zipursky, PhD, an investigator of the Howard Hughes Medical Institute, to convene a group of neuroscientists on campus from both the College of Letters and Science and the school of medicine to develop a grand challenge in brain science. On August 29, 2012, James S. Economou, MD (RES ’82, ’83), PhD, vice chancellor for research, extended invitations to approximately 30 UCLA neuroscientists to join Drs. Martin and Zipursky to consider what problems related to the brain UCLA could solve if money were not an obstacle. The experts divided into three groups and, during weekly meetings over more than 20 weeks, considered “what is memory,” “the working brain” and “the changing brain.”

Over the ensuing months, “the changing brain” group, led by Dr. Freimer, turned its attention to depression. “It’s such a huge global burden,” says Dr. Martin. “It brings in not just biology, not just clinical care, but also the social sciences, economics and the humanities. Here’s something we don’t understand about what it means to be human. That’s part of what we’re supposed to tackle as scholars at the university.”

In 2013, when President Barack Obama announced a national brain initiative, which has boosted federal funding for brain research, UCLA Chancellor Gene D. Block and Drs. Economou and Martin were his guests at the White House.

As consensus grew to focus on depression, Drs. Martin, Zipursky and Freimer met with philanthropist Garen Staglin, co-chair of the UCLA Centennial Campaign, and his wife Shari. The couple, who are dedicated to improving brain health, enthusiastically endorsed the Depression Grand Challenge and became members of its Leadership Council.

  The End of Darkness: UCLA's Depression Grand Challenge  

DRS. FREIMER AND FLINT WILL NEED THE HELP OF MANY OTHERS to locate the genes that contribute to depression. For one, sequencing the genomes of 100,000 people will create “billions of data points,” Dr. Flint says.

But new tools to look at brain function and computers that can analyze large data sets will enable UCLA researchers from across a broad swath of disciplines, including mathematics and bioinformatics, to look at a large heterogeneous population, in contrast to most genetic studies. Says Dr. Freimer: “We now have the tools that really focus on studying very large numbers of people with the disease and large numbers who don’t have the disease and comparing their genetic material throughout their genomes to identify differences.”
But before the sequencing can begin, the team must identify people within UCLA’s health system who are willing to participate.

Michelle Craske, PhD, director of UCLA’s Anxiety and Depression Research Center and co-director of the human-research component of the Depression Grand Challenge, is coordinating formulation of the project’s treatment program and is anticipating a three-tiered approach. Someone with low-level depression will receive an Internet-based self-guided cognitive-behavioral-therapy course. Someone with moderate depression will receive a peer- or coach-guided intervention. The most severely depressed will receive treatment from expert clinicians.

The screening will include suicide prevention. “Eventually, all of the subjects will be screened, and we’ll be able to identify early on who is at risk and take steps when necessary,” says Dr. Craske, who has spent 30 years studying factors that place people at risk for depression and anxiety. “I’m interested in treatment, but also prevention. My work over the years has established that there’s a scarring impact. Once depression hits, it tends to dig deeper the next time around.”

Dr. Flint echoes Dr. Craske. “We can’t just go out and screen those people and discover there’s a few hundred who are likely to kill themselves and just ignore that. We have to intervene,” he says.

After people are screened, they will be monitored for the next 10-to-15 years, using wireless apps to track daily functioning: how they’re sleeping, whether or not they are leaving their house, the sound of their voice, facial expressions, exercise levels and social interaction, to name a few. The information about functioning will inform treatment decisions. For example, “If someone is in the lowest level of treatment and we start getting information from their smart phone that says they’re starting to slow down, withdraw and isolate, that would become a signal to step in,” Dr. Craske says.

For the next two years, Robert Bilder, PhD, Tennenbaum Professor of Psychiatry, and Carrie E. Bearden, PhD, Joanne and George Miller Family Endowed Chair in the UCLA Brain Research Institute, will be trying out various mobile apps for monitoring large numbers of people at risk for depression. They will investigate patterns of sleep, activity and social contacts, as well as vocal patterns and tones — but not the content of conversations. Using this kind of “passively gathered” information, “we believe we will be able to pick up on the kind of information that will help to predict who is at greatest risk and who may be developing clinically significant or disabling depression,” Dr. Bilder says. “We’re looking at things that have never been widely examined in psychiatry.”
A core group would be brought in for more detailed monitoring in the lab. “You’ve got the whole genomes on one side and the high-level clinical outcomes on the other side,” Dr. Bilder says. “So if we examine the blood, we can determine not only what genetic variations people have that contribute to depression, but also which genes are actively being turned on or off during the initiation of the episode of depression or as a result of treatment.”

Correlating these data with other information such as patterns of brain function, electrical activity, brain blood flow and cognitive performance, the scientists hope to then develop a complete causal map of the relationships of variables at all levels of biological function that are relevant to depression, from the genome all the way up to the syndrome of depression.

By identifying and treating people who might never have sought treatment, the Depression Grand Challenge expects to reduce the burden of depression and reduce overall costs to society. But the team isn’t content to just assume that this will be the case; rather, UCLA economists will be involved in the program from the beginning to rigorously assess whether or not these interventions actually result in benefits to families, to the healthcare system, to employers and to society overall.

THE EXPECTATION THAT THE COMMUNITY WILL GET SOMETHING IN RETURN for its investment in the Depression Grand Challenge is an important point for Dr. Zipursky and others. “It’s not simply that we’re going to diagnose individuals with depression and sequence their DNA so we can identify the genetic contributions to depression. But we will be providing treatment to a large number of patients who are not now receiving it,” he says.

Better yet, they will get state-of-the-art care. Current treatments — from cognitive-behavioral therapy to antidepressants to electroconvulsive therapy — relieve depression in patients about half the time. “A lot of people improve, but not enough,” Dr. Craske says. “And there are some people who don’t improve at all. Right now, the treatments are delivered without a really good understanding of the underlying mechanisms. So we need better treatment.”

Dr. Whybrow, among others, agrees that the Depression Grand Challenge will lead to innovative approaches. “It’s a mistake to think these disorders will be fixed by a new antidepressant or a new method of deep-brain stimulation. Human beings are so varied in their complexity, and especially in their social organization, that there is no simple fix,” he says.

In this effort, the patients will be partners and beneficiaries. “Genetics can be used to better define diseases and ways of improving treatment,” Dr. Zipursky says. “It could be if you have a certain set of genetics, you may find that that individual is suited to cognitive-behavioral therapy and resistant to pharmacological treatments. You may find, conversely, someone who has a certain set of genes may be a particularly good candidate for pharmacological therapy.”

Dr. Craske has been conducting research on patients with anhedonia, which affects a third of people with depression. “How do you help somebody to experience pleasure in the moment, whether it’s a psychological or a biological approach?” she asks. “To date, the treatments that exist are not touching anhedonia at all.”

Indeed, one of the Depression Grand Challenge’s two-year demonstration projects involves the use of fast-acting treatments such as the anesthetic ketamine, which has a reputation as an illicit party drug, to boost the moods of people struggling with anhedonia. Other projects, culled from 80 applications submitted by 120 faculty members, include the remote screening and assessment programs overseen by Drs. Bearden and Bilder; a study of neuromodulators such as serotonin; a look at the role of estrogen and other hormones on brain function; a study of glial cells, non-neuronal cells that are increasingly seen as significant; and an investigation of migraines and depression. The David Geffen School of Medicine at UCLA has provided initial seed funding for these two-year projects.

  The End of Darkness: UCLA's Depression Grand Challenge  

The demonstration projects are emblematic of the multidisciplinary effort, engaging basic scientists, translational scientists and clinicians. Says Dr. Freimer, “There aren’t many universities that could do this. It requires bringing a medical school and health system together with all the resources you’d have at a large university. We’re unusual to have that on campus.”

Susan E. Fuhs, PhD, program director, is coordinating Depression Grand Challenge activities and participation from across UCLA’s campus. With years of experience running interdisciplinary programs, she could not resist the chance to participate in a program as ambitious as this one. “To really accomplish our goals, we have to get not just the science right, but also the engineering, the economics, the social science, the public health, the public policy, the business, and the arts and humanities right as well,” she says.

This potential for interdisciplinary collaboration at UCLA was refreshing for Dr. Flint. “You’re not siloed here into departments,” he says. “There’s an ability to cut across disciplines and deal with important problems in a joint fashion. Depression is a condition that has a very substantial environmental component that spans everything from a bad economy to whom you marry, a host of things that sociologists, epidemiologists and educationalists will be involved in.”

Dr. Flint, whose role is to get the genetic study up and running, has a focus of his own: how depression develops on a molecular level to “give rise to a really bad feeling.” Those “bad feelings” may be countered by the genetics of resilience: why some people living in dire circumstances never get depressed. “If I knew why these people never got depressed, and if I understood that at a molecular basis, then there is a possibility I could use that understanding to change the people who’ve got depression into those who are resilient,” Dr. Flint says. “A drug would be the obvious thing, but there might be other ways of doing it.”

Dr. Whybrow’s hope is that the Depression Grand Challenge will bring greater understanding not only about diagnosis, but also on personalized interventions, enabling individuals to recover more rapidly. “But it’s not just about the individual,” he says.

“None of us live in a vacuum. So I think the way to think about depression is not only individually, but also how does the individual relate to the social space and how does the social space relate to the individual.”

SUCH SOCIETAL CHANGES WILL REQUIRE more than the fleeting attention that follows the suicide of a celebrity like Robin Williams or the whispers after the death of a college student from suicide. With its large student population, UCLA has a particular interest in depression, which frequently manifests itself during the college years. By some counts, suicide is the No. 1 killer of adults between the ages of 18 and 49, exceeding auto accidents.

When Drs. Freimer, Martin and Zipursky spoke about the Depression Grand Challenge to a freshman seminar, a surprising number of students talked about personal struggles with depression or friends who have had suicidal thoughts. “A large fraction of the students who commit suicide have never sought treatment,” Dr. Martin says. “There are a lot of reasons for that, but one is that people are not comfortable talking about feeling depressed. One way to change that is to make it part of a public conversation.”

Through dialog and scientific discovery, the Depression Grand Challenge hopes to lift the veil of depression. “It’s like being an explorer on a globe that nobody has traveled on before,” says Dr. Martin. “We may not know exactly how the answers will affect the treatment of depression, but by understanding how the brain functions and changes with experience, we will understand how it can be changed in a positive way.”

Freelance writer Lyndon Stambler teaches journalism at Santa Monica College.


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