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Full-on Assault on Depression

Northwestern investigators advance depression research from all fronts

The numbers alone are depressing. Thirty million American adults will suffer from depression in their lives. One of the top 10 disorders causing disability worldwide, depression strikes nearly 40 percent of patients before age 18. In the United States, lost work days due to depression are estimated to cost employers $17 to $44 billion, according to the Centers for Disease Control (CDC) and Prevention.

“Depression is an incredibly common public health problem and we are not doing a very good job of treating it. There are inadequate mental health services as well as continued shame associated with seeking treatment,” says Katherine L. Wisner, MD, MS, Asher Professor of Psychiatry and Behavioral Sciences and director of the Asher Center for the Study and Treatment of Depressive Disorders at Northwestern University Feinberg School of Medicine. “While people intellectually get that depression is a brain disease and is as much a medical condition as diabetes, that knowledge hasn’t reduced the stigma.”

Katherine L. Wisner, MD, MS, Asher Professor of Psychiatry and Behavioral Sciences and Director of the Asher Center for the Study and Treament of Depressive Disorders

The complexity of depressive disorders requires multipronged solutions, ranging from psychotherapy and medications to non-drug therapies such as light therapy and transcranial magnetic stimulation. As multifaceted as the disease they study, Northwestern Medicine® investigators conduct basic and clinical research aimed at all aspects of depression. At Feinberg, the Asher Center boasts an interdisciplinary membership. Psychiatrists, psychologists, and basic neuroscientists contribute to the mission of developing cutting-edge research and clinical services that lead to more effective treatment. Dr. Wisner, a pioneer in the treatment of mood disorders in women during pregnancy and the post-partum period, joined Northwestern last July from the University of Pittsburgh to lead the center’s efforts.

Boosting women’s mental health

Watching mentally ill pregnant women throw themselves against the walls of isolation rooms infuriated Dr. Wisner early in her career. Medicating patients of childbearing age for their psychiatric issues was a big no no. She adds, “I was told not that long ago that pregnant women don’t get mentally ill because they are ‘fulfilled’ by having a baby.”

Motivated to collect “real” data, Dr. Wisner has focused her research efforts on this understudied population for more than 30 years. She was the first American psychiatrist to collect serum from mothers and their babies to monitor possible infant toxicity caused by psychotropic medication in breast milk. Her arrival has added a new dimension to the medical school’s portfolio of depression research.

Conducting  the largest scale depression screening study of postpartum women, Dr. Wisner and her colleagues found a surprisingly high number—14 percent of 10,000 individuals—who screened positive for depression. Of this group, 19.3 percent considered harming themselves—a major concern as suicide accounts for about 20 percent of postpartum deaths. Dr. Wisner has also studied fetal exposure to medications taken by depressed pregnant women. Her work, published in the March issue of the American Journal of Psychiatry, has shown that in utero exposure to major depression or commonly prescribed antidepressants like Prozac and Paxil had no effect on infant growth.

Understanding the depressive brain

Biomarkers of all types reveal much about disease status. Just as they are used to predict responses to cancer therapies, biomarkers offer depressed patients and their clinicians critical information about the potential response to specific treatments. Jacqueline K. Gollan, PhD, associate professor of psychiatry and behavioral sciences, has discovered a set of markers based on affective science that predict successful response to Behavioral Activation (BA) treatment for depression, a form of psychotherapy that modifies passivity and withdrawal and increases mastery and enjoyment to treat depression.

Jelena Radulovic, MD, PhD, Dunbar Professor in Bipolar Disease; Jacqueline K. Gollan, PhD, associate professor of psychiatry and behavioral sciences; and Joseph R. Moskal, PhD, research professor of biomedical engineering and director of the Falk Center for Molecular Therapeutics

“Identifying a predictor of response would minimize patient cost and suffering,” says Dr. Gollan, director of the Stress and Affective Disorders Laboratory (SADLAB). “In a recent trial, 68 percent of depressed patients responded to behavioral activation. Further, patients with blunted emotional reactivity to unpleasant stimuli showed a slower rate of response to BA, suggesting that they may not be able to correctly identify unpleasant scenarios, which hampers treatment response.”

Dr. Gollan and her research team have also applied functional magnetic resonance imaging to identify how women with and without major depression differ in regional brain activation. Enrolling 132 women from puberty to menopause in a clinical study, she hopes to characterize how brain activation is associated with cognitive and affective reactivity to adverse experience.

The recollection of adverse people, places, and things may have much to do with depression. Jelena Radulovic, MD, PhD, Dunbar Professor in Bipolar Disease, studies the molecular and cellular mechanisms by which memories of stressful events contribute to mood disorders. Focusing on neuronal receptors, signal transduction pathways, and gene responses, her goal is to uncover the key brain mechanisms linking cognitive and emotional processes and identify novel targets for treatment of anxiety and depression. She recently initiated a novel line of research aimed at pinpointing the key neuroanatomical and molecular components involved in the retrieval of positive and negative memories. Involved in interactions between emotion and episodic memory, retrosplenial cortical NMDA receptors—newly identified by her research group—may play a role.

Drugs that target the NMDA receptor in the brain, such as ketamine, have been used to quickly reduce depression. This class of medications works within hours versus weeks and months compared to other antidepressants. However, such drugs can have serious side effects, including hallucinations and schizophrenia-like effects. For more than 20 years, Joseph R. Moskal, PhD, research professor of biomedical engineering on the Evanston campus and director of the University’s Falk Center for Molecular Therapeutics, has been working on new therapeutics to combat depression and other neurological conditions. In December, his research group published results of a Phase IIa clinical trial of the drug compound GLYX-13. A first-of-its-kind antidepressant, GLYX-13 has been shown to rapidly, within hours, lift depression in adults who failed other drug treatment without negative consequences. This novel drug, like ketamine, takes a very different approach from most existing antidepressants by targeting the NMDA receptor, responsible for learning and memory. However, unlike ketamine, it interacts with the NMDA receptor in a new way that accentuates positive instead of negative antidepressant effects—for up to seven days in a single dose.

Preventing teen suicide

The teenage years can be trying enough without adding depression. The prevalence of depression among 12 to 17 year olds in this country is 8.3 percent, according to the Substance Abuse and Mental Health Services Administration. The CDC reports that suicide ranks as the third leading cause of death among adolescents; many teens with depression have suicidal thoughts. More so for teenagers than adults, peer pressure and the stigma of depression frequently deter them from seeking help. Their parents, too, may be in denial.

Eva Redei, MS, PhD, David Lawrence Stein Professor of Psychiatry and Behavioral Sciences, has long worked toward improving the detection of depression via objective diagnostic testing. Her research has resulted in the first blood test to diagnose major depression in teenagers by measuring a specific set of genetic markers. “A lab-based test has several advantages, among them accessing samples collected through a regular blood draw that might be taken during a physical exam,” she explains. “Kids with depression are not easy to diagnose. They are often non-verbal and in a ‘war with the world.’ To go to a psychiatrist is a big issue.”

Eva Redei, MS, PhD, David Lawrence Stein Professor of Psychiatry and Behavioral Sciences, and Mark A. Reinecke, PhD, clinical child psychologist

Testing the blood of depressed as well as non-depressed adolescents, the Redei lab examined 26 genetic blood markers. Dr. Redei discovered 11 of the markers clearly demarcated a difference between the two groups. And for the first time, another set of markers were able to distinguish between two subgroups of depressed adolescents: those who had anxiety symptoms in addition to depression and those who did not. Dr. Redei has almost completed her adult version of the test and in the future, she plans to extend this research to an older adult population.

Specializing in teen depression and suicide, clinical child psychologist Mark A. Reinecke, PhD, continues to explore aspects of the groundbreaking work of the National Institutes of Mental Health-funded multisite project known as the Treatment for Adolescents with Depression Study (TADS). Professor of psychiatry and behavioral sciences and chief of psychology, Dr. Reinecke directed Northwestern’s participation in this longest and largest study of its kind: the $17 million trial ended in 2003. The study found that combining drug therapy (Prozac) and cognitive-behavior therapy or “talk” therapy produced the best results for depressed teenaged patients. A decade later, more recent and somewhat alarming data shows a 46 percent recurrence rate, with 57 percent of girls relapsing into depression compared to 32.9 percent of boys. Preventing the slide back is a current focus of Dr. Reinecke’s lab.

Employing tech support

In today’s society, technology has become an integral part of daily life and a growing tool to influence behavior change and manage health issues, including major depressive disorders. David C. Mohr, PhD, professor of preventive medicine and director of Northwestern’s Center for Behavioral Intervention Technologies, is developing behavioral intervention technologies (BITS) ranging from simple land line to web-based mobile phone and sensor-based interventions. His earliest work explored the usefulness of the telephone as a mental health tool. Last year, he published results of the first large trial to compare the benefits of face-to-face versus telephone therapy. The study revealed that phone-based psychotherapy works as well as face-to-face sessions in reducing depression. It also improves access and compliance to ongoing therapy.

David C. Mohr, PhD, professor of preventive medicine and director of Northwestern's Center for Behavioral Intervention Technologies

Moving on to computers and the Internet, the Mohr lab has focused on the effectiveness of Web-based depression treatment. Particularly challenging are compliance issues, especially among depressed individuals who often exhibit low motivation.

“That’s part of the disease,” he says. “When left on their own, people with depression usually don’t adhere to Web-based treatment programs.” For this reason, Dr. Mohr has pursued the idea of using coaches to provide brief, supportive interactions to keep people with depression on track. He is also exploring Web-based social networks that would rely on peers with depression to help others stick with the Web-based treatment. Additionally, Dr. Mohr has been creating virtual humans or “conversational agents” that can humanize Internet interactions.

In the realm of mobile applications, Dr. Mohr is developing context-sensing apps that can analyze sensor data from the phone, for example, GPS, Bluetooth, and Wi-Fi data. This information could aid in identifying states of mind that may be related to an individual’s depression or treatment such as location, activities, and social settings. The data could be used to determine when people are doing things likely to make them feel worse, such as being at home alone on the weekend, and, conversely, when they are engaged in events likely to improve their mood, such as meeting a friend for coffee. The mobile intervention can also record the achievement of therapy goals like getting out of the house or following a regular schedule.

“People get tired of logging data and answering questions about what they are doing or who they are spending time with,” explains Dr. Mohr. “There’s been a big movement in m-health [mobile health] to start using sensors that people can wear.  We’re trying to see how much we can do with sensors that people always have with them in their phones.”

Mobile phones and computers may offer easier access to depression treatment, lower health care costs, and reach people who would not otherwise consider psychotherapy.  While not always available for certain segments of the population such as the economically-depressed or those in connectivity “dead zones,” the use of technology potentially provides a viable solution to the overwhelming numbers of people touched by depression.

“From a public health perspective, these technological interventions have an important place in our health care system,” says Dr. Mohr. “While they will never replace psychotherapists, they provide us with additional tools to help people.”

Improving all aspects of diagnosis and care for people with depression has resulted in a diverse research portfolio at Feinberg and throughout the University. Northwestern’s multidisciplinary “full assault” approach is making headway against a disease that afflicts individuals across all socio-economic and cultural boundaries.

“Depression remains the most pervasive and tragic of mental disorders,” says John G. Csernansky, MD, chair and Lizzie Gilman Professor of Psychiatry and Behavioral Sciences. “At Northwestern, we are poised to offer new treatments to our patients with depression, by combining innovations in drug therapy with psychotherapy, and by harnessing the power of mobile communication technologies.”