Emerging strategies to treat preschool-aged children with significant clinical depression as well as those severely depressed adults who do not respond to standard treatments — such as antidepressants and psychotherapy — were highlighted at a recent conference.
The options were presented at the National Alliance for Research on Schizophrenia and Depression (NARSAD) annual conference to advance research on the causes, treatment and prevention of psychiatric disorders.
During the symposium at Washington University, St. Louis-based researchers shed new light on what happens in the brains of children and adults who are affected by clinical depression, anxiety disorders and schizophrenia.
Coming at a time when more than 57 million Americans suffer from a diagnosable mental disorder, the new findings have immediate relevance in terms of new treatment options and different strategies for designing more targeted therapies for the future.
Robert Freedman, M.D., chair of the Department of Psychiatry and director of the Schizophrenia Research Center at the University of Colorado Health Sciences Center and Denver VA Medical Center, moderated the discussion.
Electrical Stimulation of the Vagus Nerve: A New Treatment for Depression
Among the most significant new developments in the field is vagus nerve stimulation (VNS), a novel procedure pioneered at St. Louis University and WUSM that acts on the brains of patients with “treatment-refractory depression,” a particularly virulent form of depression now affecting between 5-10 percent of those diagnosed with clinical depression.
Originally developed to treat epilepsy and then approved by the Food and Drug Administration (FDA) in 2005 for use in treating depression, VNS is a small electrical impulse generator attached to the large vagus nerve in the neck region that acts as a “pacemaker for the brain.”
According to Charles R. Conway, MD, associate professor of psychiatry at WUSM and formerly the medical director at the Vagus Nerve Stimulation Clinic in the St. Louis University Department of Psychiatry, approximately one-third of patients receiving VNS experience significant improvement in mood and better social and cognitive functioning, and for up to 70 percent of these individuals, the reduction in symptoms is long-lasting. An additional one-third of the patients receiving VNS have shown a limited response and the remaining third have not been helped.
VNS acts by stimulating a large nerve in the neck (vagus nerve) which sends thousands of fibers higher up into the brain. Dr. Conway reported that the existing evidence suggests that most patients who respond positively to this treatment do not see immediate results. Although some patients receiving VNS therapy experience improvements within the first few weeks after implantation, there is often a long delay (9-14 months or longer) as the brain adapts to the stimulation and develops an anti-depressive response.
VNS: A Patient’s Perspective
This was the case for St. Louis institutional bond trader, Charles E. Donovan III, who spent years being incapacitated by severe, treatment-resistant depression and was one of the first patients to be implanted with the vagus nerve stimulator in 2001 as part of an investigational trial.
“When I was implanted with VNS, I had been suffering from severe depression for several years and had gotten to the point where I was feeling completely isolated and emotionally paralyzed, “ said Donovan who wrote the book, Out of the Black Hole: The Patient’s Guide to Vagus Nerve Stimulation and Depression, to raise awareness about VNS. “It took 14 months for the complete effects of VNS to take place, but now my depression is gone. Not everyone responds to VNS as I did but my story offers hope for those who have long suffered without successful treatment that new options are now possible.”
In fact, because VNS works successfully in some depressed patients but not in others, Dr. Conway is now conducting research with neuroimaging techniques to determine which patients are likely to respond to VNS therapy. With research funding from NARSAD, Dr. Conway and his team are recruiting patients in the St. Louis area for a study that will use PET scans to look at how the stimulation of the vagus nerve can lead to short- and long-term changes in the brain’s activity and exactly what regions of the brain undergo change with long-term treatment with VNS.
“We know that the depressed brain looks a specific way on a PET scan. And when we can see what regions of the brain are positively affected by VNS therapy, our hope is to be able to identify the best candidates for this new treatment option,” Dr. Conway explained. “Having this new data will not only lead to improved treatment outcomes, but it will support current efforts to get insurance companies to reimburse for VNS implantation.” Currently, insurance companies have covered VNS on a case-by-case basis.
Depression in Preschoolers
While Dr. Conway’s research may lead to better treatments for severely depressed adult patients, Joan L. Luby, MD, associate professor of child psychiatry and founder and director of WUSM’s Early Emotional Development Program, is currently investigating the efficacy of a new treatment program for clinically depressed children as young as age 3 — a time of significant neurobiological change when there is the potential to alter the course of depression later in life.
“Clinicians used to think that very young children were not developed enough to experience depression, but studies going back to the 1980s changed this viewpoint,” said Dr. Luby. “Now, we know that depression is a major childhood illness with potentially debilitating consequences.”
A number of epidemiological studies have reported that up to 2.5 percent of children and up to 8.3 percent of adolescents in the U.S. suffer from depression. But until recently, very little was known about the impact of depression on very young children, which is why Dr. Luby and her colleagues are studying children between the ages of 3 years and 6 years old to identify what clinical depression looks like in preschool children.
Starting with a large-scale study funded by NARSAD and the National Institute of Mental Health, Dr. Luby and her team identified anhedonia — the inability to experience pleasure from activities and play — as a key symptom of depression in very young children. Another common symptom is that depressed children often use play to explore themes about death and sometimes even suicide.
“We learned that depressed children don’t derive pleasure from the same things as a typical 3- to 5-year-old child,” said Dr. Luby. “They’re less joyful when they encounter the pleasures of daily life.”
Now, Dr. Luby and her colleagues are testing a new treatment program for depressed preschoolers in their laboratory that applies these findings. Using a model similar to speech or other developmental therapies, this new program utilizes the interaction between parents and their children to teach depressed children how to experience positive emotions, manage negative emotions and more generally, how to enhance emotional development on a sustained basis. After pre-testing the new program in eight preschoolers, Dr. Luby’s team is now recruiting 30 more young children from the St. Louis area for the new treatment study.
“The normal developmental curve for any child is very steep at this point in life and being depressed and dysfunctional for a long period of time could actually impair normal development,” Dr. Luby explained. “It’s very important that we find a safe way to help them get better and to prevent future episodes.”
Understanding and Regulating Anxiety, The Most Prevalent Mental Illness
It is also important to find ways to improve the functioning of the more than 40 million Americans or 18.1 percent of the population that suffer from anxiety disorders — the most common psychiatric illnesses. For this reason, the NARSAD symposium provided the latest thinking on how anxiety disorders affect decision-making, perceptions, learning and concentration.
According to Christina Fales, Ph.D., a postdoctoral fellow in psychology at Washington University, people with general anxiety disorders (GAD) may process information differently than healthy people. They may be more susceptible to attention lapses, making reasoning and problem-solving as well as the avoidance of undesirable thought patterns more difficult.
Compared to people with low anxiety who, on a sustained basis, activate the regions of the brain involved in cognition and problem-solving — called the working memory network — Dr. Fales has found that people with high levels of anxiety access working memory in a transient manner. This doesn’t mean that anxious people are cognitively impaired but rather, they are less efficient in carrying out cognitive tasks, and have to work harder to process information. This extra effort may be necessary because unregulated emotional arousal interferes with normal cognitive processing.
What makes these findings significant is the potential for developing new therapies to improve the cognitive regulation of emotion, explained Dr. Fales. “Many GAD patients report that antidepressants have limited success in dealing with their anxiety, “she said. “The more we know about the interaction between the networks in the brain that process cognition and help regulate emotion, the easier it will be to design more targeted therapies for anxiety disorder.”
Living with Schizophrenia: Overcoming Emotional and Motivational Challenges
New research findings may also pave the way for new therapies to regulate the memories and emotions of people with schizophrenia, one of the most debilitating psychiatric disorders. Complementing NARSAD-funded research which showed people with schizophrenia can be assisted in remembering things if they are given proper cues and memory aids, Dr. Deanna M. Barch, Ph.D., director of the Conte Center for the Neuroscience of Mental Illness and chief neuropsychologist at the Washington University Treatment Units Research Network Site, is now focusing on the emotional and motivational problems that affect how people with schizophrenia function on a daily basis.
According to Dr. Barch, research has demonstrated that people with schizophrenia are able to experience the same pleasurable responses to stimuli, such as seeing a movie, listening to music, or drinking a beverage, but these reactions were much more intact than what subjects with schizophrenia reported in questionnaires that ask them to imagine how they would feel in very situations.
This inability to either retain pleasurable memories or to anticipate pleasurable experiences in the future may be a major factor contributing to what Dr. Barch calls “the negative symptoms” associated with schizophrenia – including the lack of energy, drive and motivation.
Using functional MRI, structural MRI and cognitive neuroscience methods, Dr. Barch and her research team are trying to identify the neurobiological disturbances in the brain that may cause these negative emotional symptoms. Between 50 and 70 percent of people with schizophrenia have these negative symptoms, especially those who have earlier onset of the disease, according to Dr. Barch.
“This is a very serious public health issue,” she said. “Current therapies for schizophrenia have not proven effective in treating negative emotional symptoms, making it harder for those who experience these symptoms to live independently and seek treatment. The goal is to explain what is happening in the brain so we can design better treatments in the future.”