Clinical Research at McLean

Through scientific investigations on human participants, clinical researchers try to find better ways to diagnose, prevent, and treat mental health disorders.

The human brain is a marvelous—and marvelously complex organ. It has long been known that our brain is what sets us apart from other species, allowing us to feel, hear, smell, and most of all, think. But it is also an incredibly complex organ, regulating the systems that keep us breathing and moving. And much like modern computers, the brain is capable of malfunctions, both minor and major.

Clinical research allows scientists to move discovery in the lab toward new and improved treatments or updates in processes or policy.

There are many types of clinical research. Carefully conducted clinical trials can test a new drug or treatment. Tests or surveys help to gather data. The common thread is the interaction with human volunteer participants.

From Benchtop to Bedside

Advancements in the diagnosis and care of many illnesses and conditions are often based on clinical research.

Clinical trials are often next steps beyond results from basic science laboratory research to see how findings translate to human beings. Other clinical research studies try to find trends in patient care to lead improvements in the delivery of mental health treatment.

In fields such as psychiatry, investigators conduct clinical trials to see if certain drugs or treatments are effective for mental health conditions, like anxiety, depression, or substance use disorders. These trials often have their origins in basic science laboratory studies that indicate a certain result. In many cases, these studies lead to trials using animal models. From there, full clinical trials may be conducted using human participants.

Other types of clinical research may take place within a mental health treatment program. Studies that rely on surveys, testing, or other similar measures can take place while a patient or group of patients are undergoing treatment. Though patients may be asked to take part in clinical research, participation is not required and does not affect access to care.

Researchers recruit volunteers from specific populations to participate in these studies. These groups may be people who have a specific disorder, or they may be people from different age, gender, or ethnic groups. For some studies, volunteers are people who do not have a health problem, and their participation helps set a baseline for future study.

Clinical research is not medical care, although some clinical trials test new drugs and treatments, and participants may see improvements in their condition. Because clinical trials are experiments, researchers are required to follow a plan or “protocol” for the study, meaning that the plan cannot be changed based on the condition of the participant.

Ultimately, the goal of clinical research is to gather information and answer scientific questions.

Clinical Research at McLean

One of the main goals of McLean Hospital clinical researchers is to search for clues that will help bring about tomorrow’s treatments for today’s illnesses.

In 1888, McLean became the first psychiatric hospital in the U.S. to establish basic and clinical laboratories to study the role of biological factors in mental illness. Since then, McLean researchers have used clinical trials to pioneer advances in the diagnosis, prevention, and treatment of psychiatric disorders.

Clinical researchers at McLean focus on a wide range of conditions. From investigations into depression, anxiety, and addiction, McLean investigators work with study volunteers and their patient population to further the understanding of the diagnosis, prevention, and treatment of psychiatric disorders across the life span.

Our clinical researchers conduct a broad range of investigation, from studies administering questionnaires and computerized assessments to studies using wearables and devices (like fitness trackers or smartphones) to studies using non-invasive ways to examine the brain (such as MRI and EEG).

Central to the work of these researchers is the translational approach to research. Clinical researchers collaborate with basic neuroscience investigators and clinicians at the hospital to further efforts to translate study findings into effective, real-world applications that help patients.

Our patients are also instrumental to finding out what is going on in the brain. While patient participation in clinical research is entirely voluntary, many patients are eager to volunteer—knowing that their privacy will be protected and that their participation could lead to significant advances in care.

Such potential can be seen in the work of some of our clinical researchers.

Amy C. Janes, PhD: Discovering What Addiction Looks Like

Amy C. Janes, PhD, directs the Functional Integration of Addiction Research Laboratory at the McLean Imaging Center. She uses clinical neuroimaging, like MRI, to clarify how individual differences in brain function, chemistry, and structure influence drug use and relapse. Her work focuses on what makes nicotine addictive and what can be done to treat this and other addictive behaviors.

A key to her research is the recognition that a treatment, like nicotine replacement therapy, may work for one person but not someone else—and that variance in brain function is the key to unlocking individual treatment plans.

According to Janes, “Nicotine replacement therapy is a frontline therapy for treating nicotine dependence. This medication replaces the nicotine that someone would be losing by not smoking anymore. It seems obvious that if they are getting the nicotine, they should stop smoking. The problem is that they don’t.”

Some smokers, however, don’t stop smoking when using nicotine replacement therapy. This shows that other factors come into play. A major factor is how people respond to cues in their environment that remind them of smoking, such as seeing someone else smoking or walking past the place where they typically take a smoking break.

Janes’ research involves neuroimaging of the brain’s insular cortex. Scientists believe that this area of the brain is involved in functions such as consciousness and emotions.

“We showed that individuals who had greater activation of this brain region in response to smoking cues—even before they quit—were likely to relapse, even when treated with nicotine replacement therapy,” she said. “They need something else.” Her current focus is not only to identify particular groups of people susceptible to relapse, but also to identify what that “something else” might be.

A large proportion of those with major depression are smokers. Janes’ lab is also exploring how to help these individuals. Research has shown that, when given a placebo, people with major depression have weakened communication within the brain’s rewards pathway.

“But when you give people with major depression nicotine, it makes that connection look like the connection we see in a healthy controls,” she explained. “Once we know neurobiologically what the process is, can that help us come up with treatment for nicotine dependence?”

James I. Hudson, ScD, SM: Finding Common Biological Ground

Biology is also at the foundation of the work James I. Hudson, MD, ScD, SM, has been doing for more than three decades. Together with his research group, the Biological Psychiatry Laboratory, he has published extensively on the causes, frequency, and treatment of eating disorders, mood disorders, fibromyalgia, personality disorders, and substance use disorders.

In the course of his research on eating disorders, Hudson and his colleagues observed that a substantial number of individuals experienced eating binges without the purging behavior of self-induced vomiting or laxative misuse seen in bulimia nervosa.

His group, along with others, began to call more attention to this condition as far back as the 1980s. Over the subsequent years, a large body of research has grown up surrounding this new diagnosis of binge eating disorder, which was officially recognized in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders in 2013.

“It was initially unclear whether binge eating disorder was just a non-specific pattern of eating related to obesity, where people would have some binge eating and loss of control, or whether it had an actual biological, and possibly genetic, basis,” he said.

Hudson and his lab performed a large family study of individuals with binge eating disorder and found that the disorder tended to run in families—suggesting that it might have a genetic basis.

“The results of our family study suggested that binge eating disorder was a genuine illness unto itself, rather than simply a nonspecific pattern of eating among overweight individuals,” said Hudson.

Hudson’s group has also looked at various medications to treat binge eating disorder, including antidepressant medications, antiepileptic medications, and medications similar to those that have been previously used to treat attention-deficit hyperactivity (ADHD) disorder. Many of these medications have been quite successful, suggesting that we are making substantial progress in a disorder that was only barely recognized 35 years ago.

Hudson continues to pursue research in this important area.

Mei-Hua Hall, PhD: Intersection of Genetics and Biology

Genetics is also an underlying foundation of the discovery taking place in the lab of Mei-Hua Hall, PhD. The Psychosis Neurobiology Laboratory works at the intersection of genetics and neurobiology. Studies of schizophrenia and bipolar disorder have found many risk genes and variations within the genes associated with psychotic disorders, though their effects on the brain are largely unknown. How genetic and environmental risk factors influence mental illness, cognition, brain function, and treatment outcomes are also largely unknown.

In working to link genetic risk factors to the brain’s neurophysiological characteristics, Hall and her lab use an integrative, data-driven approach—combining neurophysiological, neurochemical, genetic, clinical, and behavioral measures—to clarify the underlying causes of psychotic disorders and the considerable clinical and biological differences across psychosis syndromes. One of her principal tools is the electroencephalograph (EEG), which is often used in tests ranging from sleep disorders to epilepsy. The wave patterns that are captured can be isolated into different event-related potentials or components where specific deficits hold clues to brain mechanisms and treatments.

“Because everybody’s neurobiology is different, they may respond differently to different treatments,” said Hall. Using computational methods to carefully analyze those deficits can help to develop an algorithm to identify how someone is likely to respond, allowing the clinician to adjust a treatment plan.

“For example, if you have an intact or normal sensory gating inhibitory mechanism, your brain will automatically filter out the noise in the background at a restaurant and allow you to focus on ordering your food or carrying out a conversation with your friends,” she said. “Imagine it’s not functioning properly. Those patients are not able to ignore those background noises, so everything that comes into a sensory organ becomes equivalently important, and they are overwhelmed.”

The results of the EEGs are applied to individual cognitive remediation training programs to index treatment effectiveness and are used in models for predicting recovery trajectory and relapse risk.

“The idea is that the brain needs exercise, just as the physical body needs exercise, because if we don’t exercise, the body will decay or atrophy,” she explained. Cognitive remediation aims to build a better connection for the neurons so they can continue to grow or strengthen their connections from one part of the brain to another.

Courtney Beard, PhD: Retraining the Brain

Retraining the brain is also a fundamental component of the Behavioral Health Partial Hospital Program (BHP), a bridge between inpatient and outpatient levels of care. Patients come for an average of 3-10 days of intensive treatment but go home at night.

In addition to individual treatment plans, patients are able to volunteer for studies where study data is paired with individual patient data. Often these studies involve testing out a new treatment in areas such as depression, bipolar and anxiety disorders, and a smaller proportion of psychotic and personality disorders. Clinician-scientists like Courtney Beard, PhD, co-director of clinical research at BHP and director of the Cognition and Affect Research and Education (CARE) Laboratory, lead the way.

An important part of the program is cognitive bias modification, which focuses on “any type of repetitive, simple, usually computerized training task that is trying to target a very specific mental habit that we know maintains someone’s depression or anxiety.”

An example is interpretation bias, or how people interpret ambiguous situations or uncertainty. This can range from not getting a job or a friend not returning a call. The tendency to resolve ambiguity in a negative way is a crucial therapeutic target, according to Beard. Individuals with this cognitive vulnerability tend to get “stuck.”

“We’ve tried to help people with this specific mental habit for a long time with things like cognitive behavior therapy—helping them reappraise situations—and that can be quite effective,” she explained. “However, it’s very challenging for people to learn quickly and hard to put into practice when you’re under a lot of stress. Cognitive bias modification (CBM) is a way to put these skills into practice and speed things along.”

CBM involves a very simple task—delivered via computer or smartphone app—where people see hundreds of ambiguous situations in the form of a sentence and are repeatedly reinforced for choosing positive or benign interpretations of those situations.

“They’re given feedback like ‘you are correct, one point.’ So, it’s sort of a game. It can very efficiently show people how often their brain is jumping to a negative conclusion and not even considering a positive one. It is designed to change the brain’s automatic processes, which is hard to do in typical therapy.”

Ultimately, clinical research helps improve understanding of behaviors, habits, or biology that contributes to the mental illness. Combined with randomized controlled trials, it offers guidance on for whom a treatment works best and why.

“People think they know why a treatment works, but you can be surprised when you actually try to test out what the active ingredients are,” said Beard. “Since we are a very real-world clinical setting, a lot of our work is on the very last step of bench to bedside. We’re figuring out how to best implement treatments in a real-world clinical setting.”

Improving Mental Health Care

For years, clinical researchers at McLean have been advancing our understanding of psychiatric disorders and pioneering treatments that have helped thousands of individuals struggling with mental illness.

Working closely with clinicians, basic neuroscience researchers, and the many study participants and volunteers, these investigators constantly look for new opportunities to test and improve therapies and medications. Their work is essential to advancing psychiatry and helping individuals with mental illness live better lives.

Learn More

You may find this additional information to be helpful:

• Read issues of Discovery @ McLean Hospital, McLean’s research publication
• Find articles about the latest in clinical research news and discovery
• Meet some of our expert investigators and clinical researchers
• Read about research press coverage in the media
• Explore more information about clinical research at McLean
• Watch these videos about working in research at McLean

Glossary

Clinical Research

Medical research that involves human participants for the purpose of evaluating treatments, medications, devices, or interventions.

Types of Clinical Trials

• Diagnostic trials – Designed to determine better tests or procedures for diagnosing a particular disease or condition
• Natural history studies – Studies that seek to gain information about how disease and health progress
• Prevention trials – Studies created to better understand ways to prevent a disease in people who have never had the disease or to prevent the disease from returning
• Quality-of-life trials (or supportive care trials) – These studies explore and measure ways to improve the comfort and quality of life of people with a chronic illness
• Screening trials – Tests designed to improve detection of certain diseases or health conditions
• Treatment trials – Testing of new treatments, drugs, devices, or interventions

Informed Consent

Before someone decides to take part in a clinical research study, they must review documentation explaining the risks and possible benefits of the trial.

Institutional Review Board

An administrative panel charged with protecting the rights of human research volunteers who participate in research. All research studies that include human subjects are thoroughly reviewed prior to recruitment of participants.

Healthy Volunteer

A participant in a clinical study who has no known significant health problems.

Patient Volunteer

A participant in a clinical study who has a known health problem. This volunteer takes part in the study to help investigators better understand, diagnose, treat, or cure a given disease or condition.

Placebo

A pill or liquid with no treatment value—it simply looks like the drug or treatment being tested.

Protocol

A plan to protect the participants’ health during the study.

Principal Investigator

The leader of the clinical research team, the principal investigator coordinates and directs the trial and monitors the health and progress of the participants to ensure safety and effectiveness.

Single- or Double-Blind Studies

In these studies, participants do not know which medicine is being used, allowing them to offer researchers information free from bias.

History of Clinical Research

It’s fair to say that human beings have been conducting clinical research for as long as there have been human beings. “Trials” observing how individuals react to ingesting certain foods or drinks or how they respond to heat or cold or darkness or stress have always been a part of our existence. We human beings are curious, and we want to better understand ourselves.

Over the years, clinical research has become more sophisticated. In 1747, physician James Lind conducted what is considered the first controlled clinical trial of the modern era when he tested the impact of different foods and medicines on isolated groups of scurvy patients. By 1800, researchers began conducting experiments using placebos to determine the effectiveness of various treatments for diseases like rheumatism.

The first double-blind study was conducted in 1943-1944, when England’s Medical Research Council investigated patulin treatment for the common cold. In a nationwide trial, more than 1,000 office and factory workers with colds took part in an ambitious effort in which neither the physicians nor the patients knew who was receiving patulin and who was receiving a placebo.

Clinical research studies have evolved and expanded over the years, and they are widely used in medicine, biology, psychiatry, even education. As the field of clinical research has advanced, so have protocols and protections for human participants. In response to questionable use of participants in trials, particularly during World War II, several international regulations have been put in place to inform and protect clinical study participants.

McLean established basic and clinical laboratories in 1888 to study the role of biological factors in mental illness. At that time, the hospital founded facilities for the study of pathology, psychology, microbiology, and chemistry.

More recently, in 1973, McLean established the first Alcohol, Drug, and Addiction Research Center in a private American psychiatric hospital. It is the nation’s largest and most comprehensive research facility of its kind devoted to the study of addictive disorders.

In 1984, McLean started the first controlled outcome study evaluating the effects of psychoanalytic psychotherapy for patients with schizophrenia. The results of this study spurred a new generation of psychosocial approaches in the treatment of this disorder.

In 2007, McLean Hospital investigators conducted the first national survey of individuals with eating disorders, showing that binge eating disorder is more prevalent than either anorexia nervosa or bulimia nervosa.

Today, McLean’s clinician-scientists are at the forefront of pioneering clinical research.