New York Academy of Sciences
New Frontiers in the Neurobiology of Mental Illness
Posted December 19, 2014
Mental illness continually ranks among the top ten causes of disability worldwide. Patients, many of whom are adolescents and young adults, may be reluctant to seek help, discouraged by stigma and a lack of resources and education. On October 10, 2014, World Mental Health Day, scientists and policy makers met at the New York Academy of Sciences to discuss better approaches to the treatment and prevention of mental illness. The symposium, titled New Frontiers in the Biology of Mental Illness, highlighted advances in neuroscience that could usher in a new era in psychiatry. Topics included new drug options for major depressive disorder and posttraumatic stress disorder and holistic treatment programs for schizophrenia. Speakers also discussed technologies that are driving advances in brain research and providing insights into social interaction in autism. The Honorable Patrick J. Kennedy gave the keynote lecture, which focused on how to dispel stigma so that treatments are accessible to all patients.
Use the tabs above to find a meeting report and multimedia from this event.
Presentations available from:
The Honorable Patrick J. Kennedy (Former U.S. Representative, Rhode Island; One Mind for Research; Kennedy Forum)
Dennis S. Charney, MD (Icahn School of Medicine at Mount Sinai)
John M. Kane, MD (Zucker Hillside Hospital; Hofstra North Shore–LIJ School of Medicine)
Husseini Manji, MD (Janssen Research & Development)
Barbara O. Rothbaum, PhD (Emory University School of Medicine)
- 00:011. Introduction and overview
- 11:502. The genomic revolution; Epigenetics; Brain cell biology
- 20:323. The neuroscience revolution; Synaptic plasticity
- 28:004. Targeting the biology of recurrence
- 33:425. Looking at Bcl-2; Inhibiting Bid
- 42:226. Integrative solutions and holistic care; Partnerships; Summary and conclusio
- 00:011. Introduction and overview
- 04:192. The glutamate system and ketamine; Early and recent ketamine studies
- 13:003. Intranasal delivery; Impact on suicidal ideation; Repeated infusions
- 20:374. Maintaining the antidepressant response; Safety
- 26:165. The mechanism of action; Other antidepressants; Acknowledgements
- 31:176. Q and A sessio
New technologies in neuroscience
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Holistic care models in schizophrenia
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Rapid action of ketamine for major depression
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Understanding the social brain in autism
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Exposure therapy in posttraumatic stress disorder
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American Psychiatric Association. DSM-5 Development.
The Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) was released at the American Psychiatric Association's Annual Meeting in May 2013.
The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative is part of a new Presidential focus aimed at revolutionizing our understanding of the human brain.
A holistic treatment program sponsored by Janssen Healthcare Innovation.
CLARITY (clear, lipid-exchanged, acrylamide-hybridized rigid, imaging/immunostaining compatible, tissue hydrogel) is a brain-imaging technique that makes brain tissue transparent.
Harvard University Center for Brain Science. Brainbow.
A brain-imaging technique to label each nerve cell a different color to identify and track axons and dendrites over long distances.
Human Connectome Project
The Human Connectome Project aims to provide an unparalleled compilation of neural data, an interface to graphically navigate these data, and the opportunity to achieve new conclusions about the living human brain.
A clinical study in first-episode schizophrenic patients.
Virtually Better Inc.
A company that creates virtual reality environments for clinical therapies.
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Yale School of Medicine. Child Study Center.
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The Honorable Patrick J. Kennedy
Former U.S. Representative, Rhode Island; One Mind for Research; Kennedy Forum
The Honorable Patrick J. Kennedy served 16 years in the U.S. House of Representatives. He was the author and lead sponsor of the Mental Health Parity and Addiction Equity Act of 2008, which provides tens of millions of Americans who were previously denied care with access to mental health treatment. Kennedy is the co-founder of One Mind for Research, a national coalition seeking new treatments and cures for neurological and psychiatric diseases. The organization is dedicated to dramatic enhancements in funding and collaboration in research across all brain disorders in the next decade. Kennedy is also the founder of the Kennedy Forum on Community Mental Health, which recently highlighted the 50th anniversary of President Kennedy's signing of the Community Mental Health Act. That legislation is a foundation of contemporary mental health policy and served as a springboard to launch the new effort. The Kennedy Forum continues to advocate for mental health parity. Kennedy authored and co-sponsored dozens of bills to increase the understanding and treatment of neurological and psychiatric disorders, including the National Neurotechnology Initiative Act, the Genomics and Personalized Medicine Act, the COMBAT PTSD Act, and the Alzheimer's Treatment and Caregiver Support Act. He has been recognized by many organizations for his mental health advocacy. He is also founder of the Congressional Down Syndrome Caucus and the 21st Century Healthcare Caucus, as well as an honorary board member of SAM – Smart Approaches to Marijuana.
Dennis S. Charney, MD
Dennis S. Charney is the Anne and Joel Ehrenkranz Dean of the Icahn School of Medicine at Mount Sinai and president for academic affairs at the Mount Sinai Health System. He studies neurobiology and the treatment of mood and anxiety disorders, particularly the causes of human anxiety, fear, and depression and the discovery of new treatments for mood and anxiety disorders. He holds an MD from Pennsylvania State University and completed a psychiatry residency at Yale University School of Medicine and a biological sciences training fellowship at Connecticut Mental Health Center. Before joining Mount Sinai, Charney was a professor of psychiatry at Yale University and led the Mood and Anxiety Disorder Research Program at the National Institute of Mental Health (NIMH). At Mount Sinai, he is developing the structure for complementary clinical institutes that will serve as Centers of Excellence for cancer, heart disease, diabetes, HIV, pulmonary diseases, and more, with the anticipation that this architecture will further eliminate silos and generate game-changing models in clinical excellence and standards of care.
John M. Kane, MD
John M. Kane is vice president for behavioral health services at the North Shore-Long Island Jewish Health System and chairman of psychiatry at the Zucker Hillside Hospital. He is also chairman of psychiatry and professor of psychiatry and molecular medicine at the Hofstra North Shore-LIJ School of Medicine. Kane received his MD from New York University School of Medicine. He is a schizophrenia researcher focused on intervention and services research, particularly improving early diagnosis and treatment, as well as developing new treatments and strategies to improve long-term course and outcome. He directs the NIMH-funded Advanced Center for Interventions and Services Research in Schizophrenia at the Zucker Hillside Hospital. He has been a member of the Board of Scientific Counselors for NIMH and has served on the council of the American College of Neuropsychopharmacology. He has chaired the NIMH Psychopathology and Psychobiology Review Committee as well as the Psychopharmacologic Drugs Advisory Committee of the Food and Drug Administration.
Husseini Manji, MD
Husseini Manji is the global therapeutic head for neuroscience at Janssen Research & Development LLC, a division of Johnson & Johnson. He previously served as chief of the Laboratory of Molecular Pathophysiology & Experimental Therapeutics at the National Institutes of Health (NIH) and director of the NIH Mood and Anxiety Disorders Program. Manji received his MD from the University of British Columbia, Canada, and completed fellowship training at NIMH. His research has focused on disease- and treatment-induced changes in gene and protein networks that regulate synaptic and neural plasticity, leading to investigation of novel therapeutics for patients with refractory neuropsychiatric illnesses. Manji is the recipient of the NIMH Director's Career Award for Significant Scientific Achievement and has served as chair of the American College of Neuropsychopharmacology. He is a counselor to the Society of Biological Psychiatry and holds voluntary leadership positions in several organizations devoted to the advancement of neuroscience and advocacy for people with neuropsychiatric illnesses.
Barbara O. Rothbaum, PhD
Barbara O. Rothbaum is a professor of psychiatry and associate vice chair of clinical research at the Emory School of Medicine and director of the Trauma and Anxiety Recovery Program at Emory. Rothbaum specializes in research on the treatment of anxiety disorders, focusing on posttraumatic stress disorder (PTSD). She has served on the Board of Directors and as past president of the International Society of Traumatic Stress Studies (ISTSS) and as associate editor of the Journal of Traumatic Stress. Rothbaum is a Scientific Advisory Board member for the Anxiety Disorders Association of America (ADAA), the Obsessive Compulsive Foundation (OCF), the National Center for PTSD (NCPTSD), and McLean Hospital of Harvard University. She is also on the Board of Directors for ADAA. Her current work focuses on treating chronic PTSD in Iraq veterans using virtual reality exposure therapy combined with medication, preventing the development of PTSD in emergency room patients, and testing a CRF1 antagonist for the treatment of PTSD in women. Her outreach efforts with veterans include the BraveHeart: Welcome Back Veterans Southeast Initiative and a clinician outreach and training program with the Georgia National Guard.
Fred R. Volkmar, MD
Fred R. Volkmar is the Irving B. Harris Professor of Child Psychiatry, Pediatrics, and Psychology and director of the Child Study Center at Yale University School of Medicine. He is also the chief of child psychiatry at Yale–New Haven Hospital. He received his MD and a Master's degree in psychology from Stanford University. Volkmar was the primary author of the American Psychiatric Association's DSM-IV Autism and Pervasive Developmental Disorders Section. He is the author of A Practical Guide to Autism (Wiley Press), Asperger's Syndrome (Guilford Press), Health Care for Children on the Autism Spectrum (Woodbine Publishing), and the Handbook of Autism and Pervasive Developmental Disorders (Wiley Publishing). He is editor-in-chief of the Encyclopedia of Autism Spectrum Disorders and editor of the Journal of Autism and Developmental Disorders. In addition to directing the autism clinic, he was also director of the autism research program at Yale before becoming chair of his department. Volkmar has been the principal investigator of major grants including a CPEA (Collaborative Program of Excellent in Autism) grant from the National Institute of Child Health and Human Development and a STAART (Studies to Advance Autism Research and Treatment) Autism Center Grant from NIMH.
Jennifer Cable lives in New York City, where she experiments with different outlets to communicate science. She enjoys bringing science to scientists and nonscientists alike. She writes for Nature Structural and Molecular Biology, Bitesize Bio, Under the Microscope, and the Nature New York blog. She received a PhD from the University of North Carolina at Chapel Hill for her research in investigating the structure/function relationship of proteins.
The Honorable Patrick J. Kennedy
Former U.S. Representative, Rhode Island; One Mind for Research; Kennedy Forum
The Mental Health Parity and Addiction Equity Act of 2008 requires comparable health insurance coverage for mental and physical illnesses.
Medical advances must be coupled with efforts to dispel social stigma to fully realize the potential of new treatments to improve mental health.
According to the World Health Organization, mental illness is the top cause of years lost to disability (YDL) worldwide, with YLD defined as years lived in states of poor health or disability. In the Americas and Europe, unipolar depressive disorders rank, respectively, as the second and third highest cause of disability-adjusted life years (DALYs), a measure of overall disease burden that accounts for YDL and years of life lost to mortality (YLL). Mental illness also results in significant cost to the health care system. A 2011 World Economic Forum report determined that mental illness costs more than cancer, diabetes, and chronic respiratory diseases combined.
While mental illness is often considered a disease of the mind, its effects go further. The CDC reported more than 39 000 deaths from suicide in the U.S. in 2011, many resulting from mental illness. A recent meta-review found mental disorders also shorten expected lifespan by 10–20 years, not only because of increased suicide rates but also because of the higher rates of chronic diseases such as cardiovascular disease and type 2 diabetes among sufferers.
In the U.S., with dwindling funding for mental health and pervasive social stigma, the outlook for a mentally ill person is relatively bleak. While the deinstitutionalization movement in the 1950s decommissioned many insane asylums, it did not provide the funding or resources to set up community-based mental health services. As a result, the criminal justice system has become the front line of mental health care, with police often acting as first responders to those experiencing acute mental illness. An article in the Journal of the American Medical Association published earlier this year revealed that prisons and jails house ten times more mentally ill individuals than mental hospitals, indicating a criminalization of mental illness in society.
The civil rights movement of our time
The Honorable Patrick J. Kennedy, former U.S. Representative for Rhode Island and director and cofounder of One Mind, delivered the keynote lecture. One Mind is a nonprofit organization that seeks to accelerate research on mental health while working to reduce social stigma. During his tenure in Congress, Kennedy was a chief sponsor of the Mental Health Parity and Addiction Equity Act (MHPAEA), passed in 2008, which requires health insurance companies to provide comparable coverage for mental and physical illnesses.
Kennedy recounted how, on May 25, 2001—the 50th anniversary of President John F. Kennedy's call to Congress to send a man to the moon—he gave a speech urging a group of neuroscientists to begin a 10-year mission to "inner space": the brain. Just as NASA had organized previously disparate pieces of knowledge and science to complete its mission, so must neuroscientists integrate vast amounts of genomic, proteomic, metabolomic, and other data.
Despite the scientific challenges ahead in brain research, Kennedy asserted that we face still greater hurdles, such as securing adequate funding for research and ensuring that insurance companies provide the same level of care for mental illness as for diseases like cardiovascular disease and cancer. Kennedy said monitoring systems should be set up to assess insurance companies' compliance with MHPAEA. He also argued that outcomes and improvements in a person's life should be the measure by which insurance companies are judged—not a checked box indicating that treatment was provided.
"We're not going to get there overnight just because we passed [MHPAEA]," Kennedy said. "We have to stay true to the notion that this is going to be a long challenge. The sooner we get to it, the sooner we're going to get to a result, which is that we'll treat other people like we ourselves want to be treated. That is going to be the hallmark of this new civil rights movement."
Barriers to achieving equal care for mental illness include social stigma and the idea that patients who suffer from mental disorders have a character flaw rather than a chemistry flaw. According to Kennedy, caring for the mentally ill is a moral challenge for society; patients are injured not only by their disease but also by a society that does not consider their disease to be as real as other types of illness.
Throughout the day, speakers reminded the audience that treating mental illness is not just about making neurons act normally or relieving a patient's symptoms; it is also about giving patients their lives back. Husseini Manji summarized advances in neuroscience that promise to expand our understanding of the brain. John M. Kane discussed holistic strategies he is developing to treat schizophrenic patients. Barbara O. Rothbaum presented studies that aim to optimize exposure therapy in patients with posttraumatic stress disorder. Dennis S. Charney presented clinical data for a rapid-acting antidepressant. And Fred R. Volkmar described techniques to assess how people with autism view social situations, which researchers are using to determine which interventions are most successful.
Janssen Research & Development
Recent advances in mental illness research have been deemed the "biggest breakthroughs in psychiatry in 40 years" by the director of the National Institute of Mental Health.
A better understanding of the biological effects of current therapies can lead to new drugs by elucidating drug pathways and targets.
According to Husseini Manji of Janssen Research & Development, we are in a "golden age" of neuroscience when scientific advances have the potential to make real changes in people's lives. Manji summarized some of these advances, which he hopes will bring new energy to the field by illustrating that mental illness is a tractable problem.
The Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) initiative, launched by President Obama in 2013, has substantial funding to accelerate the development and application of technologies that help us understand the brain. As the Human Genome Project advanced genomics, so the BRAIN initiative is designed to revolutionize neuroscience, bringing together researchers from government, industry, and academia to develop technologies.
Neuroscientists are already capitalizing on recent advances. Cheaper genetic sequencing has allowed scientists to identify genes involved in psychiatric illnesses, pointing to new pathways of disease and potential drug targets. In addition, insights in epigenetics may lead to therapies that can reduce the mental health impact of traumatizing events. Epigenetics describes modifications to the genome that do not affect DNA sequence but influence the expression of certain genes. Research in animals has shown that experiences in early life can alter genes (for example, through methylation), affecting expression of those genes later in life. In the case of mental illness, these epigenetic changes can affect how people respond to stressful situations. Drugs that affect the epigenetic markings of genes may mitigate the effects of these early-life events.
Scientists also have new tools to study neurons directly. By creating neurons from human skin cells (by first engineering the cells to become induced pluripotent stem, or iPS, cells), they can study neurons with the genetic makeup of a mentally ill patient, then analyze which features of the neurons are defective and determine whether treatments can reverse the defects.
Recent developments in brain imaging include the Brainbow technique, which is used to label individual neurons in the brain different colors using fluorescent tags, allowing scientists to track axons and dendrites to visualize connections between distant neurons in brain samples. Another technique, CLARITY, uses acrylamide and hydrogel electrophoresis to make postmortem brains transparent. By staining various proteins, scientists can obtain detailed structural and molecular information from an intact brain. Finally, small microscopes are available that enable scientists to visualize the firing of nerve cells within a living animal.
Finding new drug targets for mental illness
Targeting the biology of mental illness can lead to better treatments, because an improved understanding of how current treatments work can demonstrate drug pathways and identify new targets. For example, although lithium has been used to treat bipolar disorder for decades, scientists have not understood why it works. In mouse models of bipolar disorder, lithium treatment has been found to activate genes involved in nerve cell growth and survival. Bcl-2, for example, is better known for its role in leukemia, but it also has neuroprotective effects in the brain. Lithium was found to increase Bcl-2 protein levels and mice that overexpressed Bcl-2 had lower risks of Alzheimer's disease, stroke, and Parkinson's disease. The mice were also less susceptible to stress and free radical-induced damage. While Bcl-2 itself may not be an ideal drug target because of its role in leukemia, other proteins in the Bcl-2 pathway may prove to be useful targets for new drugs.
John M. Kane
Zucker Hillside Hospital; Hofstra North Shore–LIJ School of Medicine
People diagnosed with schizophrenia often delay treatment. New strategies are needed to identify patients at risk and provide them with care.
The RAISE-ETP trial is testing a new holistic treatment program for schizophrenic patients to improve outcomes.
Introducing technology into treatment programs for the mentally ill may improve treatment while reducing costs.
Reducing the delay to treatment
Schizophrenia is a chronic condition in which patients experience psychotic breaks with reality. Patients may hear voices, hallucinate, and become paranoid, believing that others are reading their minds, controlling their thoughts, or plotting to harm them. Psychotic episodes generally begin during adolescence or early adulthood, but clues often manifest during childhood—low test scores, poor psychosocial functioning, and cognitive impairment—though none are specific or severe enough to warrant a diagnosis. When patients begin to manifest schizophrenic symptoms, it generally takes a year before they receive treatment.
John M. Kane of the Zucker Hillside Hospital and Hofstra North Shore–LIJ School of Medicine discussed several approaches to identify schizophrenia earlier and to reduce the duration of untreated psychosis. Delayed treatment is associated with lost educational opportunities, impaired psychosocial and vocational development, and reduced response to treatment when it is received.
Kane is piloting an online survey geared toward high school and college students to help identify early signs of psychosis. If the survey indicates such symptoms, students are referred to educational websites and treatment programs. In another study, Kane is interviewing early-phase patients to better understand the barriers to care they face. Finally, he is assessing whether linguistic analyses of social media updates patients write can identify mental changes linked to the beginning of symptoms. He hopes that such patterns may help parents and peers recognize warning signs before symptoms occur.
A holistic treatment program in first-episode patients
Once patients are receiving treatment, the next challenge is to maintain adherence. Because treatments are generally effective, eradicating delusions and hallucinations, patients often believe they are no longer sick and choose to discontinue medication. However, patients who do so are five times more likely to experience a relapse in symptoms than those who continue treatment. Kane stressed the need for programs designed to keep patients on treatment and prevent relapse. With each relapse, the risk of self-harm and homelessness increases: patients have more difficulty returning to school or work, and friends and family are less likely to reestablish ties. Kane emphasized that treatment programs should not only seek to remedy the biology of the disease but also provide patients and families with tools and skills to regain normal life after a psychotic episode.
Toward this goal, Kane is directing the Recovery After an Initial Schizophrenia Episode – Early Treatment Program (RAISE-ETP), a study of 404 first-episode schizophrenic patients taking place in 31 community clinics across the U.S. Each site is randomly assigned to administer a holistic intervention program, known as NAVIGATE, or to continue their current program. Experts blinded to the type of treatment will assess patients via video interviews. Because mental health funding is scarce, the study will also assess whether the intervention can reduce service utilization and costs while improving patients' quality of life and recovery rates.
NAVIGATE incorporates a computerized support system for physicians that includes materials for patient and family education. Physicians are provided with software called COMPASS, which integrates patient reports and psychiatric and medical data to enable physicians to monitor substance use, medication adherence, and side effects. In addition, patients receive resiliency training that focuses on topics such as managing distress and grief, coping with depression, improving social relationships, and reducing substance abuse. When a patient's symptoms have stabilized, the program provides support in helping them return to school or work. Results from RAISE-ETP will be presented in late 2014.
Technological approaches to treating chronic patients
Kane also described a technology-based program designed to treat chronic schizophrenic patients while reducing costs. The Improving Care Reducing Cost (ICRC) study follows 700 schizophrenic patients recently discharged from hospital. Patients are given smart phones and laptops to access software (apps) designed to help monitor medication adherence and mood and sleep patterns and provided with web-based educational materials. Patients also undergo cognitive behavior therapy, which has been shown to be effective in helping schizophrenic patients cope with voices and paranoia but is not widely available. The program provides in-person guidance in creating a personal relapse plan (to help deal with stress and substance abuse) and access to an online therapist. A website for patients and family members provides educational materials on understanding schizophrenia, managing symptoms, and identifying early warning signs.
Dennis S. Charney
Icahn School of Medicine at Mount Sinai
Ketamine is an NMDA antagonist with rapid effects in treating major depression.
Ketamine has a history of being abused as a recreational drug, so safety is a concern.
Currently, ketamine must be delivered intravenously, but studies are evaluating more convenient administration routes and safe dosing schedules for clinical practice.
Discovery of a rapid-acting antidepressant
Major depression is one of the top causes of morbidity and mortality worldwide, and suicide is the leading cause of preventable premature death. Many patients who receive treatment for major depression do not achieve remission, and those who do often relapse. Although recent treatments are more selective and better tolerated, they are not more effective.
Dennis S. Charney of the Icahn School of Medicine at Mount Sinai described the clinical development of ketamine, which has demonstrated rapid effects in patients with severe depression. Ketamine represents a new mechanism for antidepressants. Most antidepressants act by regulating the levels of monoamine neurotransmitters—serotonin, dopamine, and norepinephrine—in the brain. Ketamine targets a different neurotransmitter—glutamate—by blocking several receptors in the brain, primarily the N-methyl-D-aspartate (NMDA) receptor.
Ketamine is a dissociative drug, meaning that it produces feelings of detachment. It has been used for decades as an anesthetic and to treat chronic pain. However, it is also used recreationally, with users experiencing out-of-body sensations and hallucinations, similar to the effects of phencyclidine (PCP).
Charney became interested in ketamine because he wanted to investigate the role of glutamate in depression. Because of safety concerns, he did not intend to use it as an antidepressant. However, when he observed, in patients who had been unresponsive to prior treatments, significant improvements in depressive symptoms within 72 hours of a single dose of ketamine, Charney began to explore its use as an antidepressant. Since his first observations in 2000, several studies have demonstrated the efficacy of ketamine in major depression. Approximately 70% of patients report a decrease in symptoms of 50% or more within 1 day of a single dose.
Ketamine in suicide
Charney also described an ongoing study to investigate the effect of ketamine on suicidal ideation (suicidal thoughts or attempts). The biology behind suicide is unclear, as is why some patients with severe depression do not experience suicidal ideation while others with less severe depression do. Early studies with ketamine showed an antidepressant effect in several patients experiencing suicidal ideation, but those studies did not focus on the effect.
Charney is conducting a randomized controlled trial of patients admitted to hospital for serious suicidal ideation and an intention to commit suicide. Currently, 24 patients have been enrolled with various diagnoses, including major depression, bipolar disorder, PTSD, and borderline personality disorder. Within 24 hours, robust differences in suicidal ideation were observed between patients given midazolam and those given ketamine. These data may indicate that ketamine has an effect on suicidal ideation regardless of the underlying psychiatric diagnosis.
Strategies to bring ketamine into the clinic for major depression
To date, clinical trials of ketamine have used the same dose: 50 mg intravenously. Charney is working on a more convenient intranasal form of ketamine, which demonstrated antidepressant effects in a placebo-controlled trial. He is currently optimizing the dosage of this intranasal administration to pursue FDA approval.
Charney stressed that he thinks ketamine is safe and appropriate for routine, long-term use, but some clinicians are worried about safety. Ketamine has a history of being abused and can cause cognitive impairment among chronic users. Charney is investigating strategies to make ketamine appropriate for long-term clinical use. One strategy is to employ dosing schedules similar to those used in chronic pain, with ketamine dosed more frequently in the beginning to generate an initial response and then less frequently to maintain the response. Another possible strategy is to take advantage of ketamine's rapid activity and then switch the patient to a different antidepressant to assess whether the initial effects of ketamine can be maintained. In a study that switched patients from ketamine to riluzole, a drug that also inhibits NMDA receptors and has been studied in psychiatric conditions, the antidepressant effect of ketamine was not maintained. A similar study is underway, switching patients from ketamine to lithium.
Now that the benefit of ketamine in major depression has been established, there is new interest in determining how it works so that more-specific, safer alternatives can be developed. While the drug's precise mechanism is still an area of research, it is known that ketamine plays a role in regulating neurotransmitters that enhance neuroplasticity in brain regions that control emotion, such as the hippocampus and amygdala.
Fred R. Volkmar
Child Study Center, Yale University School of Medicine
People with autism have deficits in social communication and interaction.
Eye-tracking techniques can elucidate how autistic people view social interactions.
The social brain in autism
Autism is characterized by deficits in social communication and interaction. Autistic people may respond inappropriately during conversation and have difficulty reading nonverbal cues. They may also engage in repetitive behaviors, such as body rocking, or become intensely focused on specific items. The symptoms of autism fall on a continuum, with high-functioning individuals with mild symptoms able to lead independent lives while others with more severe symptoms require an assisted-living environment. Fred R. Volkmar of Yale University School of Medicine discussed how understanding social development in autism can inform treatment of the disorder.
While there are still many unknowns about the causes of autism and the best ways to help those with the disorder, the situation for people with autism is improving. A meta-analysis published in 2005 showed that from the 1950s to the 1970s, approximately two-thirds of people with autism had poor outcomes, defined as requiring supervision in an institutional setting. Approximately 10% had good outcomes, defined as moderate to high levels of independence and self-sufficiency. However, by the 1980s and early 2000s, up to 30% of people with autism had good outcomes. This change coincides with the Children with Disabilities Act, passed in 1976, which requires that children with mental illness be served in public schools.
People are by nature social creatures, and social development probably begins in utero. After birth, babies listen and orient to their mother's voice, and their parents' faces and voices are the most interesting stimuli in their environment. Babies also become interested in what people are doing, feeling, and communicating.
Most people carry a "social frame of reference," a set of implicit and explicit rules that define how to interact in social situations. People generally look to others—what they are looking at, how they are responding to situations—to gain information. Doing so requires integrating a vast amount of visual and auditory stimuli, such as gestures, tone of voice, and facial expression, in addition to conversational content.
In contrast, people with autism do not have a social frame. Instead of looking to other people to acquire information about the world, they look to their environment. Because they are not accustomed to processing social cues, they are not as adept at multi-tasking and often become fixated on an object or idea. This lack of social orientation leads to problems in learning, engagement, and affective development.
Learning about autism through technology
To analyze how people with autism view a dynamic social interaction, Volkmar used infrared cameras to monitor subjects' eye movements while watching a movie clip. The technology is used to monitor how people react to faces, to investigate how people with autism learn from the world.
People without autism looked back and forth between the speakers' eyes, consistent with their inclination to gain social cues from other people. However, people with autism focused on the speakers' mouths. In some ways this makes sense, Volkmar reasoned. The mouth is moving and it seems logical that it would attract attention. However, by focusing on the mouth instead of the eyes, the viewer misses up to 90% of the socially relevant information in the conversation.
Volkmar showed that treatment could result in changes in the way the brain processes faces. In autistic children who underwent 12 weeks of pivotal response treatment, a play-based therapy, fMRI and EEG brain scans showed that social stimuli activated areas of the brain utilized by children developing normally.
Barbara O. Rothbaum
Emory University School of Medicine
Exposure therapy can be used to promote fear extinction and to reduce the risk of PTSD in patients who have experienced a traumatic event.
Several strategies are being investigated to improve exposure therapy, including virtual environments, pharmacologic therapies, and early interventions.
Developing posttraumatic stress disorder
Posttraumatic stress disorder (PTSD) is a response to a traumatic event in which patients continue to feel stressed or frightened months after the event, when they are no longer in danger. Patients generally attempt to avoid thoughts, feelings, places, and people that remind them of the event. However, they continue to experience recurrent and intrusive memories, nightmares, and flashbacks, often suffering from sleep problems, irritability, anger, difficulty concentrating, and hypervigilance. Barbara O. Rothbaum from the Emory University School of Medicine described methods to reduce risk and treat PTSD.
After experiencing a traumatic event, fear and anxiety is normal. In patients with PTSD, however, these feelings do not go away. Rothbaum showed a study demonstrating that in female assault victims, PTSD symptoms were almost universal immediately following the trauma. During the following months, however, feelings of fear and anxiety subsided in many patients. At 3 months, approximately half the patients met the diagnostic criteria for chronic PTSD.
Rothbaum described PTSD as a disorder that impairs fear extinction, which is the gradual weakening of fear-based responses to a traumatic event. One way to promote fear extinction is to repeatedly expose the patient to their fear in a therapeutic setting through a process known as exposure therapy. Many trials have demonstrated the efficacy of exposure therapy in PTSD across various types of patients, including veterans, assault victims, refugees, earthquake survivors, and World Trade Center survivors. Rothbaum discussed three innovations in exposure therapy: the use of virtual reality, the addition of pharmacologic agents to augment fear extinction, and the targeted timing of exposure therapy immediately after a traumatic event.
Virtual reality in exposure therapy
In virtual reality exposure therapy, the therapist creates an interactive computer-generated environment that mimics the original event. The patient wears a head-mounted display with television screens in front of each eye, earphones, and a position tracker that changes the point of view to match head movements. A raised platform vibrates to mimic the motion of a car, the movement of an elevator, or the rumbling of an airplane engine. Several virtual environments have been created, such as scenes from the Iraq war, the inside of an airplane, and a public speaking situation. The therapist can watch everything that the patient sees on a screen and modify the environment during the therapy session. In a study of patients with a fear of flying, virtual reality exposure therapy performed as well as standard exposure therapy.
Enhancing exposure therapy with pharmacologic agents
Because exposure therapy can be emotionally taxing, Rothbaum is investigating strategies to augment its efficacy and reduce the number of sessions required. She investigated the ability of D-cycloserine, an N-methyl-D-aspartate (NMDA) partial agonist, to augment the efficacy of virtual exposure therapy in Iraq war veterans. The use of D-cycloserine in exposure therapy represents a new paradigm in psychiatric medicine in which the drug has no effect on its own but is intended to complement the exposure therapy.
Patients underwent five virtual reality sessions, as opposed to the normal nine to twelve. Before each session, the patients took either D-cycloserine, a placebo, or alprazolam (Xanax). Alprazolam is commonly prescribed to PTSD patients for anxiety and panic attacks; however, it is thought to interfere with the fear extinction process. All groups showed improvement on the Clinician-Administered PTSD Scale (CAPS) and the self-rated PTSD Symptom Scale after the five sessions, and the improvement was maintained after 12 months of follow up. There was no significant difference between the D-cycloserine and placebo groups.
Rothbaum also monitored the patients' startle response via heart rate and galvanic skin response (GSR; i.e., sweating) and assessed stress by measuring salivary cortisol. The D-cycloserine group showed a significantly greater decrease in startle response and cortisol levels at 6 months after treatment, indicating the treatment may augment exposure therapy with regard to startle response. As expected, alprazolam was associated with decreased efficacy of exposure therapy and higher rates of PTSD diagnosis during follow up.
Timing of exposure therapy
PTSD is the only mental disorder in which an external event is part of the diagnostic criteria. Because PTSD is marked by a defined event, there is an opportunity to treat patients in its earliest stages. However, there are few data on early interventions for PTSD. To assess the efficacy of early exposure therapy, Rothbaum monitored patients coming into the emergency room after a traumatic event and randomly assigned them to receive exposure therapy or assessment only. Patients in the exposure therapy group received three exposure therapy sessions: the first in the ER and then at 1 and 2 weeks following the event. At 3 months, the time at which chronic PTSD can be diagnosed, patients who received exposure therapy had half the rate of PTSD than those who did not. Rothbaum detected a genetic risk allele that correlated with risk of PTSD that she hopes could be used to identify patients who would benefit from early treatment.
How can society eliminate the stigma surrounding mental illness and ensure that sufferers receive appropriate medical attention?
How will recent commitments to neuroscience research and advances in sequencing and brain imaging translate into improved treatments for mentally ill patients?
What can the mechanisms of current antidepressants teach us about new drug pathways and targets?
Can holistic intervention programs improve adherence and outcomes in schizophrenic patients?
What are the optimal dosing strategies for ketamine to maximize efficacy while minimizing adverse events in patients with major depression?
Is there an underlying biology for suicidality regardless of underlying psychiatric diagnosis that can be targeted by therapeutics?
What treatment strategies can help autistic people learn from social cues and acquire more information from social interactions?
Which technologies can best assess how autistic people interact with other people and the environment?
How can researchers maximize the efficacy of exposure therapy in patients with PTSD?
Are there genetic risk factors that can predict which people are more likely to develop PTSD following a traumatic event?