New Frontiers in the Neurobiology of Mental Illness

Journal Articles

New technologies in neuroscience

Chung K, Deisseroth K. CLARITY for mapping the nervous system. Nat Methods. 2013;10(6):508-13.

Delorme R, Ey E, Toro R, et al. Progress toward treatments for synaptic defects in autism. Nat Med. 2013;19(6):685-94.

Drevets WC, Price JL, Simpson JR Jr, et al. Subgenual prefrontal cortex abnormalities in mood disorders. Nature. 199;386(6627):824-27.

Frasure-Smith N, Lesperance F, Talajic M. Depression following myocardial infarction. Impact on 6-month survival. JAMA. 1993;270(15):1819-25.

Krey JF, Pasca SP, Shcheglovitov A, et al. Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons. Nat Neurosci. 2013;16(2):201-9.

Kuehn BM. Criminal justice becomes front line for mental health care. JAMA. 2014;311(19):1953-4.

Livet J. The brain in color: transgenic "Brainbow" mice for visualizing neuronal circuits. Med Sci (Paris). 2007;23(12):1173-6.

Pasca SP, Portmann T, Voineagu I, et al. Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nat Med. 2011;17(12):1657-62.

Plomin R, Owen MJ, McGuffin P. The genetic basis of complex human behaviors. Science. 1994;264(5166):1733-9.

St-Pierre F, Marshall JD, Yang Y, et al. High-fidelity optical reporting of neuronal electrical activity with an ultrafast fluorescence voltage sensor. Nat Neurosci. 2014;17(6):884-9.

Wedeen VJ, Rosene DL, Wang R, et al. The geometric structure of the brain fiber pathways. Science. 2012;335(6076):1628-34.

Holistic care models in schizophrenia

Correll CU, Robinson DG, Schooler NR, et al. Cardiometabolic risk in patients with first-episode schizophrenia spectrum disorders: baseline results from the RAISE-ETP study. JAMA Psychiatry. 2014. [Epub ahead of print]

Jaakelainen E, Juola P, Hirvonen N, et al. A systematic review and meta-analysis of recovery in schizophrenia. Schizophr Bull. 2013;39(6):1296-1306.

Kane JM. Treatment strategies to prevent relapse and encourage remission. J Clin Psychiatry. 2007;68 Suppl 14:27-30.

Robinson D, Woerner MG, Alvir JM, et al. Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. Arch Gen Psychiatry. 1999;56(3):241-247.

Robinson DG, Woerner MG, McMeniman M, et al. Symptomatic and functional recovery from a first episode of schizophrenia or schizoaffective disorder. Am J Psychiatry. 2004;161(3):473-479.

Rapid action of ketamine for major depression

Aleman A, Denys D. Mental health: a road map for suicide research and prevention. Nature. 2014;509(7501):421-3.

Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351-4.

Collins PY, Patel V, Joestl SS, et al. Grand challenges in global mental health. Nature. 2011;475(7354):27-30.

Duman RS, Aghajanian GK. Synaptic dysfunction in depression: potential therapeutic targets. Science. 2012;338(6103):68-72.

Glue P, Gulati A, Le Nedelec M, Duffull S. Dose- and exposure-response to ketamine in depression. Biol Psychiatry. 2011;70(4):e9-e10.

Haber SN, Knutson B. The reward circuit: linking primate anatomy and human imaging. Neuropsychopharmacology. 2010;35(1):4-26.

Heresco-Levy U, Gelfin G, Bloch B, et al. A randomized add-on trial of high-dose D-cycloserine for treatment-resistant depression. Int J Neuropsychopharmacol. 2013;16(3):501-6.

Lapidus KA, Soleimani L, Murrough JW. Novel glutamatergic drugs for the treatment of mood disorders. Neuropsychiatr Dis Treat. 2013;9:1101-12.

Lapidus KA, Levitch CF, Perez AM, et al. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol Psychiatry. 2014;76(12):970-6.

Levkovitz Y, Tedeschini E, Papakostas GI. Efficacy of antidepressants for dysthymia: a meta-analysis of placebo-controlled randomized trials. J Clin Psychiatry. 2011;72(4):509-14.

Mathew SJ, Murrough JW, aan het Rot M, et al. Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: a pilot randomized, placebo-controlledd continuation trial. Int J Neuropsychopharmacol. 2010;13(1):71-82.

Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013;170(10):1134-42.

Murrough JW, Perez AM, Pillemer S, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. 2013;74(4):250-6.

Murrough JW, Charney DS. Is there anything really novel on the antidepressant horizon? Curr Psychiatry Rep. 2012;14(6):643-9.

Price RB, Nock MK, Charney DS, Mathew SJ. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry. 2009;66(5):522-6.

Sanacora G, Smith MA, Pathak S, et al. Lanicemine: a low-trapping NMDA channel blocker produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects. Mol Psychiatry. 2014;19(9):978-85.

Treadway MT, Pizzagalli DA. Imaging the pathophysiology of major depressive disorder — from localist models to circuit-based analysis. Biol Mood Anxiety Disord. 2014;4(1):5.

Wan LB, Levitch CF, Perez AM, et al. Ketamine safety and tolerability in clinical trials for treatment-resistant depression. J Clin Psychiatry. 2014. [Epub ahead of print]

Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856-64.

Understanding the social brain in autism

Chawarska K, Klin A, Volkmar F. Automatic attention cueing through eye movement in 2-year-old children with autism. Child Development. 2003;74(4):1108-22.

Grelotti DJ, Klin AJ, Gauthier I, et al. fMRI activation of the fusiform gyrus and amygdala to cartoon characters but not to faces in a boy with autism. Neuropsychologia. 2005;43(3):373-85.

Howlin P. The effectiveness of interventions for children with autism. J Neural Transm Suppl. 2005;(69):101-19.

Klin A, Jones W. Attributing social and physical meaning to ambiguous visual displays in individuals with higher-functioning autism spectrum disorders. Brain & Cognition. 2006;61(1):40-53.

Klin A, Jones W, Schultz R, et al. Defining and quantifying the social phenotype in autism. Am J Psychiatry. 2002;159(6):895-908.

Klin A, Jones W, Schultz R, et al. Visual fixation patterns during viewing of naturalistic social situations as predictors of social competence in individuals with autism. Arch Gen Psychiatry. 200;59(9):809-16.

McPartland J, Dawson G, Webb SJ, et al. Event-related brain potentials reveal anomalies in temporal processing of faces in autism spectrum disorder. J Child Psychol Psychiatry. 2004;45(7):1235-45.

Rogers SJ, Estes A, Lord C, et al. Effects of a brief Early Start Denver model (ESDM)-based parent intervention on toddlers at risk for autism spectrum disorders: a randomized controlled trial. JAACAP. 2012;51(10):1052-65.

Schultz RT, Gauthier I, Klin A, et al. Abnormal ventral temporal cortical activity during face discrimination. Arch Gen Psychiatry. 2000;57(4):331-40.

Volkmar F, Siegel M, Woodbury-Smith M, et al. Practice parameters for the assessment and treatment of children and adolescents with autism and pervasive developmental disorders. J Am Acad Child Adol Psychiatry. 2014;53(2):237-57.

Voos AC, Pelphrey KA, Tirrell J, et al. Neural mechanisms of improvements in social motivation after pivotal response treatment: two case studies. J Aut Devel Dis. 2013;43(1):1-10.

Exposure therapy in posttraumatic stress disorder

McSweeney FK, Swindell S. Common processes may contribute to extinction and habituation. J Gen Psychol. 2002;129(4):364-400.

Ressler KJ, Rothbaum BO, Tannenbaum L et al. Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch Gen Psychiatry. 2004;61(11):1136-44.

Rothbaum BO, Foa EB, Riggs DS, Murdock T, Walsh W. A prospective examination of post-traumatic stress disorder in rape victims. J Traumatic Stress. 1992;5(3):455-75.

Rothbaum BO, Houry D, Heekin M, et al. A pilot study of an exposure-based intervention in the ED designed to prevent posttraumatic stress disorder. Am J Emerg Med. 2008;26(3):326-30.

Rothbaum BO, Price M, Jovanovic T, et al. A randomized, double-blind evaluation of D-cycloserine or alprazolam combined with virtual reality exposure therapy for posttraumatic stress disorder in Iraq and Afghanistan War veterans. Am J Psychiatry. 2014;171(6):640-8.

Websites

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.

Autism Speaks

BRAIN Initiative
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.

Care4Today
A holistic treatment program sponsored by Janssen Healthcare Innovation.

CLARITY
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.

International Society for Traumatic Stress Studies

National Center for PTSD

RAISE-ETP
A clinical study in first-episode schizophrenic patients.

Simons Foundation Autism Research Initiative (SFARI)

Simons Center for the Social Brain at MIT

Virtually Better Inc.
A company that creates virtual reality environments for clinical therapies.

World Economic Forum, Harvard School of Public Health. The Global Economic Burden of Non-communicable Diseases. 2011.

Yale School of Medicine. Child Study Center.

Yale University. Social Brain in Autism Reading List.

Books

Reichow B, Doehring P, Cicchetti DV, Volkmar FR, eds. Evidence-based practices in autism: Where we are now and where we need to go. Evidence-based practices and treatments for children with autism. New York, NY: Springer; 2011.

Volkmar FR, ed. Encyclopedia of Autism Spectrum Disorders. New York, NY: Springer; 2012.

Sponsors

Platinum Sponsors

Highlights

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.

Introduction

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.

People with depression have higher mortality rates than others, and have a 3–4 times higher risk of death after a heart attack (left). In a 7-year study of over 6000 women, those with six or more depressive symptoms had higher mortality rates. (Image courtesy of Husseini Manji)

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.

Highlights

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.

Neuroscience advances

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.

New imaging techniques enable scientists to visualize connections between neurons within complex systems. (Image courtesy of Husseini Manji)

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.

Highlights

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.

In the RAISE-ETP trial, physicians use a computerized support system to help them monitor clinical status, medication, side effects, and treatment response in first-episode schizophrenic patients. (Image courtesy of John M. Kane)

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.

Highlights

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.

Glutamate is a key neurotransmitter that binds to several receptors on a postsynaptic cell, including the NMDA receptor. Glutamate plays a key role in synaptic plasticity, learning, and memory. (Image courtesy of Dennis S. Charney)

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.

Highlights

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.

Highlights

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.

Patients undergoing virtual reality exposure therapy are introduced to a computerized, immersive environment that mimics their description of a traumatic event. A therapist can see everything the patient sees and can intervene if necessary. (Image courtesy of Barbara O. Rothbaum)

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.

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