Qatar Foundation for Education, Science and Community Development, Weill Cornell Medical College in Qatar, and the New York Academy of Sciences
Affective Disorders: Qatar Clinical Neuroscience Conference
Posted June 20, 2014
Affective disorders, debilitating mood-related psychiatric illnesses such as depression and bipolar disorder, have often been conceptualized in psychological terms and viewed as simple problems of neurochemistry. But these illnesses also have neural bases and recent clinical research has encouraged a more complex and sophisticated understanding of their causes and mechanisms. Depression and anxiety may be neurodevelopmental disorders arising from a combination of temperament, genetic predisposition, and childhood experience, with a lifelong course; affective disorders may also involve dysfunctions in neuroplasticity, suggesting a new therapeutic approach that would focus on restoring flexibility to crucial circuits. Clinical research has also demonstrated that each disorder varies tremendously in origin and course from person to person.
The Qatar Clinical Neuroscience Conference focused on two broadly defined categories of brain disorder. Track 1: Affective Disorders focused on disorders resulting from an intrinsic or chronic dysfunction of the brain, either within the cells or in their connectivity. Affective disorders are still underdiagnosed and undertreated, but new perspectives are emerging just as new pharmacological approaches and innovative electrostimulation therapies are entering clinical trials, offering promise of a new era of precision medicine tailored to specific diagnoses and symptoms.
Track 2 of the conference focused on brain disorders caused by external conditions such as cerebrovascular disease, stroke, and TBI, which result in the damage or death of healthy, functioning cells and brain tissue. The Qatar Foundation for Education, Science and Community Development, Weill Cornell Medical College in Qatar, and the New York Academy of Sciences presented the conference on March 15–17, 2014, in Doha, Qatar.
Use the tabs above to find a meeting report and multimedia from this event.
Presentations available from:
BJ Casey, PhD (Weill Cornell Medical College)
Nicholas Craddock, PhD (Cardiff University, UK)
John F. Greden, MD (University of Michigan)
Dan V. Iosifescu, MD (Icahn School of Medicine at Mount Sinai)
Ned H. Kalin, MD (University of Wisconsin School of Medicine and Public Health)
Ziad Kronfol, MD (Weill Cornell Medical College in Qatar)
Francis Lee, MD, PhD (Weill Cornell Medical College)
Andrew H. Miller, MD (Emory University School of Medicine)
Ziad H. Nahas, MD, MSCR (American University of Beirut, Lebanon)
Charles B. Nemeroff, MD, PhD (Leonard M. Miller School of Medicine, University of Miami)
Kerry Ressler, MD, PhD (Emory University; Howard Hughes Medical Institute)
Alan F. Schatzberg, MD (Stanford University)
Jon-Kar Zubieta, MD, PhD (University of Michigan)
View the multimedia meeting report on Track 2 of the Qatar Clinical Neuroscience Conference at:
Stroke and Traumatic Brain Injury: Qatar Clinical Neuroscience Conference eBriefing
- 00:011. Altered neural circuitry underlying the risk to develop anxiety and depression
- 3:262. Translational research approach
- 12:103. Neural circuit underlying childhood risk
- 20:164. Fractional anisotropy in the uncinate fsciculus predicts Ce metabolism
- 29:515. CRH induced AT-related change in PET metabolis
- 00:011. Introduction; Placebo responses
- 04:472. Placebo administration; Background; Noise or opportunity?
- 10:563. Effects of administration; Nocebo responses
- 18:324. Trait effects; Genetic variation
- 23:485. Placebo administration in major depression; Experiment results
- 28:006. Conclusions and acknowledgement
- 00:011. Ketamine and other glutamatergic treatments in mood disorders
- 5:102. A dissociative anesthetic agent; NMDA receptor antagonist
- 13:273. Summary of acute response rates in ketamine depression studies
- 19:524. Ketamine for depression with suicidal ideation
- 25:395. Minocycline
- 29:156. Conclusion
- 00:011. Introduction
- 06:062. Shifting paradigms; Interplay between different brain regions; vmPFC functional connectivity
- 14:443. Brain stimulation techniques and their uses
- 25:344. DBS at STN and acute depression; FEAST study; Epidural prefrontal cortical stimulation
- 32:395. What's next; Conclusio
Affective disorders: a neurodevelopmental problem?
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Fox AS, Oler JA, Shelton SE, et al. Central amygdala nucleus (Ce) gene expression linked to increased trait-like Ce metabolism and anxious temperament in young primates. Proc Natl Acad Sci U S A. 2012;09(44):18108-13.
Fox AS, Shelton SE, Oakes TR, et al. Trait-like brain activity during adolescence predicts anxious temperament in primates. PloS One. 2008;3(7):e2570.
Oler JA, Fox AS, Shelton SE, et al. Amygdalar and hippocampal substrates of anxious temperament differ in their heritability. Nature. 2010;466(7308):864-8.
Pattwell SS, Duhoux S, Hartley CA, et al. Altered fear learning across development in both mouse and human. Proc Natl Acad Sci U S A. 2012;109(40):16318-23.
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Soliman F, Glatt CE, Bath KG, et al. A genetic variant BDNF polymorphism alters extinction learning in both mouse and human. Science. 2010;327(5967):863-6.
Tottenham N, Hare TA, Millner A, et al. Elevated amygdala response to faces following early deprivation. Dev Sci. 2011;14(2):190-204.
Translational medicine: new insights in the biology of mood disorder
Binder EB, Bradley RG, Liu W, et al. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA. 2008;299(11):1291-305.
Craddock N, Sklar P. Genetics of bipolar disorder. Lancet. 2013;381(9878):1654-62.
Fani N, Gutman D, Tone EB, et al. FKBP5 and attention bias for threat: associations with hippocampal function and shape. JAMA Psychiatry. 2013;70(4):392-400.
Felger JC, Mun J, Kimmel HL, et al. Chronic interferon-α decreases dopamine 2 receptor binding and striatal dopamine release in association with anhedonia-like behavior in nonhuman primates. Neuropsychopharmacology. 2013;38(11):2179-87.
Glassman AH, O'Connor CM, Califf RM, et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA. 2002;288(6):701-9.
Grozeva D, Kirov G, Ivanov D, et al. Rare copy number variants: a point of rarity in genetic risk for bipolar disorder and schizophrenia. Arch Gen Psychiatry. 2010;67(4):318-27.
Klengel T, Mehta D, Anacker C, et al. Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nat Neurosci. 2013;16(1):33-41.
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.
Purcell SM, Wray NR, Stone JL, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460(7256):748-52.
Raison CL, Rutherford RE, Woolwine BJ, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013;70(1):31-41.
Clinical approaches to affective disorders
Blasey CM, Block TS, Belanoff JK, Roe RL. Efficacy and safety of mifepristone for the treatment of psychotic depression. J Clin Psychopharmacol. 2011;31(4):436-40.
Hajcak G, Anderson BS, Arana A, et al. Dorsolateral prefrontal cortex stimulation modulates electrocortical measures of visual attention: evidence from direct bilateral epidural cortical stimulation in treatment-resistant mood disorder. Neuroscience. 2010;170(1):281-8.
Nahas Z, Short B, Burns C, et al. A feasibility study of a new method for electrically producing seizures in man: focal electrically administered seizure therapy [FEAST]. Brain Stimul. 2013;6(3):403-8.
Nahas Z. The frontiers in brain imaging and neuromodulation: a new challenge. Front Psychiatry. 2010;1:25.
Wollmer MA, de Boer C, Kalak N. Facing depression with botulinum toxin: a randomized controlled trial. J Psychiatr Res. 2012;46(5):574-81.
Matthew E. Fink, MD
Matthew E. Fink is the Louis and Gertrude Professor and chair of the Department of Neurology at Weill Cornell Medical College. He is also neurologist-in-chief at New York Presbyterian Hospital/Weill Cornell Medical Center, chief of the Division of Stroke and Critical Care Neurology Center, and vice chair of the Medical Board. Fink holds an MD from the University of Pittsburgh and served as resident and chief resident in internal medicine at the Boston City Hospital. He trained in neurology at the Neurological Institute of New York/Columbia Presbyterian Medical Center and later joined Columbia University as associate professor of clinical neurology and neurosurgery and founding director of the Neurology-Neurosurgery Intensive Care Unit at New York Presbyterian Hospital. Fink has also served at the Beth Israel Medical Center and the Albert Einstein College of Medicine. He was a founding member and chair of the Critical Care Section of the American Academy of Neurology and the Research Section for Neurocritical Care of the World Federation of Neurology. Fink is the editor of Neurology Alert and past president of the New York State Neurological Society.
Javaid I. Sheikh, MD
Javaid I. Sheikh is the dean of Weill Cornell Medical College in Qatar (WCMC-Q), which he has led since January 2010. He previously served as associate dean and professor of psychiatry and behavioral sciences at Stanford University School of Medicine and chief of medical staff at the Stanford affiliate VA Palo Alto Health Care System. Sheikh is an authority on anxiety and aging. He conducted the first studies, in the 1990s, to delineate the impact of aging on anxiety disorders, with detailed phenotypic characterizations and identification of risk factors. His group has investigated the interface of central fear circuits and sleep architecture in patients with chronic anxiety disorders. It is now looking at biomarkers and risk factors associated with perinatal depression. At WCMC-Q, Sheikh initiated a comprehensive 5-year strategic plan for the school, with a view to establishing it as the premier academic medical institution in the MENA region. Sheikh holds an MD from King Edward Medical College in Pakistan and an MBA from Golden Gate University.
Melanie Brickman Stynes, PhD, MSc
The New York Academy of Sciences
Brooke Grindlinger, PhD
The New York Academy of Sciences
Jack D. Barchas, MD
Jack D. Barchas is the Barklie McKee Henry Professor and chair of the Department of Psychiatry at Weill Cornell Medical College and psychiatrist-in-chief at Weill Cornell Medical Center. Barchas was previously the dean for both research development and neuroscience at the University of California, Los Angeles, and a professor in the Department of Psychiatry and Biobehavioral Sciences. He obtained his MD at Yale University and then completed an internship at the University of Chicago, postdoctoral training at the National Institutes of Health, and a psychiatry residency at Stanford University. As faculty at Stanford he held the Nancy Friend Pritzker Professorship; directed the Pritzker Laboratory, an interdisciplinary program focused on behavioral neurobiology; and served as associate chair of the Department of Psychiatry and Behavioral Sciences. He has held chairperson appointments on the Board on Biobehavioral Science and Mental Disorders of the Institute of Medicine and the Board of Trustees of the New York Academy of Medicine. He currently chairs the board of the Association for Research on Nervous and Mental Disorders and is president of the Pasarow Foundation, which provides awards for extraordinary scientific achievement in neuropsychiatry, cardiovascular disease, and cancer. He has also directed the Pritzker Network and served as an editor of the Archives of General Psychiatry.
Alan F. Schatzberg, MD
Alan F. Schatzberg received his MD from New York University. He completed a psychiatric residency at the Massachusetts Mental Health Center and a clinical fellowship in psychiatry at Harvard Medical School. After serving in the United States Air Force, he joined the staff at McLean Hospital and the faculty of Harvard Medical School. He later became clinical director of the Massachusetts Mental Health Center and a professor of psychiatry at Harvard Medical School, while continuing with his research program on depression at McLean Hospital. In 1991 Schatzberg moved to Stanford University to become the Kenneth T. Norris Jr. Professor and chair of the Department of Psychiatry and Behavioral Sciences. Schatzberg has been an active investigator in the biology and psychopharmacology of depressive disorders. He has explored norepinephrine systems in depression as a means of subtyping these disorders, as well as biological mechanisms that underlie the development of delusions in major depression. Schatzberg is now investigating the clinical psychopharmacology of nondelusional depression, particularly chronic depression. He is co-editor-in-chief of the Journal of Psychiatric Research and past president of the American College of Neuropsychopharmacology. In 1998 he was awarded the Gerald L. Klerman Lifetime Research Award from the National Depressive Manic-Depressive Association.
BJ Casey, PhD
BJ Casey is the Sackler Professor and director of the Sackler Institute at Weill Cornell Medical College. She is a pioneer in novel uses of neuroimaging methodologies to examine behavioral and brain development. Her program of research focuses on attention and affect regulation, particularly their development, disruption, and neurobiological bases. She examines the normal development of brain circuitry involved in attention and behavioral regulation and how disruptions in these brain systems (prefrontal cortex, basal ganglia, and cerebellum) can give rise to developmental disorders. Using a mechanistic approach, she has dissociated attentional deficits observed across the disorders of attention deficit hyperactivity disorder, obsessive compulsive disorder, Tourette syndrome, and childhood onset schizophrenia. Casey and her colleagues have begun to examine the effects of gene–environment interactions on the development of affect and behavioral regulation and related brain systems. Casey holds a PhD from the University of South Carolina and completed a postdoctoral fellowship at the National Institute of Mental Health, NIH.
Nicholas Craddock, PhD
Nicholas Craddock is a professor of psychiatry in the School of Medicine at Cardiff University. His research is focused on improving understanding of diagnosis and management of bipolar spectrum mood disorders and psychosis. He leads the Mood Disorders Research Team and the Bipolar Disorder Research Network (BDRN), heads the Cardiff University Psychiatry Service, an is an honorary consultant psychiatrist. Craddock is the scientific advisor for Bipolar UK and chairs the Academic Faculty of the Royal College of Psychiatrists. He is an editor for the British Journal of Psychiatry and directs mental health research and development for Cardiff and Vale University Health Board. He led the bipolar disorder component of the Wellcome Trust Case Control Consortium (WTCCC) and was senior author of the recent collaborative analysis that implicated two genes involved in ion channel function in the pathogenesis of the illness. He led the first efforts to explore the overlap of specific risk genes in schizophrenia and bipolar disorder. His work has related genetic findings to psychopathology and nosology, leading to the development of a scale to study the relationship between mood and psychosis that is now used widely.
John F. Greden, MD
John F. Greden is executive director of the University of Michigan Comprehensive Depression Center, the Rachel Upjohn Professor of Psychiatry and Clinical Neurosciences in the Department of Psychiatry, and a research professor in the Molecular and Behavioral Neuroscience Institute. He joined the faculty at the Medical School in 1974 and served as chair of the Department of Psychiatry from 1985 to 2007. Greden's clinical and research activities have emphasized the study of the longitudinal course of depression, linkages between stress hormones and depressive recurrences, and clinical strategies for preventing such recurrences. Greden is past president of both the Psychiatric Research Society and the Society of Biological Psychiatry. He is past editor-in-chief of the Journal of Psychiatric Research and past senior editor of scientific publications for the American College of Neuropsychopharmacology (ACNP). He currently serves as board president of the American Foundation for Suicide Prevention. Greden received his MD from the University of Minnesota Medical School, completed an internship at UCLA Harbor General Hospital, and was a resident in psychiatry at the University of Minnesota Hospitals and Walter Reed Army Medical Center. Before joining the Michigan University faculty, he served as director of psychiatry research at Walter Reed.
Dan V. Iosifescu, MD
Dan V. Iosifescu is director of the Mood and Anxiety Disorders Program and associate professor of psychiatry and neuroscience at Mount Sinai Medical School. He was previously an associate professor of psychiatry at Harvard Medical School, as well as director of translational neuroscience in the Depression Clinical and Research Program and site director of the Bipolar Trials Network at Massachusetts General Hospital (MGH). Iosifescu's research is focused on biological markers of treatment outcomes in mood disorders. He uses neuroimaging and neurophysiology techniques to investigate structural, biochemical, and functional brain abnormalities in mood disorders and their impact on clinical treatment. After receiving his MD from the Institute of Medicine and Pharmacy in Bucharest, Romania, Iosifescu completed an internship and a psychiatry residency at Massachusetts General Hospital and McLean Hospital, serving as chief resident in consultation-liaison psychiatry. His research training included a neuroimaging fellowship in the Neuroscience Laboratory at Harvard Medical School, a psychopharmacology fellowship in the MGH Mood and Anxiety Disorders Institute, and a fellowship in the Clinical Investigator Training Program at Harvard and MIT. Iosifescu also holds a Master of Medical Science degree from Harvard University.
Ned H. Kalin, MD
Ned H. Kalin is a professor in the Department of Psychology at the University of Wisconsin–Madison, where he is also director of the HealthEmotions Research Institute, director of the Lane Neuroimaging Laboratory, an affiliate scientist at the Wisconsin National Primate Center and Harlow Primate Laboratory, and a principal investigator at the Conte Adolescence Center. Kalin's research combines molecular studies, preclinical animal models, and human functional imaging to determine the mechanisms underlying the pathophysiology of anxiety and affective disorders. This work combines selective lesion strategies with functional brain imaging to demonstrate the importance of the amygdala, bed nucleus of the stira terminalis, and orbitofrontal cortex in mediating maladaptive responses to stress. His studies elucidate brain mechanisms in adaptive and maladaptive emotion regulation and show the importance of emotion regulation in understanding individual differences related to risk for stress-related psychopathology. Kalin holds an MD from Jefferson Medical College. He completed residency training at the University of Wisconsin School of Medicine and Public Health and a fellowship in neuropsychopharmacology at the National Institute of Mental Health, NIH.
Ziad Kronfol, MD
Ziad Kronfol is a professor of psychiatry and the director of psychiatry clerkship at Weill Cornell Medical College in Qatar. He was previously an associate professor of psychiatry and the director of the Psychoimmunology Program at the University of Michigan, Ann Arbor. Kronfol is past vice president of the Asian Federation of Psychiatric Associations, a distinguished life fellow of the American Psychiatric Association, and a member of the section on education of the World Psychiatric Association. He is associate editor of the Asian Journal of Psychiatry and editorial board member of several journals, including the Journal of Clinical and Health Psychology. Kronfol is internationally known for his work in psychoneuroimmunology, as one of the first to report on immunological changes in patients with major depression. His current work includes the establishment in Qatar of the Arab Psychogenomic Repository for patients with bipolar affective disorders, as well as research into college students' mental health in the Middle East. Kronfol is the author/editor of Cytokines and Mental Health. He holds an MD from the American University Beirut. He completed residency training in psychiatry at the University of Iowa and was a research fellow in biological psychiatry at the University of Michigan, Ann Arbor.
Francis Lee, MD, PhD
Francis Lee is a professor and vice chair for research in the Department of Psychiatry, a professor in the Department of Pharmacology, and an attending psychiatrist at New York Presbyterian Hospital/Weill Cornell Medical College. Lee obtained his MD and PhD from the University of Michigan, followed by psychiatry residency training at Weill Cornell Medical College. He completed postdoctoral training in molecular neuroscience at the Skirball Institute of New York University and the University of California, San Francisco. He currently directs a laboratory researching molecular and neural mechanisms that are relevant to neuropsychiatric disorders. In particular, his research is focused on using genetic models to delineate the role of growth factors such as BDNF in complex behaviors related to the pathophysiology and treatment of affective disorders.
Andrew H. Miller, MD
Andrew H. Miller is William P. Timmie Professor of Psychiatry and Behavioral Sciences and director of psychiatric oncology at the Winship Cancer Institute at Emory University. Miller attended medical school at the Medical College of Georgia and completed a residency in psychiatry at the Albert Einstein College of Medicine. His work focuses on the impact of the activated innate immune system on behavior and health. He is also interested in the role of glucocorticoid hormones in the regulation of inflammatory responses. Miller is examining the mechanism and treatment of cytokine-induced depression as represented by the cytokine interferon-α, which is used for the treatment of infectious diseases and cancer. His interferon-α studies provide a model to understand and treat depression, fatigue, and cognitive dysfunction in medically ill patients. Miller is a board certified psychiatrist and an examiner for the American Board of Psychiatry and Neurology. He is also the recipient of three teaching awards, a NARSAD Independent Investigator Award, and a National Institute of Mental Health Research Scientist Development Award. Miller is the editor of Depressive Disorders and Immunity.
Ziad H. Nahas, MD, MSCR
American University of Beirut, Lebanon
website | publications
Ziad H. Nahas received his MD from Saint Joseph University in Lebanon. He completed an internship in psychiatry at the Institut Paul Silvadon and Hopital Charles Foix in Paris, France. Nahas completed a psychiatry residency at Baylor College of Medicine, and then a research fellowship in functional neuroimaging and psychopharmacology and an MS in clinical research at the Medical University of South Carolina (MUSC). He later became an associate professor of psychiatry and behavioral sciences at MUSC, medical director of the Brain Stimulation Laboratory, and director of the Mood Disorder Program at the Institute of Psychiatry. His is currently department chair and professor of psychiatry at the American University of Beirut, Lebanon
Charles B. Nemeroff, MD, PhD
Charles B. Nemeroff is a geriatric psychiatrist, director of the University of Miami Center on Aging, and chairman of the Department of Psychiatry and Behavioral Sciences at the University of Miami. His research has concentrated on the biological basis of the major neuropsychiatric disorders, including clinical research on the use of genetic, neuroendocrine, neuroimaging, and neurochemical methods to understand the pathophysiology of depression. He uncovered the neurobiological mechanisms that mediate the increased risk for depression in victims of child abuse and has contributed to research on the relationship of depression to cardiovascular disease and to identifying predictors of specific antidepressant treatment responses. Nemeroff has received the distinguished Menninger Prize from the American College of Physicians and the Research Award from the American Foundation for Suicide Prevention. He has served on the Mental Health Advisory Council of the National Institutes of Mental Health and the Biomedical Research Council for NASA. He is past president of both the American College of Neuropsychopharmacology and the American College of Psychiatrists. He is a member of the Board of Directors of the American Foundation for Suicide Prevention. He received his MD and PhD in neurobiology from the University of North Carolina at Chapel Hill.
Kerry Ressler, MD, PhD
Kerry Ressler is a Howard Hughes Medical Institute investigator researching the molecular and cellular mechanisms of fear learning and the process of extinction of fear in mouse models. Ressler is also a practicing psychiatrist with an interest in translational and clinical research on fear-based psychiatric disorders. His clinical psychiatry research at Grady Memorial Hospital focuses on post-traumatic stress disorder (PTSD). Ressler hopes a better understanding of fear in the mammalian brain will lead to translational treatments and possibly prevention for fear-based disorders such as PTSD, phobic disorders, and panic disorder. Ressler is a member of the National Institutes of Health Learning and Memory Study Section, the Simons Foundation Grant Review Board for Genetics of Autism, the Scientific Advisory Board for the Department of Defense (DOD)-funded InTrusT program for PTSD and traumatic brain injury, and the Scientific Advisory Board of the NIH/DOD-funded Army Study To Assess Risk/Resilience in Service members (STARRS). Ressler holds an MD and PhD from Harvard Medical School.
Alan F. Schatzberg, MD
Jon-Kar Zubieta, MD, PhD
Jon-Kar Zubieta is a research professor with appointments in the Departments of Psychiatry and Radiology at the University of Michigan. Zubieta uses anatomical and functional MRI, PET, and SPECT imaging to quantify metabolism, blood flow, and neuroreceptor sites in human subjects. His research focuses on the neurobiological mechanisms underlying the regulation of stress responses. He is applying this work understand mood disorders and affect regulation and to identify conditions where physical and emotional stressors play significant roles in affective disorders, most notably in substance abuse disorders and pain. The goal of these studies is to provide a systems-level understanding of stress vulnerability and resiliency, incorporating neurochemical, functional, genetic, and psychophysical information directly in humans. Zubieta holds an MD from the Universidad Del Pais Vasco, Spain. He completed a psychiatry residency at University of Michigan Health System, a nuclear medicine residency at Johns Hopkins Medical Institutions, and a fellowship in nuclear medicine at University of Michigan Health System.
Kat McGowan is a freelance magazine writer specializing in science and medicine.
Affective disorders are highly variable and heterogeneous but tend to be labeled broadly, and current treatments follow a one-size-fits-all model. Precision medicine holds great promise for improving the diagnosis and treatment of these disorders, but many scientific and practical challenges remain.
It is inherently difficult to study affective disorders because mood and affect are hard to define, quantify, and model, as Huda Akil of the University of Michigan pointed out in her opening keynote address. Compounding the challenge, disorders like depression and anxiety have a wide range of causes and manifestations. Neurobiological research on psychiatric disorders has generally focused on neural signaling, but scientists are now considering the roles of other factors, including immune responses, growth factors, and hormones.
Some of our ideas about mood disorders may have led us astray. Depression is not one disease but many: "We're dealing with depressions and bipolar illnesses," John F. Greden explained. Our current conceptual frameworks do not reflect the evolving and dynamic nature of these disorders, which have lifelong courses of remission and relapse and typically become more severe over time. Our models capture only some of the brain changes involved in depression and do not reflect the 30% of cases that are treatment-resistant. We do not yet have good biomarkers that could reveal the pathophysiology of the disorders and predict treatment responses.
Research in clinical neuroscience is, however, generating new ideas about how affective disorders emerge and change over time. Several lines of evidence suggest that anxiety and depression involve dysfunctions in neurodevelopment. Research on the role neuroplasticity plays in affective disorders provides a new perspective that can generate leads in the search for causes and treatments. The link between affective disorders and other biological changes is also increasingly evident. Charles B. Nemeroff presented compelling evidence that depression is a risk factor for cardiovascular disease, and Andrew Miller outlined the role of inflammation in depression.
Molecular genetics is providing a more sophisticated understanding of vulnerability to mood disorders. Many gene variants increase the risk for all psychiatric illnesses, undermining the traditional view that psychotic disorders are biologically distinct from mood disorders, as Nicholas Craddock observed. Several of these variants modify the function of ion channels, consistent with other research pointing to dysregulated neuronal excitability in psychiatric disorders. At the same time, as Dan V. Iosifescu described, the surprising success of ketamine in treatment-resistant depression has attracted new attention to the glutamate signaling system.
In practice, drug therapy for depression has not changed much in the past few decades. Several promising candidates have recently failed in clinical trials, but treatment options may soon change. Alan Schatzberg described ongoing trials of compounds with novel mechanisms of action, such as the melatonin receptor agonist agomelatine and the glucocorticoid receptor antagonist mifepristone. Ziad H. Nahas previewed techniques for brain stimulation that are more precise and specific than older techniques and could provide the same benefits with fewer side effects. The complexity of affective disorders may be daunting, but research revealing their diversity and pervasiveness also offers the promise of a new era of precision medicine, prevention, and treatment.
Francis Lee, Weill Cornell Medical College
BJ Casey, Weill Cornell Medical College
Ned H. Kalin, University of Wisconsin School of Medicine and Public Health
Jon-Kar Zubieta, University of Michigan
- Anxiety may be a neurodevelopmental disorder.
- Early life stress leads to early and persistent alterations in amygdala function in humans and mice.
- Fear extinction is impaired during adolescence in humans and mice.
- Strong placebo response is tied to increased release of dopamine and opioids in basal ganglia.
A mouse model for anxiety: a new view of BDNF
Parallel studies in humans and animal models can shed light on the biology of affective disorders in humans. A mouse model for mood disorders developed by Francis Lee of Weill Cornell Medical College is inspiring a new understanding of the role of neurodevelopment in the risk for affective disorders.
Using gene knock-in technology, researchers can introduce genes that may be involved in multiple mood disorders into mice models and explore the circuitry and behavioral phenotype of that gene or gene variant. Brain-derived neurotrophic factor (BDNF) is a neural growth factor and so-called master molecule that may influence many affective disorders. Knocking out BDNF in mice leads to anxiety and depression-like phenotypes and impairs fear-learning extinction, the ability to learn that a cue that previously signaled an adverse outcome no longer does. The BDNF polymorphism val66met, present only in humans, is found in about 25% of the U.S. population. Knocking the SNP into mice increases anxiety-related behaviors and impairs fear extinction. BJ Casey, also at Weill Cornell, has found that humans with the Met allele also have impaired fear extinction. One important implication is that cognitive behavioral therapy (CBT), which involves unlearning fearful associations and is the only evidence-based technique to treat anxiety, may be an inefficient therapy for such people.
Surprisingly, fear extinction is normal in heterozygous BDNF knockout mice, which have 50% less BDNF. They are capable of learning new associations to previously frightening stimuli at a normal rate. Efforts to understand why heterozygote knockouts differ from mice with one Met allele led Lee's group to a discovery: while the mature BDNF protein sustains and encourages neural growth, the BNDF Met prodomain causes neurons to stop growing and shrink in vitro. The SNP had been thought to result in a loss of function (to impair the function of BDNF), but Lee's finding suggests it instead causes a gain in function by downregulating neuronal growth. The SNP may alter the development of circuits that link the prefrontal cortex (PFC) and hippocampus, in turn altering how fear memories are modified: "humans who have this [SNP] have the Met prodomain running around in the brain, potentially suppressing the circuitry during a specific point in development," Lee said.
The implication is that simply increasing BDNF in the brains of people with this polymorphism might be deleterious, if the Met prodomain is also upregulated. "You'll have to come up with a much more elegant strategy of increasing one and decreasing the other," Lee said.
Adolescence and anxiety
Related work by BJ Casey at Weill Cornell Medical College suggests that adolescence is a critical period for the onset of anxiety. During this stage, brain development is uneven: subcortical limbic regions that subserve affect develop quickly, but projections from the prefrontal regions involved in emotional regulation mature more slowly. In anxious people, this prefrontal–limbic circuitry functions differently in response to images of faces with fearful expressions.
Early life experience shapes the risk for anxiety. Behavioral and neuroimaging studies of children who spent their first months or years in an orphanage revealed heightened amygdala response to fearful faces, correlated with less-frequent eye contact with an adoptive parent. In a parallel study in mice, pups reared by stressed and inattentive mothers had heightened amygdala response and were rated high in a measure of anxiety that tested willingness to search for a sweet food reward in an exposed, brightly lit cage.
In both mice and humans, fear extinction is impaired during adolescence in comparison to preadolescence and adulthood. CBT is also less effective at this age. "There may be a developmental window in which cognitive behavioral therapy shows a diminished effect for treatment," Casey said. Better treatment for anxiety in adolescence might involve techniques that do not place demands on the underdeveloped PFC. One promising option is reconsolidation, which might be used to modify memories while they are reactivated. Considering nuances such as age, genetics, and environment in tailoring treatment is another step toward precision medicine.
Anxious temperament in rhesus macaques and humans
The behavior and neural circuitry of non-human primates makes these animals good models for human affective disorders. Ned H. Kalin of the University of Wisconsin School of Medicine and Public Health is working on parallel studies in humans and a rhesus macaque colony on Cayo Santiago to explore the developmental origins of inhibited or anxious temperament—an extreme behavioral inhibition to novel situations or individuals at a young age. In humans, this temperament increases the later risk of social anxiety disorders by 7-fold.
Intruder tests measure the responses of children and young monkeys when confronted by a stranger, testing behavioral inhibition in humans and its analog, freezing, in young animals. Using this technique, Kalin's group has determined that anxious temperament (AT) is 30%–40% heritable in both monkeys and humans.
PET scans of hundreds of young monkeys indicate individual differences in anxiety are reflected in differences in the metabolism of the central nucleus of the amygdala and anterior hippocampus—but only differences in the hippocampus show a heritable pattern. In AT animals, many distinctive changes in gene expression are related to neuroplasticity. Higher levels of AT were associated with reduced expression of neuroplasticity genes. Using viral vectors to influence gene expression in specific brain regions, Kalin found that introducing the CRH gene increased anxious behavior (CRH, corticotropin-releasing hormone, is secreted by the hypothalamus in response to stress).
Other regions, including the orbital frontal cortex and the periaqueductal gray, are also affected in AT. "We're not just talking about one brain region, but a whole network that seems to be overactive in individuals with this disposition," Kalin said. Functional connectivity analysis with resting fMRI and metabolic analysis in PET point to reduced coupling between the dorsolateral PFC and the amygdala in both anxious animals and human children. This pattern, similar to that seen in Casey's research, suggests the PFC regulates anxiety, with metabolism in dorsal regions of the central nucleus of the amygdala as an intermediary.
Placebo and depression
The placebo effect is not just a vexing confounder in clinical trials; it is a potentially useful signal. Jon-Kar Zubieta of the University of Michigan explained: "This noise in the signal of antidepressants has a biological meaning that has the potential to point to new targets for medication discovery or treatments." Placebo responses in drug trials for affective disorders might result from spontaneous recovery or be caused by the Hawthorne effect, in which symptoms improve when patients are closely observed. But a placebo effect is not merely a subjective impression, Zubieta cautioned: naloxone, which blocks opioid analgesia, also blocks placebo in pain studies.
In a PET study of volunteers subjected to pain and given a placebo, endogenous opioid release increased 12%–34%, with marked individual variation. Opioid release correlated with pain relief and with changes in brain regions such as the subgenual cingulate that are involved in the affective experience of pain. Analgesia also correlated with increased dopamine release in the basal ganglia, and variations in dopamine release accounted for about one-fourth of the variation in placebo response. Similarly, a neuroimaging exploration of participants who reported a "nocebo" effect (the converse phenomenon, when an inactive substance causes side effects or illness) showed a similar but opposite brain circuitry response, with reduced endogenous opioids and dopamine in the basal ganglia.
But placebo is not merely a dopamine effect. Agreeableness, neuroticism, and a variable called "ego resiliency" explain 28% of the variance in placebo analgesia and are associated with opioid system activation and cortisol suppression. Placebo response also interacts with polymorphisms in genes for mu-opioid receptors, for BDNF, and for the FAAH enzyme, which is involved in metabolizing endocannabinoids.
Given the overlap in pain circuitry and emotional circuitry, pain placebo mechanisms may generalize to depression. A 2-week randomized placebo study in depression revealed inter-individual variability in mood responses, but the greatest improvements in mood were associated with a high release of endogenous opioids in regions involved in mood regulation such as the nucleus accumbens, amygdala, and medial thalamus. In a 10-week open study of placebo and antidepressant, placebo responders showed higher opioid release in those regions, greater mood improvement, and higher remission compared to nonresponders. Those who responded strongly to placebo also responded to the antidepressant, suggesting a common mechanism.
Charles B. Nemeroff, Leonard M. Miller School of Medicine, University of Miami
Kerry Ressler, Emory University; Howard Hughes Medical Institute
Nicholas Craddock, Cardiff University, UK
Dan V. Iosifescu, Icahn School of Medicine at Mount Sinai
Andrew H. Miller, Emory University School of Medicine
- Depression increases heart disease risk as strongly as does cigarette smoking.
- Antidepressants may improve outcomes in heart disease.
- In victims of early childhood abuse, FKBP5 genotype (involved in cortisol receptor regulation) predicts risk of post-traumatic stress disorder in adulthood.
- The diagnostic distinction between psychotic and mood disorders may not be valid.
- Ketamine has rapid effects and an up to 70% response rate in treatment-resistant depression.
Depression and the heart
Depression is now considered an official risk factor for heart disease and for a poor prognosis in several cardiac diseases. Charles B. Nemeroff of the University of Miami explained the history of this classification. In the 1990s, epidemiological studies documented links between depressed affect and ischemic heart disease, as well as a 4-fold increase in mortality in depressed patients following myocardial infarction. Further observational studies established that cardiac mortality worsens as depression becomes more severe. The cardiac risk of depression is equal to better-known risk factors such as cigarette smoking and elevated blood lipids.
Given this strong relationship, Nemeroff argued, it makes sense both to intervene to treat depression before the onset of cardiac diseases and to treat aggressively. "It highlights the importance of treating patients to remission," he said. Some argue that this phenomenon is primarily artifact, since depressed patients exercise less, have poorer nutrition, and are less likely to adhere to medications or stop smoking. But some biological changes in depressed people point to intermediary factors such as changes in platelet function, which can lead to thrombosis or clotting. Depressed patients have abnormal platelet function, exaggerated platelet reactivity, and accelerated conversion of prothrombin to thrombin, the first step in platelet aggregation. Treatment with selective serotonin reuptake inhibitors (SSRI) partly normalizes platelet function. Two other heart disease risk factors, inflammation and heart rate variability (changes in heart rate in response to increased demand), are also abnormal in depressed patients.
A study of the SSRI sertraline for major depression in patients with acute myocardial infarction or unstable angina found statistically non-significant reductions in death and a slight reduction in myocardial infarction. Nemeroff proposed a Framingham-like study to test the efficacy of treating cardiac patients with very low doses of SSRIs, which he predicts would have a more powerful effect than low-dose aspirin on platelet function.
The biology of PTSD: genes, epigenetics, and early life experience
Post-traumatic stress disorder (PTSD), marked by hypervigilance, flashbacks, and difficulty inhibiting fear, is difficult to predict. Genetic and epigenetic factors influence risk, explained Kerry Ressler of Emory University and the Howard Hughes Medical Institute, as does the interaction between early life experience and genetics.
The fear circuitry that is dysfunctional in PTSD is conserved in mammals and therefore particularly suitable for studies in animal models. The amygdala is the essential node in the circuit, modulated by activity in the hippocampus, prefrontal cortex, insula, and cingulate cortex. This circuitry underlies hard-wired fear responses and fear conditioning—learned associations between aversive and neutral stimuli.
A consortium study of genetic variation and PTSD is now scaling up to a goal of 20 000 cases. Polymorphisms in the OPRL1 gene in the nociceptin pathway are associated with differential risk for PTSD. An agonist in this pathway blocks memory consolidation of fear conditioning, suggesting that PTSD could one day be prevented with a drug that would block the formation of a fearful memory after a traumatic incident. Neuromodulators such as D-cycloserine might also enhance plasticity to potentiate the effects of exposure therapy, which is currently ineffective in many cases.
Dysregulated feedback in the hypothalamic–pituitary–adrenal (HPA) axis is a well-replicated finding in PTSD. Ressler's group determined that variants of FKBP5, which regulates the sensitivity of the glucocorticoid receptor, interact with adverse childhood experiences to influence risk for the disorder. The risk allele genotype is also associated with unusual hippocampal connectivity.
Experiences of trauma in childhood (but not adulthood) are associated with demethylation and enhanced transcription of the risk allele of FKBP5. The finding suggests a critical period for emotional development and PTSD risk, in which the amygdala is modulated during development by cortisol so that the risk allele interacts with early life stress to change lifelong sensitivity to stressful events. Epigenetic effects may persist into subsequent generations; Ressler is exploring mechanisms of transgenerational trauma transmission with a model based on fear learning and the rodent olfactory system.
The genetics of bipolar disorder
Unlike many other affective disorders, bipolar disorder, which involves episodes of mania and depression, is highly heritable. Nicholas Craddock of Cardiff University pointed to studies in molecular genetics that suggest the longstanding distinction between bipolar disorder and schizophrenia may not be clear cut. A major population registry of 2 million Swedish families revealed significant overlap in genetic susceptibility between schizophrenia and bipolar disorder.
In recent years, large genome-wide association studies (GWAS) identified replicable risk genes in bipolar, coding proteins such as ANK3, a scaffold that tethers proteins such as sodium channels in position across the neuronal membrane, and a variant in CACNA1C, a subunit of the voltage-gated calcium channel. Both variants influence neuronal excitability, and there is evidence that other episodic neurological disorders such as forms of epilepsy and migraine may also be due to ion channelopathies. So far, 12 genes have been strongly implicated by GWAS for bipolar disorder. However, copy number variations, which increase the risk for developmental disorders and some neuropsychiatric disorders, do not seem to play a significant role here.
Most candidate risk genes identified by GWAS, including CACNA1C, have nonspecific effects, potentiating the risk of both mood disorders and psychosis. "This has all the hallmarks of something not specific to bipolar disorder, but a general increase in susceptibility," Craddock said.
Hundreds of common variants with small effects on susceptibility have been identified. Each alone increases risk on the order of 1.3-fold, but the small risks summed together can accurately differentiate people with a psychiatric diagnosis on a group level.
The ketamine mystery
The serendipitous discovery that the anesthetic ketamine rapidly lifts depressive symptoms is inspiring an effort to identify compounds that work the same way but are more suitable as treatments. Dan V. Iosifescu of the Icahn School of Medicine at Mount Sinai discussed studies aiming to identify how the drug works. At the doses used in studies of mood disorder, ketamine induces a potent antidepressant effect within 24 hours. At higher doses, the drug can cause hallucinations, which is why it is also used recreationally.
In a study comparing ketamine to the benzodiazepine midazolam in patients who had failed more than five treatments on average, 64% responded to ketamine, with an average improvement on a depression scale of nearly 8 points, about twice the effect of most antidepressants. Those who responded had relief for 23 days on average. "This is definitely not a cure, but a very exciting method for a single intervention," Iosifescu said. Ketamine may also rapidly reduce suicidal ideation.
Results from several trials suggest that ketamine does not cause psychotic side effects at the lower doses used in depression. Some patients experienced dissociation that resolved within 2 hours of infusion. The drug also increased blood pressure and heart rate: 10%–15% of participants in the most recent study needed a beta blocker. While heavy recreational use of ketamine may cause cognitive deficits, single infusions do not seem to pose this risk.
Multiple lines of evidence suggest glutamatergic signaling is abnormal in depression; ketamine is known to act on NMDA receptors in this system. Ketamine may upregulate BDNF release, which is often associated with response to depression treatment. Many antidepressant candidates with targets in the glutamatergic pathway are now in early clinical trials. Iosifescu's group is exploring minocycline, an antibiotic that may also have antidepressant efficacy.
Intranasal ketamine administration is controversial. This method is an effective and convenient way to deliver the drug but may encourage abuse, a concern raised by many discussants in the conversation following Iosifescu's presentation. Ketamine is not yet understood well enough to be suitable as a treatment, Iosifescu agreed. Nonetheless, given the potential of the drug to help desperate patients, he added, "it pains me that we're not doing the follow-up studies" more quickly.
Inflammation and depression
The inflammatory activity of the innate immune system plays a role in many common diseases, from cancer to cardiovascular disease, and it is increasingly clear that inflammation also plays a role in depression. Inflammatory proteins such as cytokines are increased in roughly 20%–30% of depressed patients.
Andrew H. Miller of Emory University is studying interferon-α (IFN-α), which induces other cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and causes depressive symptoms in humans and non-human primates. PET studies show IFN-α decreases activity in PFC and increases activity in parts of the basal ganglia such as the putamen and globus pallidus. IFN-α reduces the basal ganglia response to reward and increases activity in the dorsal anterior cingulate cortex, the "neural alarm system" active in anxiety disorders. In non-human primates, 4 weeks of IFN-α administration caused extracellular dopamine in the caudate nucleus to plummet, as measured by microdialysis.
The monoclonal antibody infliximab, a TNF-α antagonist with highly specific action, improves depressed mood in patients with inflammatory disorders and cancer. A double-blind randomized study in treatment-resistant depression showed no effect overall but found a clinically significant effect in the 35% of participants with the highest levels of C-reactive protein, a measure of inflammation. Symptoms related to motivation and psychomotor retardation, which recruit the basal ganglia, particularly improved, consistent with the idea that cytokines target these regions.
Ziad Kronfol, Weill Cornell Medical College in Qatar
John F. Greden, University of Michigan
Alan F. Schatzberg, Stanford University
Ziad H. Nahas, American University of Beirut, Lebanon
- Bipolar disorder in Arab populations is characterized by higher rates of psychosis and medical co-morbidity and lower rates of psychiatric co-morbidity.
- Approaching depression as a deficit in cognitive flexibility offers new perspectives and ideas for therapy.
- Location and frequency are essential parameters in treating depression with brain stimulation.
Bipolar disorder in the Arab world
The unique characteristics of bipolar disorder in the Arab world are not yet well understood. Most genomic studies in psychiatry have been conducted on European populations. Ziad Kronfol of the Weill Medical College in Qatar described an effort to study bipolar disorder among Qataris and Lebanese, which aims to establish an Arab repository for biological samples and identify genetic variants unique to this population. Genomic studies in the Arab world are advantaged by a high rate of consanguinity—some estimates hold that 25%–50% of marriages are between cousins or distant cousins. This study includes 30 consanguineous families.
Preliminary results from 166 subjects suggested a high frequency of psychotic symptoms and a much lower rate of alcohol and drug use among this sample as compared to studies on European and American populations. Medical comorbidity in bipolar patients was higher, particularly with diabetes and hypertension. Preliminary analysis of genome sequencing of 62 bipolar type 1 participants identified three significant associations and a novel loss-of-function SNP in a psychiatric target gene, AUTS2, that has not previously been identified in European and American data sets.
Treatment-resistant depression: a serious challenge
A paradigm shift will be required to tackle treatment-resistant depression, which is disabling, destructive, and common, explained John F. Greden of the University of Michigan. Although affective disorders have many causes and take different forms, current practice is to prescribe the same agents to all patients. "We frankly do not have any way to match patients with the right treatments," Greden said. The biggest real-world study of major depression, Star-D, revealed that only 37% of patients improve with a first-line intervention, and with each subsequent treatment failure remission rates decrease and relapse rates increase. Treatment-resistant depression may develop as a result of inadequate or inappropriate treatment.
Biomarkers, longitudinal studies, and big data sets that include samples in the thousands will be required to improve outcomes. The National Network of Depression Centers has coordinated one registry, providing a rich source of data, but such efforts need to be larger and better coordinated.
New antidepressant agents like ketamine and scopolamine could be valuable tools to examine who responds and to probe mechanisms of treatment response. Prospects for biomarkers include cortisol measurements, BDNF dynamics, inflammatory cytokines, serotonin receptor gene variants, and structural and functional imaging. Preliminary research has identified potential markers, as several discussants in the conversation that followed mentioned, but the field as a whole has not come together to evaluate promising biomarker candidates.
New ideas in antidepressant therapy
On one hand, the future of antidepressant therapy looks bright: therapies with entirely new modes of action are being developed and tested. But on the other, the future looks tenuous: recent negative results in clinical trials for deep brain stimulation (DBS) and drug augmentation are disappointing and many pharmaceutical companies are exiting this research space. Challenges for antidepressant trials include high placebo response, inadequate understanding of therapeutic dosage, and difficulty defining "depression," a biologically inexact term.
Clinical psychopharmacologist Alan Schatzberg of Stanford University explained that the success of ketamine may be hard to build upon: although ketamine is an NMDA antagonist, some evidence suggests its antidepressant effects may be due to its influence on other neurotransmitters such as glycine or mu-opioids. Other NMDA antagonists such as memantine and lamotrigine do not have antidepressant effects. In a clinical trial, an AstraZeneca drug that acts like an NMDA antagonist without inducing depersonalization or psychosis was no more effective than placebo. However, GLYX-13, a glycine partial agonist and NMDA agonist, showed efficacy and a "reasonable" effect size in an early-stage clinical trial. Augmenting with high-dose d-cycloserine in treatment-resistant depression also showed some effect in a small randomized trial.
Ketamine is not the only surprise in antidepressant therapy; several unconventional compounds are now being evaluated for depression. Injections of botulinum toxin (Botox) in the brow improved mood in about half of subjects in a study with 74 participants. Given known links between brow furrowing and emotional regulation, it is possible that the injection serves as a signal to change emotional regulation.
The glucocorticoid receptor antagonist mifepristone (approved as an abortifacent) is now in phase III trials for psychotic major depression, which is linked to excessive activity in the HPA axis. In earlier tests, the drug reduced psychotic symptoms in 44% of participants after one week of treatment, which is somewhat better than placebo. The melatonin-1 and melatonin-2 agonist agomelatine, approved in Europe, is now in phase III studies in the U.S.
Altering the circuitry of depression
Chronic depression could be thought of as a systems problem, suggested Ziad H. Nahas of the American University of Beirut. The mind and brain are trapped in one pattern of response and resist transitioning. "For me, the opposite of depression is mental flexibility," he said. Neurostimulation technologies that improve plasticity or modify neuronal function may be effective in restoring that flexibility. Brain stimulation technologies for depression include electroconvulsive therapy (ECT), DBS, vagal nerve simulation (VNS), and transcranial magnetic stimulation (TMS), as well as newer techniques such as focal electrically-administered seizure therapy (FEAST) and bilateral epidural prefrontal cortical stimulation (EpCS).
Location, frequency, and stimulation are important features of neurostimulation technologies. Applying TMS to anterior and lateral regions of the dorsolateral PFC in unmedicated depressed patients improves outcomes; stimulation applied to the wrong areas can cause acute depression. Nahas suggested weak results in DBS studies might be due to poor targeting. In technologies like TMS, stimulation frequency influences response, as does the time course of vagus nerve stimulation. Concurrent brain activity also modifies response, suggesting that pairing psychotherapy or medication with stimulation might offer added benefits.
To illustrate scientists' evolving understanding of brain circuitry involved in depression, Nahas cited an aphorism from mathematics: "All models are false, but some are useful." Brain stimulation does not merely affect one hub or node, but an entire network or set of networks. Along with sadness and emotional pain, people suffering from depression have motivational problems and become socially isolated. Within the PFC, the more lateral portion of the middle frontal gyrus is more involved in attending to the outside environment, while the frontal pole is more engaged in attending to the internal environment, control of emotion, and motivation.
New stimulation technologies
By targeting stimulation more precisely, FEAST may produce some of the antidepressant effects of ECT without side effects such as memory loss and cognitive impairment. EpCS, in which stimulating electrode leads are placed on the surface of the cortex, is a simpler and less-invasive procedure than DBS. In a small trial, EpCS led to remission in 3 of 5 severely depressed patients over a period of more than 5 years.
Stimulating technologies can also be used to better understand brain circuitry. In one patient with a long and well-documented history of depression, frontopolar PFC activation via EpCS increased activation in circuitry related to empathy, while dorsolateral activation influenced attention and emotional arousal, as measured by the late positive potential response to negative stimuli. This procedure provided the first direct demonstration of how the lateral circuit influences negative affect. EpCS technology is promising and should be tested in a randomized trial, Nahas noted.
Developing new therapies for affective disorders is essential, since these conditions are chronic and marked by frequent relapses. Better treatments will arise from a fuller understanding of the heterogeneity of these disorders, improvements in individualized therapy, and the ability to precisely tailor the treatment to the particular genetics, biology, and life history of the patient. But in the discussion that followed the session on new therapeutics, Schatzberg also emphasized the role of serendipity. The discovery that ketamine can rapidly relieve depressive symptoms is one example; the recent suggestion that a Botox injection in the corrugator muscles of the brows might improve depression is another: "We need to keep our minds open," he concluded.
Why is the val66met SNP so common in some human populations?
What factors predict the risk of developing anxiety?
What factors predict treatment response for anxiety?
How should the more than half of people who do not respond to cognitive behavioral therapy for anxiety be treated?
How does early anxious temperament predispose children to later develop social anxiety disorder and depression?
How are deficits in neural plasticity related to anxiety?
What is the biological mechanism behind the placebo effect?
Could individual variability in placebo response be useful in predicting vulnerability to depression?
Why does anxiety or depression spontaneously remit?
Can treating depression improve outcomes in cardiovascular disease?
How does childhood trauma interact with genetic risk factors and epigenetic mechanisms to account for adult risk of disorders like PTSD?
Why do many genes increase risk of both bipolar and schizophrenia?
How can we advance our classification of psychiatric disease to reflect what we know about the biology?
Given its rapid effects, could ketamine be used to treat suicidal ideation in depressed patients?
Why does ketamine work quickly in treatment-resistant depression, while most therapies require at least 6 weeks?
How do cytokines and other inflammatory molecules contribute to depression?
Can some patients with treatment-resistant depression be helped by anti-inflammatory therapies?
What are distinctive features of mood disorders in Arab populations?
What are the best potential biomarkers in treatment-resistant depression?
How can we move toward an era of personalized or precision treatment for depression?
What is the mechanism by which ketamine rapidly relieves depressive symptoms?
Can electroconvulsive therapy be made more precise, with fewer side effects?