Thomas R. Insel, MD; Remi Quirion, PhD, FRSC, CQ
Genomics and neuroscience, 2 areas of science fundamental to psychiatry, have undergone revolutionary changes in the past 20 years. Yet methods of diagnosis and treatment for patients with mental disorders have remained relatively unchanged. Indeed, during the same time, the public health burden of mental disorders has grown alarmingly. Mental disorders are now among the largest sources of medical disability worldwide1 and, like AIDS and cancer, they are urgent and deadly.2-3
In this commentary, we argue that psychiatry's impact on public health will require that mental disorders be understood and treated as brain disorders. In the past, mental disorders were defined by the absence of a so-called organic lesion. Mental disorders became neurological disorders at the moment a lesion was found. With the advent of functional neuroimaging, patterns of regional brain activity associated with normal and pathological mental experience can be visualized, including detection of abnormal activity in brain circuits in the absence of an identifiable structural lesion. If mental disorders are brain disorders, then the basic sciences of psychiatry must include neuroscience and genomics and the training of psychiatrists in the future needs to be profoundly different from what it has been in the past. Throughout this commentary, we suggest opportunities for the discipline of psychiatry to change. We also recognize that psychiatry presents to the rest of medicine a unique blend of interpersonal skills and behavioral expertise that will be increasingly needed in this era of care dominated by technology. The challenge will be to incorporate neuroscience without losing the discipline's sophisticated understanding of behavior and emotion.4
Mental Disorders as Complex Genetic Disorders
Mental disorders are considered genetically complex, similar to hypertension, diabetes, and cancer. This means they are not the result of a single causative mutation as in cystic fibrosis; rather, several common genetic variations likely contribute to risk.5 Scores of genes will likely be involved in risk for schizophrenia, autism, bipolar disorder, and even the vulnerability to addiction, but, as we have seen in hypertension and certain types of cancer, their function may aggregate around key intracellular pathways. In the past few months, the map of human haplotypes has been added to the map of the human genome (http://www.hapmap.org/External Link: Please review our disclaimer.). This new map provides a guide to individual variation, a critical tool for identifying the vulnerability genes for genetically complex disorders. Defining the risk architecture of the major psychiatric disorders appears now limited only by being able to identify the phenotypes and endophenotypes of the illnesses, having access to DNA from enough patients and their relatives, and learning to detect critical gene-environment interactions.
It is also important to recognize the limitations of genetics for complex illnesses, such as schizophrenia. Although identifying the alleles associated with psychopathology may indicate risk, it is not clear that genetics research will yield a binary diagnostic test for most of the psychiatric disorders. Nevertheless, identifying genetic variations associated with disease should provide a gateway into pathophysiology, revealing new targets for treatment. Genomics should also yield an approach to understanding risk and thus possible strategies for preventive interventions.
Twin studies and genetic epidemiological research indicate that the environment, in both a social and physical sense, interacts with genetic vulnerability to exert a powerful influence on the development of mental disorders.6 Psychiatry has spent much of the last century investigating the infantile roots of adult psychopathology. The current era is extending this investigation to molecular mechanisms, asking how environmental factors during critical intervals of development exert long-term effects on gene expression. Exploring the mechanisms of gene-environment interactions for depression is not substantially different from understanding how environmental toxins contribute to cancer or how diet influences cardiovascular diseases. However, for mental disorders the trigger may be psychosocial experiences, the exposure may only have an impact at specific stages of development, and the effects may be limited to a narrow range of cells in the brain.
The recent experimental work by Weaver and colleagues,7 in which infant rats receiving the most maternal licking and grooming were subsequently less stress-responsive in adulthood, may prove an instructive paradigm. This long-term effect may be mediated by an enduring increase in hippocampal glucocorticoid receptors, which serve as a brake on the brain's stress response system. How could maternal behavior increase hippocampal glucocorticoid receptors? In the first 6 days of life, high levels of maternal licking and grooming were associated with a decrease in methylation of a key segment of the promoter region of the glucocorticoid receptor. Methylation is a common mechanism in the genome that leads to silencing of specific genes. In each cell, only about 15% of the genome is active8; the remainder is silenced by methylation and other mechanisms, with the exact pattern of activation or silencing varying from cell to cell. The proposed mechanism by which nurture affects nature is straightforward: maternal care reduces methylation, reduced methylation increases expression of the receptor, and with more receptors in the hippocampus, there is less reaction to stress. However, there is no change in gene sequence; the changes are only in DNA methylation and gene expression. Hence, these kinds of effects are called epigenetic. Epigenetic mechanisms can provide a potential pathway by which early experience can have lasting effects on behavior. In this case, the effects are localized to a single region of the genome (glucocorticoid receptor promoter), a single cell type (within the hippocampus), and a discrete developmental window (first 6 days after birth).
Genomics in psychiatry will need to grapple not only with classical genetics but also with the molecular mechanisms conferring long-term effects on gene expression. Although measuring exposure to a traumatic human experience appears more complex than measuring exposure to carcinogens or a high-cholesterol diet, the more vexing problem is the range of individual responses. How is it possible for stressful circumstances to destroy hope and opportunity in one individual and build character in others? Can genetic variations be identified that not only confer vulnerability or resilience to risk but alter behaviors that increase the exposure to risk? Can a quantifiable science of exposure to psychosocial trauma be developed as was done for environmental toxins? These are some of the questions that will be addressed by a new generation of clinical neuroscience researchers in the genomic era.
New Approaches to Neural Regulation
One of the major insights from the Human Genome Project has been the discovery of the number of human genes: roughly 23 000, with perhaps 50% of these expressed in the brain.9 It is likely that, until very recently, 99% of the literature on the neurochemistry of mental disorders has focused on less than 1% of the genome.10 Most genes code for many proteins, so the number of proteins in the brain undoubtedly exceeds 100 000. Theories of mental disorders based on a few monoamines, such as serotonin and dopamine, while helpful, will no doubt appear naive as research reveals vast numbers of new proteins found in the brain. In a sense, neuroscience is in a discovery phase, often called neurogenomics, with a goal of understanding where and when all of the genes in the brain are expressed.11
Neurogenomics will provide maps of RNA in the brain and should alter our understanding of neuroanatomy, but is unlikely to yield a biomarker for any mental disorder. Newer approaches, proteomics and metabolomics, attempt to measure all of the available proteins or metabolic pathways to detect potential biomarkers associated with major mental disorders.12-13 It seems likely that among the vast sea of RNAs or proteins, some unique patterns will be associated with specific mental disorders, providing either a trait or state marker that will permit a finer grain of diagnosis than has been possible with clinical observation.14 These may come from cerebrospinal fluid, central nervous system cells, or peripheral cells grown in culture, but the significances of these results may be limited by our inability to sample cells in the relevant brain circuits. Early results in schizophrenia,15-16 posttraumatic stress disorder,17 and autism18 are just emerging.
Although the number of DNA variations, RNA expression patterns, or protein changes that have been linked to mental disorders remain limited, molecular and cellular neuroscience studies are already pointing to critical principles of neural regulation. For example, the increasing recognition of neurogenesis in the adult brain has led to a novel hypothesis of the pathophysiology and treatment of depression. Clinical imaging studies have reported decreased hippocampal volume in people with major depressive disorder.19 Although it is not clear that depression is associated with reduced neurogenesis and changes in hippocampal volume have yet to be shown to be part of the pathophysiology of depression, animal studies have demonstrated that stress reduces neurogenesis in these regions19-20 and several classes of antidepressants increase the rate of neurogenesis in the hippocampus.21 In one study, a selective blockade of a drug's effect on neurogenesis also reduced the behavioral effect of the antidepressant.22 The resulting hypothesis is that chronic stress reduces the rate of neurogenesis in a critical pool of forebrain neurons, leading to a depressive episode in genetically vulnerable individuals. The importance of this hypothesis is that it introduces a long roster of known molecular mechanisms for neurogenesis as novel targets for developing new classes of pharmacological and behavioral treatments.
Revealing Brain Systems as Biomarkers
Ultimately, biomarkers for mental disorders may not be proteins or neurotransmitters but may emerge from neuroimaging (functional magnetic resonance imaging, single-photon emission computed tomography, etc). Logically, if these are disorders of brain systems, then the visualization of abnormal patterns of brain activity should detect the pathology of these illnesses. One can imagine studies in which patterns of brain activation following stimulation may be diagnostic, just as cardiac imaging during a stress test is now used to diagnose coronary artery disease.
Multiple approaches to identifying abnormal functional activity in the brain already are emerging, from functional magnetic resonance imaging to in vivo neurochemistry and studies of brain receptors. One approach uses functional imaging to identify differences in regional activity. For instance, evidence from several different approaches implicates circuitry involving ventral, medial prefrontal cortex (Area 25) with major depressive disorder.23 In addition to structural studies reporting decreased gray matter volume in this region,24 positron emission tomographic studies comparing responders and nonresponders to selective serotonin reuptake inhibitors, treatment with selective serotonin reuptake inhibitors and cognitive behavior therapy, and even placebo responders with nonresponders have all shown that recovery from depression is associated with a decrease in activity in this region.25 This region has nearly the highest serotonergic innervation in the human forebrain as measured by the expression of the serotonin transporter.26 Individuals with the short allele of the serotonin transporter gene have reduced expression of the transporter and appear to be at a higher risk for developing depression following stressful life events.27-28 Recently, this short allele has been shown to be associated with reduced gray matter volume of Area 25 and uncoupling of an anterior cingulate-amygdala circuit necessary for extinction of negative affect, providing a model for linking genetic risk and environmental stress to a specific neural circuit implicated in depression.29 Studies of this circuit might soon be used to predict response to treatment, just as imaging is used to predict treatment response in other areas of medicine.
As another approach, imaging of receptors may reveal regional abnormalities that could serve as a biomarker or diagnostic test. However, only a few applications to date are promising for patient care.30 Although there is a recent report of reduced serotonin 1a receptor binding in the cingulate cortex of patients with panic disorder31 and there are remarkable reports of enduring changes in striatal dopamine D2 receptors following psychostimulant abuse,32 no receptor studies exist for the diagnosis or treatment of major mental disorders. Unfortunately, relatively few radioligands for membrane-bound receptors have been identified, and the technique may fail to detect small, localized changes or intracellular changes distal to the receptor. Despite these shortcomings, it seems likely that imaging receptors or cell signaling pathways could allow a quantitative approach to biodiagnosis of mental disorders in the coming decade.
Training in Clinical Neuroscience
The recognition that mental disorders are brain disorders suggests that psychiatrists of the future will need to be educated as brain scientists. Indeed, psychiatrists and neurologists may be best considered clinical neuroscientists, applying the revolutionary insights from neuroscience to the care of those with brain disorders.33 The study of unconscious processes, motivation, or defenses, while at one time the sole province of psychoanalytic therapies, is now also in the domain of cognitive neuroscience.34-35 Systems neuroscience will be reformulating our notions of attention and emotion in the next decade just as it reformulated our understanding of language and perception in the last decade.
Will a deep understanding of the psyche remain a central focus of psychiatry? The need for a sophisticated understanding of interpersonal relationships along with the use of evidence-based, nonpharmacological treatments (from psychoeducation to cognitive behavioral treatments) will be the tools of the effective healer in the future as much as in the past. Just as the need for rehabilitation following acute care for any serious injury or medical illness has been recognized, ideally the psychiatrist will increasingly be part of a team that provides culturally valid psychosocial rehabilitation along with medications to help those with mental disorders recover and return to a productive and satisfying life. What will be different is having the ability to target these treatments to specific aspects of the disease process.
Redefining the foundation of psychiatry as clinical neuroscience also accelerates the integration of psychiatry with the rest of medicine. The separation of psychiatry from other medical specialties has contributed to the stigma of those who treat mental disorders as well as those who have them. Even beyond stigma, this separation has led to inadequate care. The recent scientific recognition of the importance of effective treatments of mental illnesses in cardiovascular disease and diabetes36-37 mandates the incorporation of psychiatry into truly integrated and effective treatment teams.
Where to Go From Here?
The 1990s were identified as the "decade of the brain" with major new insights into brain circuitry and function. The current decade may be recognized in retrospect as the "decade of discovery," during which many of the major candidate molecules, cells, and circuits for normal and abnormal brain function will be identified for the first time. A goal of the Decade of Discovery must be the description of the basic pathophysiology of each of the major mental disorders (Figure 1). Currently, patients with mental disorders are treated episodically with medications that are focused on symptoms and not on the core pathology. The available treatments are slow, incomplete, and can be limited by adverse effects. In mental disorders, just as in the rest of medicine, better understanding of pathophysiology should yield diagnosis based on biomarkers and treatments based on rational designs targeting the pathophysiology.38 It is critical to realize that clinical neuroscience does not entail designing exotic technologies for a few privileged patients. The ultimate goal is personalized or individualized care for a broad spectrum of patients with mental disorders. Recently a better understanding of pathophysiology has led to a strategy for individualizing treatment of cancer.39-40 Currently in psychiatry, specific treatments for any given patient are largely developed empirically. With more knowledge about the pathophysiology of mental disorders, treatments should become more specific, more effective, and ultimately more accessible.
Clinical neuroscience can now look forward to an "era of translation" with more accurate diagnoses and better treatments as well as very early detection and prevention. Early detection will require a thorough understanding of risk, based on a comprehensive understanding of genetics and experience. For example, preventive interventions might be available to prevent a first psychotic episode in an adolescent at high risk for schizophrenia.41
At the intersection of an age of discovery in the neurosciences, behavior, and the complexities of human mental life, psychiatry should emerge once again as among the most compelling and intellectually challenging medical specialties. This promise of the future will depend on psychiatry's incorporation of the insights and tools of modern neuroscience, integration into the mainstream of medicine by focusing on the public health needs of those with mental disorders, and retention among the medical specialties of a unique focus on the contribution of human experience and behavior to health and disease.
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- Kessler RC, Berglund P, Borges G, Nock M, Wang PS. Trends in suicide ideation, plans, gestures, and attempts in the United States, 1990-1992 to 2001-2003. JAMA. 2005;293:2487-2495.
- Cole TB, Glass RM. Mental illness and violent death: major issues for public health. JAMA. 2005;294:623-624.
- Kandel ER. A new intellectual framework for psychiatry. Am J Psychiatry. 1998;155:457-469.
- Cowan WM, Kopnisky KL, Hyman SE. The human genome project and its impact on psychiatry. Annu Rev Neurosci. 2002;25:1-50.
- Moffitt TE, Caspi A, Rutter M. Strategy for investigating interactions between measured genes and measured environments. Arch Gen Psychiatry. 2005;62:473-481.
- Weaver IC, Cervoni N, Champagne FA, et al. Epigenetic programming by maternal behavior. Nat Neurosci. 2004;7:847-854.
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- Sandberg R, Yasuda R, Pankratz DG, et al. Regional and strain-specific gene expression mapping in the adult mouse brain. Proc Natl Acad Sci U S A. 2000;97:11038-11043.
- Insel TR, Collins FS. Psychiatry in the genomics era. Am J Psychiatry. 2003;160:616-620.
- Boguski MS, Jones AR. Neurogenomics: at the intersection of neurobiology and genome sciences. Nat Neurosci. 2004;7:429-433.
- Marcotte ER, Srivastava LK, Quirion R. cDNA microarray and proteomic approaches in the study of brain diseases: focus on schizophrenia and Alzheimer's disease. Pharmacol Ther. 2003;100:63-74
- Prabakaran S, Swatton JE, Ryan MM, et al. Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress. Mol Psychiatry. 2004;9:684-697.
- Pennington K, Cotter D, Dunn MJ. The role of proteomics in investigating psychiatric disorders. Br J Psychiatry. 2005;187:4-6.
- Tsuang MT, Nossova N, Yager T, et al. Assessing the validity of blood-based gene expression profiles for the classification of schizophrenia and bipolar disorder: a preliminary report. Am J Med Genet B Neuropsychiatr Genet. 2005;133:1-5.
- Swatton JE, Prabakaran S, Karp NA, Lilley KS, Bahn S. Protein profiling of human postmortem brain using 2-dimensional fluorescence difference gel electrophoresis (2-D DIGE). Mol Psychiatry. 2004;9:128-143.
- Segman RH, Shefi N, Goltser-Dubner T, Friedman N, Kaminski N, Shalev AY. Peripheral blood mononuclear cell gene expression profiles identify emergent post-traumatic stress disorder among trauma survivors. Mol Psychiatry. 2005;10:500-513.
- Amaral DG, et al. Immunophenotyping and Proteomic and Metabolomic Profiling of Children with Autism. In: Program and abstracts of the 4th International Meeting for Autism Research: May 5-7, 2005; Boston, Mass.
- Duman RS. Depression: a case of neuronal, life, and death? Biol Psychiatry. 2004;56:140-145.
- Vollmayr B, Simonis C, Weber S, Gass P, Henn F. Reduced cell proliferation in the dentate gyrus is not correlated with the development of learned helplessness. Biol Psychiatry. 2003;54:1035-1040.
- Coyle JT, Duman RS. Finding the intracellular signaling pathways affected by mood disorder treatments. Neuron. 2003;38:157-160.
- Santarelli L, Saxe M, Gross C, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science. 2003;301:805-809.
- Goldapple K, Segal Z, Garson C, et al. Modulation of cortical-limbic pathways in major depression: treatment-specific effects of cognitive behavior therapy. Arch Gen Psychiatry. 2004;61:34-41.
- Drevets WC, Price JL, Simpson JR Jr, et al. Subgenual prefrontal cortex abnormalities in mood disorders. Nature. 1997;386:824-827.
- Mayberg HS. Modulating dysfunctional limbic-cortical circuits in depression: towards development of brain-based algorithms for diagnosis and optimised treatment. Br Med Bull. 2003;65:193-207.
- Varnas K, Halldin C, Hall H. Autoradiographic distribution of serotonin transporters and receptor subtypes in human brain. Hum Brain Mapp. 2004;22:246-260.
- Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301:386-389.
- Kendler KS, Kuhn JW, Vittum J, Prescott CA, Riley B. The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression: a replication. Arch Gen Psychiatry. 2005;62:529-535.
- Pezawas L, Meyer-Lindenberg A, Drabant EM, et al. 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. Nat Neurosci. 2005:828-834
- Abi-Dargham A, Rodenhiser J, Printz D, et al. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci U S A. 2000;97:8104-8109.
- Neumeister A, Bain E, Nugent AC, et al. Reduced serotonin type 1A receptor binding in panic disorder. J Neurosci. 2004;24:589-591.
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A Vision for Mental Health Research
Pathophysiologic descriptions of mental disorders will permit diagnoses validated by biological measures and treatments aimed at core pathology. Care will become personalized via an understanding of individual risk, allowing for strategic approaches to prevention and treatment. These ambitious goals require application of genomics and proteomics to mental disorders.
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