Front Matter

Contributors

Foreword

Helen Mayberg, M.D.

Preface

Precision Psychiatry: The Path Forward

Laura Weiss Roberts, M.D., M.A.

Introduction

Laura M. Hack, M.D., Ph.D., and Leanne M. Williams, Ph.D.

Part 1: Neuroimaging of Circuits

1 A Neural Circuit–Informed Taxonomy for Precision Psychiatry

Laura M. Hack, M.D., Ph.D., Tali M. Ball, Ph.D., and Leanne M. Williams, Ph.D.

2 The Future of Precision Transcranial Magnetic Stimulation in Psychiatry

Noah S. Philip, M.D., Amin Zandvakili, M.D., Ph.D., and Yosef A. Berlow, M.D., Ph.D.

3 Neural Mechanisms of Bipolar Disorder

Toward Personalized Markers of Future Illness Risk

Mary L. Phillips, M.D.

Part 2: Neurocognition, Neurophysiology, and Behavior

4 Information Processing Impairments as Transdiagnostic Treatment Targets in Psychiatric Disorders

Sophia Vinogradov, M.D., Jyoti Mishra, Ph.D., Mor Nahum, Ph.D., and Ian S. Ramsay, Ph.D.

5 State-Sensitive Biomarkers of Specific Computational Processes for Monitoring Symptoms and Predicting Outcomes in People With Schizophrenia

Steven M. Silverstein, Ph.D., Docia L. Demmin, M.S., and Samantha I. Fradkin, M.S.

Part 3: Blood Markers

6 Using Inflammatory Biomarkers to Identify and Treat Transdiagnostic Subtypes in Psychiatric Disorders

Carolina Medeiros Da Frota Ribeiro, M.D., Jennifer C. Felger, Ph.D., Michael T. Treadway, Ph.D., David R. Goldsmith, M.D., Ebrahim Haroon, M.D., and Andrew H. Miller, M.D.

7 Pharmacogenetic Testing

A Tool for Precision Prescribing in Psychiatry

Chad A. Bousman, Ph.D., Malcolm P. Forbes, M.B.B.S., and Boadie W. Dunlop, M.D.

Part 4: Translational Neurobiological Approaches

8 Treatment Prediction Biomarkers for Major Depressive Disorder

Matthew D. Sacchet, Ph.D., Christian A. Webb, Ph.D., and Diego A. Pizzagalli, Ph.D.

9 Translational Neurobiological Approaches to Precision Medicine for Fear and PTSD

Nathaniel G. Harnett, Ph.D., Antonia V. Seligowski, Ph.D., Daniel Pine, Ph.D., and Kerry J. Ressler, M.D., Ph.D.

Part 5: New Approaches and Computational Models That Bridge Neuroscience Insights and Clinical Application

10 Latent Variable–Based Predictive and Explanatory Disease Models

Martin P. Paulus, M.D.

11 Computational Cognitive Methods for Precision Psychiatry

Quentin J.M. Huys, M.D., Ph.D.

12 Toward Precision Cognitive-Behavioral Therapy via Reinforcement Learning Theory

Yael Niv, Ph.D., Peter Hitchcock, Ph.D., Isabel M. Berwian, Ph.D., and Gila Schoen, M.D.

Part 6: Developing the Academic Discipline of Precision Psychiatry

13 Moving From Precision to Personalized Psychiatry

Clinical Perspectives on the New Era

Giampaolo Perna, M.D., Ph.D., and Charles B. Nemeroff, M.D., Ph.D.

14 Preparing for the Future of Precision Psychiatry

The Critical Role of Neuroscience Education

David A. Ross, M.D., Ph.D., Joseph J. Cooper, M.D., Melissa R. Arbuckle, M.D., Ph.D., Ashley E. Walker, M.D., and Michael J. Travis, M.D.

Index

Professor of Psychiatry, Columbia University Irving Medical Center; Vice Chair for Education and Director of Resident Education, Department of Psychiatry, Columbia University Irving Medical Center and the New York State Psychiatric Institute, New York

Instructor, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine; Psychologist, Stanford Health Care, Stanford, California

Assistant Professor, Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University and the VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, Providence, Rhode Island

Postdoctoral Research Associate, Princeton Neuroscience Institute, Princeton University, Princeton, New Jersey

Associate Professor, Departments of Medical Genetics, Psychiatry, Physiology, and Pharmacology, University of Calgary, Calgary, Alberta, Canada; Department of Psychiatry, University of Melbourne, Melbourne, Victoria, Australia

Associate Professor of Clinical Psychiatry, Director of Medical Student Education in Psychiatry, and Co-Director of Behavioral Neurology and Neuropsychiatry Fellowship, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois

Doctoral Student, Department of Psychology, and University Behavioral Health Care, Rutgers, The State University of New Jersey, Piscataway, New Jersey

Professor and Director, Mood and Anxiety Disorders Program, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia

Associate Professor and Laboratory Director, Behavioral Immunology Program, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia

Clinical Senior Fellow, Department of Psychiatry, University of Melbourne, Melbourne, Victoria, Australia

Doctoral student, Department of Psychology, University of Rochester, Rochester, New York

Assistant Professor; Faculty, Behavioral Immunology Program; Co-Director, Persistent Symptoms: Treatment, Assessment, and Recovery (PSTAR) Clinic, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia

Postdoctoral Fellow, Advanced Fellowship in Mental Illness Research and Treatment, Palo Alto Veterans Affairs Health Care System, Sierra-Pacific MIRECC; Clinical Instructor and Director of the Translational Precision Mental Health Clinic, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California

Instructor, Neurobiology of Fear Laboratory, Division of Depression and Anxiety, McLean Hospital, Belmont, Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts

Associate Professor and Medical Director, Behavioral Immunology Program, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia

Postdoctoral Research Associate, Laboratory of Neural Computation and Cognition, Department of Cognitive, Linguistic and Psychological Sciences, Brown University, Providence, Rhode Island

Clinical Associate Professor, Division of Psychiatry and Max Planck UCL Centre for Computational Psychiatry and Ageing Research, University College London; Honorary Consultant Psychiatrist, Camden and Islington NHS Foundation Trust, London, United Kingdom

Assistant Professor, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia

William P. Timmie Professor, Vice Chair of Research, and Director, Behavioral Immunology Program, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia

Assistant Professor, Department of Psychiatry, University of California—San Diego, La Jolla, California

Senior Lecturer, School of Occupational Therapy, Faculty of Medicine, Hebrew University, Jerusalem, Israel

Chair and Professor, Department of Psychiatry; Director, Institute for Early Life Adversity Research, University of Texas Austin, Dell Medical School, Austin, Texas

Professor and Co-Director, Rutgers-Princeton Center for Computational Neuropsychiatry (CCNP), Princeton Neuroscience Institute and Psychology Department, Princeton University, Princeton, New Jersey

Scientific Director and President, Laureate Institute for Brain Research, Tulsa, Oklahoma

Professor, Department of Biological Sciences, Humanitas University, Milan, Italy; Chair, Department of Clinical Neurosciences, Villa San Benedetto Menni, Hermanas Hospitalarias, Como, Italy

Associate Professor, Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University and the VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, Providence, Rhode Island

Pittsburgh Foundation—Emmerling Endowed Chair in Psychotic Disorders; Professor in Psychiatry and Clinical and Translational Science; Director of the Center for Research on Translational and Developmental Affective Neuroscience; Director of the Mood and Brain Laboratory, University of Pittsburgh, Pittsburgh, Pennsylvania

Chief, Section on Developmental and Affective Neuroscience, and Co-Chief, Emotion and Development Branch, National Institute of Mental Health, Bethesda, Maryland

Professor of Psychiatry; Director, Center for Depression, Anxiety, and Stress Research; Director, McLean Imaging Center, McLean Hospital, Harvard Medical School, Belmont, Massachusetts

Assistant Professor, Department of Psychiatry and Behavioral Sciences, University of Minnesota Medical School, Minneapolis, Minnesota

Chief Scientific Officer; Chief, Center of Excellence in Depression and Anxiety Disorders; James and Patricia Poitras Chair in Psychiatry; and Director, Neurobiology of Fear Laboratory, McLean Hospital, Belmont, Massachusetts; Professor of Psychiatry, Department of Psychiatry, Harvard Medical School, Boston, Massachusetts

Associate Professor, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut

Instructor in Psychiatry and Assistant Neuroscientist, Center for Depression, Anxiety, and Stress Research, McLean Hospital, Harvard Medical School, Belmont, Massachusetts

Psychiatrist, Child and Adolescent Division, Geha Mental Health Center, Petah Tikva, Israel

Assistant Neuroscientist, Neurobiology of Fear Laboratory, Instructor in Psychology, Division of Depression and Anxiety, McLean Hospital, Belmont, Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts

George L. Engel Professor of Psychosocial Medicine; Associate Chair of Research, Department of Psychiatry; Professor of Psychiatry, Neuroscience, and Ophthalmology; and Center for Visual Science, University of Rochester Medical Center, Rochester, New York

Associate Professor and Director of Residency Training, Department of Psychiatry, University of Pittsburgh School of Medicine, UPMC Western Psychiatric Hospital, Pittsburgh, Pennsylvania

Associate Professor and Director, TReAD Lab, Department of Psychology, Emory University, Atlanta, Georgia

Donald W. Hastings Endowed Chair in Psychiatry and Department Head of Psychiatry and Behavioral Sciences, University of Minnesota Medical School, Minneapolis, Minnesota

Associate Professor and Director of Residency Training, Department of Psychiatry, University of Oklahoma School of Community Medicine, Tulsa, Oklahoma

Assistant Professor of Psychiatry and Director, Treatment and Etiology of Depression in Youth (TEDY) Laboratory, Center for Depression, Anxiety, and Stress Research, McLean Hospital, Harvard Medical School, Belmont, Massachusetts

Professor and Associate Chair of Translational Neuroscience and Director of the Precision Psychiatry and Translational Neuroscience Lab (PanLab), Stanford Department of Psychiatry and Behavioral Sciences; Director of the Stanford Center for Precision Mental Health and Wellness at Stanford University School of Medicine; and Director of Precision Medicine at the Department of Veterans Affairs, Sierra-Pacific MIRECC, California

Assistant Professor, Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University and the VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, Providence, Rhode Island

DISCLOSURE OF COMPETING INTERESTS

Yosef A. Berlow, M.D., Ph.D.—Dr. Berlow’s work is supported by grants from the National Institute of Mental Health (NIMH R25 MH101076) and the VA RR&D Center for Neurorestoration and Neurotechnology. The author reports no financial relationships with commercial interests.

Boadie W. Dunlop, M.D.—Dr. Dunlop has received honoraria for consulting services to Myriad Neuroscience, which markets the GeneSight Psychotropic Test.

Helen Mayberg, M.D.—Dr. Mayberg receives consulting and IP licensing fees from Abbott Neuromodulation.

Andrew H. Miller, M.D.—Dr. Miller is a paid consultant for Boehringer Ingelheim.

Charles B. Nemeroff, M.D., Ph.D.—Dr. Nemeroff reports the following: Research/Grant: National Institutes of Health (NIH); Consulting (last three years): Xhale, Takeda, Taisho Pharmaceutical, Signant Health, Sunovion Pharmaceuticals, Janssen Research & Development, Magstim, Navitor Pharmaceuticals, TC MSO, Intra-Cellular Therapies, EMA Wellness, Gerson Lehrman Group, Acadia Pharmaceuticals, Magnolia CNS, Compass Pathways, Epiodyne, Sophos, Axsome; Stockholder: Xhale, Celgene, Seattle Genetics, AbbVie, OPKO Health, Antares, BI Gen Holdings, Corcept Therapeutics Pharmaceuticals Company, TC MSO, Trends in Pharma Development, EMA Wellness; Scientific Advisory Boards: American Foundation for Suicide Prevention, Brain and Behavior Research Foundation, Xhale, Anxiety Disorders Association of America, Skyland Trail, Signant Health, Laureate Institute for Brain Research, Magnolia CNS; Board of Directors: Gratitude America, ADAA, Xhale Smart; Income sources or equity of $10,000 or more: American Psychiatric Association Publishing, Xhale, Signant Health, CME Outfitters, Intra-Cellular Therapies, Magstim, EMA Wellness; Patents: Method and devices for transdermal delivery of lithium (US 6,375,990B1), Method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (US 7,148,027B2), Compounds, compositions, methods of synthesis, and methods of treatment (CRF receptor binding ligand) (US 8,551, 996 B2).

Giampaolo Perna, M.D., Ph.D.—Dr. Perna is a consultant for Pfizer, Lundbeck, Menarini, and Mediobio Ldt.

Noah S. Philip, M.D.—Dr. Philip’s work is supported by grants from the U.S. Department of Veterans Affairs (VA) (I01 RX002450), and the VA RR&D Center for Neurorestoration and Neurotechnology. In the past, Dr. Philip has received grant support from Janssen, Neosync, and Neuronetics through clinical trial contracts and has served as an unpaid scientific advisory board member for Neuronetics.

Diego A. Pizzagalli, Ph.D.—Dr. Pizzagalli has received consulting fees from Akili Interactive Labs, BlackThorn Therapeutics, Boehringer Ingelheim, Posit Science, and Takeda Pharmaceuticals, as well as an honorarium from Alkermes.

Kerry J. Ressler, M.D., Ph.D.—Dr. Ressler is on the Scientific Advisory Boards for Resilience Therapeutics, Sheppard Pratt–Lieber Research Institute, Laureate Institute for Brain Research, The Army STARRS Project, UCSD VA Center of Excellence for Stress and Mental Health—CESAMH, and the Anxiety and Depression Association of America. He provides fee-for-service consultation for Alkermes and Resilience Therapeutics. He holds patents for use of D-cycloserine and psychotherapy, targeting PAC₁ receptor for extinction, targeting tachykinin-2 for prevention of fear, and targeting angiotensin to improve extinction of fear. He receives or has received research funding from NIMH, HHMI, Brainsway, Genomind, and NARSAD.

Matthew D. Sacchet, Ph.D.—Dr. Sacchet has received consulting fees from Vorso Corporation.

Michael T. Treadway, Ph.D.—Dr. Treadway has received consulting fees from Avanir Pharmaceuticals and BlackThorn Therapeutics. No funding or sponsorship was provided by these companies for the current work.

Sophia Vinogradov, M.D.—Dr. Vinogradov has received grant/research support from the Lynne and Andrew Redleaf Foundation and other financial or material support from Mindstrong Alkermes, Psyberguide, and Verily Life Sciences.

Leanne M. Williams, Ph.D.—U.S. Patent Applications 10/034,645 and 15/820,338: Systems and methods for detecting complex networks in MRI image data.

Amin Zandvakili, M.D., Ph.D.—Dr. Zandvakili’s work is supported by grants from the National Institute of General Medical Sciences (NIGMS U54GM115677) and the VA RR&D Center for Neurorestoration and Neurotechnology. The author reports no financial relationships with commercial interests.

Tali M. Ball, Ph.D.

Isabel M. Berwian, Ph.D.

Chad A. Bousman, Ph.D.

Docia L. Demmin, M.S.

Jennifer C. Felger, Ph.D.

Malcolm P. Forbes, M.B.B.S.

Samantha I. Fradkin, M.S.

David R. Goldsmith, M.D.

Laura M. Hack, M.D., Ph.D.

Nathaniel G. Harnett, Ph.D.

Ebrahim Haroon, M.D.

Peter Hitchcock, Ph.D.

Quentin J.M. Huys, M.D., Ph.D.

Carolina Medeiros Da Frota Ribeiro, M.D.

Jyoti Mishra, Ph.D.

Yael Niv, Ph.D.

Martin P. Paulus, M.D.

Mary L. Phillips, M.D.

Daniel Pine, Ph.D.

Ian S. Ramsay, Ph.D.

Gila Schoen, M.D.

Antonia V. Seligowski, Ph.D.

Steven M. Silverstein, Ph.D.

Michael J. Travis, M.D.

Christian A. Webb, Ph.D.

While our strategies may vary, the vision of precision psychiatry is to optimize treatment for each and every patient. Toward this mission, dependable treatment selection algorithms, regardless of the indication, should not only match an individual to their best treatment option but also avoid an ineffective or potentially harmful one. Although this goal is seen by some as an impractical or, at best, naïve blue-sky goal, contemporary clinical neuroscience research speaks to the ultimate achievability of this holy grail quest. The contributors to this book provide clear evidence that the goal is indeed within sight.

The need has never seemed more urgent. Amplifying our impatience is the fact that current treatment selection continues to rely on experiential trial and error—the perennial stopgap. It is assumed that, while inefficient, this approach is generally effective, although the evidence is increasingly clear that the more treatments that are tried and failed, the less likely it is that any subsequent one will work, so getting the “right treatment” at the time of first intervention is paramount. More ominous is the hypothesis that exposure to the “wrong” treatment may itself contribute to the development of treatment resistance over time. Further underscoring this need is that patients are understandably suspect when told a treatment works well “on average,” when what they really want to know is what treatment will work best for them. While frustration with this status quo serves as a useful scientific catalyst for many of us, despair, not frustration, is the upshot for many patients who have exhausted their available options. It is in this context that past ambivalence about the use of biomarkers to guide treatment is lessening, and development of biomarkers is now seen as a critical clinical need, complementing studies of disease pathophysiology and ultimately development of preventions and cures.

This book highlights the tremendous progress in the field toward these many important goals. Although the concept of “precision psychiatry” is not new, suitable tools to deconstruct and validate the multitude of putative moderators and mediators of illness risk, symptom severity, and phenotypical heterogeneity are relatively recent additions. Basic clinical and computational strategies are now routinely applied to address the complex interaction of molecular, developmental, chemical, structural, and environmental contributors to specific disorders and syndromes. As the precision psychiatry field has grown and matured, there are now means and methods to move beyond hypothesis-driven experiments in small prospective cohorts. Studies now include large-scale genetic, behavioral, and imaging phenotyping of increasingly larger cohorts of well-characterized patients and their families, informed by basic and translational studies in strategic animal models. The symbiosis of these multimodal strategies is at the core of precision psychiatry, with key examples highlighted in the various chapters of this book.

The tremendous progress of the field broadly provides the opportunity to reflect on just how far we have come since the 1980s toward actionable precision approaches for the treatment of major depression. My own studies, beginning in the mid-1980s, first examined brain metabolic patterns of depression in neurological patients. In those early days of functional neuroimaging using PET, the capacity to move beyond conducting static correlational analyses of postmortem or X-ray computed tomography lesions to mapping the living brain in action was a paradigm shift for the study of behavioral disorder when there were no pathognomonic markers. Resting-state studies of blood flow and metabolism identified a similar pattern of limbic-frontal abnormalities in depressed patients with stroke, Parkinson’s disease, and Huntington’s disease, a pattern also seen in unipolar depressed patients, suggesting a common depression signature, independent of etiology, and thus providing core elements for a putative depression circuit model (Mayberg 1994).

The simple-minded notion of a common depression pathway, while short-lived, did provide an anchor to interpret the variability revealed through studies of antidepressant treatment effects. In these early experiments, frontal abnormalities, common across all subjects at pretreatment baseline as previously noted, were accompanied by differential anterior cingulate metabolism that distinguished eventual medication responders from nonresponders. The concept of ongoing adaptive changes in patients prior to seeking care that might impact their ultimate response to treatment, although representing a shift from our initial hypothesis, was an important first clue to the notion of depression subtypes tied to treatment rather than symptom variability. We noted that the “presence of this metabolic signature in individual patients may prove useful in identifying those at risk for a difficult disease course” (Mayberg et al. 1997), a conclusion that unwittingly foretold the trajectory of our future work and defined what has become a cornerstone of the precision psychiatry mission—treatment selection biotyping.

These initial observations next led to a series of studies designed to characterize treatment mechanisms, starting with first-line antidepressant medications (Mayberg et al. 2000). In addition to identifying a nonlinear time course of brain changes over the course of 6 weeks of treatment, these studies also revealed distinct differences between responders and nonresponders (Mayberg 1997, 2000). Studies of single medications and placebo led to the natural next step—a complementary study of cognitive-behavioral therapy (CBT), an alternative first-line treatment. Interestingly, it was this experiment, designed to define a common response pathway independent of treatment type, that first demonstrated that different treatment classes target a common set of brain regions in complementary but non-overlapping patterns (Goldapple et al. 2004). These findings further enabled explicit testing of simple causal models and identification of putative treatment-specific “circuit” subtypes (Seminowicz et al. 2004). These preliminary studies also served to guide trial design and analytic strategies to define baseline imaging patterns that might differentially predict remission or failure to both medication and CBT (Mayberg 2003). Consecutive studies in distinct cohorts using fluorodeoxyglucose-PET and resting-state functional MRI to explore functional connectivity, respectively, independently defined two distinct imaging-based biotypes, both suitable for precision treatment selection in prospective trials (Dunlop et al. 2017; McGrath et al. 2013). In parallel, these data-driven depression models were also foundational to the development and testing of deep brain stimulation (DBS) of the subcallosal cingulate—a key node in our depression network—for treatment-resistant patients (Mayberg et al. 2005). Ongoing DBS studies continue to emphasize the importance of precision imaging, with surgical implantation of DBS leads now optimized using individualized tractography-guided methods (Riva-Posse et al. 2014), verified by predictable and reproducible intraoperative behavioral effects with therapeutic stimulation at predefined target locations (Riva-Posse et al. 2018).

Whether one uses a hypothesis-driven study in a small patient cohort or a model-free, “big data” approach, we share a common goal: to develop biomarkers and algorithms that will discriminate patient subgroups and optimize treatment selection in the management of individual patients across all stages of illness. Treatment selection is not a negotiation, but rather the best option given the current evidence. Ultimately, clinical use of such discoveries will require biomarkers that are not only robust but scalable. While the complexity of psychiatric disorders will always require a holistic approach, our evolving methodological toolkit now puts us in position to align our approaches with those in the fields of cardiology, oncology, and infectious disease, where treatment selection is routinely based not on preference or expediency but on explicit molecular, imaging, and biological markers. What is clear is that one size does not fit all; so the pursuit of a true precision approach, in all of its complexity, is our future.

Helen Mayberg, M.D.

Much of the world’s health burden, measured in years lost to disability or premature mortality, is attributable to mental disorders. Every nation, every community, every family, and every person is affected, directly or indirectly, by these brain-based health conditions—conditions that are poorly understood, are often underrecognized, go untreated for years or for a lifetime, and are as yet incurable.

Psychiatry is the field of medicine that is dedicated to understanding mental disorders and helping people with these conditions to live fulfilling lives and to adapt to the unique challenges they face. In their clinical practice, psychiatrists work with courageous people who experience great distress and despair and also exhibit great resilience and dignity. Psychiatry also advances knowledge of the prevention, diagnosis, and treatment of mental disorders and awareness of how mental health and physical health go hand in hand.

Basic and clinical neuroscientists seek to discover the brain-based causes of different mental disorders and to discern patterns associated with mental disorders. Such discoveries will allow for better prevention, swifter treatment, and improved outcomes, benefiting people and populations today and in the future. This work has been hard going, however. The brain comprises nearly a hundred billion neurons, and these neurons connect in nearly a hundred trillion ways. These neurons adapt and change over the course of development, as do their many connections, and both are influenced by innumerable inherited and environmental factors. The phenomena that suggest or demonstrate the existence of an underlying mental disorder in people of different ages, genders, and across a continuum of cultures may be highly consistent or highly inconsistent. In this complexity one marvels that the brain works at all, rather than the fact that disorders may predictably arise.

Precision psychiatry represents a path forward, integrating findings from basic and clinical neuroscience, clinical practice, and population-level data. Precision psychiatry focuses on differentiating characteristics and patterns and, in an evidence-driven manner, developing therapeutic approaches that may be most helpful to specific individuals with a specific constellation of health issues, characteristics, strengths, and symptoms. In this book, the authors highlight progress in the treatment of common disorders such as depression, bipolar disorder, PTSD, and schizophrenia. Though treatment is remarkably effective in improving quality of life and reducing the burden of symptoms and impairments, finding the right treatment is too often a process of months or years. Moreover, mental disorders may complicate and worsen the risks associated with other health conditions. For example, depression increases the risk of cardiovascular-related deaths threefold. Addressing these challenges requires the very best, most cutting-edge approaches to prediction, prevention, and preemption that population science can possibly provide.

Harnessing advances in the fields of biomedical sciences, medicine, engineering, education, social sciences, and ethics will increasingly be the key to revolutionizing the diagnosis and treatment of mental illness with greater precision. With this book, we begin this new approach, advancing the care of our patients and advancing the field, which is dedicated to serving people living with mental disorders, and, ultimately, human health.

Laura Weiss Roberts, M.D., M.A.

A revolution is under way in psychiatry—one that integrates the scientific foundations of the discipline with recent advances in the neurosciences, data sciences, and technology in order to narrow the gap between discovery and clinical translation. This integration is motivated by the search for a model that connects a neurobiological understanding of mental disorder with clinical observation, in order to improve the precision of classification and treatment decisions. We feel the urgency to accelerate clinically applicable precision psychiatry and address the impact of major mental disorders on the very functions that enable us to live productive and satisfying lives. An estimated 970 million people worldwide experienced a mental or substance disorder in the past few years, and one in five people in the United States live with a mental disorder at some point in their lives.

Progress in precision medicine in disciplines outside of psychiatry, such as oncology and cardiology, has inspired progress reflected in the contributions in this book. In these disciplines, biomarkers are combined with clinical features to stratify patients into subtypes that are more coherent than are overarching diagnostic categories. This approach allows for identifying subtypes that are underserved by available therapies. It also allows for developing novel therapies aimed at targets that are based on specific mechanisms that affect measurable outcomes and that are closer to underlying disease processes than are traditional clinical endpoints.

We are gratified to offer this book to illustrate timely advances emerging in precision medicine in psychiatry. Contributors to this book have a common view that we require a neuroscience- and data-informed approach to advancing precision medicine in psychiatry. We believe that is it past time for mental health providers and educators to have ready access to the latest research in precise classification, treatment planning, and early identification across a spectrum of psychiatric disorders. While the scientific breakthroughs discussed in this book are exciting in their own right, they will only move our field forward if they are disseminated to trainees, clinicians, and, ultimately, our patients. Hence, throughout the chapters, our authors have included case examples of the applications of their topics, and the last chapter discusses the critical role of neuroscience education in precision psychiatry.

We are fortunate for the opportunity to bring together authors across a range of expertise who have played fundamental roles in the development of the discipline of precision psychiatry. They discuss biomarkers in neuroimaging, electrophysiology, and peripheral serum, as well as variations in genetic markers, neurocognition, and behavior. They examine the importance of computational approaches and machine learning. They take us on a journey through their topics from the history, sometimes dating back to the Middle Ages through the influential work of scholars like Gall and Kraepelin, through current knowledge, to what is needed to continue to progress the field. Our expert authors also review the precise application of multiple treatment modalities that include pharmacotherapy, cognitive-behavioral therapy, neurostimulation, and cognitive training programs on the individual level. Finally, throughout this book, they discuss issues of scalability and implementation, including the need for the tests we disseminate to our patients to have analytic and clinical validity as well as clinical utility.

We have elected to focus on mood and anxiety disorders as well as schizophrenia in adults given that the most robust evidence in precision psychiatry currently exists for these disorders and this age group. However, evidence is emerging in precision medicine for obsessive-compulsive, neurodevelopmental, and eating disorders and across the age range. We hope that future editions of this book will include chapters covering those disorders, a wider spectrum of age ranges, and the precise application of emerging therapies in mental health, including virtual reality, psychedelic medications, targeted delivery of drugs to specific regions of the brain, and digital therapies. While we are delighted with the topics covered in this book, we recognize that we were not able to include several emerging areas in precision psychiatry for which the evidence base is growing, such as epigenomics, proteomics, metabolomics, and induced pluripotent stem cells.

Our hope is that psychiatry will continue to follow the path of other fields that have advanced further in precision medicine, in its development of biological subtyping and tailored treatments in order to create a better future for our patients suffering from these devastating illnesses. We envision a future where providers will have access to mental health profiles that incorporate biological, clinical, and environmental information into an easily digestible format. Ideally, these profiles will be utilized collaboratively with our patients in conjunction with clinical expertise for the purpose of case formulation and treatment planning. These formulations and treatment plans will be updated through an iterative process that incorporates both active and passive information from mobile devices, wearables, and applications. In this way, we have the opportunity to merge technological advances with decades of research on the neurobiological, neurophysiological, genetic, and inflammatory mechanisms underlying mental illness and response to treatment into improved outcomes. Through this new understanding we also hope to help dissolve the stigma of mental disorders and the consequent discrimination and barriers to care. We hope that you will find this book engaging and enlightening and that it will serve as a stepping stone in your continual journey toward better care for your patients.

Laura M. Hack, M.D., Ph.D.

Leanne M. Williams, Ph.D.