Support teaching, research, and patient care.
Leanne Williams, PhD, is the inaugural Vincent V.C. Woo Professor of Psychiatry and Behavioral Sciences and Associate Chair of Translational Neuroscience at Stanford University School of Medicine. She is the founding director of the Stanford Center for Precision Mental Health and Wellness and of the Stanford PanLab for Precision Psychiatry and Translational Neuroscience. She holds a joint appointment as Director of the Precision Medicine Core at the Palo Alto VA Mental Illness Research, Education and Clinical Center.Prior to joining the Stanford community, Dr. Williams was the Professor of Cognitive Neuropsychiatry and Director of the Brain Dynamics Center at Sydney Medical School. Her PhD was completed with a British Council Scholarship for study at Oxford University.She has developed a precision neuroscience approach for application in psychiatry. This approach is grounded in a taxonomy of biotypes for depression and anxiety and a new image processing system to quantify these biotypes. Her research uses biotypes for more individualized diagnosis and for personalizing and tailoring the treatment. She evaluates pharmacotherapies, behavioral interventions, novel selective medicines, neuromodulation, and exploratory therapeutics. To tie together findings across studies, she integrates common neuroimaging, behavioral, and clinical measures. Computational approaches are used to further refine and expand her approach to precision mental health. Dr. Williams' research programs are supported by funding from the National Institutes of Health. She has published the first book on Precision Psychiatry and contributed over 360 scientific papers to the field.
The goal of this research is to revolutionize our approach to treating depression by identifying underlying brain circuitry disruptions and malfunctions in each patients and guiding personalized treatments that correct them. We are personalizing treatment by targeting brain circuitry with advanced imaging technology. This is a Clinical Translational Biomedical Innovation project within the School of Medicine.
In the last several years there have been incredible advances in human neuroscience, many of them due to groundbreaking research done right here at Stanford. Now, a unique collaboration between researchers, educators, and clinicians in the Stanford Psychiatry Department is beginning to bring these advances into clinical care. This study, the first of its kind in the nation, is a joint initiative of Dr. Leanne Williams, Director of the PanLab for Precision Psychiatry and Translational Neuroscience, and Dr. Chris Hayward, Chief of Adult Psychiatry and Director of Residency Training. The initiative’s implementation is led by Dr. Tali Ball, PanLab Fellow, in collaboration with Dr. Belinda Bandstra, Director of the Continuity Clinic. Patients entering the Continuity Clinic are offered a thorough assessment of symptoms, cognition, genetics, and brain circuit functioning. For half of participating patients, their doctor will receive information from the assessment to their first appointment. The remaining patients receive the information 12 weeks later, to allow the research team to test the impact of receiving information from neuroscience assessments relative to usual care. The research team also provides advanced training in neuroscience models and their applicability to clinical care to the PGY3 residents rotating in the clinic. This study establishes Stanford as a national leader in neuroscience-informed psychiatry in both training and practice.
The RAD-AT study is developing a precision psychiatry approach to testing new treatments for anhedonia. We focus on the reward circuits of the brain that underlie the experience of pleasure and motivated behavior. People with anhedonic depression have lost the ability to feel pleasure and have disrupted reward circuit function. Current treatments are not effective for them. We are assessing two novel treatments that target anhedonia and reward circuit dysfunction. One of these is Pramipexole, a drug that acts on the major neurotransmitter system involved in reward processing. The other is repetitive transcranial magnetic stimulation (rTMS), a direct neurostimulation treatment. Using a personalized, precision approach, we identify people experiencing anhedonia. We offer either pramipexole or rTMS for 8-12 weeks and examine anhedonia and reward-associated circuits before and after these treatments. The purpose of the study is to offer participants experiencing anhedonia a treatment that is alternative to ones that have failed them in the past, and to apply the knowledge we gain to help personalize mental health treatments in the future. This project extends on our RAD Project and NIH study # 11255773.
Short title "Research criteria for Anxiety and Depression; RAD Project". The RAD project is an R01 project funded under the NIMH Research Domain Criteria (RDoC) program. It is designed to use functional imaging to define dimensional constructs for reactivity and regulation of potential threat, within the Negative Valence system of RDoC. This is a novel study determining the cohesion with which these constructs relate to specific aspects of behavioral performance, features of anxious arousal and apprehensive expectations, and functional capacity.Grant Number: 1R01MH101496-01
Using brain scans, mobile technology, and virtual-reality experiments, we are investigating how the brain responds to two integrated behavioral therapies to help patients with co-existing obesity and depression to manage both conditions. We will then try to optimize the therapy and follow the further changes in the brain and improvements in mood and weight loss. The study is based on our understanding of the large-scale human brain circuits involved in self-regulation. Adopting and sticking to lifestyle changes is a reflection of a person’s ability to self-regulate, or manage their health issues on their own. By knowing more about how the brain changes or adapts in response to behavioral therapy, especially areas involved in self-regulation, then we can begin to tailor therapy to individual patients.The three-year study is first phase of a two-phase, five-year project funded through the NIH Common Fund’s Science of Behavior Change roadmap initiative. The project involves a collaboration between investigators at the University of Illinois Chicago, Stanford University School of Medicine, Palo Alto Medical Foundation Research Institute, and the University of Washington, Seattle, We will enroll 100 adults with co-occurring obesity and depression who are currently part of RAINBOW, a five-year randomized controlled trial led by PI Jun Ma (UIC) and Lisa Goldman Rosas, assistant scientist at the Palo Alto institute and an instructor of medicine at Stanford’s Prevention Research Center, and also funded by the NIH.Functional magnetic resonance imaging (fMRI) brain scans will be done before the start of behavioral therapy and after four weeks and six, 12 and 24 months of therapy to track changes in brain function. The participants’ brain activity will be compared to control subjects who didn’t receive the intervention. In collaboration with Stanford’s Virtual Human Interaction Lab, we will also assess emotional, cognitive, and self-reflective regulation by exposing participants to simulations of real-world situations in a virtual environment. We will also collect information on the subjects’ social engagement through an app on their smartphones. We aim to make real steps forward in the field of precision lifestyle medicine. The study will let us develop and validate the tools we need to be able to adjust and guide behavioral therapies based on neurobiological mechanisms — so that they are precise and personalized for the individual, and are scalable and sustainable for population health management.
Background: Clinically useful treatment moderators of Major Depressive Disorder (MDD) have not yet been identified. The aim of iSPOT-D is to identify pretreatment measures that predict or moderate MDD treatment response or remission to escitalopram, sertraline or venlafaxine; and develop a model that incorporates multiple predictors and moderators.Methods/Design: The International Study to Predict Optimized Treatment - in Depression (iSPOT-D) is a multi- centre, international, randomized, prospective, open-label trial. It is enrolling MDD outpatients (ages 18-65) from primary or specialty care practices (672 per treatment arm; 672 age-, sex- and education-matched healthy controls). Study-eligible patients are antidepressant medication (ADM) naïve or willing to undergo a one-week wash-out of any non-protocol ADM, and cannot have had an inadequate response to protocol ADM. Baseline assessments include symptoms; distress; daily function; brain imaging; cognitive performance; electroencephalogram and event- related potentials; heart rate and genetic measures. A subset of these baseline assessments are repeated after eight weeks of treatment. Outcomes include the 17-item Hamilton Rating Scale for Depression (primary) and self- reported depressive symptoms, social functioning, quality of life, emotional regulation, and side-effect burden (secondary). Participants may then enter a naturalistic telephone follow-up at weeks 12, 16, 24 and 52. The first half of the sample will be used to identify potential predictors and moderators, and the second half to replicate and confirm.Discussion: First enrolment was in December 2008, and 1700 patients have been tested, including 204 with brain imaging (structural MRI, functional MRI and diffusion MRI).
401 Quarry Road, Stanford Univ., Stanford University, Palo Alto, CA 94304, USA
Data acquisition for 101 relatives and 101 non-relative matched controls is complete. Opportunities exist for graduate students and post-doctoral fellows to analyze the data in new ways, for publication.This study was funded by the Australian Research Council from 2007-13. The aims of the study were as follows:The aim of this project is to understand vulnerability for depression in individuals. By understanding how depression develops, we can develop prevention and early intervention strategies. While factors in the environment, such as a difficult family environment, or stressful life events, are major contributors to the likelihood of a person developing MDD, part of the risk for depression depends on an individual’s biological predisposition. Because MDD is a heritable disorder, the relatives of people with depression can give provide us with information about the biological predisposition for vulnerability and resilience.We have investigated a range of contributing factors including genetics, brain structure and function (using neuroimaging and EEG/ERPs), behavior, personality and experienced symptoms, as well as the impact of life events. We will follow participants up one year after the initial visit to see how the initial measures relate to wellbeing and symptom development overtime. Integration across these measures will contribute to a deeper understanding of the development of depression.
401 Quarry Road
Data acquisition for this study is complete. There are opportunities for graduate student and post-doctoral involvement in new ways to analyze the data for publication. The study tested the following aims:AIMS: Schizophrenia is a disorder of cognition. Cognitive impairment is the strongest contributor to burden of illness. Yet, there are currently no routine tests for diagnosing cognitive impairments in schizophrenia, nor treatments for ameliorating these impairments.The evidence base for developing new cognitive treatments requires cognitive measures that link to functional capacity on the one hand, and to brain changes involved in schizophrenia pathophysiology on the other. Specific aims are to identify:1. What cognitive impairments characterize schizophrenia patients at first onset. 2. Whether functional capacities are predicted by these impairments at first onset. 3. What brain systems are involved. 4. How cognitive impairments, and their relationships with functional capacity and brain function, progress over 12 months. RESEARCH PLAN: A longitudinal design, targeting a total of 50 first onset schizophrenia patients and matched healthy controls. Eligibility Patient eligibility is a primary diagnosis of schizophrenia or schizophrenia spectrum disorder, according to DSM-IV criteria and confirmed by at least one psychiatrist independent of the study.First onset status is defined by; first contact with a mental health service with psychotic symptoms, and testing occurs within 3 months of this contact. It is not possible in these clinical services to test patients prior to medication. However, since patients are first onset, medication will be limited in duration. For consistency, testing will occur once patients are on a maintenance dose. Healthy controls will be screened for lack of psychiatric status, and matched to patients for age, sex, years of education, premorbid IQ and geographic region. Exclusion criteria for both groups are: (1) treatment with antidepressants during past month, (2) meeting diagnostic criteria for primary depressive disorder, (3) illicit substance dependence, (4) mental retardation, (5) medical condition or disease that might interfere with the assessments (e.g. hearing impairment); (6) did not provide sign informed consent to take part. DesignTest-retest from Baseline to 6 months follow up testing:(a) Baseline: Clinic status will be assessed to confirm diagnosis in patients, and healthy status in controls. Cognition will be assessed in both groups with the computerized touchscreen battery, IntegNeuro, and functional capacity with performance-based measures. EEG (for Gamma synchrony) and fMRI will be recorded to test the brain basis of cognition. (b) 6 months follow up: Repeat testing of both groups with clinical status, cognitive performance, functional outcome using the same performance-based measures, and both EEG and fMRI recording. AssessmentsClinical status. Diagnosis: The Structured Clinical Interview for DSM disorder (SCID) will be used to confirm diagnosis in patients and screen for absence of psychiatric symptoms in healthy controls. Symptoms: Symptoms will be rated using the Positive and Negative Syndrome Scales (PANSS), summed for positive and negative symptoms according to standard criteria. Medication: Medication dose will be quantified in chlorpromazine equivalent units. Patients at study sites are typically receiving risperidone or quetiapine, routine atypical antipsychotics. Functional capacity and outcome.
401 Quarry Road, Stanford
Background: The ACTION study (Attention deficit hyperactivity disorder Controlled Trial Investigation Of a Non- stimulant) is a multi-center, double-blind, randomized cross-over trial of the non-stimulant medication, Atomoxetine, in children and adolescents with attention deficit hyperactivity disorder (ADHD) and associated anxiety. The primary aims are to examine the efficacy of atomoxetine for improving cognition and emotional function in ADHD and whether any improvements in these outcomes are more pronounced in participants with comorbid anxiety; and to determine if changes in these outcomes after atomoxetine are more reliable than changes in diagnostic symptoms of ADHD. Methods: Children and adolescents aged 6 - 17 y with ADHD have been enrolled. Clinical interview and validated scales were used to confirm diagnosis and screen for exclusion criteria, which include concurrent stimulant use, and comorbid psychiatric or neurological conditions other than anxiety. Three assessment sessions were conducted over the 13-week study period: Session 1 (Baseline, pre-treatment), Session 2 (six weeks, atomoxetine or placebo), and Session 3 (13 weeks, cross-over after one-week washout period). The standardized touch-screen battery, “IntegNeuroTM”, will be used to assess cognitive and emotional function. The primary measure of response will be symptom ratings, while quality of life will be a secondary outcome. Data acquisition is now complete and analyses are underway.The goal of this study is to make a significant step towards a ‘personalized medicine’ (and therefore a more efficient) approach to treatment of ADHD and comorbid anxiety.
Sydney, NSW; Stanford, CA
Despite significant advances, we still have limited knowledge about endophenotype markers of which aspects of brain function cause risk for mental disorder and which aspects confers resilience. The TWIN-E study (The Twin study in Wellbeing using Integrative Neuroscience of Emotion) aims to establish endophenotype markers of mental health across cognitive, brain imaging and autonomic measures by testing the heritability, clinical plausibility, and reliability of each of these measures in a large adult twin cohort. The specific gene and environmental mechanisms that moderate prospective links between endophenotype- phenotype markers and the final outcome of wellbeing will also be identified. TWIN-E is a national prospective study with three phases: I) baseline testing on a battery of online questionnaires and cognitive tasks, and EEG, MRI, and autonomic testing; II) 12-month follow-up testing on the online assessments; and III) randomized controlled trial of brain training. Minimum target numbers include 1,500 male/female twins (18–65 years) for the online assessments (Phase I and II), 300 twins for the EEG testing component, and 244 twins for the MRI testing component. For Phase III, each twin out of the pair will be randomized to either the treatment or waitlist control group to test the effects of brain training on mental health over a 30-day period, and to confirm the gene–environment and endophenotype contributions to treatment response. Data acquisition is now complete and analyses are underway.
LIMCA is a longitudinal imaging study to understand how the healthy brain changes and develops with age. Changes in the brain, especially the limbic regions, have been commonly linked to a number of psychiatric disorders. Most of these disorders emerge at an early age, mainly during childhood and adolescents. The aim of this study is to use a new brain imaging technique to understand how the healthy brain changes and develops during this critical period. Using this information we can then identify the differences in brain development that predict mental illness. These results will help us develop better early intervention strategies to maintain good mental health.
Sydney Medical School and Stanford University
National Health and Medical Research Council Project Grant 1087560Chief Investigator A, Mayuresh Korgaonkar, PhD Chief Investigator B, Stuart Grieve, MD, PhDChief Investigator C, Anthony Harris, MD, PhD Chief Investigator D, Philip Boyce, MDChief Investigator E, Leanne Williams, PhD
Precision mental health
American Psychiatric Association
collaborative human clinical neuroscience
research and community
A revolution is under way in psychiatry. We can now understand mental illness as an expression of underlying brain circuit disruptions, shaped by experience and genetics. Our challenge is to now accelerate the translation of these insights into new models of mental disorder, and improve lives. Right now, mental disorders are our number one cause of ruined lives. At least 1 in 10 of us is affected by these disorders but only a fraction get access to treatment. Fewer still get better after the first treatment they try.My lab is finding solutions to these problems. We are defining precision brain circuit biotypes for mood, anxiety and attention disorders. We integrate across large amounts of brain imaging, behavior and other data and computational approaches. Biotypes are used in personalized intervention studies with selective drugs, neuromodulation and exploratory therapeutics. To close the loop, field ready insights are applied in practice.We are advancing a neuroscience-informed approach to Precision Mental Health for Psychiatry.1. Neural circuit taxonomy We have developed a novel brain-based taxonomy for understanding mental disorders. Each person's experience of mental disorder is characterized as an expression of the way in which underlying circuits are disrupted. Our model accounts for how circuit disruptions are shaped by early life experience, by daily function, and by genetic contributions. 2. Advanced computational models To continually refine our taxonomy, and to discover new types, we use advanced machine-learning approaches. By choosing to use common data elements, we have amassed the largest available databank of integrated imaging, physiological, behavioral and genetic data on a spectrum of mood, anxiety and attention disorders, people at risk of these disorders and healthy people. With these large amounts of data, we are accelerating the discovery of new types, and the detailed mapping between brain circuits, behavior and experience. 3. Mapping human connectomes In a new human connectome study, we are adding higher resolution imaging of brain connectivity to our brain circuit model. With these connectome data, we extend our taxonomy to the precise mapping of how each person's brain circuits connect and communicate, and how "short circuits" in these connections cause particular types of symptom experiences.4. Biomarkers to predict treatment Our lab led the first multi-site international studies to identify imaging and genetic biomarkers that predict the right treatment for the right person at the right time. With these advances, we can double the number of people who recover from depression. We have launched new precision medicine in mental health studies that use biotypes to guide selection of interventions. Our intervention studies span selective drugs, targeting particular biotypes, neuromodulation techniques such as transcranial magnetic stimulation and rapid acting exploratory therapeutics, including ketamine, MDMA and psilocybin. 5. Accelerating translation into practice There is a giant chasm between neuroscience insights and their application in practice to improve lives for people experiencing mental disorders. To close this loop, we lead first-in-nation studies to accelerate the translation of field-ready insights into clinical practice and education. Because our focus is on changing the way we understand mental disorder, our lab embraces the heterogeneity of these disorders. We focus on the commonly co-occurring experiences of mood, anxiety and attentional disruption in adults and in young people. We also investigate other commonly associated experiences such as substance use. For more about what motivates us check out the websites for our Center for Precision Mental Health and Wellness, the Williams PanLab and our Youtube channel:http://med.stanford.edu/pmhwhttps://williamspanlab.comhttps://youtu.be/ys9I8hax-To
Neural Circuit Biomarkers of Transcranial Magnetic Stimulation Study
This study is currently recruiting Veterans only. The objective of this observational study
is to test whether neuroimaging biomarkers of repetitive transcranial magnetic stimulation
(TMS) can be prospectively replicated in a large ecologically valid sample. We focus on
cognitive network connectivity as a predictive biomarker of the clinical effect of TMS, and
as a response biomarker of change with TMS. We address this objective through a pragmatic
approach in which we recruit patients undergoing routine clinical care and program evaluation
in a Veterans Administration multi-site clinical TMS program.
View full details
Stanford Regulating Circuits of the Brain Study - MDMA
This study is a biomarker study designed to characterize how MDMA impacts the reward circuits
of the human brain.
Research Aimed at Improving Both Mood and Weight
The RAINBOW study is an NIH R01-funded randomized controlled trial to evaluate the clinical
and cost effectiveness and implementation potential of a primary care integrated
multicondition intervention program to help improve mood and weight for obese adults with
clinically significant depressive symptoms. The ENGAGE study is a mechanistic investigation
added to the main trial with funding through the NIH common fund for the Science of Behavior
Change roadmap initiative. Beginning Jan 11, 2016, at least 100 of newly enrolled trial
participants will be consented to undergo additional assays evaluating neurobiological
mechanisms of self-regulation.
Stanford RAD-AT Study (Research on Anxiety and Depression - Anhedonia Treatment)
This research study is aimed at understanding behaviors and brain circuits that relate to
anxiety and depression. Our goal is to learn which circuits of the brain are involved in
anxiety and how these circuits might affect daily functioning.
This study has recently added an additional treatment component: participants undergo a 12
week course of either Pramipexole medication or rTMS therapy (explained below). The ultimate
goal of the study is to offer participants experiencing anxiety and depression a treatment
that is alternative to ones that have failed them in the past, and to apply the knowledge we
gain from investigating the brain circuits involved in anxiety and depression to help
We invite anyone who has recently experienced any symptoms of anxiety and/or depression to
participate (no diagnosis is required to participate).
International Study to Predict Optimised Treatment - in Depression
The aim of this study is to identify genetic, physical (brain) and psychological (cognitive)
markers (or combinations of them) that predict specific response to a range of
antidepressants treatment (Escitalopram, Venlafaxine, Sertraline) in patients diagnosed with
major depressive disorder. This study is focused on outcomes which may impact on how
"personalised medicine" is implemented in depression.