A slide from Dr. Charney’s introduction, showing that depression is the leading cause of disability worldwide.

The Department of Psychiatry’s seventh annual symposium took place on Friday, February 8. The speakers covered emerging treatments for depression including ketamine, deep brain stimulation, and personalized treatment.

“This symposium was an opportunity for researchers, clinicians, and individuals from the community to come together to take stock of the magnitude of the problem of depression, and discuss the latest in treatment innovations,” said James Murrough, MD, PhD, who organized and presented at the event. “Despite the large scale problems of depression and suicide in our country, the research presented at the symposium is cause for great optimism. We believe that we will have breakthrough treatments for patients suffering for depression in the near future.”

The Depression and Anxiety Center

Dennis S. Charney, MD, Anne and Joel Ehrenkranz Dean, Icahn School of Medicine at Mount Sinai, and President for Academic Affairs, Mount Sinai Health System, opened the symposium by announcing Mount Sinai’s new Depression and Anxiety Center for Discovery and Treatment (DAC), headed by Dr. Murrough. DAC will build upon its previous iteration, the Mood and Anxiety Disorders Program, via its mission to advance the treatment of depression, anxiety, and related disorders through innovative clinical and translational research, and to provide exceptional evidence-based clinical care to patients.

“To come up with a breakthrough is not easy—to do so requires intelligence that involves not just memory, but creativity,” Dr. Charney said. “There are only a few places in the country that have the resources and scientists that make discoveries that change the lives of patients, and we’re fortunate to have that here at Mount Sinai.”

Stress and epigenetics

The first keynote was delivered by Bruce McEwen, PhD, of The Rockefeller University, on the role of stress and epigenetics in the causes and treatment of depression. Epigenetics refers to the study of differences in gene expression that come as a result of environmental factors throughout the course of an individual’s life. Experiences change the brain, and a history of chronic stress can alter the brain’s physical structure. Dr. McEwen said that “gene expression is a one-way street, and we can’t turn back the clock; we must focus on resilience and redirection, as opposed to reversal.”

Translational neuroscience driving novel antidepressant development

Dr. Murrough moderated the first panel: Scott Russo, PhD, on immune mechanisms, Ming Hu Han, PhD, on hyperpolarization-activated cyclic nucleotide-gated (HCN) channel targets, and Gerard Sanacora, MD, PhD, from the Yale School of Medicine, on glutamate and GABA.

Dr. Russo discussed his research into how the immune system plays a causal role in stress vulnerability, specifically the pro-inflammatory cytokine interleukin 6. He showed that individual differences in the inflammatory response to stress can lead to social avoidance in animal models, and he is investigating these differences. Similarly, Dr. Han is exploring why some people are stable after experiencing stress and others are not, and his lab is exploring HCN channels for potential drug discovery, as HCN channels are involved in mediating ketamine effects. Dr. Sanacora discussed how glutamate and GABA contribute to depression on the molecular and cellular level. He highlighted a new drug in development, brexanolone, that binds to the GABA receptor, as well as various ketamine studies.

Biosignatures for personalized treatment

Madhukar Trivedi, MD, from UT Southwestern Medical Center, presented the second keynote talk on biomarkers for diagnostic purposes.

“We need to look at the interaction of an array of clinical, EEG, neuroimaging, and serum markers,” he said. “This approach can lead to customized treatments for individuals.” His research underscores the importance of tracking physiological biomarkers based on neuroimaging, neurophysiology, genomics, proteomics, and metabolomics measures to understand depressive symptoms and treatment effects.

Therapeutic innovations for treatment resistant depression

Manish Jha, MD, moderated the second panel: Dr. Murrough on rapidly acting antidepressants including ketamine, Corey Keller, MD, PhD, of Stanford, on the mechanisms of antidepressant response to transcranial magnetic stimulation (TMS), and Helen Mayberg, MD, on deep brain stimulation (DBS).

Dr. Murrough brought the backstory on ketamine as the first drug to show rapid antidepressant effects within hours, and noted that Mount Sinai conducted the first experiments on repeated dosing, the first study of intranasal ketamine, and the first randomized controlled trial of ketamine for suicidal ideation. Dr. Keller discussed his aims for maximizing clinical response to TMS by enhancing specificity and plasticity. Regarding “metaplasticity,” he notes that “previously induced plasticity can modify a synapse’s ability to induce future plasticity,” and hopes to use computational models to predict changes in the brain. Dr. Mayberg spoke about her DBS work, which involves implanting electrodes into the subcallosal cingulate near the center of the brains of patients whose depression “couldn’t be drugged down, talked down, or shocked down with ECT.” Her pioneering work takes place in collaboration with other Mount Sinai researchers at the new Center for Advanced Therapeutics.

A slide from Dr. Murrough’s presentation.

Take-home message

The consensus? When you make a change, you create a new version of the brain. “The brain is flexible and plastic, which is cause for great optimism in the future of treating depression.”

This symposium was made possible thanks to a generous gift from Dr. Karen Davis and the Elkins Foundation.

This year’s American Psychiatric Association (APA) conference takes place May 18-22 in San Francisco. The schedule of sessions presented by faculty from the Department of Psychiatry is listed below.

Saturday, May 18

Computers and Psychiatry: How Might Our Practice Change?
Chair: Cheryl Corcoran, MD
When: 8:00-9:30 am
Where: Room 158, Upper Mezzanine, Moscone South

Creating and Implementing a Program for the Mental Health and Wellbeing of Medical Students and Trainees: The Mount Sinai Health System Experience
Chairs: Jeffrey Newcorn, MD; Paul Rosenfield, MD
Presenters: Sabina Lim, MD, MPH; Daniel Safin, MD; Jonathan Ripp, MD, MPH
When: 10:00-11:30 am
Where: Room 151, Upper Mezzanine, Moscone South

Sunday, May 19

Sex, Drugs, and Culturally-Responsive Treatment: Addressing Substance Use Disorder in the Context of Sexual and Gender Diversity
Presenter: Faye Chao, MD
When: 8:00-9:30 am
Where: Room 24, Exhibition Level, Moscone North

Advances in the Understanding and Treatment of Treatment Resistant Depression
Chair: James Murrough, MD, PhD
Presenter: Martijn Figee, MD, PhD
When: 8:00-9:30 am
Where: Room 156, Upper Mezzanine, Moscone South

Imminent Suicide Risk Assessment in High-Risk Individuals Denying Suicidal Ideation or Intent
Director: Igor Galynker, MD, PhD
Faculty: Paul Rosenfield, MD
When: 8:00 am-12:00 pm
Where: Room 7, Exhibition Level, Moscone South

The Multiple Faces of Deportation: Being a Solution to the Challenges Faced by Asylum Seekers, Mixed Status Families, and Dreamers
Presenter: Gabrielle Shapiro, MD
When: 10:00-11:30 am
Where: Room 308, Third Level, Moscone South

Disrupting the Cycle of HIV Transmission: The Role of Mental Health Providers in the Inclusive Use of PrEP to Address Disparities
Chair: Kenneth Ashley, MD
When: 3:00-4:30 pm
Where: Rooms 310/311, Third Level, Moscone South

Transitioning from Methadone to Buprenorphine At An Urban Opioid Treatment Program
Chair: Timothy Brennan, MD
Presenters: Annie Levesque, MD; Prameet Singh, MD
When: 3:00-4:30 pm
Where: Room 25, Exhibition Level, Moscone North

Monday, May 20

Trauma Inflicted to Immigrant Children and Parents Through Policy of Forced Family Separation
Chair: Gabrielle Shapiro, MD
When: 8:00-9:30 am
Where: Room 303, Third Level, Moscone South

Medical History Mystery Lab
Presenter: Kenneth Ashley, MD
When: 8:00-11:00 am
Where: Room 22, Exhibition Level, Moscone North

A Blueprint for Providing Free, Comprehensive, Integrated Adolescent Health, Transgender Services and Mental Health Care in NYC for $1,000 per Patient
Chair: Kashmira Rustomji, MD
Presenter: John Steever, MD
When: 8:00-9:30 am
Where: Room 314, Third Level, Moscone South

Facing the Challenges of Misuse and Abuse of Stimulant Medications for ADHD: From Neurobiology to Clinical Care
Chair: Jeffrey Newcorn, MD
Presenters: Iliyan Ivanov, MD; Jeffrey Newcorn, MD
When: 8:00-9:30 am
Where: Room 25, Exhibition Level, Moscone North

Rebels With a Cause: Nurturing the Provider for Successful Program Evolution
Chair: Shilpa Taufique, PhD
Presenter: Brandon Johnson, MD
When: 8:00-9:30 am
Where: Room 206, Second Level, Moscone South

Diagnostic Categories or Dimensions? How Studying the Neural and Genetic Bases of Dimensional Traits Can Help Us Find New Treatments
Chair and presenter: Maria de las Mercedes Perez-Rodriguez, MD, PhD
When: 8:00-9:30 am
Where: Room 213, Second Level, Moscone South

Walking the Walk: Resident Roadmap to Leadership in Psychiatry
Presenter: Adjoa Smalls-Mantey, MD, DPhil
When: 10:00-11:30 am
Where: Room 208, Second Level, Moscone South

No Blacks, Fats, or Femmes: Stereotyping in the Gay Community and Issues of Racism, Body Image, and Masculinity 
Chair: Kenneth Ashley, MD
When: 3:00-4:30 pm
Where: Room 214, Second Level, Moscone South

Training the Next Generation of Community Psychiatrists: Science and Recovery
Chair: Paul Rosenfield, MD
Presenters: Joy Choi, MD;  Tomas Felipe Restrepo Palacio, MD
When: 3:00-4:30 pm
Where: Room 210, Second Level, Moscone South

Tuesday, May 21

Scaling Behavioral Health Integration: One Academic Health Care System’s Approach
Chair: Sabina Lim, MD, MPH
Presenters: Hansel Arroyo, MD; Kimberly Klipstein, MD; Rajvee Vora, MD
When: 10:00-11:30 am
Where: Room 314, Third Level, Moscone South

Management of Psychiatric Illness During Pregnancy and Postpartum: What Every Psychiatrist Needs To Know
Chair: Verlee Bergink, MD, PhD
When: 1:00-2:30 pm
Where: Rooms 201/209, Second Level, Moscone South

Typical or Troubled?®: Program Update and Further Development Discussion
Presenter: Gabrielle Shapiro, MD
When: 1:00-2:30 pm
Where: Room 308, Third Level, Moscone South

A Patient-Centered Approach to School Refusal: A Day Program’s Guide to Tackling One of Child and Adolescent Psychiatry’s Most Difficult Problems
Chair: Brandon Johnson, MD
Presenter: Shilpa Taufique, PhD
When: 3:00-4:30 pm
Where: Room 158, Upper Mezzanine, Moscone South

Separating Parents and Children: Impact on Mental Health and Resilience
Chairs: Adriana Feder, MD; Rachel Yehuda, PhD
When: 3:00-4:30 pm
Where: Room 204, Second Level, Moscone South

From Genetics to Stress Response to Treatment of Personality Disorders
Chair: Maria de las Mercedes Perez-Rodriguez, MD, PhD
When: 3:00-4:30 pm
Where: Room 153, Upper Mezzanine, Moscone South

Wednesday, May 22

New Onset Psychosis: What Trainees, Residents and Early Career Psychiatrists Should Know
Presenters: Cheryl Corcoran, MD; Iliyan Ivanov, MD; Dolores Malaspina, MD, MS, MSPH; Gabrielle Shapiro, MD
When: 8:00-9:30 am
Where: Room 156, Upper Mezzanine, Moscone South

Training Physician-Scientists in Psychiatry: A Road Map to Academic Success
Chairs: Antonia New, MD; Maria de las Mercedes Perez-Rodriguez, MD, PhD
Presenters: Kenechi Ejebe, MD, PhD; Rene Kahn, MD, PhD; Drew Kiraly, MD, PhD
When: 3:00-4:30 pm
Where: Room 208, Second Level, Moscone South

The 2018 NARSAD Young Investigator grantees from the Brain and Behavior Research Foundation include four faculty members from the Department of Psychiatry at the Icahn School of Medicine at Mount Sinai. Their research aims are listed below.

Rebecca Sue Hofford, PhD, hopes to lay the groundwork for a drug to treat addiction to cocaine and other psychostimulants. She previously found a link between cocaine-induced behaviors and the activity of granulocyte-colony stimulating factor, or G-CSF, which is a cytokine—a signaling protein released by the immune system. Her team now hopes to identify which neurons are affected by G-CSF in the nucleus accumbens, a brain region that is associated with reward processing and involved in addiction. They will study how affected neurons change their activity in response to G-CSF.

Eva Velthorst, PhD, will explore how parental genes that are not passed on to the child may nevertheless help explain the link between childhood adversity and the development of psychosis. It is theorized that such non-inherited genes are able to affect the child through their parents’ contribution to the child’s environment. This phenomenon, called “genetic nurturing,” has been largely ignored in genetic studies but may point to preventable exposures, Dr. Velthorst suggests. Leveraging the Avon Longitudinal Study of Parents and Children study, the team will integrate genetic and developmental data on 3,000+ individuals followed from birth up to age 24, and their parents. This will provide the opportunity to examine the effect of non-transmitted genes of the mother and father separately (accounting for the transmitted genes) in the childhood adversity-psychosis relationship.

This year’s American College of Neuropsychopharmacology (ACNP) conference takes place December 9-13 in Hollywood, Florida. Faculty from the Department of Psychiatry at the Icahn School of Medicine at Mount Sinai will be contributing via panels, study groups, and posters. The schedule of panels and study groups is listed below.

René Kahn, MD, PhD, left, and Dolores Malaspina, MD, MPH, MSc

Panels

Novel Technological Strategies to Assess Suicidality and Develop Suicidal Phenotypes
Co-chair: M. Mercedes Perez-Rodriguez, MD, PhD
When: Monday, 3 – 4:15 pm
Where: Diplomat 1-2

Neural Computations as Markers of Stress, Anxiety, and Trauma
Co-chair and presenter: Daniela Schiller, PhD
When: Monday, 3 – 5:30 pm; Dr. Schiller presents 4:20 – 4:55 pm
Where: Atlantic Ballroom 3

Larger-Scale Transcriptome and Epigenome Mappings, Modeling and Analyses in Developing and Diseased Human Brain
Presenters: Schahram Akbarian, MD, PhD, and Kiran Girdhar, PhD
When: Tuesday, 8:30 – 11 am; Dr. Akbarian presents 8:30 – 8:40 am; Dr. Girdhar presents 9:50 – 10:25 am
Where: Atlantic Ballroom 2

Neuroimaging as a Novel Tool to Enhance the Development of Psychotherapeutic Strategies
Chair: Harold Koenigsberg, MD
When: Thursday, 8 – 8:10 am; Dr. Koenigsberg presents 8:10 – 8:45 am
Where: Diplomat 1-2

Genomic Mechanisms in the Etiology of Bipolar Disorder
Presenter: Eli Stahl, PhD
When: Thursday, 8 – 10:30 am; Dr. Stahl presents 9:20 – 9:55 am
Where: Atlantic Ballroom 2

Challenges and Solutions to Elucidating Psychiatric Disease Biology From Genomic Association Using Human Induced Pluripotent Stem Cell-Based Assays
Presenter: Kristen Brennand, PhD  
When: Thursday, 12 – 2:30 pm; Dr. Brennand presents 12:10 – 12:45 pm
Where: Regency Ballroom 3

Study Groups

What is the Importance of Animal Models to Neuropsychiatric Disease?
Participant: Eric Nestler, MD, PhD
When: Tuesday, 8:30 – 11 am
Where: Great Hall 5

No Longer Tarred With the Same Brush? Evidence for the Therapeutic Potential of Cannabidiol: Implications for Regulatory Policy
Participant: Yasmin Hurd, PhD
When: Tuesday, 3 – 5:30 pm
Where: Atlantic Ballroom 3

Challenges and Strategies for Strengthening the Pipeline of Physician Scientists in Psychiatry and Neuroscience
Participants: René Kahn, MD, PhD, and Eric Nestler, MD, PhD
Moderator: Antonia New, MD
Co-chair: M. Mercedes Perez-Rodriguez, MD, PhD
When: Tuesday, 3 – 5:30 pm
Where: Great Hall 5

The Debate Regarding Maintenance Treatment With Antipsychotics In Schizophrenia
Participants: René Kahn, MD, PhD, and Dolores Malaspina, MD, MPH, MSc
When: Wednesday, 3 – 5:30 pm
Where: Great Hall 5

Lotje De Witte, MD, PhD, is one of the few experts on “mini brains,” or cerebral organoids—stem cells grown into small balls of human brain tissue. This video shows a mini brain in her lab, showing the dividing cells in red. Video courtesy of Dilara Ilhan.

Until very recently, there was no way to watch human brain activity in action. Imaging, postmortem brain specimens, and animals, though useful in many respects, can only reveal so much about how a live human brain functions. Enter the “mini brain,” or cerebral organoids: stem cells grown into small balls of human brain tissue.

Aided by a biochemical cocktail of proteins and minerals, they grow and self-assemble in the lab dish, mimicking the development of fetal brains in the womb and forming regions such as the hippocampus and retina. Cerebral organoids were first used in 2013 to model microcephaly, and are now used for studying neurological and psychiatric conditions such as autism and schizophrenia. An important distinction between mini brains and real ones is their lack of vasculature and an immune system—both vital aspects.

Rapid evolution

In March of this year, researchers at the UC Davis Institute for Regenerative Cures found a way to induce vascularization. They encased the mini brains in a nutritious gel containing endothelial cells (the cells that line the insides of blood vessels) so the organoids could grow their own blood vessels. After marinating for three weeks, they were implanted into rodent brains. Over the course of their time in vitro and then for two weeks in the rodents, the endothelial cells grew into functioning blood vessels that expanded into the organoid.

The following month, researchers at the Salk Institute for Biological Studies showed in Nature that organoids implanted in mice connected to the hosts’ circulatory systems. The organoid’s neurons fired in conjunction with the mouse-host’s neurons, suggesting a level of integration that could illuminate long-elusive secrets about many brain conditions.

Dr. De Witte’s breakthrough

Lotje de Witte, MD, PhD, one of the few experts in this field, is interested in the role of microglia cells, the immune cells of the brain. Microglia are involved in both inflammation and construction of the brain (believed to be associated with schizophrenia). Incredibly, she and her team discovered that these cells can innately develop within organoids. This greatly increases the potential of mini brains to illuminate how microglia contribute to human brain development and disease. Dr. De Witte’s team published their groundbreaking findings in Nature Communications in October.

“We have known for a long time that the immune system is somehow involved in causing neurodevelopmental disorders such as schizophrenia and autism. Now, we finally have a human model to study how microglia contribute to neurodevelopment and neurodevelopmental disorders. This is very exciting because if we find a disease mechanism, these organoids can be used to screen for potential new drugs to help our patients,” said Dr. De Witte.

The ethics of mini brains

Understandably, ethical and philosophical concerns have been raised, most notably in Nature earlier this year. What are the ethics of working with these organoids? Could a mini brain feel pain, or achieve consciousness?

“I’ve read about these issues with great interest,” said Dr. De Witte. “If it’s even possible to create a fully functioning brain or fetus in a dish, it’s far, far in the future. Regardless, it’s certainly critical to think ahead and discuss where the boundaries should be drawn. Our ultimate goal is always to more effectively treat the millions of people worldwide afflicted with neurological and psychiatric conditions, and mini brains are uniquely valuable for research in service of that goal. Optimizing the protocols to use this technology should be encouraged.”

Dr. De Witte is Assistant Professor of Psychiatry at the Icahn School of Medicine at Mount Sinai, where her lab investigates the connection between the immune system and the pathogenesis of psychiatric disorders. She is also affiliated with the MIRECC at the James J. Peters VA Medical Center in the Bronx, where she is establishing a lab to culture organoids. Her PhD is in molecular biology and immunology.