2020 Leading Research Achievements

We are pleased to present you with the 2020 Leading Research Achievements by BBRF Grantees, Prizewinners & Scientific Council Members. They are presented in the order of their publication in scientific journals.

Inhibiting the Threat Response in the Presence of a “Safety” Signal
Next-Generation Therapies: Anxiety Disorders

• Dylan Gee, Ph.D., Yale University; 2015 BBRF Young Investigator

Researchers identified a neural circuit projecting from a part of the brain’s hippocampus that enables people to inhibit their response to a perceived threat in the presence of a learned “safety” signal. Targeting this circuit could lead to a new therapeutic approach to fear-related anxiety. The pathway the researchers discovered diverges from the circuitry involved in “extinction learning” which is central in cognitive behavioral therapy (CBT) often prescribed to reduce fear- and stress-related anxiety. Read more.

Proceedings of the National Academy of Sciences, December 2019

In 2 Trials, Ketamine Added to Behavioral Therapy Helped People with Cocaine and Alcohol Dependencies to Abstain
Next-Generation Therapies: Addiction, Substance-Use Disorders

• Frances R. Levin, M.D., Columbia University; 2000 BBRF Independent Investigator

In separate randomized clinical trials published in February 2020 and November 2019, a research team at Columbia University and the New York Psychiatric Institute reported success in combining existing forms of behavioral-modification therapy and a single infusion of the drug ketamine (at a sub-anesthetic dose) to enable people with alcohol and cocaine dependencies to maintain abstinence. In the cocaine trial, ketamine was combined with mindfulness-based behavioral training; in the alcohol trial, it was paired with motivational enhancement therapy. Ketamine provided protection against a lapse in abstinence evolving into continued use—i.e., relapse—or into a dropout from treatment. The team suggests that ketamine may affect brain biology in ways that make the behavioral therapy component more effective than when given alone, a concept to be tested in larger trials. Read more.

American Journal of Psychiatry, February 2020

Mechanism in Brain’s Blood-Vessel Cells That Promotes Stress Resilience
Basic Research: Depression, Anxiety

• Caroline Ménard, Ph.D., Laval University / CERVO Brain Research Centre, Canada; 2016 BBRF Young Investigator

Researchers discovered molecular mechanisms in blood-vessel cells that form the blood-brain barrier (BBB) which may protect the brain against stress and depression, and which might be targeted in future therapies. The BBB selectively allows certain nutrients and other essential factors in the blood to pass into brain tissue, while keeping out pathogens, pro-inflammatory immune signals and other harmful elements. Dr. Ménard’s team explored mechanisms that give rise to leaks in the blood-brain barrier, promoting depression, and identified several potentially targetable immune pathways that help keep the BBB strong amid challenges like stress or inflammation. Read more.

Proceedings of the National Academy of Sciences, February 2020

Discovery of a Way to Potentially Extend Ketamine’s Antidepressant Effects
Next-Generation Therapies: Depression, PTSD

• Chadi G. Abdallah, M.D., Yale University / VA National Center for PTSD; 2014 and 2012 BBRF Young Investigator

Pre-treating refractory depression patients with the FDA-approved antibiotic drug rapamycin before giving them a ketamine infusion was found in a clinical trial to extend ketamine’s antidepressant effects. When patients took rapamycin prior to receiving ketamine, 41% still showed a clinical antidepressant response after two weeks, with 29% in full remission. This compared with 13% response and 7% remission when placebo was given prior to ketamine instead of rapamycin. In most patients, when ketamine is given alone, its effects are robust for several days and fade after about a week. The researchers note that rapamycin is a potent suppressor of inflammation, which has often been suspected of involvement in the biology of depression. They speculate that the anti-inflammatory effects of rapamycin may protect new or restored synaptic connections between neurons in the cortex that are forged after a ketamine infusion. Read more.

Neuropsychopharmacology, February 2020

Integrating Stem-Cell Technology and CRISPR Gene Editing Makes New Insights Possible on Disruptions in Brain Development
New Technologies, Basic Research: Schizophrenia, Autism, Developmental Disorders

• Kristen Brennand, Ph.D., Icahn School of Medicine at Mount Sinai /Yale University; BBRF Scientific Council, 2018 BBRF Maltz Prize, 2016 BBRF Independent Investigator, 2012 BBRF Young Investigator
• Schahram Akbarian, M.D., Ph.D., Icahn School of Medicine at Mount Sinai; BBRF Scientific Council, 2018 BBRF Lieber Prize, 2012 BBRF Distinguished Investigator, 2000, 1995, 1993 BBRF Young Investigator, 1997 BBRF Klerman Prize

Researchers harnessed the power of a gene-editing technology called CRISPR to make stem cell-based studies of psychiatric disorders much more powerful. Skin and blood cells sampled from patients can be reprogrammed to revert to a stem cell-like state and then be directed to redevelop as immature brain cells which can reveal pathologies caused by the patient’s genetic variations. Using CRISPR to create “isogenic” cell lines enables researchers to distinguish the specific biological changes associated with the presence or absence of a single “risk gene” or combinations of them, irrespective of DNA differences between cell donors. Drs. Brennand and Akbarian are pioneers in “integrating” the two technologies, thus helping to enhance the collective power of the field to explore causation and identify new treatments, especially for disorders such as schizophrenia and autism with strong genetic roots whose pathologies in many cases likely begin before birth as the fetal brain is developing. Read more.

Schizophrenia Research, March 2020

Remarkable Remission Rate Reported in Patients Who Received SAINT, a Non-Invasive Brain-Stimulation Treatment for Refractory Depression
Next-Generation Therapies: Depression

• Nolan Williams, M.D., Stanford University; 2019 BBRF Klerman Prize, 2018, 2016 BBRF Young Investigator

In a pilot trial involving 21 patients who had not responded to previous depression therapies, researchers employed a form of non-invasive brain stimulation treatment called iTBS (intermittent theta-burst stimulation). In this test, five times as much total stimulation was delivered over a 5-day period than currently FDA-approved depression treatments for iTBS and rTMS deliver in 6 weeks. After 5 days of treatments 90% of the participants achieved remission of their depression symptoms. One month later, 70% of patients continued to experience an antidepressant “response”—a reduction in initial symptoms of at least 50%. A larger trial is now in progress to confirm the rapid anti-depressant effects seen in the pilot trial. Read more.

American Journal of Psychiatry, April 2020

Study Finds Important Changes in the Treatment of Bipolar Disorder Over 20 Years
Next-Generation Therapies: Bipolar Disorder

• Samuel Wilkinson, M.D., Yale University; 2016 BBRF Young Investigator

Based on outpatient treatment records, researchers found that compared with 20 years ago, bipolar disorder outpatients today are much more likely to be prescribed an antipsychotic and/or an antidepressant medication rather than a mood stabilizer like lithium. Second-generation antipsychotics have in large measure replaced lithium and other mood stabilizers, the team noted, in the absence of any comparative effectiveness data that would indicate superior outcomes for patients. The researchers also noted a consistent lack of evidence for the efficacy of antidepressants in outpatients with bipolar disorder. In view of the trends they identified, the team strongly recommended initiating comparative effectiveness studies for mood stabilizers vs. second-generation antipsychotics, as well as efficacy studies for antidepressants in bipolar disorder outpatients. Read more.

American Journal of Psychiatry, April 2020

In Pregnant Women with COVID-19, Higher Choline Levels May Protect Fetal Brain Development
Diagnostic Tools/Early Intervention: Psychosis, Schizophrenia, Developmental Disorders

• Robert R. Freedman, M.D., University of Colorado Denver School of Medicine; BBRF Scientific Council, 2015 BBRF Lieber Prize, 2006 and 1999 BBRF Distinguished Investigator
• M. Camille Hoffman, M.D., University of Colorado Denver School of Medicine; 2015 BBRF Baer Prize

New research suggests that having higher levels of the nutrient choline via diet or supplements may protect brain development of the fetus in pregnant women who develop COVID-19 infection by early in the 2nd trimester. When faced with an infection, the mother’s body mounts an immune response, which poses a potential health risk to the fetus. The team drew upon data collected in their prior studies of women who developed bacterial and viral infections during the first 16 weeks of pregnancy—the point at which the fetus is most vulnerable to maternal inflammation. The data indicated that higher choline levels obtained through diet or supplements may protect fetal development and support early behavioral development even if the mother contracts a viral infection in early gestation when the brain is first being formed. Choline levels, they note, are most important early in pregnancy—levels beginning at 22 weeks were not observed to affect infant outcomes. Read more.

Journal of Psychiatric Research, May 2020

Researchers Discover a Role for Immune Cells Called Microglia in Inhibiting Brain Activity and Regulating Behavior
Basic Research: Schizophrenia, Depression, Epilepsy, Alzheimer’s

• Anne Schaefer, M.D., Ph.D., Icahn School of Medicine at Mount Sinai; 2010 BBRF Young Investigator

Researchers discovered a new way in which the brain keeps neural activation within normal bounds: immune cells specific to the brain, called microglia, sense neural activity and respond by locally inhibiting it. Failure of this mechanism may be involved in illnesses ranging from Alzheimer’s and epilepsy to depression and schizophrenia. The study puts a fresh spotlight on these cells as partners of neurons in the regulation of neuronal activity and behavior. When inflammation is present, Dr. Schaefer explains, or in neurodegenerative diseases like Alzheimer’s, microglia lose their ability to regulate neural activity—perhaps a factor in the pathology associated with these conditions. Since dysregulated neuronal activity is part of the pathology of an illness like Alzheimer’s, it means the regulatory role played by microglia also has an impact, indirectly, on behavior—something not previously recognized. Read more.

Nature, September 2020

Psychotherapy in Addition to Medication Helps Bipolar Disorder Patients Avoid Relapse and Manage Their Symptoms, Study Reveals
Next-Generation Therapies: Bipolar Disorder

• David Miklowitz, Ph.D., University of California, Los Angeles; 2011 BBRF Colvin Prize, 2001 BBRF Distinguished Investigator, 1987 BBRF Young Investigator

An analysis of 39 randomized clinical trials involving 3,863 individuals diagnosed with bipolar disorder concluded that when medication is supplemented with various forms of psychotherapy, the rate of recurrence in the next 12 months declines, and symptoms are better managed. The study found that psychoeducation with “guided practice of illness management skills” was superior when delivered in a family format (i.e., patients with their caregivers) or a group format (patients with other patients) than when delivered in an individual (one-on-one) format. Patients were more likely to stick with their combined treatment regimens over a year’s time when they received therapy in family or group formats, or when they received brief psychoeducation as opposed to more formalized versions of psychoeducation given individually. The team also concluded that medication combined with cognitive behavioral therapy (CBT), and with lesser certainty, family therapy or interpersonal therapy (IPT), was more effective than medication with “treatment as usual” in stabilizing depressive symptoms in patients. Read more.

JAMA Psychiatry, October 2020