Depression is the leading cause of disability worldwide, with an estimated $2 trillion annual economic impact. The cost in terms of human suffering is, of course, incalculable. Each year about 8% of adults—nearly 20 million Americans—experience major depression; 8% of adolescents experience at least one depressive episode; and an estimated 3 million American adults make a suicide plan. Unfortunately, more than 50% of Americans with depression remain untreated. And while many who are treated respond to therapy, at least one-third do not respond or do not have a full response. Non-responders have “treatment-resistant depression” (TRD).
Many of these facts are known to the broad public. Not so well known are the activities of researchers in this country and around the world who have dedicated their lives to studying the basic biology of the human brain. The purpose of this article is to bring some of the more consequential fruits of their labors to light—beginning with new treatments for treatment-resistant major depression.
The First Rapid-Acting Antidepressants
In the spring of 2019, the U.S. Food and Drug Administration granted approval for two breakthrough medicines that act rapidly to alleviate symptoms of major depression. Esketamine, a drug administered via a nasal spray, was approved for use in treatment-resistant major depression. Weeks later, brexanolone, administered intravenously, was approved for use in postpartum depression.
Both events are milestones: Esketamine is the first antidepressant with a novel mechanism of action to be approved since the FDA’s 1959 approval of imipramine. Esketamine’s beneficial effects have been described as profound and astonishing, often beginning within an hour or two after administration. (Widely prescribed SSRI antidepressants typically take weeks or months to provide relief.) Brexanolone is the first medicine ever approved specifically to treat depression that begins just before or in the months following childbirth. Its beneficial effects are usually felt within about 2 days of administration.
The development of both medicines exemplifies the power of investing in basic research. Both medicines emerged after years of careful clinical testing. But the research that led to their testing was driven by prior inquiries over many years in dozens of labs into the fundamental biology of the brain. In basic investigations of this kind, direct links between research and goal are not known, or even knowable, when grants are awarded that make the work possible.
The Brain & Behavior Research Foundation (BBRF, formerly “NARSAD”) has since its inception 36 years ago stressed grant-making of this kind. In fact, 90 grants awarded by BBRF over more than two decades and totaling over $6.5 million substantially contributed to the development of the first two rapid-acting antidepressants.
Transcranial Magnetic Stimulation (TMS) to Treat Depression
The modern application of electroconvulsive therapy (ECT) has enabled people with severe, treatment-resistant depression to carry on with their lives. But it involves a medical procedure that must be performed under general anesthesia, usually in a clinic or hospital, and is usually considered a treatment of last resort due to side effects, which can include short-term memory loss.
In the 1990s, a researcher used BBRF grants to study and develop a very different way of using “neuromodulation” to alter connectivity in brain circuits implicated in depression. Called rTMS (repetitive transcranial magnetic stimulation), this technology is non-invasive and is delivered on an outpatient basis. Patients experience only minor side effects such as headaches, which typically pass in minutes, and have no loss of memory. BBRF grantees demonstrated that rTMS was effective in a substantial percentage (one-third or more) of treatment-resistant depression patients. This led to FDA approval in 2009. The treatment is used around the country and across the globe today, including as a first-line treatment in some depressed patients. More powerful and equally safe rapid-acting versions of TMS are being tested in clinical trials and show promise not only in TRD but as treatments for hospitalized patients experiencing a suicidal crisis. A protocol named SAINT developed by a BBRF grantee was given the go-ahead for commercialization by the FDA last September. In three clinical trials, it has enabled nearly 80% of refractory major-depression patients to achieve remission after only 5 days of accelerated, individually targeted non-invasive stimulation. Other advanced neuromodulation therapies are being tested in PTSD, OCD, and other psychiatric disorders.
Clozapine in the Treatment of Schizophrenia
Schizophrenia is a chronic and often disabling brain disorder that affects 1 in 100 (about 2.5 million) American adults. Symptoms include delusions, hallucinations, disorganized speech, trouble with thinking, and lack of motivation. With treatment, some symptoms of schizophrenia can greatly improve. Yet roughly 750,000 Americans have “treatment-resistant schizophrenia” (TRS).
Clozapine was the first antipsychotic drug proven to be effective in treating TRS and remains the “gold-standard” treatment. It has also been found to significantly lower the risk of suicidal behavior in schizophrenia patients. Clozapine’s effectiveness in treating schizophrenia was demonstrated in a clinical trial in the 1980s co-led by a scientist who was working on a BBRF research grant. His work provided a scientific underpinning for the FDA’s approval of clozapine in 1989. This, in turn, led to the development of a whole new “second generation” of antipsychotics such as Abilify, Risperdal, and Seroquel—medicines that are now treating millions of patients globally.
Decreasing Schizophrenia Risk Via Maternal Choline Supplements
Prevention might be considered the ultimate goal of neuropsychiatric research. It is intriguing to consider, for instance: what if something could be done to reduce the risk of schizophrenia developing?
BBRF grantees and others have shown that the illness is highly complex. Factors thought to contribute to its causation are remarkably diverse. Chief among these are genetics: variations in one’s DNA that one carries from the beginning of life, along with environmental factors in the months and years following birth. BBRF-funded research has shown that complications during pregnancy can increase the chance that genetic risk factors in the fetus actually trigger changes in the brain’s development. These can affect the formation of neural cells and circuits in the fetal brain and the crucial thinning of synaptic connections early in life.
What if something as simple as taking a nutritional supplement by the mother during pregnancy could be shown to reduce risk or even prevent the future onset of schizophrenia? Researchers with BBRF funding have performed pioneering clinical studies that supplemented the diet of pregnant women with the essential nutrient choline. This research has shown that choline supplements during pregnancy do indeed appear to reduce the risk that a child will go on to develop psychotic disorders including schizophrenia. While the research is ongoing, the American Medical Association now recommends including choline in prenatal vitamin supplements.
Optogenetics Launches a Revolution in Brain Research
The 6200+ grants awarded over 36 years by BBRF have helped enable a rising generation of neuroscientists to shape a revolution in brain science. In addition to their contributions to the development of new treatments, grantees also have developed new technologies that help identify mechanisms in the brain that give rise to depression, anxiety, schizophrenia, autism, and other brain and behavior disorders.
These new technologies help them establish direct linkages between the devastating symptoms of mental illnesses and biological processes that alter the structure and function of the brain’s genes, cells, and circuitry. It’s very hard to examine or perform experiments in the living brain. But grantees have devised remarkable methods and new technologies that have catapulted research forward.
BBRF support for basic research was instrumental, for instance, in the development of optogenetics, a game-changing technology that gives researchers precise control over brain circuitry in animals. In 2021 a BBRF-funded scientist won the prestigious Albert Lasker Basic Medical Research Award for his role in developing the technology. Optogenetics involves the use of colored beams of laser light to rapidly open and close the membrane channels that make neurons fire and cease firing. This allows observation of the effects on behavior. This technology is now in use at thousands of labs all over the world and promises breakthroughs in the identification of mechanisms that give rise to depression, anxiety, schizophrenia, autism, and other brain and behavior disorders.
Stem-Cell Technology Provides a Window on Developing Brain Cells and Circuits
One of the challenges in studying the brain is not being able to sample living brain cells in patients with psychiatric disorders. To figure out how pathology related to mental illness arises, BBRF grantees have harnessed stem-cell technology to obtain views of the brain in its earliest stages of development, a time when pathologies associated with autism, schizophrenia, and other disorders are thought to begin.
Taking advantage of the unique properties of stem cells, BBRF-funded scientists have harmlessly sampled skin cells from people diagnosed with illnesses such as autism and schizophrenia, both of which are thought to have a strong genetic component, and “reprogrammed” these cells to return to the stem-cell state that marks the beginning of every cell’s life. These cells can then be induced to re-develop as mature brain cells.
Using this method, scientists can study such “reborn” brain cells with the hope of seeing when and how abnormalities develop. This remarkable technology has already yielded insights into abnormalities in autism and schizophrenia that can be traced to the earliest stages of life.
Peter Tarr, PhD, is Chief Science Writer and Jeffrey Borenstein, MD, is President & CEO at the Brain & Behavior Research Foundation.
