In the spring of 2019, The 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.

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.

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—most notably, in patients who have not been helped by multiple existing antidepressant treatments—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.)

Ninety grants awarded by BBRF over more than two decades and totaling over $6.5 million have substantially contributed to the development of these first two rapid-acting antidepressants. This record of productive grant-making can be traced back to two initial grants. One was a 1997 BBRF Independent Investigator award to John H. Krystal, M.D., of Yale University, which supported the study of brain circuit mechanisms underlying the effects of ketamine. The other was a 1995 BBRF Young Investigator award to Cynthia Neill Epperson, M.D., then also at Yale, for her early study of conventional antidepressant treatments in postpartum depression.

BASIC SCIENCE LEADING TO BREXANOLONE

Dr. Epperson’s grant marked the beginning of a multiyear quest that led from analyzing the effects of conventional antidepressants in women with postpartum depression to the search for more effective therapeutic options. In addition to the severe pain and suffering postpartum depression causes new mothers—about 10%–15% are affected—it is also associated with elevated suicide risk and is known to have profound effects on mothers’ ability to care properly for their newborns. As historic longitudinal research led by BBRF Scientific Council member, prizewinner, and multiple grant recipient Myrna Weissman, Ph.D., has shown, children of mothers with untreated depression have elevated risk of longer-term behavioral and psychiatric disorders as they move through childhood and adolescence.

The research performed by Dr. Epperson, who received three BBRF grants from 1995 to 2005, and others, ultimately revealed the possible role of the inhibitory neurotransmitter GABA in postpartum depression. Working with Dr. Krystal and colleagues in the Yale Magnetic Resonance Center, Dr. Epperson was able to map changes in cortical GABA levels across the menstrual cycle and in postpartum women. Brexanolone enhances the activity of one of the cellular receptors of GABA, which is repressed due to hormonal action following childbirth. This may be part of the mechanism responsible for symptoms in postpartum depression.

Another member of the team that performed clinical tests of brexanolone, Steven Paul, M.D., a member of the BBRF Scientific Council, is a pioneer in the study of the GABA receptors and their modulators. Handan Gunduz-Bruce, M.D., a 2003, 2005, and 2007 BBRF Young Investigator, of Yale University, was also part of the research team that tested brexanolone.

BOLD EARLY RESEARCH ON KETAMINE

The Foundation this year awarded its Colvin Prize for Outstanding Achievement in Mood Disorders Research to Dr. Krystal, a three-time BBRF grantee and member of the BBRF Scientific Council, and his mentor and collaborator, Dennis S. Charney, M.D., an emeritus Scientific Council member. Each of Dr. Krystal’s BBRF grants has supported work pertinent to the search for rapid-acting antidepressants, while Dr. Charney’s 2007 Distinguished Investigator grant supported the first clinical test of intranasally delivered ketamine for treatment of resistant major depression.

At this fall’s BBRF Mental Health Symposium, Drs. Krystal and Charney recounted the circumstances that led them, together, to initially test ketamine in a small group patients with major depression. Dr. Charney had long been studying the two neurotransmitter systems—serotonin and norepinephrine—whose function was thought to be affected by so-called monoamine antidepressants. (These include SSRIs such as Prozac, Paxil, and Zoloft and SNRIs such as Cymbalta and Effexor. These medicines, respectively, elevate levels of serotonin and norepinephrine in the brain, thought to generate therapeutic effects.)

Looking closely at the mechanisms of action of SSRIs and SNRIs, Dr. Charney began to realize that “we had arrived at a kind of conceptual crisis.”

For example, their research revealed that depleting serotonin in healthy people did not lead those people to become depressed. It was the same when they depleted norepinephrine, and also dopamine, another neurotransmitter. So it was not a simple deficit in these brain chemicals that was causing depression. Something more complicated was going on.

Dr. Krystal, who trained with Dr. Charney, also had a lab at Yale in the late 1990s. He describes how “I used to go up to his office at the end of the day and we’d toss around ideas for research studies.” One day, they had a brainstorm. As Dr. Krystal tells it: “We said, what if the pathology of depression doesn’t lie in the norepinephrine and serotonin systems? What if these are systems that can be recruited to try to treat depression—but are not the source of the problem?”

This change of perspective led them to begin thinking about other neurotransmitter systems and their cellular receptors. Specifically, they thought about glutamate and GABA—which together mediate the bulk of signaling in the brain’s cortex and limbic systems. “We thought: what would be the best way to probe the role of glutamate in depression?” Glutamate is by far the most prevalent excitatory neurotransmitter. Excitation is what causes a neuron to fire, the essential action in cell-to-cell communication. GABA is an inhibitory neurotransmitter whose crucial function is to apply a braking action to excitation. If there is too much excitation, the brain can seize up, as it does in epilepsy.

Dr. Krystal, in his own lab, had been working on glutamate pharmacology, and was studying the drug ketamine, an anesthetic, as a tool for studying aspects of psychosis in schizophrenia. This was the subject of Dr. Krystal’s 1997 BBRF Independent Investigator grant.

Dr. Charney continues the story. “We wanted to push the envelope, and in one of our late-night meetings we had the thought that maybe NMDA receptors [which engage with glutamate] are involved in depression.” It so happened that the drug that Dr. Krystal was studying, ketamine, was thought to inhibit the activity of NMDA receptors.

Drs. Charney and Krystal decided to test ketamine at a very low “sub-anesthetic” dose in a small group of depressed patients. The dose was critical, since ketamine at high dosages was known to cause dissociative symptoms—“out-of-body” experiences that are similar to those sometimes experienced by people with psychosis. Ketamine was also known to be addictive. Although Dr. Krystal became interested in the drug as a way of experimentally probing the biology of psychosis and schizophrenia, he and Dr. Charney would now try to harness it at very low doses as a therapeutic.

The dose they agreed upon for the pilot study was quite low—but as they would learn, not low enough to prevent ketamine from having an impact on seven severely depressed patients in their initial double-blinded, placebo-controlled trial, conducted at the VA Connecticut Healthcare System in West Haven, CT. Most of the participants responded, and with a minimum of side effects. “The antidepressant response was apparent within 72 hours,” Dr. Charney remembers, “and in some cases, within just a few hours. We were smart enough to know that maybe we were on to something—but with only seven patients we weren’t positive.”

In 2000, Drs. Charney, Krystal and colleagues published a paper in Biological Psychiatry announcing their results. In the meantime, they continued to study ketamine’s antidepressant potential. “While ketamine is a short-acting drug, we were showing that at 3 days, 4 days, even 7 days in some, a response was still there,” Dr. Charney says. “We believed it—but almost nobody else did. So when we published the paper, it kind of sat there. Other groups didn’t replicate the findings.”

‘PEOPLE REALLY STARTED BELIEVING IN KETAMINE’

In 2000, Dr. Charney left Yale to lead the Mood Disorders and Anxiety Program at the National Institute of Mental Health. “I had a great group there,” he recalls, “and I suggested to [Drs.] Carlos Zarate and Husseini Manji that we needed to try to replicate that initial ketamine finding. That led to the second study, published in 2006.”

In 2005, Dr. Zarate was awarded a BBRF Independent Investigator grant to perform this work. His NIMH collaborator, Dr. Manji, had been awarded the Foundation’s Falcone Prize in 1999—the predecessor of the Colvin Prize for mood disorders research. He was a member of BBRF’s Scientific Council, as, by this time, were Drs. Charney and Krystal. As Dr. Zarate explains, the 2006 study with Drs. Charney and Manji went beyond the 2000 Charney-Krystal paper in that it tested ketamine in treatment-resistant patients with major depression—participants who had in fact tried six or more other antidepressant treatments but had not been helped. The onset of response for these patients was within two hours, Dr. Zarate says. “Ever since, the field has moved rapidly forward.”

With continued BBRF grant support, Dr. Zarate, who was awarded BBRF’s Colvin Prize for his work on rapid-acting antidepressants in 2011, was able to push the line of research further. He was able to demonstrate for the first time that patients with treatment-resistant bipolar depression can respond to ketamine within one hour. Subsequently, his team was able to replicate this finding. “The Brain & Behavior Research Foundation has had an important impact on my career and permitted me to pursue a line of research that will hopefully help the field in developing next-generation treatments for our patients that are more efficacious and work more rapidly than existing treatments,” he says.

Dr. Zarate and his colleagues believed that if ketamine was given under carefully controlled hospital conditions, and to depressed people who had run out of treatment options, it might prove beneficial. “The key in generating interest in the study of ketamine was when we replicated the 2006 results some time later, and then again in a third study,” he says. “People really started believing in ketamine’s rapid antidepressant efficacy.” Then, in early 2013, a larger NIMH-funded study with ketamine in treatment-resistant depression was completed and essentially confirmed the results of these earlier studies.

MAKING A KETAMINE-BASED MEDICINE

There still was critical work to do. Following the lead of Dr. Charney’s team, which demonstrated the feasibility of intranasal delivery of ketamine, a team at Janssen Pharmaceuticals took up the work. Janssen was a subsidiary of Johnson & Johnson, where Dr. Manji had moved from NIMH to head global therapeutic neuroscience research. Now Dr. Manji and colleagues worked on a molecule called esketamine, a chemical derivative of ketamine, with the aim of bringing it to market for treatment of resistant depression.

In the spring of 2018, the Janssen-led team tested esketamine’s effects in 68 patients, aged 19–64, with severe depression and considered at imminent risk of suicide. All participants in the trial were voluntarily hospitalized and received standard-of-care medications for their depression. Importantly, all patients’ symptoms improved during the trial. But symptom reductions were greatest and most rapid among those who also received intranasal esketamine twice weekly, instead of a placebo. In addition to Dr. Manji, the team included Wayne Drevets, M.D., and Gerard Sanacora, M.D., Ph.D., and the paper’s lead author, Carla M. Canuso, M.D., a 1998 BBRF Young Investigator who was senior director of clinical development at J&J. Dr. Drevets, a 1999 Independent Investigator and 1996 Young Investigator, was awarded the Colvin Prize in 2014. Dr. Sancora, a professor at Yale, is a 2014 BBRF Distinguished Investigator, 2007 Independent Investigator, and 2001 and 1999 Young Investigator.

When the FDA’s advisory panel met to assess intranasal ketamine in early 2019, it considered this and nine other clinical studies, including five Phase 3 randomized, placebo-controlled studies in patients with treatment-resistant depression. The esketamine product recommended for approval was marketed under the name Spravato and took the form of a nasal spray, packaged in a delivery device that would contain two doses of 14 mg each.

All the while, BBRF grants continued to support researchers investigating esketamine’s mechanism of action as well as other potential applications, not only in bipolar disorder but possibly in PTSD and other mood disorders as well.

A study by Dr. Zarate and colleagues including Todd Gould, M.D., a three-time BBRF grantee, suggested in 2018 that another receptor in addition to the NMDA receptor—another glutamate receptor called the AMPA receptor—might also be involved in ketamine’s therapeutic mechanism. They also found evidence that a metabolite of ketamine called HNK might be the key to its antidepressant effects. This work remains under study, as is research by a Stanford University team that included BBRF Scientific Council member and 2005 Falcone Prizewinner Alan Schatzberg, M.D., 2014 and 2009 BBRF Young Investigator Carolyn Rodriguez, M.D., Ph.D.,and Nolan Williams, M.D., which suggested in 2019 that ketamine cannot exert an antidepressant effect without engaging the body’s internal opioid system. This study was supported by Dr. Williams’ 2016 BBRF Young Investigator award.

The secret to ketamine’s remarkable antidepressant effects—which are experienced by about 70% of patients with treatment-resistant major depression—remains to be discovered. So too whether it will prove effective as a preventive in patients at very high risk of suicide, and separately, whether it can be used as a treatment for depressed patients who have not proven resistant to other treatments, as well as for patients with other disorders including PTSD.

BBRF grants continue to support this research, which will likely inform still other efforts to discover additional rapid-acting agents for depression and other disorders. A new stage in the battle against depression and other disorders has surely begun.

— Written By Peter Tarr

Click here to read the Brain & Behavior Magazine's December 2019 issue