COULD AN OVERACTIVE IMMUNE SYSTEM make you depressed? In the late 1990s, psychiatrist Andrew Miller and his colleagues began to notice that patients with cancer, cardiovascular disease, obesity and Crohn’s disease—all conditions that cause higher than normal levels of inflammation—often suffered from elevated rates of depression. He also observed that many patients who took medication to tamp down their immune system, thereby reducing inflammation, also saw their depressive symptoms ease.

But when Miller tried to interest pharmaceutical companies in studying the effect of immunosuppressants on depression, he got turned down again and again. “I lost count of the number of lunches I had with drug company executives, but the answer was always no,” says Miller, who also serves as the director of the Immunology Program at Emory University School of Medicine in Atlanta. Drugmakers didn’t want to risk having a depressed patient attempt suicide while taking their medication, forever branding the drug with the “black-box warning” of potential suicide that every conventional antidepressant medicine already carried.

Finally, a research proposal from Miller won a competition sponsored by Centocor, a drug company eager to develop neuropsychiatric treatments; with funding from the National Institute of Mental Health (NIMH), Miller and his colleagues launched the first trial of immunosuppressants in 2008 for severely treatment-resistant depression with 60 patients. When Miller reported in 2013 that severely depressed trial participants who had significant inflammation got well after three infusions of infliximab, an antibody used to treat Crohn’s disease and rheumatoid arthritis, other drug companies finally took notice. Although it has taken a while for this fledgling field to develop, there are now several trials testing immunosuppressants for treatment of depression, bipolar disorder and schizophrenia.

That research, like other work aimed at finding new and better treatments for major depression, must seem long overdue to the more than 16 million adults in the United States who suffer from the condition—which may involve profound, unrelenting sadness and an inability to muster what’s required for day-to-day living. “Yet progress in developing therapies has been glacial,” says David Mischoulon, director of the depression clinical and research program at Massachusetts General Hospital.

The first drugs with antidepressant properties were discovered serendipitously in the 1950s, and most people who are diagnosed with depression today are prescribed medications intended to have similar effects. “We’ve invented the same drugs over and over again,” says psychiatrist and researcher Roy Perlis, director of the Center for Quantitative Health in the psychiatry department at MGH.

Those conventional antidepressants often work, but they’re not effective for everyone, and usually they begin helping only after many weeks. The landmark NIMH STAR*D trial, completed in 2006, found that only 27% of depressed people taking antidepressants experienced remission within the first 12- to 14-week course. Others didn’t feel better until they had tried several different drugs, and one-third never got full relief.

The immunosuppressant approach, like virtually every other treatment for depression, new or old, works only for some people. In Miller’s trial, just the participants with the highest levels of inflammation experienced significant relief from their depressive symptoms, and those with low levels of inflammation actually tended to fare worse than the placebo group. Moreover, the side effects of drugs that suppress the immune system may mean that using such treatments is worth the risk only in the most severe cases.

Knowing more about how depression functions in the brain would help in the search for new treatments, and in recent years researchers have made great strides in learning how both to map and to alter the physiology of brains that malfunction in mood disorders. “We now have a vast number of tools available to study the biology of depression, from the molecular level to the cellular level to brain circuits,” says Carlos Zarate, chief of experimental therapeutics and pathophysiology branch at NIMH. “Optogenetics, for example, allows researchers to use light to control brain cells. That helps them isolate particular circuits in the brain and see how they interact with each other.”

That more intimate knowledge has led to a new generation of possible therapies, including short-term treatments that may work quickly to resolve an episode of depression without committing a patient to long-term maintenance doses of antidepressants. The search for better treatment has also led to promising, if unconventional, approaches that include whole-body hyperthermia and the use of psychoactive drugs, two areas studied by Charles Raison, a professor at the School of Human Ecology and School of Medicine and Public Health at University of Wisconsin, Madison. “After decades of the antidepressant doldrums,” he says, “this is a very exciting time in depression research—one that I didn’t think I would see in my lifetime.”


SOME OF THE MOST widely used antidepressants originated in the middle of the past century as drugs to treat tuberculosis and schizophrenia. They failed to cure those diseases, but physicians noticed that using them made patients decidedly happier. Researchers worked backward to figure out how the treatments functioned, and by 1965 they had found that the drugs affected the concentrations of three neurotransmitters that serve as chemical messengers in the brain and play primary roles in depression. Serotonin is vital to regulating sleep, appetite, mood and pain perception; norepinephrine is involved in energy and arousal systems; and dopamine is important in motivation and reward. The most widely prescribed antidepressants are selective serotonin reuptake inhibitors, or SSRIs, which temporarily increase the amount of serotonin in the brain.

But three sometimes-faulty neurotransmitters scarcely offer a complete explanation of what goes awry in the brain during major depression. Many other neurotransmitters may also be implicated, and there are billions of chemical reactions related to mood, along with exquisitely complicated circuitry connecting the many brain regions that regulate emotions. This complexity means that what is monolithically labeled depression actually arises from a wide variety of causes, grouped into multiple subtypes that are still largely undefined. “A handful of subtypes probably account for most depression, but there are likely to be many others that affect fewer people,” says Perlis. Those differences in how depression arises and manifests help to explain a phenomenon that has long plagued researchers: Possible treatments, hailed because of their clear effectiveness in some patients, fail in clinical trials involving wide swaths of the population because one size does not fit all.

As some depression pathways become clearer, researchers have been able to devise novel therapies that target different points along the way—from drugs that quiet or rev up brain signaling to more precisely targeted electrical devices that can sense when and where there’s a problem. “If you interrupt the chain of events that leads to depression at any point, then the patient gets better,” says Miller.

ONE OF THE MOST promising recent discoveries is the use of the anesthetic ketamine and its derivatives. Ketamine blocks receptors for glutamate, a neurotransmitter involved in cognition and emotion. Researchers believe that excess glutamate in someone who is depressed, along with high levels of the stress hormone cortisol, lead to reduced neuronal resilience in response to stress. By blocking glutamate receptors, ketamine launches a cascade of events in the brain, including release of GABA (gamma-aminobutyric acid), a calming neurotransmitter, as well as increased levels of proteins that help new synapses form within a day.

Ketamine was approved by the Food and Drug Administration in 1970 as a short-acting anesthetic, and the drug, which distorts the senses and causes dreamy detachment as well as euphoria, was used on injured soldiers in Vietnam and emerged as a recreational drug in the mid-1990s. In 2000, ketamine was tried for the first time with depressed patients. A single 40-minute intravenous infusion of the drug lifted symptoms for a handful of patients within four hours and continued its antidepressant effects for up to 72 hours. When the same patients got a placebo infusion, it didn’t help at all. Several follow-up studies also showed the potential of the drug.

The success of these trials was a milestone in the search for new treatments. “Ketamine’s rapid and profound antidepressant effects showed us that it was possible to develop truly new antidepressants, and that has encouraged the entire field to come up with new approaches,” says Perlis. Many physicians now administer ketamine to depressed patients “off label,” because that use of the drug has not yet been approved by the FDA.

But several trials of ketamine-like drugs are now in progress. At least one new treatment is likely to pass muster with the FDA by late this year or early 2019. That drug, esketamine, can be delivered through a nasal spray. Janssen, a subsidiary of Johnson & Johnson, recently completed part of a phase 3 trial of the therapy, and the FDA has granted it “breakthrough therapy” status for its possible use as a depression and imminent suicide risk treatment.

Ketamine’s fast action may also prove valuable for preventing suicide. Michael Grunebaum, associate professor of psychiatry at Columbia University Medical Center, conducted a study of 80 severely depressed people—half of whom were already taking antidepressants—who said they were considering suicide. Half of the patients, by random assignment, were given intravenous ketamine, and the others received the intravenous sedative midazolam, a benzodiazepine sedative that lasts in the body about as long as ketamine, but with no established antidepressant or antisuicidal effects. Among those receiving ketamine, 55% showed a robust reduction in suicidal thoughts in one day, versus 30% of those who got midazolam. “It’s quite dramatic to see the people in the ketamine group be more hopeful, have more energy and talk about wanting to get on with their lives within 24 hours,” says Grunebaum.

Esketamine and all ketamine drugs stimulate an opioid receptor in the brain, and have the potential for addiction and abuse. Chronic, heavy ketamine use is known to cause long-term memory and cognitive problems. If approved by the FDA, however, esketamine will be administered only in physicians’ offices, perhaps once or twice a week, and at much lower doses than it would take to get high. “The onus will be on physicians who treat depression with esketamine to make sure the drug is not diverted,” says Michael Thase, an investigator for the esketamine trials and director of the Mood and Anxiety Program at the Perelman School of Medicine at the University of Pennsylvania.


PSYCHIATRIST CHARLES RAISON WAS a co-investigator with Andrew Miller on the immunosuppressant trial for treating depression. Raison’s most recent research is inspired by ancient practices for adjusting mental states. “Sweat lodges, which cause hyperthermia, and psychedelic drugs are two of the oldest strategies that people have employed to alter consciousness,” says Raison. Rather than “gerrymandering the brain” with a steady stream of antidepressant medications, he explains, it might be more effective to investigate treatments that deliver a single, profound shift to brain pathways—physical events that cause prolonged antidepressant effects.

For a whole-body hyperthermia study published in JAMA Psychiatry in August 2016, Raison put subjects into a Heckel device: a bed equipped with infrared lights and coils and covered by a fabric tent. Half of the depressed participants received a mild-intensity heat treatment designed to raise core body temperature to 101.3 degrees Fahrenheit, which took an average of 107 minutes, while the placebo group received only slight warming. Actual core body temperatures of both those who were given the active treatment and those who received the placebo varied among participants, and those who became the hottest experienced the strongest antidepressant effects. Raison found that the treatment boosted levels of interleukin-6, a signaling molecule of the immune system that has inflammatory and anti-inflammatory effects. (Intense exercise can also hike interleukin-6.) While some people got no benefit from the heat treatments, those who did respond continued to feel less depressed throughout the six weeks of the study.

In Raison’s view, treating psychiatric disorders with controlled psychoactive substances in a safe environment also revives an approach that may have been effective before the advent of modern medicine. The FDA has given a group called the Multidisciplinary Association for Psychedelic Studies approval to conduct large-scale clinical trials of MDMA, also known as molly or ecstasy, for people with post-traumatic stress disorder (PTSD). This approval stems from several previous studies by the same researchers. In one of these, 68% of participants who had suffered PTSD for an average of 18 years no longer had symptoms one year after a single treatment of MDMA. Equally dramatic results were found for depression. A group of Johns Hopkins researchers treated 51 people with depression and life-threatening cancer with a single dose of hallucinogenic psilocybin mushrooms or a placebo. After six months, 60% of participants who received psilocybin were no longer depressed, and 67% cited the drug-induced experience as one of the five most meaningful in their lives. Psychedelics are currently being studied for the treatment of several other conditions, including obsessive-compulsive disorder and alcohol and drug abuse, as well as for smoking cessation.

Raison is developing additional large-scale studies to evaluate the use of psilocybin as a clinical treatment for major depression. Psilocybin and other psychedelics, he says, acutely reduce the activity of the brain’s default mode network, composed of brain regions that become active when the brain is resting and not engaged by a cognitive task. In depression, the default mode network may be overactive, leading to negative ruminations and preoccupations. By suppressing the default mode network, psychedelic agents allow contact among brain areas that don’t normally communicate, helping break the tenacious hold of negative emotions. “These brain changes appear to induce powerful emotional experiences that help the brain reassemble itself differently and with more flexibility, leading to long-term changes,” says Raison.

In a very different approach to a similar end, deep brain stimulation (DBS) provides pulses of electricity from an implanted battery pack to electrodes implanted in the brain. DBS has long been used to treat Parkinson’s disease, obsessive-compulsive disorder and epilepsy. But its path to federal approval as a therapy for depression has been rocky, despite persistent evidence that DBS can have an effect.

In 2003, neurologist Helen Mayberg, a neurosurgeon and a psychiatrist then at the University of Toronto, implanted the first DBS device in a severely depressed patient in a brain region called Area 25, deep in the brain’s cingulate cortex. Area 25 is involved in regulating emotions, motivation and the way people evaluate themselves relative to others. The brain region is overactive in depression and suppressed after the condition is successfully treated. Delivering a continuous current to Area 25 is the most direct, powerful way to affect depression, according to Mayberg’s data. “DBS doesn’t repair what is broken; it puts the brain in a different rhythm that allows normal functioning to occur,” she says.

One subject whose depression had failed to respond to 100 treatments of electroconvulsive therapy—a treatment of last resort—recovered after DBS. “It was transformative for her,” says Mayberg. Encouraged by such results, both St. Jude Medical (now Abbott) and Medtronic in 2009 were pursuing FDA approval for DBS devices to treat depression. Both trials were stopped early, however, when patients showed only mild improvement. In the randomized St. Jude trial—in which all patients had DBS devices implanted, but only half had them turned on—22% of treated patients reported improvement, versus 17% in the group with inactive devices. Results of the Medtronic trial were similar, also falling short of researchers’ hopes.

But here, says Mayberg, is where it gets interesting. When the St. Jude trial ended, participants were given the option of either having their devices removed or allowing them to continue to stimulate their brains while researchers followed the patients’ progress. Of the 90 participants originally recruited, 77 opted to keep their DBS, which was switched on for all of them. Two years later, the depression symptoms of half of the trial subjects had been reduced by at least half. One in four participants had no lingering symptoms of depression. Those were very promising results in patients who had been severely depressed for an average of 12 years, says Mayberg. At Medtronic, 28 of the 30 study participants opted to keep their devices and most of them also experienced significant improvements.

Now, Mayberg, who heads the new Center for Advanced Circuit Therapeutics for the Icahn School of Medicine at Mount Sinai in New York City, has a grant from the NIMH BRAIN Initiative to study the mechanism of Area 25 DBS and how the brain changes in response. Also being funded by NIMH BRAIN Initiative, along with $30 million from the federal Defense Advanced Research Projects Agency (DARPA), is a parallel DBS project at Massachusetts General Hospital to treat soldiers and veterans with severe depression and PTSD. Darin Dougherty, director of the neurotherapeutics division at MGH, who served as lead investigator for the Medtronic DBS trial, is taking a different approach this time, alongside the project’s 50 other researchers. Instead of using DBS electrodes to stimulate the brain constantly, the new devices record brain activity and provide a pulse of electricity only when they detect problems in a brain area associated with symptoms of depression.

“Because depression is so heterogeneous, there is no single neurocircuit for it,” says Dougherty. The device he and his fellow researchers are developing for DARPA measures signals associated with dysfunction in known behavioral circuits, such as those associated with reward and fear, and delivers electrical pulses to normalize those signals when needed. “This is a personalized, responsive approach that treats specific symptoms of depression,” says Dougherty. “The brain is an electrochemical organ, and I’m confident we’ll find an approach with electricity that works on this circuit-based disorder. We just need to crack the code, and now we have the tools to do that.”

DRUGS AND DEVICES AREN’T the only tools for treating depression. Psychotherapy has long been an effective alternative, with effects comparable to taking antidepressants but with less than half the drugs’ risk of disease relapse. “Antidepressants modify a stress response, but they don’t cure depression,” says Penn’s Thase, who studies cognitive behavioral therapy (CBT), which teaches depressed patients strategies to break harmful habits and negative thought patterns. “When you stop taking an antidepressant, the therapeutic element is gone and you’re again at risk of getting depressed.”

While CBT isn’t new—it was developed in the 1960s—researchers are now experimenting with novel methods of delivering it. Thase is investigating ways to make CBT more accessible—for example, with therapy delivered primarily through web-based modules. In a recent study, that approach was compared with traditional weekly CBT sessions with a therapist. “We took the material that therapists cover in good CBT and put it in an interactive format with video vignettes, self-help exercises and guidance through homework assignments,” says Thase. Depressed participants who received the Internet-assisted therapy also received five hours of face-to-face contact with therapists—compared with 13 hours of in-person therapy in the conventional CBT group. At the end of 16 weeks, the groups reported nearly identical rates of recovery, but the computer-assisted therapy cost participants $928 less. “Internet-assisted therapy makes therapists three times more efficient and reduces the cost of treatment by two-thirds,” says Thase.

Another new strategy tries to predict which treatment pathway will have the best effect. Many patients get talk therapy and antidepressant medications, which can be more powerful in combination, but for most patients neither approach succeeds at first. Now there is evidence that some depressed brains may respond to one approach and not the other. That makes it important to choose the right therapy from the start.

Helen Mayberg has conducted a series of brain-imaging studies to find biomarkers that will predict which patients are most likely to respond to either approach. Using positron emission tomography (PET) and functional magnetic resonance imaging, Mayberg has found distinct patterns of neural activity and connectivity in people who get better taking antidepressants versus those who respond to CBT. The diagnostics can help predict optimal treatments as well as which ones to avoid.

“On a PET scan, for example, if you have high metabolic activity in the insula, you’ll do great on drugs but terrible in CBT,” Mayberg says. “And if you have low activity in that region, the reverse is true. Understanding these different brain patterns should eventually help us find a clinical test that will predict who is a candidate for which therapy.”

Never before have there been so many new breakthroughs. David Mischoulon of MGH finds the new research lines both promising and a call for renewed efforts. “The more we learn, the more we realize the limitations of the current available treatments,” he says, “and how much work we still need to do before we can get a handle on this disorder.”