Self-help books often extoll the value of resilience. Last year one such primer—Bounce: Overcoming Adversity, Building Resilience and Finding Joy—proclaimed: “By strengthening your inner power, your ability to handle stressful situations and your skill in persevering after setbacks threaten to fell you, you’ll develop real resilience—you’ll develop grit.”
This implies weathering adverse life events is a character trait to be cultivated. Exercising, eating right and giving yourself mental pep talks certainly may help. But neuroscientists are learning the story is not quite so simple, and that some people are likely better equipped from birth to deal with adversity. During the last 15 years discoveries about why some brains excel at resisting stress have initiated a search for new drugs to treat depression and post-traumatic stress disorder by enhancing psychological resilience. One of these compounds has now entered early-stage clinical trials.
If the drug is safe and works, it will undoubtedly encounter strong demand; depression—the world’s leading cause of mental disability—never enters full remission in more than half the patients treated with psychotherapies and existing antidepressants.
But depression does not affect everyone, and the molecular biology of resilience for psychiatric disorders can be clearly seen by inspecting the brains of lab animals. About a third of mice exposed to severe stress (in the form of aggressive attacks by other rodents) seem to breeze through these assaults without developing the social withdrawal, listlessness or other depression and traumalike symptoms displayed by most of their rodent lab-mates.
Observing this seemingly adaptive behavior, investigators started to probe the genetics and neurochemistry that distinguish the more resistant animals. In stressed mice there is a dramatic rise in the activity of certain genes in the nervous system—as if these rodents’ brains had set in motion a set of protective measures to cope with the trauma. “Manyfold more genes were regulated in the resilient animals than in the susceptible animals across several brain regions,” says Eric Nestler, director of The Friedman Brain Institute at Icahn School of Medicine at Mount Sinai. “That was a real surprise to us.” (Nestler was at The University of Texas Southwestern Medical Center when his group started studying what researchers call chronic social defeat stress.)
New York City’s Mount Sinai Hospital has become a nexus for resilience research, with studies conducted by several laboratories on both the psychology and neurobiology of adapting to stress. In 2014 pharmacologist and neuroscientist Ming-Hu Han and a group of his Mount Sinai colleagues published a paper in Science showing how out-of-whack electrical signaling in neurons populating the brain’s reward system could explain why some lab animals were susceptible to depression whereas others remained resilient.
Looking inside the brains of animals exposed to chronic social defeat stress, the scientists observed hyperactive firing of neurons in the ventral tegmental area (VTA), a critical part of a reward circuit. When things go awry, this manic firing of cells in the VTA contributes to the lack of motivation experienced in depression.
The resilient mice, however, held a surprise for Han and his team. The VTAs in their brains exhibited even greater levels of frenzied electrical activity than those of their more vulnerable counterparts—but only for a brief period. In the naturally resilient animals the higher neural activity seemed to induce a counterreaction that resulted in the subsequent quieting of overactive neurons. “This is one of the most important unexpected findings in the 2014 Science paper,” Han says. “Too big a pathophysiological alteration triggers a compensatory rebound.”
The Han team took things one step further to see if they could help the nonresilient animals through artificial means. When the researchers gave the mice a drug called lamotrigine, often prescribed for bipolar disorder, the animals’ brain activity mimicked that of their resilient counterparts: The neurons in the already hyperactive VTA started firing even more intensely, followed by a lull and abatement of depression symptoms.
Around this time the various resilience research groups at Mount Sinai convened for a monthly gathering referred to informally as “The Depression Club.” Han told the group about a set of compounds—all existing drugs—that help open channels in the outer membrane of cells in the VTA. When dosed with the drugs, these neurons, which produce the signaling molecule dopamine, let positively charged ions leave the cell, thereby damping the cells’ hyperactive firing. This in turn tamps down depression symptoms. Based on Han’s presentation to the Depression Club, the group decided to move forward with a clinical trial in patients. The study—led by James Murrough, associate professor of psychiatry and director of the Mood and Anxiety Disorders Program at Mount Sinai—chose the epilepsy drug ezogabine, which was given to 18 patients in a pilot trial.
Brain scans showed the drug affected the same reward circuit that it did in animals. “It was successful in the sense that we did see antidepressant effects, with the important caveat that there was no placebo group,” Murrough says. A larger placebo-controlled clinical trial, sponsored by the National Institute of Mental Health (NIMH), is now underway. (GlaxoSmithKline has decided to stop marketing ezogabine but other existing drugs that also operate by tweaking potassium channels in brain cells—or a wholly new class of compounds—could serve in its place.)
The idea of a resilience pill seems compelling to some researchers not directly involved with the Mount Sinai research. “The ability to provide a treatment that can increase stress resiliency at the cellular level, and hopefully also the behavioral level, would be a much welcomed addition to our antidepressant armamentarium,” says Gerard Sanacora, a professor of psychiatry at Yale University School of Medicine and director of the Yale Depression Research Program. He cautions, however, about drawing too many conclusions from animal studies and early-stage clinical trials. He cites his own group’s experience with a novel antidepressant candidate that initially looked promising but failed in a placebo-controlled trial.
Moving forward with a potential resilience pill is warranted, however, notes Robert Sapolsky, a Stanford University professor of neuroscience. “There’s such a massive number of people with serious depression who aren’t helped by current drugs that it’s most definitely worth a try.” The approach pursued by Mount Sinai investigators “has been really novel,” Sapolsky says, “focusing on very reductive mechanisms explaining why VTA neurons become hyperactive in mice destined for stress-induced depression, and not in resistant animals.”
One caveat comes from David Nutt of Imperial College London. He points out that like new resilience drug candidates, standard depression treatments like Prozac diminish hyperactivity in neurons—but in a different set of cells. “I think that resilience is how the current antidepressant drugs work,” Nutt says. The neuropsychopharmacologist suggests a more novel approach might involve psychedelic drugs such as psilocybin, which have potential antidepressant effects.
Ezogabine represents only one means to potentially enhance resilience. Researchers at Mount Sinai and elsewhere are considering other ways of regulating the reward system as well as modulating gene activity and the brain’s signaling molecules, or neurotransmitters.
Unlike many clinical trials that emphasize relief of symptoms as their primary objective, the ezogabine study’s goal is to gauge how well the therapy addresses some of the biological underpinnings of depression—in this case, whether the drug lessens the hyperactivity of the reward circuit that includes VTA neurons. The NIMH has focused recently on targeting disease mechanisms in research it funds, because symptoms overlap for many psychiatric disorders. Whether this approach works better in developing drugs for psychiatric disorders remains to be proved. But it is worth exploring; conventional clinical trials have repeatedly come up empty.