When approaching diseases, scientists usually look for two things — ways to cure them and ways to prevent them.
But with mental illnesses, we have neither. For example, SSRIs are the most popular antidepressant medications, but they only suppress symptoms. Yet pharmaceutical research has focused almost entirely on fine-tuning these drugs rather than looking for ways to prevent mental disorders from occurring in the first place.
Eight years ago, Brachman stumbled upon a drug that proved to protect against the detrimental effects of acute or chronic stress — a potentially paradigm-shifting discovery that’s opening up a new field of preventative psychopharmacology.
Now Brachman, who is a Jacobs Institute Runway Fellow at Cornell Tech supported by Schmidt Futures, and her colleagues are creating prophylactic compounds that could prevent mental illness from taking hold by fortifying our bodies’ natural stress resilience. If these efforts are successful, we could not only inoculate people against the negative effects of trauma but perhaps also reduce the overall incidence of depression — the leading cause of disability worldwide, according to the WHO — in the general population.
The idea to use drugs as a preventative against mental illness is a new idea in medicine. In fact, Brachman discovered the possibility by accident when she was doing routine preliminary work to start experiments using an emerging rapid-acting antidepressant.
“I had done a baseline test to verify there were no long-term effects of the compound in mice, like on their movement or memory, that might interfere with experiments. As expected, there were no persistent effects,” she says.
Later, once the drug had long passed out of their systems, she used the same mice to perform a totally separate baseline test — this time for stress.
Something seemed off — and she realized that, instead of being affected by the stress, some of the mice appeared to be happy and social. She says, “This particular stressor normally induces depression. At first, I thought the stressor just didn’t work, but when I dug into the data, it worked as expected — except for one group. It was as though those mice were protected against the stress they’d experienced.”
As it turns out, the happy mice happened to be those that had participated in the drug baseline test, so the drug had had an effect after all.
That’s when Brachman realized that these findings meant we could someday possibly inoculate against the effects of stress, just as a vaccine prevents disease from developing in a person’s body. She christened this new class of drugs “alexigents” — from the Greek alexo, meaning “to protect.”
Scientists don’t know for sure what causes depression, but they do know that for both depression and PTSD, the body’s capacity for resilience in the face of trauma plays a part. “Stress resilience” is the ability to recover from a stressful experience, for the body to bounce back to homeostasis. Resilience can protect against developing a psychiatric disorder in the face of stress; it varies from person to person and can fluctuate over the course of one’s life.
“We haven’t known for long that stress resilience is an active biological property,” she says. “It was more thought of as an ‘absence of risk factors.’ People with a genetic predisposition or environmental exposure in childhood were considered at risk for depression. Meanwhile, people without those factors were assumed, by default, to be comparatively resilient.”
Today scientists know that’s not the whole story. “The risk factors for depression and the factors that promote resilience are not all necessarily on the same spectrum,” Brachman explains. “Instead, we now know that resilience involves a separate, active biological process — which also means we might be able to enhance it.”
There’s one accepted idea that Brachman thinks needs to change — that cortisol and other stress hormones are all bad. It‘s not true, she says. “At the NIH, I did another set of experiments with my colleague, Dr. Michael Lehmann, where we showed that if you block corticosterone (the main stress hormone in mice), you lose the beneficial antidepressant effect of exercise. You need the stress hormones.”
This is because stress hormones are essential and part of the body’s self-protective response. Brachman explains that cortisol makes sugar available for extra energy and increases blood pressure.
“Cortisol makes more resources — energy, oxygen, and so on — available to your body to respond appropriately to a stressor so you can run away from danger, for example. In fact, people who have Addison’s disease, whose bodies don’t make enough cortisol, need an injection of it at times of trauma, or they can die from adrenal crisis. Clearly, cortisol is not all bad. It’s more like you need the right amount to match the stressor you’re experiencing. Yes, too much cortisol is bad, but so is too little.”
Brachman offers the metaphor of diabetes as a corollary to understanding stress metabolism.
“You need insulin in proportion to the amount of sugar you consume, because hypoglycemia and hyperglycemia are both dangerous. High sugar coupled with low insulin is bad, but high insulin coupled with low sugar is also bad. It’s really about the tight tuning of that metabolic response to the amount of sugar you’re consuming.”
She also points out that stress hormones keep the immune system in check. “People tend to think ‘cortisol equals stress which equals bad,’ without realizing these are the same compounds used in over-the-counter anti-inflammatory creams, asthma inhalers, and even to treat severe COVID-19.”
What makes someone “resilient” isn’t their ability to not experience stress at all — but how quickly their nervous systems bounce back from stressful episodes. There are many things we do on a daily basis that can enhance our nervous systems’ quick recovery from stressors — exercising, sleeping, socializing, eating a healthy diet, and so on.
But in the face of a significant enough stressor, these things are sometimes not enough.
“What we see in some of the models of depression is a general dysregulation of the stress response. Ideally, the body should automatically be matching the stress response to the stress,” says Brachman. “But when it doesn’t, things go wrong and depression can develop.”
Preventing depression and PTSD, then, may be a question of fine-tuning the body’s stress resilience system. With resilience-enhancing alexigents like the one Brachman that accidentally discovered in the lab, the mouse still experiences stress in the moment but its body has a more effective stress response. This allows it to appropriately respond to the acute trauma and protects it from a lasting negative effect.
Since her initial discovery, Brachman has been working to make these prophylactic compounds available for use in humans and to identify other types of alexigents — including ones using our own immune cells (!).
Prior to her discovery of resilience-enhancing compounds, Brachman and her colleagues at the NIH had discovered that white blood cells can also be primed to protect against stress. Unlike the compounds, which primarily prevent depression, primed white blood cells additionally protect against anxiety.
Brachman hypothesizes that, beyond PTSD and depression, prophylaxis might also be possible for such brain disorders as generalized anxiety disorder, postpartum depression, and even to mitigate traumatic brain injury and concussion. “We won’t know if preventing other disorders is possible until we test them, but perhaps that’s the heart of it. Alexigents tell us we should look; conceptually, they expand the map.”
Meanwhile, Brachman, her colleagues and researchers in other labs have tested and retested the alexigent’s effects, with promising results. If these treatments become available, they could be given to first responders and frontline workers, military personnel, refugees, cancer patients and other people in vulnerable populations, allowing for the body’s natural stress responses to kick in well enough to do the job at hand but preventing the debilitating PTSD that often develops later.
“Take the pandemic, for example,” says Brachman, “the effects of chronic traumatic stress have been devastating, especially in healthcare workers and vulnerable populations. Imagine the impact if we could prevent even a fraction of these cases.” Alexigents could save public services millions in subsequent medical costs, as well as save families the grief and emotional costs that comes from mental illness and suicide.
But it’s going to take a while — within traditional pharmaceutical development models, it could take 10 years to bring alexigents to market. On the face of it, it should be quick and easy to repurpose existing FDA-approved medicines for use as alexigents, but Brachman explains that the economics of pharmaceutical development offer little incentive for companies to repurpose already-approved drugs, as they’re available at low cost generically.
“The market incentives just don’t align,” says Brachman. “Why would a pharmaceutical company invest in repurposing an inexpensive drug that you’d only give once and that prevents diseases which represent a large part of their market share? Antidepressants are prescribed for a lifetime.”
That’s why Brachman and her colleagues are identifying novel alexigents, knowing that any new compound will be more expensive and much slower to make it through FDA approval to market.
Parallel to their drug development work, Brachman is also trying to bypass these challenges with a novel finance model. “We’re looking for a different source of revenue,“ she says. ”Say a repurposed alexigent has the potential to prevent 20 percent of cases of PTSD in the military, for example, which could save millions a year in healthcare costs and social impact. Capturing the value of those savings would make this kind of research fundable for the first time.” Beyond alexigents, this financing model can be applied to any repurposing of generic drugs, she says, and it could be funded by healthcare systems, public and private insurers, and federal and state governments.
The idea of preventing mental illness from taking root in people in the first place will require a shift in perception for many. It’d be a fair question to ask why it took so long for medicine to have this a-ha moment, says Brachman.
“The brain is an organ in the body, and we think about prevention in all the other medical diseases,” she says. “It took us until the 1950s to put the mind into the brain — when we discovered antidepressants and realized that we could treat mental illness with pharmaceuticals. But in many ways, conceptually, we’ve been slow to put the brain into the body. New evidence suggests that viruses may be an underlying cause of dementia, for example, which means in some cases we could potentially prevent dementia with vaccines and antivirals. If we’d regarded the brain as an organ in the body, the possibility of this might have been quite obvious. But we’re just figuring it out now.”
To learn more, watch Dr. Rebecca Brachman‘s TED Talk now: