Preventing depression

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.

That may change, thanks in part to work done by neuroscientist (and TED Fellow) Rebecca Brachman PhD.

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 rapidacting antidepressant. 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

What if we could inoculate people against depression and trauma?

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 selfprotective 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.”

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.

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.

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 resilienceenhancing alexigents like the one Brachman that accidentally discovered in the lab, so the body would still experience stress in the moment but it would have a more effective stress response.

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 resilienceenhancing 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.

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.

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 alreadyapproved drugs, as they’re available at low cost generically.

“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.”

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.”

And

Was January a tough month for you?

Traditionally supposed to be the most depressing month of the year; cold, dark, and summer seems a long way off. Even here in Spain the days are shorter, and the temperatures lower. The postfestive buzz, has well and truly worn off, the credit card statement is in, and most of our New Year’s resolutions went up in smoke by the end of Three Kings.

Was one of your resolutions to cut back on the booze? Did you try, and found you couldn’t? Has your drinking increased? Are you struggling to stop completely, even for a short period of time? Is your alcohol use, making you, or those around you, miserable?

Maybe lockdown was the trigger for you, feelings of isolation and loneliness led to a change in your drinking habits, perhaps larger volumes, or more frequent binges. Possibly it was the move to Spain, living here full-time is entirely different to a twoweek vacation, and it is easy to get sucked into daily-drinking. Or it could be for a completely different reason.

If you regularly drink more, or for longer than you planned to; have tried to cut back (or stop) and found you couldn’t; drink to deal with feelings and emotions; or if your drinking is interfering with your life, then you could have a problem with alcohol.

There is a solution, Alcoholics Anonymous (AA) - a 12 Step fellowship; a peer-support group that has helped millions of people, all over the world, with their problem drinking. If the consequences of your alcohol use are getting too much, if you are ready to stop drinking, or want support to help you try, then don’t wait until it gets any worse.

Here two members of AA, talk about how their drinking led them to AA, and how they now enjoy life and all the benefits of being sober:

“My name is Lydia; I am 65 years of age and I have been sober for 23 years. I am not perfect, nor will I ever be, and neither is my life, but that is ok. I have all that I need, and a few of my wants. The point is, I now have a life. I came into AA, lonely, hopeless, and broken. Today I have hope, gratitude, friends, and so much more.

The simple fact is, I was completely sick of the consequences of my drinking, and I had to be ready to stop. I had to do it for myself; and I had to give myself completely to this simple program.

I would say to anyone worried about their drinking, if it is costing you more than money (relationships, health, jobs), it is very likely that you have a problem. If you decide you want to give AA a try, you will never be alone again, you don't have to continue in the misery.

The fact is, untreated alcoholism, will (and does) kill in the end. I have lost friends because of their drinking. Alcoholics Anonymous and the 12-step program have saved my life, and the lives of countless others. It has given me a life with a purpose, and it's available to anyone who wants it!”

“My name is Jacob, I am in my 50’s, happily married with no children. I run a successful business, based on the Costa del Sol. But my life wasn’t always like that.

The comments first started in my twenties, people would say; maybe I should have water with my wine, or a bit more tonic in my gin. A couple even called me an alcoholic, but I brushed it off. I was functioning, I still held down a good job (two in fact), I still had a wife and a car!

By the end, I had to have a drink in the morning to stop the shakes, my whole day was centred around where the next drink was coming from. I wasn’t eating properly, and there were a lot of arguments, slamming doors, and shouting. I was lying and being dishonest, I was leading a double life. Till my wife made me get help.

The most amazing thing about AA is there are no rules. Not on what you must do, or what you should believe. It is not like a church or a school, it is a group of people trying to get themselves off the drink, and into a better way of living, using a spiritual program, and a set of principles as guidelines…. And it is completely free.

If you think you might need to look at your drinking, or need some help to stop, then get in touch with AA. Come along to a meeting (or a few) and just listen.”

There are meetings of Alcoholics Anonymous, with friendly people who will understand, held daily throughout the Costa del Sol. Meetings are free to attend, and anyone who thinks they may have a problem with alcohol is welcome.