One Day, There Might Be a Drug for a Broken Heart
For Tony Y., 37, healing from heartbreak is slow and incomplete. Each of several exes is associated with a cluster of sore memories. Although he loves the Blue Ridge Mountains, he can't visit because they remind him of a romantic holiday years ago.
If a new drug made rejections less painful, one expert argues, it could relieve or even prevent major depression.
Like some 30 to 40 percent of depressed patients, Tony hasn't had success with current anti-depressants. One day, psychiatrists may be able to offer him a new kind of opioid, an anti-depressant for people suffering from the cruel pain of rejection.
A Surprising Discovery
As we move through life, rejections -- bullying in school, romantic breakups, and divorces -- are powerful triggers to depressive episodes, observes David Hsu, a neuroscientist at Stony Brook University School of Medicine in Long Island, New York. If a new drug made them less painful, he argues, it could relieve or even prevent major depression.
Our bodies naturally produce opioids to soothe physical pain, and opioid drugs like morphine and oxycodone work by plugging into the same receptors in our brains. The same natural opioids may also respond to emotional hurts, and painkillers can dramatically affect mood. Today's epidemic of opioid abuse raises the question: How many lives might have been saved if we had a safe, non-addictive option for medicating emotional pain?
Already one anti-depressant, tianeptine, locks into the mu opioid receptor, the target of morphine and oxycodone. Scientists knew that tianeptine, prescribed in some countries in Europe, Asia, and Latin America, acted differently than the most common anti-depressants in use today, which affect the levels of other brain chemicals, serotonin and norepinephrine. But the discovery in 2014 that tianeptine tapped the mu receptor was a "huge surprise," says co-author Jonathan Javitch, chief of the Division of Molecular Therapeutics at Columbia University.
The news arrived when scientists' basic understanding of depression is in flux; viewed biologically, it may cover several disorders. One of them could hinge on opioids. It's possible that some people release fewer opioids naturally or that the receptors for it are less effective.
Javitch has launched a startup, Kures, to make tianeptine more effective and convenient and to find other opioid-modulators. That may seem quixotic in the midst of an opioid epidemic, but tianeptine doesn't create dependency in low, prescription doses and has been used safely around the world for decades. To identify likely patients, cofounder Andrew Kruegel is looking for ways to "segment the depressed population by measures that have to do with opioid release," he says.
Is Emotional Pain Actually "Pain"?
No one imagines that the pain from rejection or loss is the same as pain from a broken leg. Physical pain is two perceptions—a sensory perception and an "affective" one, which makes pain unpleasant.
Exploration of an overlap between physical and what research psychologists call "social pain" has heated up since the mid-2000s.
The sensory perception, processed by regions of the brain called the primary and secondary somatosensory cortices and the posterior insula, tells us whether the pain is in your arm or your leg, how strong it is and whether it is a sting, ache, or has some other quality. The affective perception, in another part of the brain called the dorsal anterior cingulate cortex and the anterior insula, tells us that we want the pain to stop, fast! When people with lesions in the latter areas experience a stimulus that ordinarily would be painful, they don't mind it.
Science now suggests that emotional pain arises in the affective brain circuits. Exploration of an overlap between physical and what research psychologists call "social pain" has heated up since the mid-2000s. Animal evidence goes back to the 1970s: babies separated from their mothers showed less distress when given morphine, and more if dosed with naloxone, the opioid antagonist.
Parents, of course, face the question of whether Baby feels alone or wet whenever she howls. And the answer is: both hurt. Being abandoned is the ultimate threat in our early life, and it makes sense that a brain system to monitor social threats would piggyback upon an existing system for pain. Piggybacking is a feature of evolution. An ancestor who felt "hurt" when threatened by rejection might learn adaptive behavior: to cooperate or run.
In 2010, a large multi-university team led by Nathan DeWall at the University of Kentucky, reported that acetaminophen (Tylenol) reduced social pain. Undergraduates took 500 mg of acetaminophen upon awakening and at bedtime every day for three weeks and reported nightly about their day using a previously-tested "Hurt Feelings Scale," rating how strongly they agreed with questions like, "Today, being teased hurt my feelings."
Over the weeks, their reports of hurt feelings steadily declined, while remaining flat in a control group that took placebos. In a second experiment, the research group showed that, compared to controls, people who had taken acetaminophen for three weeks showed less brain activity in the affective brain circuits while they experienced rejection during a virtual ball-tossing game. Later, Hsu's brain scan research supported the idea that rejection triggers the mu opioid receptor system, which normally provides pain-dampening opioids.
More evidence comes from nonhuman primates with lesions in the affective circuits: They cry less when separated from caregivers or social groups.
Heartbreak seems to lie in those regions: women with major depression are more hurt by romantic rejection than normal controls are and show more activity in those areas in brain scans, Hsu found. Also, factors that make us more vulnerable to rejection -- like low self-esteem -- are linked to more activity in the key areas, studies show.
The trait "high rejection sensitivity" increases your risk of depression more than "global neuroticism" does, Hsu observes, and predicts a poor recovery from depression. Pain sensitivity is another clue: People with a gene linked to it seem to be more hurt by social exclusion. Once you're depressed, you become more rejection-sensitive and prone to pain—a classic bad feedback loop.
"Ideally, we'd have biomarkers to distinguish when loss becomes complicated grief and then depression, and we might prevent the transition with a drug."
Helen Mayberg, a neurologist renowned for her study of brain circuits in depression, sees, as Hsu does, the possibility of preventing depressions. "Nobody would suggest we treat routine bad social pain with drugs. But it is true that in susceptible people, losing a partner, for example, can lead to a full-blown depression," says Mayberg, who is the founding director of The Center for Advanced Circuit Therapeutics at Mount Sinai's Icahn School of Medicine in New York City. "Ideally, we'd have biomarkers to distinguish when loss becomes complicated grief and then depression, and we might prevent the transition with a drug. It would be like taking medication when you feel the warning symptoms of a headache to prevent a full-blown migraine."
A Way Out of the Opioid Crisis?
The exploration of social pain should lead us to a deeper understanding of pain, beyond the sharp distinctions between "physical" and "psychological." Finding our way out of the current crisis may require that deeper understanding. About half of the people with opioid prescriptions have mental health disorders. "I expect there are a lot of people using street opioids—heroin or prescriptions purchased from others--to self-medicate psychological pain," Kreugel says.
What we may need, he suggests, is "a new paradigm for using opioids in psychiatry: low, sub-analgesic, sub-euphoric dosing." But so far it hasn't been easy. Investors don't flock to fund psychiatric drugs and in 2018, the word opioid is poison.
As for Tony Y., he's struggled for three years to recover from his most serious relationship. "Driving around highways looking at exit signs toward places we visited together sometimes fills me with unbearable anguish," he admits. "And because we used to do so much bird watching together, sometimes a mere glimpse of a random bird sets me off." He perks up at the idea of a heartbreak drug. "If the side effects didn't seem bad, I would consider it, absolutely."
This man spent over 70 years in an iron lung. What he was able to accomplish is amazing.
It’s a sight we don’t normally see these days: A man lying prone in a big, metal tube with his head sticking out of one end. But it wasn’t so long ago that this sight was unfortunately much more common.
In the first half of the 20th century, tens of thousands of people each year were infected by polio—a highly contagious virus that attacks nerves in the spinal cord and brainstem. Many people survived polio, but a small percentage of people who did were left permanently paralyzed from the virus, requiring support to help them breathe. This support, known as an “iron lung,” manually pulled oxygen in and out of a person’s lungs by changing the pressure inside the machine.
Paul Alexander was one of several thousand who were infected and paralyzed by polio in 1952. That year, a polio epidemic swept the United States, forcing businesses to close and polio wards in hospitals all over the country to fill up with sick children. When Paul caught polio in the summer of 1952, doctors urged his parents to let him rest and recover at home, since the hospital in his home suburb of Dallas, Texas was already overrun with polio patients.
Paul rested in bed for a few days with aching limbs and a fever. But his condition quickly got worse. Within a week, Paul could no longer speak or swallow, and his parents rushed him to the local hospital where the doctors performed an emergency procedure to help him breathe. Paul woke from the surgery three days later, and found himself unable to move and lying inside an iron lung in the polio ward, surrounded by rows of other paralyzed children.
Hospitals were commonly filled with polio patients who had been paralyzed by the virus before a vaccine became widely available in 1955. Associated Press
Paul struggled inside the polio ward for the next 18 months, bored and restless and needing to hold his breath when the nurses opened the iron lung to help him bathe. The doctors on the ward frequently told his parents that Paul was going to die.But against all odds, Paul lived. And with help from a physical therapist, Paul was able to thrive—sometimes for small periods outside the iron lung.
The way Paul did this was to practice glossopharyngeal breathing (or as Paul called it, “frog breathing”), where he would trap air in his mouth and force it down his throat and into his lungs by flattening his tongue. This breathing technique, taught to him by his physical therapist, would allow Paul to leave the iron lung for increasing periods of time.
With help from his iron lung (and for small periods of time without it), Paul managed to live a full, happy, and sometimes record-breaking life. At 21, Paul became the first person in Dallas, Texas to graduate high school without attending class in person, owing his success to memorization rather than taking notes. After high school, Paul received a scholarship to Southern Methodist University and pursued his dream of becoming a trial lawyer and successfully represented clients in court.
Paul Alexander, pictured here in his early 20s, mastered a type of breathing technique that allowed him to spend short amounts of time outside his iron lung. Paul Alexander
Paul practiced law in North Texas for more than 30 years, using a modified wheelchair that held his body upright. During his career, Paul even represented members of the biker gang Hells Angels—and became so close with them he was named an honorary member.Throughout his long life, Paul was also able to fly on a plane, visit the beach, adopt a dog, fall in love, and write a memoir using a plastic stick to tap out a draft on a keyboard. In recent years, Paul joined TikTok and became a viral sensation with more than 330,000 followers. In one of his first videos, Paul advocated for vaccination and warned against another polio epidemic.
Paul was reportedly hospitalized with COVID-19 at the end of February and died on March 11th, 2024. He currently holds the Guiness World Record for longest survival inside an iron lung—71 years.
Polio thankfully no longer circulates in the United States, or in most of the world, thanks to vaccines. But Paul continues to serve as a reminder of the importance of vaccination—and the power of the human spirit.
““I’ve got some big dreams. I’m not going to accept from anybody their limitations,” he said in a 2022 interview with CNN. “My life is incredible.”
When doctors couldn’t stop her daughter’s seizures, this mom earned a PhD and found a treatment herself.
Twenty-eight years ago, Tracy Dixon-Salazaar woke to the sound of her daughter, two-year-old Savannah, in the midst of a medical emergency.
“I entered [Savannah’s room] to see her tiny little body jerking about violently in her bed,” Tracy said in an interview. “I thought she was choking.” When she and her husband frantically called 911, the paramedic told them it was likely that Savannah had had a seizure—a term neither Tracy nor her husband had ever heard before.
Over the next several years, Savannah’s seizures continued and worsened. By age five Savannah was having seizures dozens of times each day, and her parents noticed significant developmental delays. Savannah was unable to use the restroom and functioned more like a toddler than a five-year-old.
Doctors were mystified: Tracy and her husband had no family history of seizures, and there was no event—such as an injury or infection—that could have caused them. Doctors were also confused as to why Savannah’s seizures were happening so frequently despite trying different seizure medications.
Doctors eventually diagnosed Savannah with Lennox-Gaustaut Syndrome, or LGS, an epilepsy disorder with no cure and a poor prognosis. People with LGS are often resistant to several kinds of anti-seizure medications, and often suffer from developmental delays and behavioral problems. People with LGS also have a higher chance of injury as well as a higher chance of sudden unexpected death (SUDEP) due to the frequent seizures. In about 70 percent of cases, LGS has an identifiable cause such as a brain injury or genetic syndrome. In about 30 percent of cases, however, the cause is unknown.
Watching her daughter struggle through repeated seizures was devastating to Tracy and the rest of the family.
“This disease, it comes into your life. It’s uninvited. It’s unannounced and it takes over every aspect of your daily life,” said Tracy in an interview with Today.com. “Plus it’s attacking the thing that is most precious to you—your kid.”
Desperate to find some answers, Tracy began combing the medical literature for information about epilepsy and LGS. She enrolled in college courses to better understand the papers she was reading.
“Ironically, I thought I needed to go to college to take English classes to understand these papers—but soon learned it wasn’t English classes I needed, It was science,” Tracy said. When she took her first college science course, Tracy says, she “fell in love with the subject.”
Tracy was now a caregiver to Savannah, who continued to have hundreds of seizures a month, as well as a full-time student, studying late into the night and while her kids were at school, using classwork as “an outlet for the pain.”
“I couldn’t help my daughter,” Tracy said. “Studying was something I could do.”
Twelve years later, Tracy had earned a PhD in neurobiology.
After her post-doctoral training, Tracy started working at a lab that explored the genetics of epilepsy. Savannah’s doctors hadn’t found a genetic cause for her seizures, so Tracy decided to sequence her genome again to check for other abnormalities—and what she found was life-changing.
Tracy discovered that Savannah had a calcium channel mutation, meaning that too much calcium was passing through Savannah’s neural pathways, leading to seizures. The information made sense to Tracy: Anti-seizure medications often leech calcium from a person’s bones. When doctors had prescribed Savannah calcium supplements in the past to counteract these effects, her seizures had gotten worse every time she took the medication. Tracy took her discovery to Savannah’s doctor, who agreed to prescribe her a calcium blocker.
The change in Savannah was almost immediate.
Within two weeks, Savannah’s seizures had decreased by 95 percent. Once on a daily seven-drug regimen, she was soon weaned to just four, and then three. Amazingly, Tracy started to notice changes in Savannah’s personality and development, too.
“She just exploded in her personality and her talking and her walking and her potty training and oh my gosh she is just so sassy,” Tracy said in an interview.
Since starting the calcium blocker eleven years ago, Savannah has continued to make enormous strides. Though still unable to read or write, Savannah enjoys puzzles and social media. She’s “obsessed” with boys, says Tracy. And while Tracy suspects she’ll never be able to live independently, she and her daughter can now share more “normal” moments—something she never anticipated at the start of Savannah’s journey with LGS. While preparing for an event, Savannah helped Tracy get ready.
“We picked out a dress and it was the first time in our lives that we did something normal as a mother and a daughter,” she said. “It was pretty cool.”