4

Anxiety

Nothing to Panic About

THE LINE OF questioning began innocuously enough, with the lawyer asking about my background, the books I’ve written, my areas of expertise. The courtroom was drab and the mood dull, in stark contrast to the underlying drama. Aside from the usual financial considerations, the custody of several children was at stake for the defendant, a patient of mine — I’ll call her Amy — who was being divorced by her husband. I had taken the witness stand at the behest of her legal team, to testify about her mental state, and now I was under cross-examination.

Amy is intelligent and attractive, but shy and anxious. She worried all the time, about everything. As her jet-setting husband grew less and less interested in being her husband, and his steady stream of criticism grew into a torrent, she began to fear the worst — a repeat of her childhood. The breakup of her family was precisely what she didn’t want to happen. When it became clear that divorce was inevitable, she didn’t see how she could live with the situation, and in a fit of panic she threatened to kill herself and fled three thousand miles away. Her rash reaction became her legal undoing. The court granted her husband full custody of the children pending the outcome of the trial, restricting her from seeing them except for twice a week. Worse, on the suspicion that she might be unstable, her visits had to be supervised by a court-appointed monitor.

Her husband’s lawyer zeroed in on Amy’s treatment.

“Is the defendant taking any medication?” she asked, perfectly aware of the answer.

“No, not at the moment,” I answered.

“Have you ever prescribed medication for the defendant?”

“Yes. Prozac.”

“That’s an antidepressant.”

“Yes. And it’s very effective in treating generalized anxiety disorder.”

“And your patient has generalized anxiety disorder?”

“Yes.”

“I see. And she’s not taking Prozac now. Did you tell her to stop?”

“No. She asked permission, and I told her it was OK.” I saw where this was headed: The lawyer was painting Amy as somebody who didn’t want to get well. In the eyes of the court, treatment means taking medication, so she must not be interested in feeling better. How could someone be trusted to watch over her children if she wouldn’t take care of herself?

“But she’s been exercising,” I interjected. “And she’s doing great!”

“Exercise? That’s not a proven treatment, is it, doctor?”

“Absolutely. Exercise works a lot like Prozac and our other antidepressants and antianxiety drugs — ”

“That’s your opinion,” the lawyer interrupted, “but what does it do, exactly?”

“Do you really want to know?” I asked, smiling. “I’m writing a book on the subject.”

“Yes, I do.”

Perhaps she expected a fuzzy explanation about runner’s high. Instead, I cited a few of the clinical trials showing that exercise is as effective as certain medications for treating anxiety and depression. Then I launched into a twenty-minute monologue about what exercise does for the brain, and, specifically, how it had tamed Amy’s anxiety and allowed her to master her chaotic feelings in the nine months she’d been my patient. If it was exercise this lawyer wanted to put on trial, I was all for it.

THE CASE

Anxiety is a natural reaction to a threat that happens at a certain point in the stress response, when the sympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis shift into high gear. When you’re facing an upcoming speech or a brewing confrontation with your boss, anxiety sharpens your attention so you can meet the challenge. The physical symptoms range from feeling tense, jittery, and short of breath to experiencing a racing heart, sweating, and, in the case of full-blown panic attacks, severe chest pains. Emotionally, what you feel is fear. If you’re in a plane that suddenly drops several hundred feet, you and everyone else on board will be edgy and acutely concerned — are we going to make it? The nervous system stays alert for a while, hypersensitive to any further turbulence. That’s normal.

But if you worry when there’s no real threat, to the point where you can’t function normally, that’s an anxiety disorder. The symptoms crowd your consciousness, your brain loses perspective, and you can’t think straight. Clinical anxiety affects about forty million Americans, or 18 percent of the population, in any given year and can manifest in a number of ways. They include generalized anxiety disorder, panic disorder, specific phobias, and social anxiety disorder. They all share the physical symptoms of the severe stress response as well as a similar dysfunction in the brain, namely a cognitive misinterpretation of the situation. The common denominator is irrational dread. The differences are mostly a matter of context.

Someone with generalized anxiety disorder tends to respond to normal situations as if they were threatening — the Nervous Nelly who is afraid of her own shadow or the worrier who sees stressors everywhere. People who suffer from panic disorder seem perfectly at ease most of the time but then are blindsided by crippling fear and physical pain that can be mistaken for a heart attack. Panic is the most intense form of anxiety, and it is at the root of all phobia — a paralyzing fear of a specific object or situation that instills a powerful and often unreasonable compulsion to avoid the source (spiders for the arachnophobe, open spaces for the agoraphobe). Probably the most common phobia is social anxiety disorder, which I think of as performance anxiety in everyday interactions. Most of us experience social anxiety at some point or in certain situations, but the disorder is more intense than just being shy on occasion. It’s a consuming fear of any social situation that might involve meeting or talking to people or even being seen by others, and it’s more common than most people realize, afflicting fifteen million Americans. Social anxiety disorder takes a serious toll on quality of life.

All of these forms of anxiety can bleed into and feed off one another, and they often seed other disorders such as depression. It’s possible to have panic disorder without having generalized anxiety disorder and vice versa, but often panic disorder turns into generalized anxiety due to fear of the next attack. Some people also have anxiety sensitivity, which complicates any form of the disorder. Your heart rate or breathing might increase for an unrelated reason, and when you sense this physical arousal, that awareness alone can trigger a state of anxiety or panic. You lose control because you feel like you’re going to lose control. If you begin to fear the fear — whether it’s mental or physical — anxiety can quickly spiral out of control.

Amy is a textbook case of generalized anxiety disorder, with shades of panic disorder and social anxiety disorder. She displays both the state — hyperalert, tense, expecting the worst — and the trait, which is the deeper, more ingrained tendency to slip into the state. All her life, she’s had anxiety sensitivity, and as her marriage crumbled it only intensified. She began responding to every stressor, whether or not it was truly threatening, as if it were a matter of survival, overreacting and doing a lot of damage to herself and her relationships in the process.

You couldn’t ask for a more anxiety-prone situation than the one Amy fell into. Her husband held de facto control over her time with the kids; she had to visit a psychologist who reported back to the court; and everyone in town knew what was going on. Her social anxiety was in full bloom during her supervised visits — she essentially had to perform for the court-appointed monitor — and she was afraid that she would slip up and somehow give her husband more legal ammunition. She was being judged on her mental health, and the more she worried about how she came off, the worse her symptoms became. In this environment, Amy began to doubt her own abilities as a mother, even though she’d been perfectly competent. She desperately wanted to rescue herself and get her children back, but she was in no condition for a fight, feeling like a nervous wreck with no control over her anxiety. It was a sickening spiral: constantly on the verge of panic, she felt like she couldn’t stand up for herself or accomplish anything.

When we are in this state, we begin to anticipate that everything is going to be a disaster, and so we try to avoid everything, and our world begins to shrink. Amy had retreated inside her new apartment since her marriage derailed and had become completely withdrawn from her friends and family.

THE DEFENSE

Unlike the lawyer’s portrayal, Amy was keenly interested in getting better. It’s not criminal or even unusual that she didn’t like the idea of taking medicine, but she tried Prozac for a stretch anyway. Although it calmed her nerves, it left her feeling unmotivated, and she stopped. She had been practicing Kripalu yoga, which also calmed her down, but still she suffered, so I encouraged her to add in aerobic exercise. She bought an elliptical trainer for her apartment, by far a more palatable option than stepping outside her safety zone.

Gradually, she got into a routine, logging thirty minutes every morning. She had very little she could enjoy during this period, but she started having fun with the exercise. She described how she incorporated upper-body twists while pumping away on the trainer, and she followed her aerobic session with an hour of yoga (which has been proven to reduce anxiousness). She was gaining a sense of control over her state of anxiety, a vital step toward conquering the trait. She quickly learned that if she became anxious or panicky at home, she could jump on the elliptical for ten or fifteen minutes to quell the feelings on the spot (in the same way my patient Susan used her jump rope to cope with stress).

Amy rediscovered her motivation through the movement. Not only did she stop worrying all the time, but she also began to see herself as being active rather than passive. She didn’t feel frozen anymore, and she reengaged in other areas of her life. She got back to her hobbies and friends, which allowed her to reconnect with the good things about herself. Now she doesn’t feel like a rat in a corner, cowering or startling at every disturbance. A casual observer might say that Amy has come out of her shell, but the ripple effects of exercise on her personality are much more profound. She carries herself as if she were on solid ground.

The truth is, her situation hasn’t changed all that much — just her response to it and thus her attitude. She says she uses exercise the same way someone else might take a shot of whiskey or alprazolam (Xanax) to calm her nerves. Her strategy has noticeably lowered her anxiety sensitivity, which allows the brain to learn its way out of the trap.

THE EVIDENCE

In 2004 a researcher named Joshua Broman-Fulks from the University of Southern Mississippi tested whether exercise would reduce anxiety sensitivity. He found fifty-four college students with generalized anxiety disorder who had elevated anxiety sensitivity scores and who exercised less than once a week. He randomly divided his sedentary subjects into two groups, both of which were assigned six twenty-minute exercise sessions over two weeks. The first group ran on treadmills at an intensity level of 60 to 90 percent of their maximum heart rates. The second group walked on treadmills at a pace of one mile per hour, roughly equal to 50 percent of their maximum heart rates.

Both regimens tended to reduce anxiety sensitivity, but rigorous exercise worked more quickly and effectively. Only the high-intensity group felt less afraid of the physical symptoms of anxiety, and this distinction started to show up after just the second exercise session. The theory is that when we increase our heart rate and breathing in the context of exercise, we learn that these physical signs don’t necessarily lead to an anxiety attack. We become more comfortable with the feeling of our body being aroused, and we don’t automatically assume that the arousal is noxious.

This is a key finding given the notion of anxiety as a cognitive misinterpretation. By using exercise to combat the symptoms of anxiety, you can treat the state, and as your level of fitness improves, you chip away at the trait. Over time, you teach the brain that the symptoms don’t always spell doom and that you can survive; you’re reprogramming the cognitive misinterpretation.

The fact that aerobic exercise works immediately to fend off the state of anxiety has been well established for many, many years. It’s only more recently, however, that researchers have started to pin down how this works.

In the body, physical activity lowers the resting tension of the muscles and thus interrupts the anxiety feedback loop to the brain. If the body is calm, the brain is less prone to worry. Exercise also produces calming chemical changes. As our muscles begin working, the body breaks down fat molecules to fuel them, liberating fatty acids in the bloodstream. These free fatty acids compete with tryptophan, one of the eight essential amino acids, for slots on transport proteins, increasing its concentration in the bloodstream. The tryptophan pushes through the blood-brain barrier to equalize its levels, and once inside, it’s immediately put to use as the building block for our old friend serotonin. In addition to the boost from tryptophan, the higher brain-derived neurotrophic factor (BDNF) levels that come along with exercise also ramp up levels of serotonin, which calms us down and enhances our sense of safety.

Moving the body also triggers the release of gamma-aminobutyric acid (GABA), which is the brain’s major inhibitory neuro transmitter (and the primary target for most of our antianxiety medicines). Having normal levels of GABA is crucial to stopping, at the cellular level, the self-fulfilling prophecy of anxiety — it interrupts the obsessive feedback loop within the brain. And when the heart starts beating hard, its muscle cells produce a molecule called atrial natriuretic peptide (ANP) that puts the brakes on the hyperaroused state. ANP is another tool the body uses to regulate the stress response, which I’ll explain more later.

As for the trait, the majority of studies show that aerobic exercise significantly alleviates symptoms of any anxiety disorder. But exercise also helps the average person reduce normal feelings of anxiousness. One interesting study in 2005 measured the physical and mental effects of exercise in a group of Chilean high school students for nine months. The researchers divided 198 fifteen-year-olds into two groups: the control group continued with a once-a-week, ninety-minute gym class, and the other embarked on a program of its own design, rigorously exercising during three ninety-minute sessions per week throughout the school year. The study was meant to assess general mood changes in a healthy population, but scores relating to anxiousness really stood out on the students’ psychological tests. The experimental group’s anxiety scores dropped 14 percent versus a statistically insignificant 3 percent for the control group (an improvement that could be explained by the placebo effect). Not coincidentally, the experimental group’s fitness levels improved 8.5 percent versus 1.8 percent for the control group. Clearly, there is a connection between how much you exercise and how anxious you feel.

FEAR ITSELF

Anxiety is fear, but what is fear? In neurological terms, fear is the memory of danger. If we suffer from an anxiety disorder, the brain constantly replays that memory, forcing us to live in that fear. It all starts when the amygdala sounds the survival call, but unlike the normal stress response, in anxiety the all-clear signal isn’t working properly. Our cognitive processors fail to tell us there is no problem or that it has passed and we can relax. There is so much noise in the mind from the sensory input of physical and mental tension that it clouds our ability to clearly assess the situation.

The misinterpretation stems partly from an amygdala that isn’t effectively controlled by the prefrontal cortex. One of the correlations scientists have found among people with generalized anxiety disorder is brain scans that show the area of the prefrontal cortex responsible for sending cease-and-desist signals to the amygdala as being smaller than it should be. Left unchecked, the overexcited amygdala tags too many situations as challenges to survival and burns them into memory. The fear memories form connections with each other, and the anxiety snowballs. Eventually, the amygdala overwhelms attempts by the hippocampus to tone down the fight-or-flight response by putting the fear in context. As the snowball grows and more and more memories become associated with fear, your world shrinks.

A patient of mine who suffers from social anxiety disorder is a good example of how the fear can snowball, as well as how we can rein it in. She’s a late-twenties office manager who dreaded social gatherings, meeting new people, and even small talk with someone she already knew. Ellen, I’ll call her, would get butterflies and a dry mouth just thinking about going to a cocktail party, and once there, she couldn’t wait for the first drink to hit. Like most people with social anxiety, she felt on display, terrified that she would do something embarrassing or humiliating. Afterward, she would go home and berate herself for her “performance.”

All this made it extremely stressful for Ellen to manage her seven employees. She wished she could stop apologizing for assigning tasks, but her anxiety kept her from acting like a boss. It wasn’t right, she knew, to plead with people to do their jobs, but she felt terribly guilty for asking anything of them and then worried that she was asking too much. As her sense of authority eroded, she only became more anxious and began avoiding contact with anyone in the office for fear someone would spot her weaknesses.

What makes anxiety so tricky to treat is that survival-related memories trump existing memories. Say you walk by a certain house every night on your way home from work, and then one night a dog comes rushing out and attacks you. From that moment on, you’ll skirt that house, because the memory of the attack stands out against all the times you passed by safely. Even if a fence is built and you’re the most logically minded person on earth, you’ll still feel a little jumpy walking by. Once the fear memory is wired in, that particular circuit stays there. Which is to say, fear is forever.

Contrary to what scientists originally assumed, studies comparing MRI scans of brain activity in adults with and without anxiety disorders show no difference in how the amygdala responds to a legitimately frightening stimulus (such as pictures of fear-stricken faces, which have a powerful effect because human beings are programmed to interpret facial expressions as survival cues). The difference is in how they respond to a nonthreatening stimulus. Whereas most people will show a sharp decrease in amygdala activity when presented with a benign picture, those with anxiety disorder have almost the same activity level as if they were confronting fear — they cannot discriminate between danger and safety. Research psychiatrist Daniel Pine, who is the chief of the section on development and affective neuroscience at the National Institutes of Mental Health, sees it this way: “Patients with anxiety disorders have a learning deficit.”

There may be genetic factors underlying the dysfunction of learning circuits in anxiety. Researchers recently studied a gene variation that prevents BDNF from fostering nerve connections, which results in impaired memory. In the experiment, mice with the mutant BDNF gene that were put in an anxiety-provoking situation didn’t get the relief they should have from Prozac. The antidepressant worked fine for normal mice under the same circumstances. This suggests that BDNF might be an essential ingredient in combating anxiety, probably because it helps wire in positive memories that create a detour around the fear.

I think this is a big reason why exercise is so effective at treating not just the state of anxiety — by relieving muscle tension and increasing serotonin and GABA — but also the trait of anxiety. Exercise gives neurons everything they need to connect, and if we direct that process we can have a huge impact on teaching the brain to cope with the fear.

My patient Ellen came to me on the usual selective serotonin reuptake inhibitor (SSRI) antidepressant, and while the medicine helped, it didn’t solve the underlying problem. Naturally, I talked to her about exercising. She acknowledged that she felt less anxious after running but said she was too busy to make it a priority. I told her the irony was that she’d feel less harried if she took the extra time to exercise, and after a bit of goading (and fine-tuning her medication), she began going to the gym before work. It quickly became clear that on the days she missed her workout, she felt more flustered and less willing to interact with anyone at work, including new clients. Then she shifted into high gear and made a point of going every morning. If she missed her favorite aerobic class, she would run on the treadmill for twenty minutes, and she’s been at it for a year or so.

Now Ellen feels like she’s able to be more assertive and straightforward with her employees, and the more she interacts with them, the bolder she becomes. A huge part of the problem with social anxiety, whether it’s at the level of Ellen’s phobia or milder social apprehension, is that the more we withdraw, the less practice we get interacting, and the scarier the prospect becomes. It might sound silly that someone would need to practice what comes naturally to many people, but it’s not silly at all. This is the genius of Paul Zientarski’s freshmen square dance class at Naperville Central High School — all the kids practice small talk in the same situation, incrementally over the course of the semester, neutralizing any fear they might have. For Ellen, exercise was a tool that calmed her nerves enough for her to test the waters. Just as anxiety can feed on itself, so can courage.

THE PAIN OF PANIC

Panic is the most painful form of anxiety, and it illustrates in the extreme how paralyzing any of this family of disorders can be. When I first came across a case of panic disorder, I was shocked at how debilitating it was. I was a third-year psychiatric resident at Massachusetts Mental Health Center and was also seeing patients at outlying social services offices. A woman had been dragged in by her husband because she was depressed and all but refused to leave the house. She had been to the emergency room on more than one occasion for what felt like a heart attack, and she described in vivid detail how she had been certain she was dying. Each time, the doctor reported that her heart was fine, and she started to wonder if she was crazy.

Panic doesn’t cause heart failure, but it sure feels that way. Muscle tension and hyperventilation cause severe chest pains. Then, because the rapid, shallow breathing expels too much carbon dioxide, the blood’s pH level drops, triggering an alarm from the brain stem that causes muscles to constrict even more. (This is why breathing into a paper bag stops us from hyperventilating: it forces us to rebreathe the carbon dioxide.)

Living with panic means avoiding anything that might set off another frightening episode. You withdraw into an emotional fetal position, and the fear leads to a desperate need for control — whatever is necessary to maintain a stable and safe environment. This manifests itself in various ways: passive-aggressiveness, which is one way of trying to control others; compulsiveness, to keep the fear triggers at bay; and overall inflexibility. My patient knew something was wrong, but the panic had taken over to such an extent that the constellation of symptoms warped the picture of the real problem.

The major treatment for anxiety and depression at the time, in the late 1970s, was psychotherapy. We just didn’t use drugs much. But the field was beginning to shift toward a biological interpretation of mental health, and studies were cropping up about treating anxiety with imipramine, a tricyclic antidepressant that had been around for twenty years. It manipulates the interaction of norepinephrine and serotonin in a part of the brain stem known as the locus coeruleus, which regulates basic life functions such as breathing, waking, heart rate, and blood pressure. As such, this area monitors blood pH levels and is the origin of the alarm signals that trigger the amygdala in a panic attack. The drug stabilizes the arousal system so the panic button isn’t so easily tripped. It worked almost immediately for my patient, and over days and weeks in the absence of anxiousness she slowly let down her guard. By controlling the fear, we were able to move forward in therapy. Imipramine gave her back her freedom.

Another class of drug that became popular for treating various forms of anxiety around the same time was beta-blockers, which calm down the sympathetic nervous system. They block epinephrine receptors in the brain and the body and thus prevent epinephrine from elevating blood pressure, heart rate, and breathing during times of stress or anxiety. Often used for heart patients to reduce blood pressure, beta-blockers break the anxiety feedback loop to the brain that otherwise keeps the amygdala on alert. In quelling the bodily symptoms of anxiety, beta-blockers diffuse panic attacks before they explode. They’re also useful for people with social anxiety or stage fright. It’s exceedingly common for classical musicians to take beta-blockers before performances because it prevents them from sweating and tensing up, which can really interfere with their ability to play. (It must be hard to play a trombone with stiff lips!)

Sometimes people with panic disorder are treated with both imipramine and beta-blockers — the first to quash the fear and the second to relax the body. The real point of understanding how these drugs work is that they provide an explanation for how exercise works. As it turns out, exercise impacts the same pathways as these medications — it puts a safety on both triggers.

PUSHING THROUGH THE PAIN

For several decades, common medical wisdom suggested that patients suffering from panic should avoid exercise. It could be dangerous! Or so we thought, based on research from the late 1960s. Some patients reported that the physical manifestations of exercise — increased heart rate, blood pressure, rapid breathing — magnified their fear, presumably because they felt just like the symptoms of anxiety. It turned out that some people with anxiety disorders had elevated levels of lactic acid in their blood compared to nonanxious exercisers, and researchers found that infusing anxiety patients with lactic acid induced panic attacks. Doctors began advising patients with any form of anxiety to avoid exercise, lest it trigger an attack. Better to stay still.

This logic persisted despite a number of follow-up studies that disproved the hypothesis. Although the medical literature tells us that a handful of patients did panic during exercise, the vast majority showed just the opposite effect. In fact, 104 studies on exercise and anxiety reported between 1960 and 1989, showed that exercise alleviates anxiety, but most of them didn’t meet the randomized, double-blind, placebo-controlled trial criteria necessary for scientists to count them as medical fact. While analytical researchers might say there isn’t sufficient data to prove that exercise reduces anxiety, others will tell you that they don’t bother studying the issue because it’s just common sense.

Consequently, the first randomized, placebo-controlled study to compare exercise to drugs in treating clinically diagnosed panic disorder was undertaken in 1997. German psychiatrist Andreas Broocks conducted a ten-week trial in which he divided forty-six patients with at least mild panic disorder into three groups: regular exercise, a daily dose of clomipramine (a close relative of imipramine), or a daily placebo pill.

All three treatments improved symptoms in the first two weeks, including the placebo! The clomipramine had the quickest and most dramatic effect, immediately and steadily relieving symptoms. In the exercise group, after initial relief anxiety scores leveled out somewhat until the last four weeks, when they rapidly decreased. (The placebo group experienced a return of symptoms as the trial progressed.) At the end of ten weeks, the clomipramine group and the exercise group ended up at the same level of improvement on a variety of tests. Both groups were in remission.

Why did exercise take longer? According to another scientifically rigorous study, by Andreas Ströhle in 2005, it shouldn’t have. Ströhle showed that thirty minutes of treadmill running significantly reduces panic attacks as compared with quiet rest (by a ratio of two to one), indicating that its effect can be immediate in some cases. The lag in exercise-induced relief in Broocks’s study probably had to do with the way it was set up. All but one person in the exercise group had agoraphobia, some of them quite severely, and others regarded exercise as flat-out “dangerous,” which means they believed the very act of walking or running outside would be difficult. They had to confront their fear to follow the study’s instructions. You can’t simply tell someone with agoraphobia to go for a four-mile run and everything will be OK, so Broocks had them ease into the regimen. They were asked to find a four-mile route near their home and merely complete it three or four times a week — walking at first if necessary. They were then encouraged to include short stints of running and gradually increase them in length; they weren’t expected to run the entire route until after the sixth week. Two of the patients actually had panic attacks while running but kept going and they subsided.

In the Broocks experiment, everyone in the clomipramine group stuck with the therapy throughout the study, despite significant side effects, including dry mouth, sweating, dizziness, tremors, erectile dysfunction, and nausea. The exercise group, which along with the placebo group had several patients drop out, reported minor side effects of the sort expected for someone starting up a new exercise routine, including temporary muscle and joint discomfort.

In a six-month follow-up, the exercise patients who were the most fit had the lowest anxiety scores. In the end, the exercise group landed in the same healthy place as the clomipramine group, and they did so of their own accord. There’s certainly nothing wrong with taking medicine, but if you can achieve the same results through exercise, you build confidence in your own ability to cope. This is a significant advantage not just for patients with full-blown anxiety disorders, but for anyone. We all face situations in everyday life that cause fear and anxiousness. The trick, as my patient Amy illustrates, is in how you respond.

THE MISSING CONNECTION

The mind-set that any sound treatment for anxiety must involve medicine isn’t restricted to the courtrooms of divorce proceedings. In 2004 the New England Journal of Medicine (NEJM) published a review of treatments for generalized anxiety disorder that failed to even mention exercise. It was primarily a rundown of our most common antianxiety drugs, with a nod to therapy and relaxation. Of the thirteen pharmaceuticals charted in the review, all bear a formidable list of possible side effects. None have been endorsed by the U.S. Food and Drug Administration as explicitly safe during pregnancy — not an incidental point given that women are twice as likely to suffer from anxiety and depression as men.

The article was positioned as advice for doctors, but how is it that a summary of treatments for general anxiety disorder in the bible of medical research simply left out exercise? It’s a case of what I would call clinical blindness. The mounting research on the neurological and psychological benefits of exercise seems to be hidden in plain sight.

Interestingly, it was the cardiologists who spoke up. The NEJM published a letter from doctors Carl Lavie and Richard Milani of the Ochsner Clinic Foundation in New Orleans. It read, in part, that the author “discusses generalized anxiety disorder and its treatment with pharmacologic agents and psychotherapy. We are surprised, however, that there is no mention of exercise as an additional means of treating anxiety.” The letter noted that cardiologists are interested in anxiety as a risk factor for heart problems, and then pointed out, “Exercise training has been shown to lead to reductions of more than 50 percent in the prevalence of the symptoms of anxiety. This supports exercise training as an additional method to reduce chronic anxiety.”

The letter was a polite way of saying that the original article missed the boat. Lavie has written more than seventy papers on exercise and the heart, eleven of which focus on anxiety. Every single one of his studies has shown a marked improvement in anxiety and depression.

The importance of this exchange is that it’s a case of cardiologists (“real” doctors) taking psychiatrists to task about how to treat the whole patient. If we go all the way back to Hippocrates, the wisdom of the day was that emotions come from the heart and that that’s where treatment should start for maladies of mood. Modern medicine has separated mind and body, but it turns out that, in a very concrete way, Hippocrates had it right from the start. Just in the past ten years scientists have begun to understand how a molecule that originates in the heart plays on our emotions.

ANP is secreted by heart muscles when we exercise, and it makes its way through the blood-brain barrier. Once inside, it attaches to receptors in the hypothalamus to modulate HPA axis activity. (ANP is also produced directly in the brain, by neurons in the locus coeruleus and in the amygdala — both key players in stress and anxiety.) ANP has been shown in both animal and human studies to have a calming effect, and researchers suspect it to be a major link between exercise and anxiety. In 2001 one of the first studies to verify the role of ANP in anxiety compared patients with panic disorder to those without. They were randomly assigned an injection of ANP or placebo, and then received a dose of an abdominal hormone called cholecystokinin tetrapeptide (CCK-4), which induces anxiety and panic. ANP significantly reduced panic attacks in both groups, while the placebo did not.

During a panic attack, there is a surge of corticotropin-releasing factor (CRF), which induces anxiety in its own right and also floods the nervous system with cortisol. ANP seems to work against CRF’s efforts to put us into a frenzy, like a drag brake on the HPA axis. And studies in women show that levels of ANP triple during pregnancy, suggesting a built-in survival strategy to protect the baby’s developing brain from the potentially toxic effects of stress and anxiety.

In one study of patients with severe heart failure, those with the highest ANP levels had the lowest levels of anxiety. None of them had anxiety disorders, but doctors were interested in their anxiety because it has a major influence on how well heart surgery patients recover. ANP directly dampens the sympathetic nervous system’s response by stemming the flow of epinephrine and lowering the heart rate, and it also seems to reduce the feeling of anxiousness, which is paramount. And we know that among panic disorder patients, those who have frequent attacks have a deficit of ANP in their bloodstreams.

In 2006 a group of neuropsychiatrists from Berlin led by Andreas Ströhle looked at whether ANP was a critical element in the calming effect of aerobic exercise. For ten healthy patients who agreed to have panic-inducing injections of CCK-4, walking for thirty minutes on a treadmill (at a moderate pace) significantly increased concentrations of ANP while simultaneously lowering feelings of anxiety and panic. Ströhle pointed out that correlations don’t equal causality, but he wrote, “ANP may be a physiologically relevant link between the heart and anxiety-related behavior.”

FACING THE FEAR

If fear is forever, how can we hope to snuff out anxiety? The answer lies in a neurological process called fear extinction. While we can’t erase the original fear memory, we can essentially drown it out by creating a new memory and reinforcing it. By building up parallel circuitry to the fear memory, the brain creates a neutral alternative to the expected anxiety, learning that everything is OK. By wiring in the correct interpretation, the trigger is disconnected from the typical response, weakening the association between, say, seeing a spider and experiencing terror and a racing heart. Scientists call it reattribution.

We can force the brain to trade fear memories for neutral or positive ones through a form of psychology called cognitive behavioral therapy (CBT). Studies show that CBT is about as effective as SSRIs in treating anxiety, although varied results suggest that the quality of the therapy is crucial. The strategy is to expose the patient to the source of fear in small doses in the company of the therapist. When we experience the symptoms without the panic, the brain goes through a cognitive restructuring. We build connections in the prefrontal cortex that help calm the amygdala, which makes us feel safe, and then the brain records a memory of that feeling. When we add in exercise, we get the neurotransmitters and neurotrophic factors bolstering the circuits between the prefrontal cortex and the amygdala, providing further control and creating a positive snowball effect.

Psychologist and distance runner Keith Johnsgard found that conducting CBT in the context of exercise has particularly powerful results. In his book Conquering Depression and Anxiety through Exercise, he explains how he uses running as a mode of cognitive restructuring to treat agoraphobia. After several rapport-building sessions, he accompanies patients to an empty mall parking lot in the early morning and has them do a series of sprints. Nobody else is around, and they feel safe in his presence. He has already determined how far they can sprint before coming to exhaustion, and — this is the clever part — Johnsgard marks off that distance from the main door of the mall, and then has them sprint from his side toward the mall. The idea is that they reach the height of their fear in a state of full physical arousal, without the panic. If they feel a panic attack coming on, they are instructed to stop, turn, and walk back to him. They run toward fear and walk toward safety.

Eventually they should overcome the anxiety of entering the mall and be able to venture inside for increasingly longer stretches. He says that often he sees improvement after only a half dozen sessions. “In essence,” he writes, his approach is a matter of “getting back on the horse that threw you.” Teaching the brain that we can survive is crucial to overcoming the anxiety.

This approach fits into a broader concept highlighted by New York University neuroscientist Joseph LeDoux, a renowned fear expert. Shortly after the terrorist attacks of September 11, 2001, LeDoux and coauthor Jack Gorman published an article in the American Journal of Psychiatry titled, “A Call to Action: Overcoming Anxiety through Active Coping.” Essentially, active coping means doing something in response to whatever danger or problem is causing anxiety rather than passively worrying about it. It doesn’t specifically imply physical activity, but certainly exercise qualifies as a mode of active coping. And as it turns out, movement may not be an incidental aspect of active coping.

LeDoux discusses how, by making a decision to act in the face of anxiety, we literally shift the flow of information in the brain, forging new pathways. An area of the amygdala called the central nucleus is responsible for creating the negative snowball effect — linking nonthreatening stimuli with legitimately threatening stimuli. The resulting fear memory is the connection between the trigger and the anxiety.

LeDoux has shown in rats that the signals can be redirected so that instead of pulsing through the central nucleus of the amygdala, they go through the basal nucleus, which connects to the body’s motor circuits. If the same is true in humans, simply by taking action we’re circumventing the mechanism for the fear memory. The basal nucleus is the action pathway, and we can even spark it with thought. For one of my patients, who was traumatized by losing both his job and his girlfriend, I suggested that he start each day by getting to the gym, to keep from stewing in the trauma. He could also shift the flow from fear to action circuits by making a list of potential employers to call — a more classic example of active coping — but it wouldn’t affect the brain as broadly. By doing something other than sitting and worrying, we reroute our thought process around the passive-response center and dilute the fear, while at the same time optimizing the brain to learn a new scenario. Everyone’s initial instinct in the face of anxiety is to avoid the situation, like a rat that freezes in its cage. But doing just the opposite, we engage in cognitive restructuring, using our bodies to cure our brains.

OUTRUNNING THE FEAR

The elegance of exercise as a way to deal with anxiety, in everyday life and in the form of a disorder, is that it works on both the body and the brain. Here’s how:

1. It provides distraction. Quite literally, moving puts your mind on something else, just as using the elliptical trainer helped my patient Amy break out of her acute state of anxiety and focus on something other than the fear of her next panic attack. Studies have shown that anxious people respond well to any directed distraction — quietly sitting, meditating, eating lunch with a group, reading a magazine. But the antianxiety effects of exercise last longer and carry the other side benefits listed here.

2. It reduces muscle tension. Exercise serves as a circuit breaker just like beta-blockers, interrupting the negative feedback loop from the body to the brain that heightens anxiety. Back in 1982 a researcher named Herbert de Vries conducted a study showing that people with anxiety have overactive electrical patterns in their muscle spindles and that exercise reduced that tension (just as beta-blockers do). He called it the “tranquilizing effects of exercise.” Reducing muscle tension, he found, reduced the feeling of anxiety, which, as I’ve explained, is important to extinguishing not just the state but the trait of anxiety.

3. It builds brain resources. You know by now that exercise increases serotonin and norepinephrine both in the moment and over the long term. Serotonin works at nearly every junction of the anxiety circuitry, regulating signals at the brain stem, improving the performance of the prefrontal cortex to inhibit the fear, and calming down the amygdala itself. Norepinephrine is the arousal neurotransmitter, so modulating its activity is critical to breaking the anxiety cycle. Physical activity also increases the inhibitory neurotransmitter GABA as well as BDNF, which is important for cementing alternative memories.

4. It teaches a different outcome. One aspect of anxiety that makes it so different from other disorders is the physical symptoms. Because anxiety brings the sympathetic nervous system into play, when you sense your heart rate and breathing picking up, that awareness can trigger anxiety or a panic attack. But those same symptoms are inherent to aerobic exercise — and that’s a good thing. If you begin to associate the physical symptoms of anxiety with something positive, something that you initiated and can control, the fear memory fades in contrast to the fresh one taking shape. Think of it as a biological bait and switch — your mind is expecting a panic attack, but instead it ends up with a positive association with the symptoms.

5. It reroutes your circuits. By activating the sympathetic nervous system through exercise, you break free from the trap of passively waiting and worrying, and thus prevent the amygdala from running wild and reinforcing the danger-filled view of what life is presenting. Instead, when you respond with action, you send information down a different pathway of the amygdala, paving a safe detour and wearing in a good groove. You’re improving alternate connections, actively learning an alternative reality.

6. It improves resilience. You learn that you can be effective in controlling anxiety without letting it turn into panic. The psychological term is self-mastery, and developing it is a powerful prophylactic against anxiety sensitivity and against depression, which can develop from anxiety. In consciously making the decision to do something for yourself, you begin to realize that you can do something for yourself. It’s a very useful tautology.

7. It sets you free. Researchers immobilize rats in order to study stress. In people too, if you’re locked down — literally or figuratively — you’ll feel more anxious. People who are anxious tend to immobilize themselves — balling up in a fetal position or just finding a safe spot to hide from the world. Agoraphobics feel trapped in their homes, but in a sense any form of anxiety feels like a trap. The opposite of that, and the treatment, is taking action, going out and exploring, moving through the environment. Exercising.

PLAN A COUNTERATTACK

One big difference between combining exercise with antianxiety medicine and using medicine alone is that while drugs like benzodiazepine — and alcohol for people who are self-medicating — quickly stifle anxiety, they don’t guarantee that you’ll learn a different response to the fear. People with anxiety often have a hard time knowing or choosing what they want from life. In fact, all that most chronically anxious people want is not to be anxious. Activity or exercise can help them move toward something.

I don’t look at exercise and medicine as an either-or proposition. Exercise is another tool at your disposal, and it’s handy because it’s something you can prescribe for yourself, whether you have a definable disorder or just feel anxious at times. Like most people do. And I’m certainly not a pharmacological Calvinist — I don’t tell people to pull themselves up by their bootstraps or that it’s a sin or weakness to rely on medicine.

I recently took on a patient with panic disorder who is a high school senior. He had his first episode when he was six, which implies that he has a predisposition to it, and of late it has been getting worse because of the pressures of preparing for college. Whenever he goes for a run, as soon as his heart starts pumping he feels anxious about the possibility of panicking, and he worries that he’ll drop dead of a heart attack and that nobody will find him. Sometimes he’ll stop and just start crying. But he also knows, rationally, that if he pushes through his sensitivity to the physical arousal, the feeling subsides. Would I recommend that he quit taking Zoloft? Absolutely not.

First of all, he’s deeply phobic about a panic attack coming on. And because panic disorder is so frightening, I usually start with medicine. Taking a pill doesn’t require a lot of effort, and in some cases it works like flipping a switch to diffuse the trigger. But, as I mentioned, it doesn’t necessarily lead to a permanent change, and the relearning process needs to happen for long-term relief. Why not come out with both guns blazing? I think combining medicine with exercise can be a great approach. Medicine provides immediate safety, and exercise gets at the fundamentals of anxiety.

This is particularly important with respect to children, because kids who have anxiety are more likely than their peers to develop depression later in life. One long-term study followed seven hundred children into adulthood. Of those who suffered from anxiety as children, most grew out of it. But of those who developed a mood disorder, in two-thirds of the cases the problem started as preadolescent anxiety. What’s tragic here is that anxiety is relatively easy to treat, but it often goes undiagnosed in children — the anxious kids are sitting quietly at the back of the class, terrified. Nobody notices there is something wrong because these kids are well behaved. Meanwhile, the anxiety is wearing in negative patterns in their brains that can become entrenched and set these kids up for future problems.

I told the young man that the A-number-one thing he needed to do was exercise with somebody. That goes for anyone who is panicky. It offers a sense of safety, but it also increases levels of serotonin immediately, just from being around another person. In his case, I suggested that he exercise at home, or close to it, until he started to associate his elevated heart rate with a positive experience. He needed to find a type of exercise he enjoyed, and, because his panic seemed to have a strong genetic component, I told him he’d really have to work at it. He’d have to start doing at least fifteen minutes of rigorous aerobic exercise a day — running, swimming, biking, rowing, or whatever would get his heart pounding. Intensity was particularly important in his case because of the evidence that only rigorous exercise alleviates sensitivity to the physical arousal of anxiety.

Like almost every adolescent I’ve seen, this young man didn’t want to be on medicine. He asked if he could stop taking it, and I told him that over time, if he got into the exercise and maybe CBT, he should be able to lower his anxiety sensitivity. Eventually, I said, my guess was that he’d be able to reduce his medication and maybe eliminate it altogether. But nobody really knows whether exercise can entirely replace medication. Our brains are just too complex.

A lot of people who are treated for panic disorder can go on to have a completely different kind of life. The farther they get from their last panic episode, the less likely they are to have another panic episode. The same holds true for any brand and any degree of anxiety. The more your life changes, the more you engage with the world, the more likely you are to put the anxiety behind you for good. Exercise can have an even more dramatic effect on milder anxiety, the kind that isn’t bad enough for medication but is still troublesome.

My high school patient needed the full complement of treatments: medicine, exercise, and talk therapy. But for my patient Amy, physical activity alone helped tremendously, both in the moment and day to day, and it cleared the way for talk therapy to get at the underlying issues. Aerobic exercise complemented her yoga and provided the calm necessary to look inside and observe herself, rather than spend all of her emotional energy on the task of not being overwhelmed. She became much more aware of her own psychology and behavior than she had ever been. She came to recognize that there is a natural ebb and flow to her challenges and negative feelings, and to realize that she has to ride the waves — and that she can. Equally important, she noticed the improvement in herself and described it well: the divorce was like an earthquake that nearly reduced her life to rubble, but exercising had solidified her foundation; she knew there would be aftershocks, but she felt strong enough to withstand them.

It’s astonishing how much Amy has changed. Her lawyer, her parents, her family therapist — even her husband, to some degree — have all commented that she seems like a different person. She’s more in command of herself and her situation, refreshingly self-assured and realistically optimistic. The court battle may continue for years, but she’s no longer overwhelmed by it, and exercise has been her best defense.