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Panic Disorder: The Heart That Goes Thump in the Night--and Day by Marian Segal Every night for five years, Sherry Menter would postpone sleep as long as she could. When it beckoned, she would clean the house, sew, read, bake cookies--do anything to avoid the terror she had come to expect once she drifted off. But eventually, sleep overtook her, and with it, the inevitable. "I could hear a noise like a siren or freight train coming in my head," she says. "I could feel my jaw lock, my teeth grind, and my limbs become totally immobilized, yet shaking uncontrollably, while this freight train comes charging into my head, and by the time the train gets there I'm consumed by fear. I feel my heart pounding and there have been times when I thought I stopped breathing. I guess my conscious mind takes over and I think, 'Oh my God, your heart's not beating. You're going to die.' And I scream at the top of my lungs for anybody to wake me." Menter is describing a panic attack. She says that while it's happening, she's aware that she's asleep and that in order to make the fear stop, she has to wake up. So she screams for someone to wake her. But those who have heard her "screams" tell her that, in reality, they are just "squeaky little noises." More than a million Americans, like Menter, suffer from panic disorder, according to a statement issued by a panel of experts at a National Institutes of Health (NIH) consensus development conference last September. It is not a new phenomenon; among its many past rubrics it has been known as "housewife's disease" and "soldier's heart. For most, the attacks begin in the middle teens or early adult years, but they can start at any age. FDA recently approved panic disorder as an additional indication for a drug already approved for treating anxiety. Other marketed drugs, although not specifically approved for panic disorder, have been reported helpful in treating the condition. The illness is characterized by episodes of intense fear that occur "out of the blue," says Thomas W. Uhde, M.D., chief, Section on Anxiety and Affective Disorders at the National Institute of Mental Health in Bethesda, Md. "They typically last from 2 to 10 minutes and are associated with a number of different psychological and physiological symptoms." Unlike Menter, whose attacks occur only during sleep, most patients experience attacks while awake. Uhde says that 60 to 69 percent of patients will have at least one severe sleep panic attack in their lifetime, about a third of patients have recurring sleep panic attacks, and 5 percent have panic attacks more often during sleep than while awake. Many patients experiencing a panic attack for the first time rush to an emergency room complaining of chest pain, shortness of breath, flushes or sweating, and rapid, irregular heartbeat. Many fear they are dying or going crazy. They may have chills, dizziness, shaking or trembling, choking, nausea or abdominal discomfort, and numbness or tingling sensations as well. "Some people also have a profoundly altered perception of the environment. They might perceive objects as particularly bright or dull, sounds can be experienced as dull or unusually sharp, and there may be alterations in the sense of time," Uhde says. Patients sometimes feel "depersonalized," as if they're somehow strange or different and disconnected from the immediate environment. "Distancing" a Symptom Patti Griffith (not her real name) felt herself becoming "distanced" from the people and things around her when she had her first attack a year ago at age 35. It happened suddenly during a business meeting that ended for Griffith in a four-hour hospital emergency room stay, where doctors tried in vain to discover what was wrong. "I had a sensation almost like going into a tunnel and the light was receding. I could hear people talking, but they were like 'other.' I had to recede from the activity and try to focus all my thoughts on trying to stay calm, because I knew that if I could talk myself into calming down, maybe I could get my heart to slow down." Panic attacks do not inevitably signal panic disorder. Some people have only one isolated incident of a panic episode or perhaps experience them just occasionally, with no lasting impact on their well-being. According to the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, panic disorder is diagnosed only in people who have at least four attacks within four weeks, or one or more attacks followed by at least a month of persistent fear of having another. At least some of the attacks must occur spontaneously and unexpectedly, not in response to a phobic trigger such as snakes, closed spaces, public speaking, or other objects or situations that evoke fearful avoidance in some people. "If panic attacks continue without treatment, people begin to wonder about the causes," says Uhde. "Are they crazy? Is it something they did or didn't do? Or is there something about the situation in which they had the attack that somehow makes them vulnerable?" Context Not the Cause In trying to come up with an answer, he says, people may misattribute the cause of the attacks to the context in which they occurred. For example, if someone has an attack while driving a car, that person may begin to believe there is something about driving--or about their destination--that causes the panic attack. This often leads to development of agoraphobia, a condition in which the person begins to avoid places where they fear a panic attack may occur. They may develop a fear of bridges, tunnels, shopping malls, grocery stores, or travel by public transportation, for example. "What really underlies the fear is whether or not they'll be in a place or situation that is safe and where they can get immediate help in the case of a sudden or unexpected panic attack," says Uhde. "These patients have an increasingly constricted lifestyle. Ultimately, they can become homebound and, in some cases, patients may become totally constricted to a room within their house." Approximately one-third of patients with panic disorder develop agoraphobia, although there is no way to predict whether or not it will develop in a particular patient. Griffith stopped going on business trips because, she says, "I had experienced enough of the 'heart jumping' thing that I thought, 'I don't want to be that far away from home. I don't want to be in a strange hotel room somewhere and have this happen to me.'" She also stopped eating at restaurants for a time, because she initially thought the attacks might have been related to eating out. "I would go out to dinner and have a sense of my heart skipping or start to get flushed and, because I was trying to diagnose myself, it seemed to me that it happened frequently when I went out to dinner. So I thought it might be spices or something in the food." ther disorders and diagnosis is often elusive. According to the NIH panel, many patients see 10 or more doctors before being accurately diagnosed. Bad Nights Menter's attacks began in 1981, when she was 20 years old. They occurred about twice a month. At first, she simply attributed them to "bad nights" or bad nightmares, even though she now says she knew they weren't nightmares. "A nightmare is a story, a bad dream," she says. "When you wake up from a nightmare, you know the source of your fears. It's easy to examine it and reason it away. It's more abstract. A panic attack is just a sensation with no context. They're so real, and they can't be reasoned away." Over time, Menter's attacks came more frequently, and finally, after two years of having attacks every night, she went to the doctor. He prescribed a low dose of the benzodiazepine alprazolam (Xanax) to relieve stress, but the medication didn't seem to help. Menter didn't seek help again until three years later when, in late 1989, she heard Uhde discussing sleep panic attacks in a radio interview. "I was just stunned that somebody was describing what I thought I had exclusively all to myself," she says. "That was the major step--identifying it--because at that time I was almost convinced that I was just crazy. Finally, I could stick a label to it." She called the National Institute of Mental Health in Bethesda, Md., the next day and entered a research program on panic disorder. Drugs May Help Treatment is not clear-cut; it must be tailored to the individual, taking into account the patient's history, other medical and psychological conditions, and degree of impact of the disorder on the patient's life. Only one drug, alprazolam (Xanax), has been approved by FDA for treating panic disorder. Originally approved by the agency in 1981 to treat anxiety, alprazolam received approval for this new indication in November 1990. Side effects include drowsiness and lightheadedness, but the most serious risk is dependence. "Withdrawal symptoms are common in patients who are trying to come off Xanax," says Thomas Laughren, M.D., of FDA's division of neuropharmacological drug products. "The risk of dependence and its severity appear to be greater in patients treated with relatively high doses [above 4 milligrams per day] and for longer periods of time [more than 8 to 12 weeks]. A higher dose may be an especially important predictor of the development of physical dependence." Because dosages of more than 4 milligrams per day are often required in treating panic disorder, the risk of dependence among these patients may be greater than in those taking the drug at lower doses for less severe anxiety. The drug's labeling carries a warning about the risk of dependence and provides recommendations for initial dosing and increasing the dose in specific increments at specific intervals until therapeutic levels are achieved. Other drugs have been reported to help reduce or eliminate panic attacks; however, FDA has not received any well-controlled studies to review them for this use. They include tricyclic antidepressants, such as imipramine (Tofranil), and monoamine oxidase (MAO) inhibitor antidepressants, such as phenelzine (Nardil). While the tricyclics have no risk of dependence, they can cause a variety of adverse side effects, including low blood pressure, abnormal heart rhythms, weight gain, tremors, and seizures. Patients with certain heart problems, urinary retention, narrow-angle glaucoma, and other medical conditions should not take these drugs. MAO inhibitors have also been used and also carry a low risk of dependence. Their side effects include low blood pressure, sexual dysfunction, and weight gain. In addition, patients on these drugs must follow a diet low in tyramine. This means avoiding high-protein foods that have been aged, fermented, pickled, or smoked, including cheeses, beer, wine, liver, salami, and yogurt. Psychotherapy Behavioral therapy, aimed at helping patients confront fearful situations and develop coping skills, and cognitive therapy, aimed at treating panic attacks directly by restructuring self-defeating thought processes, may also be incorporated into the treatment plan. Uhde is not convinced that psychotherapy alone can combat panic disorder. He feels it is of value in helping patients get back on the subway or into their cars or offices and function despite their anxiety. "But that may not be treating the whole syndrome," he says. He points specifically to sleep panic attacks, which he views as probably representing a pure physiological form of panic attack, with no psychological component (see accompanying article, "Why Panic? Search for the Cause"). The NIH panel recommended that any treatment that fails to produce an effect within eight weeks should be reassessed. One question that looms large is, "When should therapy stop?" Little is known about the long-term course of panic disorder. In most cases, according to the NIH panel, it is a chronic disorder that waxes and wanes in severity. Some people, however, experience only a short-term problem that never recurs, while others may suffer a severe, chronic illness. Patients with agoraphobia tend to have a more severe and complicated illness, according to the panel. Long-Term Outlook Much remains to be learned also about the long-term effectiveness of maintenance doses of medication, psychotherapy, and lifestyle changes. Uhde says that, in general, he keeps patients on medication from 6 to 12 months before attempting a drug-free trial. After that, he says, there is a wide range of relapse. "My experience is that approximately 60 percent of patients will require drug treatment again within two years after the medication was stopped." Regarding Xanax, Laughren says there are inadequate data to guide physicians in how to use the drug beyond the acute treatment phase. "Because panic disorder is a chronic condition," he says, "it may require continued treatment. The labeling suggests that the necessary duration of treatment for patients who respond is unknown, but it recommends that gradual dose reduction and withdrawal be attempted after 'a period of extended freedom from attacks'." However, the labeling provides only rough guidance about how to withdraw patients from Xanax. "While the necessary research to establish optimal withdrawal strategies has not been done," Laughren says, "clinical experience has led to more conservative recommendations in labeling for withdrawing patients." At a September 1989 meeting of FDA's Psychopharmacological Drugs Advisory Panel, one participant likened the dilemma of Xanax to taking off in a plane without landing instructions. "He suggested that we know how to get patients up in the air, but it isn't clear how long to keep them there or how best to get them down," says Laughren. "That is, we don't know how long it is necessary to maintain responding patients on the drug, and we don't know how best to withdraw them from treatment." With all its uncertainties, treatment seems to be working for both Menter and Griffith. Both are in programs at the National Institute of Mental Health. Menter started treatment with imipramine, but is now in a "blind" study, so she doesn't know what drug or combination she's receiving. She still has about two panic attacks a month, but she's not as apprehensive about sleeping now. "Even though the episodes of panic are as frightening as always," she says, "I know I'm not crazy and I'm trying to do something about it. I can deal with it. One of my biggest fears, I think, was giving in to this thing and maybe one day becoming a crazy person who couldn't take care of herself." Griffith is taking Xanax and an antidepressant, and is being tapered off Xanax. She hasn't had an attack for several months and is back to traveling to business meetings and eating out at restaurants. n Marian Segal is a member of FDA's public affairs staff. Gender Differences? Panic disorder affects both men and women. The condition is, however, diagnosed about twice as often in women as in men, and twice as many women as men go on to develop agoraphobia. The reasons why are not known; they may be cultural or biological, or perhaps a combination. "Physicians are probably more likely to recognize psychological disorders in women, while attributing the same symptoms in men to physical ailments," says Wayne Katon, M.D., professor of psychiatry at the University of Washington Medical School. "Before inquiring about a psychiatric disorder, the examination of the male patient would most likely involve multiple tests such as an echocardiogram or a stress test," he says. Another reason panic disorder may not be detected as readily in men is their response to the attacks; men are often reluctant to seek help in dealing with emotional stress and attempt to self-treat instead. "For example," says the National Institute of Mental Health's Thomas W. Uhde, M.D., "there is some evidence to suggest that men resort to the use of alcohol to alleviate their symptoms and eventually are diagnosed with alcoholism rather than panic disorder. In fact, if you look in clinics that specialize in alcoholism and drug addiction, you'll find a high rate of anxiety disorders in patients with alcoholism." n --M.S. Why Panic? The Search for a Cause Unknowns cry out for answers, and so it is that researchers are trying to discover the elusive culprit responsible for panic disorder. "There is a general difficulty in knowing how best to classify psychiatric disorders that relates in part to the difficulty in understanding their pathophysiology," says Thomas P. Laughren, M.D., of FDA's division of neuropharmacological drug products. This may make the search a bit more complicated, but clues can appear if you know how to look for them. Thomas W. Uhde, M.D., a researcher with the National Institute of Mental Health, points to several factors he views as suggesting that there is, indeed, a biological basis for panic disorder: - It affects two to three times as many women as men. - Genetic factors appear to influence its transmission. - Attacks occur spontaneously and are different in quality from other forms of anxiety (often described by patients as totally different from anything else they've experienced). - Attacks can be induced or blocked with specific drugs. - Sleep panic attacks occur during non-dream sleep stages, and therefore are not associated with disturbed thoughts, vivid images, or dreams. Studies have shown that injections of lactate, a chemical normally produced by the body, will induce panic attacks in people with panic disorder; but in normal individuals given the same dose, panic attacks will occur less frequently or not at all. Caffeine increases lactate and, in sufficient quantity (four to five cups), can induce panic attacks in panic-prone individuals, but not in normal control subjects. Patti Griffith (not her real name) is convinced that caffeine precipitated her first panic attack. While out of town for a business meeting, she had drunk several cups of strong tea in the evening, had chocolates after dinner, and then drank more tea the following day at breakfast and lunch. During her meeting that day, she had a panic attack. "All of a sudden, my heart was beating out of my chest, and I thought I was going to die," she says. "Finally, I had to go into the other room and lie still. My heart was beating irregularly and my head, chest and hands were hot and sweaty. This went on for quite some time, until I had to end the meeting and call for an ambulance." Caffeine influences noradrenaline, a chemical messenger produced by the body that affects state of arousal and perhaps human emotion. One hypothesis is that panic disorder is caused by central nervous system "excitability" related to noradrenergic hyperactivity. Xanax and other benzodiazepines may work to block the effects of these chemical messengers. "In studying noradrenergic activity in panic disorder patients," Uhde says, "scientists stumbled on the finding that these patients have lower levels of growth hormone than other adults, opening new areas of investigation into other avenues of treatment." It also raised questions of whether or not children also have panic disorder, and, if so, whether it could lead to short stature or other growth abnormalities. "We have seen two children with panic disorder who have fairly significant disturbances in stature or growth velocity," Uhde says, "and we are now investigating the prevalence of panic disorder in children and its effect on growth and development." Researchers also speculate that the underlying mechanism causing panic disorder in a subgroup of patients is increased levels of carbon dioxide. "These patients tend to be chronic hyperventilators," says Uhde. "The hyperventilation causes alterations in respiratory system sensitivities. When they relax or go to sleep, they have a lowered respiratory rate and relative increase in carbon dioxide, which sets off a panic episode much as carbon dioxide inhalation will do." In fact, carbon dioxide inhalation-induced panic and sleep panic may be caused by the same underlying mechanism--increased exposure to carbon dioxide, says Uhde. When patients become relaxed, they seem to be more vulnerable to having a sleep panic episode. "The current view," according to Uhde, "is that panic disorder patients need to maintain their level of arousal within a very narrow window, because if they become too relaxed or overly aroused, they are vulnerable to a panic attack."<