Panic disorder and agoraphobia

PANIC DISORDER AND AGORAPHOBIA

RAYMOND R. CROWE, M.D. RUSSELL NOYES, Jr., M.D.

0011-5029/86/07-0389-0444-$9.95 �9 1986, Year Book Medical Publishers, Inc.

C O N T E N T S

SELF-ASSESSMEnT QU~ STIO~S . . . . . . . . . . . . . . 392

DIAGNOSIS . . . . . . . . . . . . . . . . . . . . . . 3 9 4

HISTCRY . . . . . . . . . . . . . . . . . . . . . . 397

EPIDEMIOLOGY . . . . . . . . . . . . . . . . . . . . 3 9 9

PREVALENCE . . . . . . . . . . . . . . . . . . . . 3 9 9

SEX BAT10 . . . . . . . . . . . . . . . . . . . . . 401

AGE CF ONSET . . . . . . . . . . . . . . . . . . . 401

GENETICS . . . . . . . . . . . . . . . . . . . . . . 401

FAI~ ILY STUDIES . . . . . . . . . . . . . . . . . . 4 0 2

TWIN STUDIES . . . . . . . . . . . . . . . . . . . 403

MOEE OF INHERITANCE . . . . . . . . . . . . . . . . 4 0 4

B]CLCOIC FACTO19 S . . . . . . . . . . . . . . . . . . 4 0 5

EXPERIMENTALLY INDUCED PANIC ATTACKS . . . . . . . 4 0 7

PANIC DISORDER AND MITRAL VALVE PROLAPSE . . . . . 4 1 0

NEUROTRANSMITTERS . . . . . . . . . . . . . . . . 4 1 2

THE BENZODIAZEPINE RECEPTOR . . . . . . . . . . . . 413

PSYCHOLOGICAL FACTORS . . . . . . . . . . . . . . . 4 1 4

PERSONALITY . . . . . . . . . . . . . . . . . . . 4 1 4

EARLY FXPER]ENCE . . . . . . . . . . . . . . . . . 4 1 5

LIFE EVE~ TS . . . . . . . . . . . . . . . . . . . . 4 1 5

SOCIAL FACTORS . . . . . . . . . . . . . . . . . . 4 1 6

CLINICAL PICTURE . . . . . . . . . . . . . . . . . . 4 1 6

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C O U R S E AND O U T C O M E . . . . . . . . . . . . . . . . 4 1 9

O N S E T . . . . . . . . . . . . . . . . . . . . . . 4 1 9

C C U R S E AND COMPLICA~IIONS . . . . . . . . . . . . . 420

OU~I COME . . . . . . . . . . . . . . . . . . . . . 4 2 1

D I ~ F ~ R Z N T I A L D I A G N O S I S . . . . . . . . . . . . . . . 4 2 2

FHYSIC AL I r LNESS . . . . . . . . . . . . . . . . . . 4 2 2

FS~/CH] A T H C ILLI~ ELS . . . . . . . . . . . . . . . . 4 2 5

T R E A T M E N T . . . . . . . . . . . . . . . . . . . . . 4 2 6

M E D I C A L M A N A G E M E N T . . . . . . . . . . . . . . . 4 2 6

D R U G T H E R A F Y . . . . . . . . . . . . . . . . . . . 4 2 7

E E H A V ] O R T H E R A P Y . . . . . . . . . . . . . . . . . 4 3 2

FS'~ C H O ~ H E R A P Y . . . . . . . . . . . . . . . . . . 4 3 3

S E L F - R E G U L A T I O N T H E R A P I E S . . . . . . . . . . . . . 4 3 3

C C G N I T I V E T H E R A P Y . . . . . . . . . . . . . . . . . 4 3 4

S O C I A L S K I L L S T R A I N I N G . . . . . . . . . . . . . . . 4 3 5

F S u C H O S U R G E R Y . . . . . . . . . . . . . . . . . . 4 3 5

C O N C L U S ] O N . . . . . . . . . . . . . . . . . . . . . 4 3 5

S E l F - A s s E S S M E N T AN~CW~RS . . . . . . . . . . . . . . 4 4 3

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SELF-ASSESSMENT QUESTIONS

1. Describe the epidemiology of panic disorder, including its population prevalence in men and women and average age of onset. What is the evidence suggesting tha t it may be a genetic trait?

2. Describe the clinical course of panic disorder, including the usual manner in which it begins, the development of agoraphobic complications, and the long-term outcome.

3. Discuss the differential diagnosis and include some of the more common medical illnesses and medications that need to be considered in the differential.

4. Describe the medical t reatments available for panic disorder and give an indication of their effectiveness in ar- resting panic attacks.

5. Describe the onset, duration, and the signs and symptoms of a typical panic attack.

Answers appear at the end of the article.

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graduated from Vanderbilt Medical School in 1966, in- terned at the University of Kentucky Hospitals, and completed his residency in Psychiatry at the University of Iowa in 1972 after serving two years in the Army as a mili tary psychiatrist. Dr. Crowe completed a fellowship in human genetics at the University of Michigan in 1975 and since that time has been on the faculty at the Uni- versity of Iowa College of Medicine in Iowa City, where he is currently a Professor of Psychiatry. His research interests are in the genetics of anxiety disorders.

is Professor of Psychiatry in the Department of Psychia- try at the University of Iowa College of Medicine in Iowa City. He received his M.D. degree from the Indiana Uni- versity School of Medicine. After an internship at the Philadelphia General Hospital and residency training at the Institute of Living and the University of Iowa, Dr. Noyes joined the faculty at the University of Iowa Col- lege of Medicine. His research interests include anxiety disorders and psychosomatic medicine.

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PANIC D I S O R D E R A N D A G O R A P H O B I A

Panic disorder, formerly called anxiety neurosis, is a disease with which physicians should be familiar. Effective treatment in the form of medication and behavior therapy has recently been introduced. As a result, the disorder is receiving increasing public attention and, as more people are becoming aware of the meaning of their symptoms, they are seeking medical attention. Five classes of drugs have been shown to have a role in the management of this illness: tricyclic antidepressants, monoamine-oxiadase inhibitors, benzodiazepines, the beta-adrenergic blocking agents, and azospirodecanediones. The proper use of these agents can greatly reduce or eliminate panic attacks, placing the management of an uncomplicated panic disorder within the province of the nonspecialist. Another reason for nonpsychiatric physicians to be aware of panic disorder is that patients with this condition often consult their per- sonal physicians. They do so on account of symptoms--palpitations, dyspnea, and chest pain-- that suggest heart or other physical disease. In fact, the history of panic disorder suggests that internists and military physicians have been as concerned with these patients as have psychiatrists.

DIAGNOSIS

The sine qua non for the diagnosis of panic disorder is a history of recurrent spontaneous panic attacks. These are sudden paroxysms of severe anxiety accompanied by a variety of cardiac and respiratory symptoms in the absence of

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extreme physical exertion or emotional stress. They typically begin abruptly without warning, last for minutes to hours before they subside, and leave the pat ient feeling ex- hausted for the remainder of the day. The "frequency of the at tacks can vary from several per day to fewer than one per year. In order to qualify for the diagnosis, at least three at tacks must occur in a three-week period at some time in the course of the illness. Also, at tacks must include at least four criterion symptoms from those listed in Table 1.1

The other anxiety disorders are shown in Table 2 along with their principal distinguishing features. Generalized anxiety disorder is distinguished from panic disorder by the absence of panic attacks. It is characterized by persis-

T A B L E 1.

Diagnostic Cri ter ia for Panic Disorder*

A. At least three panic at tacks wi th in a three-week period in circum- \ stances other t han dur ing marked physical exert ion or in a l ife-threatening situation. The a t tacks are not precipitated only by exposure to a circumscribed phobic st imulus.

B. Panic at tacks are manifested by discrete periods of apprehension or fear and at least four of the following symptoms appear dur ing each attack:

1. Dyspnea 2. Palpi ta t ions 3. Chest pain or discomfort 4. Choking or smother ing sensations 5. Dizziness, vertigo, or unsteady feelings 6. Feelings of unreal i ty 7. Pares thes ias (t ingling of hands and feet) 8. Hot and cold flashes 9. Sweat ing

10. Fa in tness 11. Trembling or shaking 12. Fear of dying, going crazy, or doing something uncontrolled dur ing

an a t tack C. Not due to a physical disorder or another menta l disorder, such as

major depression, somatization disorder, or schizophrenia. D. The disorder is not associated with agoraphobia.

*From Diagnostic and Statistical Manual of Mental Disorders, ed 3 (DSM III). Washington, DC, American Psychiatr ic Association, 1980. Used by permission.

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TABLE 2. Anxiety Disorders and Their Principal Features

Panic disorder Generalized anxiety disorder Phobic disorders

Agoraphobia Social phobia Simple phobia

Obsessive-compulsive disorder

Post-traumatic stress disorder

Spontaneous recurrent panic attacks Continuous anxiety without attacks Anxiety in response to a phobic

stimulus

Anxiety associated with obsessions and compulsions

Anxiety associated with a catastrophic event

tent anxiety without the specific symptoms of the other anxiety disorders. The anxiety is manifested by symptoms of motor tension (e.g., restlessness), autonomic hyperactivity (e.g., palpitations), apprehensive expectation (e.g., apprehension), and vigilance (e.g., insomnia). The phobic disorders are distinguished from panic disorder by the fact that anxiety only arises when the individual is exposed to a specific object, activity, or situation. The phobic individual recognizes that his fear is unjustified and excessive in comparison with the actual danger involved, but he is un- able to overcome it. For example, simple phobias include fear of animals, closed spaces, and heights. Social phobia involves an unreasonable fear of social situations in which the individual fears embarrassment . Obsessive-compulsive disorder is characterized by anxiety-provoking, recurrent, persistent ideas, thoughts, images, and impulses. Many of these thoughts and images are associated with compulsive rituals, such as washing, counting, and checking, and anxiety mounts when they cannot be carried out. In post-traumatic stress disorder anxiety symptoms are due to a catastrophic event in the person's life, such as a fire, flood, or war experience.

A number of other psychiatric disorders may present with panic attacks. Depression is the most common, and this diagnosis should be considered before a diagnosis of panic disorder is made. Many other psychiatric and medical conditions can be associated with acute anxiety, and the

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differential diagnosis of these disorders will be discussed below. Thus, an anxiety at tack should be viewed as a symptom complex rather than a disease, and the diagnosis of panic disorder should be withheld until illnesses that may be associated with panic at tacks have been excluded.

One of the most intriguing aspects of panic disorder is its relationship to agoraphobia. The term refers to a fear o f ' being alone or in public places from which help might not be available in the event of sudden incapacitation. Clinical experience suggests that agoraphobia may begin with uncomplicated panic attacks. These at tacks give rise to the fear of leaving the safety of the home, and the individual may begin to restrict travel. Situations that typically evoke agoraphobic avoidance are large public gatherings and travel, especially that involving highways, bridges, or tunnels. Unlike other phobias, in which the situation itself is feared, agoraphobia is the fear of something catastrophic happening in a situation where help is unavailable.

HISTORY

The recent history of anxiety disorders has been dominated by contrasting beliefs about their basic nature. Those who observed the disorders among mil i tary populations believed the cause to be physcial stress, while those who observed the disorders among civilians thought that psychological factors were critical. In 1871 Da Costa, 2 a prominent Philadelphia surgeon, published a classic description of a common affliction he observed among soldiers of the Union Army. The most constant features were cardiac in nature, including palpitations, chest pain, and shortness of breath. He believed it was an abnormal reaction of the hear t to exertion and gave the label "irritable heart" to what was later known as Da Costa's syndrome. During World War I the disorder was a common cause of disability among the fighting men and was renamed effort s yndrome 3 and neurocirculatory as thenia 4 by observers who regarded somatic symptoms as pr imary (Table 3).

In 1895, Freud published a description of what he termed anxiety neurosis. ~ He separated the disorder from the

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TABLE 3. Terms Formerly Used for Panic Disorder

Anxiety neurosis Anxiety state Anxiety reaction Da Costa's syndrome Irritable heart Soldier's heart/effort syndrome Neurocirculatory asthenia Cardiovascular neurosis

broader category of neurasthenia tha t Beard 6 had popular- ized earlier. Neurasthenia, or nervous exhaustion, was prevalent among women and was distinguished by a wide variety of somatic and psychological symptoms. Freud believed that anxiety was the pr imary disturbance and that somatic symptoms were secondary. Although he believed heredi tary factors were important, he, like Da Costa, saw environmental influences playing a critical role. However, while physical exertion had seemed to produce the disturbance among men on the battlefield, sexual repression was considered by Freud to be a source of conflict among women of the Victorian era.

In the absence of a clearly defined cause or abnormali ty of an organ system, there has continued to be uncertainty about whether these disorders are medical or psychiatric. During World War II more general recognition of the role of environmental stress developed, and mili tary personnel who complained of typical symptoms were diagnosed as having anxiety disorders that were managed by psychiatrists. However, many internists have continued to specu- late upon the cardiovascular mechanisms underlying functional hear t disturbances, with little regard for the role of anxiety. And, for their part, many psychiatrists have con- t inued to entertain highly speculative and unproved no- tions about psychological mechanisms without regard for biologic factors.

The first account of the agoraphobic syndrome, now regarded as a more severe variant of panic disorder, is cred-

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ited to Westphal. 7 In 1872 he published a monograph de- scribing three men who feared streets and public places. He named the disorder with a word derived from the Greek, meaning '~fear of the marketplace." Although still in use, the term is a misnomer, for what the agoraphobic person fears is separation from a source of security. Apart from the fact tha t most agoraphobics are women, Westphars description remains a classic. Agoraphobia was introduced into the current classification by Marks, s who distinguished it from social phobia and simple phobia.

EPIDEMIOLOGY

The epidemiologic features of panic disorder have been appreciated for many years: it is one of the more common diseases in medicine, it begins early in life, and women are affected more frequently than men. Until recently, these observations have been based largely on clinic samples, the findings of which often conflicted with one another, and the true epidemiology of the illness as it exists in the commu- ni ty remained uncertain. Fortunately, a recent increase in interest in epidemiology in psychiatry has produced a number of studies tha t have corrected many of these deficien- cies (Table 4).

PREVALENCE

Thanks to the Environmental Catchment Area Study of the National Insti tute of Mental Health, we now have re-

TABLE 4. Epidemiology of Panic Disorder and Agoraphobia

PANIC DISORDER AGORAPHOBIA

Lifetime prevalence 1.4% 6.1% Women 1.9% 8.4% Men 0.9% 2.8%

Six-month 1.0% 4.1% prevalence Mean age of onset, yr 25 25

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liable data on the epidemiology of panic disorder and agoraphobia.9, lo This was a community interview study of nearly 10,000 persons living in three U. S. cities (New Ha- ven, Baltimore, and St. Louis). Lifetime and six-month prevalence rates for the major psychiatric disorders were evaluated using the current diagnostic criteria of the American Psychiatric Association. ~~ Lifetime prevalence refers to the presence of the disease at some time in the person's life up to and including the t ime of the interview. It est imates the proportion of the population that has ever had the illness. The six-month prevalence refers to the presence of the disease within six months of the interview and is used to obtain an est imate of the number of active cases in the community.

In this s tudy the lifetime prevalence of panic disorder was practically identical across the three sites, and the combined prevalence was 1.4%. The prevalence of agoraphobia varied from 3.7% to 9.7%, with an overall prevalence of 6.1%. Undoubtedly, most of the agoraphobics had experienced panic at tacks and many would have met criteria for panic disorder at some point in their course. Thus, panic disorder and its variant, agoraphobia, are among the more common medical illnesses.

The high prevalence of panic disorder is reflected in clinical practice as well. Marks and Lader 11 reviewed published reports on the prevalence of anxiety disorders in practice populations. In Western societies they account for 10% to 14% of patients with cardiovascular symptoms, 27% of those with psychiatric symptoms, and 8% to 27% of pa- t ients in psychiatric practice.

The six-month prevalence of panic disorder varied from 0.6% to 1.0%, with an overall prevalence of 0.97%. That of agoraphobia ranged from 2.9% to 6.1%, with a total prevalence of 4.1%. The six-month prevalence also varied across age groups, being the lowest in those aged 18 to 24 and over 65 and highest in those 25 to 64 years of age. The low prevalence among the young can be explained by the fact that many have not developed the disease, but it is more difficult to explain among the old. It may reflect a

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remission in symptoms, a greater reluctance to report symptoms, or impaired memory.

SEX RATIO

Most studies have found an excess of affected women in both panic disorder and agoraphobia. 11 In the Environmen- tal Catchment Area Study a preponderance of women was confirmed. 9 The prevalence of panic disorder was 1.9% in women and 0.9% in men, giving a sex ratio of 2.1 to 1. Agoraphobia was diagnosed in 8.4% of women and 2.8% of men, yielding a sex ratio of (3.0 to 1). These and earl ier findings indicate tha t twice as many women as men are affected with panic disorder and tha t three t imes as many are affected with agoraphobia.

AGE OF ONSET

Panic disorder typically begins in the third decade, although the age of onset ranges from childhood into the sixth decade. 12-14 Sheehan et al. 12 found the mean age of onset of panic attacks in agoraphobics to be 24 years, with a s tandard deviation of 8.9 years. Four teen percent began before the age of 15 and 2% after the age of 50. Viewed another way, 26% were affected before the age of 20, and

13 79% before they were 30 years old. Thyer et al. reported practically identical findings, except tha t they separated panic disorder pat ients from those with agoraphobia. The mean age of onset for panic disorder was 26.6 years, with a s tandard deviation of 11.5 years. For agoraphobics with panic attacks, the mean onset was 26.3 years and the standard deviation 9.1 years.

G E N E T I C S

Data from a var ie ty of sources suggest tha t panic disorder is a genetic disease. Relatives of pat ients have a high rate of the disease, and the concordance ra te among monozygotic twins is increased (Table 5). Of course, these obser-

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TABLE 5. Genetic Findings in Panic Disorder*

Familial findings Two thirds of patients have affected family members 15% to 20% of first-degree relatives are affected Families show transmission from generation to

generation Twin findings

MZ concordance is 30% to 40% DZ concordance is 4% to 9%

Mode of inheritance Familial transmission fits either a single-locus or a

polygenic model

*MZ indicates monozygotic; DZ, dizygotic.

va t ions alone do not prove genet ic t ransmiss ion; behaviora l t ra i t s can be t r a n s m i t t e d e n v i r o n m e n t a l l y as well as genet- ically. However , t h e y ce r ta in ly suggest genet ic t ransmis- sion, and in concer t wi th the growing evidence of a biologic subs t ra te to panic disorder, t hey m a k e the genet ic hypothesis inc reas ing ly l ikely.

FAMILY STUDIES

The famil ia l n a t u r e of panic disorder has been recognized for over a cen tury . In all, t en fami ly s tudies have appeared, and all of the ones t ha t included a control group found h ighe r ra tes of panic disorder in the famil ies of pa t ien ts wi th panic disorder. 15-24 For example , Cohen et al. ~1 found affected me m be r s in the famil ies of 67% of t he i r chronic p a t i e n t s - - a conclusion based solely on the h i s to ry from the pa t ien t . These f indings were suppor ted by a more recent s tudy in which the major i ty of the re la t ives were inter- v iewed and 61% of famil ies had an affected re la t ive . 16

A recent s tudy of 112 famil ies found an 18% l i fe t ime morb id i ty r isk amon~g f irs t-degree re la t ives (parents , sib- lings, and ch i ld ren)2 ~ An in te rv iew s tudy of 41 of these famil ies found panic disorder in 17% of the f i rs t -degree rel- a t ives and panic a t t acks in a n o t h e r 7%. 16 An increased r a t e was also found among second-degree relat ives: 9.8%

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among grandparents, aunts, and uncles, or approximately half the rate found among first-degree relatives. 25 Al- though not all investigators have found rates this high, 1~ the majority of the studies agree in placing panic disorder among the more common familial conditions in medicine.

An excess of affected females is also apparent among relatives. Five studies have reported sex-specific rates and in all five, women were found to have higher rates, the modal ratio being about 2 to 1.12-16' 21-23 For example, in the family study by Noyes et al., the respective rates among women and men were 24% and 13%, and among the inter- viewed families 33% and 17%. 16' 23 These findings substan- tiate the sex distribution noted by the epidemiologic investigations.

If agoraphobia is a form of panic disorder, one would expect panic disorder and agoraphobia to have similar familial findings. In one study the relatives of agoraphobics had an 8.6% morbidity risk for agoraphobia and 7.7% for panic disorder. 24 Families of patients with panic disorder had a 20.5% morbidity risk for panic disorder, but the rate of agoraphobia (1.9%) was not increased over tha t in control relatives. Thus, the total rate of affected relatives was roughly the same in the panic disorder and the agoraphobic families, but agoraphobia was increased only in the families of agoraphobic patients. These results support the idea that agoraphobia is a complication of panic disorder. More- over, they suggest that the predisposition to this complication may itself be familial.

TWIN STUDIES

Only two twin studies of anxiety disorders have been reported. 26-2s Slater and Shields 26 found seven of 17 monozygotic (MZ) twin pairs (41%) concordant for anxiety disorders compared with only one of 28 dizygotic (DZ) pairs (4%). Torgersen's prel iminary results were similar. 27 Nine (31%) of 30 MZ pairs were concordant compared with five (9%) of 56 DZ pairs. Torgersen has published his final results, and this study provides the only twin data available on panic disorder diagnosed by current criteria. 2s Two of 13

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MZ co-twins had panic disorder, two had panic attacks, and two had other anxiety disorders. Thus, the concordance rate is 46% for any anxiety disorder, 31% for panic attacks, and 15% for panic disorder. Only four (25%) of 16 DZ twins had an anxiety disorder, and none had panic attacks or panic disorder. Both concordant MZ twin pairs included one twin with panic disorder and one with agoraphobia.

Although these findings are based on small numbers of twins, the results are in the direction expected for a genetic disease, but the low MZ concordance rates indicate nonge- netic etiologic factors as well. Finally, the overlap of panic disorder and agoraphobia in the concordant MZ twin pairs supports the clinical impression tha t these are both manifestations of the same disease.

MODE OF INHERITANCE

With polygenic (multiple gene) transmission one would expect to find affected relatives on both paternal and maternal sides of the family more often than with a mendelian (single gene) disorder. In fact, under polygenic inheritance pairs of affected ancestral relatives should be unilateral (both members of the pair on the same side of the family) twice as often as bilateral (one member on the paternal and the other on the maternal side). Any deviation from this expected 2:1 ratio in the direction of excess unilateral pairs would be evidence for mendelian inheritance. 29 This model was tested with extended pedigrees of panic disorder with the finding tha t 37 of 41 ancestral pairs of affected relatives were unilateral, strongly favoring the mendelian hypothesis. 3~

A mendelian model was tested on the same set of pedigrees, and it provided a very close fit to the observed data indicating tha t a single gene could account for the transmission of panic disorder. 31 The best-fitting model pre- dicted a relatively common gene frequency of 1.4%, 75% penetrance, an average age of onset of 22 years, and tha t 95% of those who become ill are affected by age 34.

The above models fail to account for the pronounced sex ratio of panic disorder. Sex effect can be incorporated into

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a genetic analysis by assuming that the less frequently affected sex has a higher threshold for developing the illness, and therefore a greater number of genetic and environmental etiologic factors must be present to cause the illness in that sex. Sex thresholds were tested in this way using both a mendelian and a multifactorial (polygenic) model on panic disorder families. 16 Both models gave an acceptable fit to the data, indicating tha t the transmission of panic disorder can be explained by a multifactorial, as well as a mendelian, model.

While these studies have not succeeded in clarifying the genetics of panic disorder, they have indicated tha t a single gene is a reasonable possibility. This is an important finding in view of the progress in recombinant DNA research in other areas of medical genetics. Mendelian diseases are the most likely ones to result in significant progress in this area.

BIOLOGIC FACTO RS

Many symptoms of panic disorder, such as palpitations, dyspnea, tremor, and diaphoresis, are suggestive of increased sympathetic tone. Therefore, it is not surprising that a number of investigators have examined the function of the autonomic nervous system in these patients. The resting pulse is often increased and is found to be in the range of 90 to 100 beats per minute. 39' 33 In addition, a number of electrocardiographic (ECG) abnormalities are found more frequently in patients with panic disorder than in heal thy controls. 34 These include episodes of sinus tachycardia unrelated to physical exertion, some in excess of 150 beats per minute, sinus and ventricular premature beats, and nonspecific ST-T wave changes. On the other hand, not all investij~ators have noted these abnormalities. Freed- man et al. ~176 studied ambulatory ECGs and found the resting pulse to be the same as tha t of heal thy controls. The episodes of tachycardia tha t they observed were always associated with panic attacks. It is of interest tha t the tachycardia often began before the patients indicated with an event marker tha t they were experiencing an attack.

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Since one of the most consistent complaints of patients with panic disorder is fatigue, a number of investigators have examined these patients during physical exertion.36, ~7 During standard treadmill tests, these patients develop higher heart rates than healthy controls performing the same amount of work, and they often terminate the test prematurely owing to fatigue. Moreover, the blood lactate levels following physical exertion are higher in patients with panic disorder than in normal persons. These findings indicate impaired maximum oxygen consumption in patients with panic disorder. Although the data are consistent in indicating impaired exercise tolerance in these patients, the reason for this impairment remains unclear. It may reflect the fact that these patients are in poor physical condition because of lack of exercise. On the other hand, it may also reflect dysfunctional autonomic regulation of the cardiovascular system.

Further evidence of autonomic dysfunction comes from studies of forearm blood flow and galvanic skin response in patients with anxiety disorders. Kelly and Walter ~2 found increased forearm blood flow in patients with chronic anxiety states compared with healthy controls. It is of special interest that the chronic anxiety disorders had higher forearm blood flow than is found in other psychiatric conditions, including anxious depressions, phobic states, and obsessional disorders. Skin conductance and the galvanic skin response provide another measure of autonomic function. Lader 3s examined both modalities in patients with chronic anxiety disorders, two thirds of whom had had weekly panic attacks. The patients with anxiety disorder had higher rates of spontaneous fluctuation in skin conductance than did controls, and the~ also had slower habit- uation in their galvanic skin response following a novel stimulus. Both findings of changes in the forearm blood flow and the galvanic skin response are consistent with the hypothesis of increased sympathetic activity in patients with chronic anxiety and panic disorders.

The neurotransmitters involved in sympathetic transmission are the catecholamines, and several groups have studied these transmitters in panic disorder patients. Cir-

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culating epinephrine is increased in resting patients with panic disorder, and its principal metaboli te 3-methoxy-4- hydroxyphenylethylene glycol (MHPG), correlates with pa- t ient rat ings of anxiety in agoraphobics who are exposing themselves to feared situations. 3~'39

If panic disorder is caused by increased sympathetic tone, then pharmacologically increasing sympathetic activity should precipitate panic at tacks in these patients. The response to isoproterenol infusions is variable, with some au- thors reporting panic at tacks 4~ and others noting not only an absence of panic at tacks but a decreased hear t rate response compared with normal persons. ~3 On the other hand, patients with panic disorder were found to have an increased sensitivity to yohimbine, a centrally acting alpha-2 receptor antagonist tha t increases noradrenergic outflow from the locus ceruleus. 41

EXPERIMENTALLY INDUCED PANIC ATTACKS

Panic disorder is unique among psychiatric illnesses in that the symptoms can be reproduced in the laboratory with physiologic challenges. This was first demonstrated in a classic experiment by Pit ts and McClure in 1967, 42 and their observations have been replicated by numerous others. Other physiologic challenges have been shown to precipitate the symptoms as well. This research continues to be one of the more promising avenues of investigation into panic disorder.

In the experiment of Pitts and McClure, sodium lactate and glucose were infused under double-blind conditions into 14 patients with panic disorder and into 14 control subjects. The lactate precipitated panic at tacks in 13 patients but in only two controls. Moreover, when lactate was mixed with ionized calcium to complex with the lactate it no longer precipitated panic attacks. These results led Pit ts and McClure to propose a model of panic disorder which held that endogenous lactate complexes with ionized calcium at the nerve cell membrane to produce t ransient hy- pocalcemia, the symptoms of which are interpreted as an anxiety a t tack by the pa t i en tY Their hypothesis has been

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criticized on the grounds that the amount of lactate infused was insufficient to reduce the concentration of ionized calcium to a symptomatic level. 43 In addition, sodium lactate is readily metabolized to sodium bicarbonate in the body and, indeed, measurements of blood lactate following lactate infusions have failed to reveal elevated lactate levels. 44

While the lactate hypothesis may no longer be a tenable explanation for panic disorder, the provocation of panic attacks by lactate infusion in patients with panic disorder has been consistently replicated. A recent review suggests that lactate precipitates attacks in 70% to 100% of patients with panic disorder. 45 Moreover, the fact that lactate-induced attacks can be suppressed by imipramine, which blocks spontaneous panic attacks, is further evidence that these are true panic attacks. If so, lactate may be a clue to the biochemical etiology of the disease.

Panic attacks have been reported following infusions of epinephrine and of isoproterenol. One problem with these reports is that the side effects of both drugs overlap with the symptoms of panic disorder, so that it is difficult to de- termine whether one is dealing with a true panic attack or simply the effects of beta-adrenergic stimulation. A more convincing account was reported by Frohlich et al., 4~ who described panic during isoproterenol infusion in a number of patients with the hyperdynamic beta-adrenergic state. The findings in their patients are characterized by cardiac awareness, hypertension, and frequently systolic murmurs, but many of these patients would probably have been found to have panic disorder if screened for it. On the other hand, Nesse et al. 33 observed no panic attacks in patients with panic anxiety who were infused with boluses of up to 4 }xg of isoproterenol. In fact, the latter investigators speculated that in their patients the beta receptors were down-regu- lated.

Yohimbine is a centrally acting presynaptic alpha-2 adrenergic antagonist that increases noradrenergic outflow from the locus ceruleus of the pons. When yohimbine was administered to patients with agoraphobia and panic attacks, it produced increased anxiety, palpitations, hot and

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cold flashes, tremors, and piloerection. 41 It is not surprising that the patients reported that the effects of the drug were similar to the symptoms of a panic attack. Healthy controls did not experience these symptoms to the same degree as did the patients with panic disorder, suggesting increased sensitivity to noradrenergic stimulation in patients with panic disorder. However, as Gorman 46 has pointed out, yohimbine-induced anxiety is atypical of panic attacks because imipramine augments the effects of yohimbine while it suppresses true panic attacks.

The hyperventilation that often accompanies panic attacks may be viewed as precipitating the attack (by causing a respiratory alkalosis) or as secondary to the attack. Gorman et al. 47 examined both hypotheses in a double- blind fashion by having panic disorder patients breathe 5% CO2 (which causes hyperventilation without alkalosis) and by having them hyperventilate room air. Seven of 13 patients reported panic attacks with CO2 inhalation compared with only three with hyperventilation of room air. None of the controls experienced panic attacks under either condition. These results are similar to those of Cohen et al., 36 who precipitated panic attacks by having patients re- breathe.

Carr and Sheehan 4s have taken a number of these observations to develop a hypothesis for the etiology of panic disorder. They observe that three challenges that produce panic attacks--lactate, CO2, and hyperventilation--all have the effect of lowering intracellular pH. They propose that these stimuli have their effect at respiratory chemo- receptor centers in the medulla, and that in patients with panic disorder these centers may be oversensitive to pH al- terations, triggering the prominent respiratory symptoms. The autonomic symptoms of the attack are viewed as secondary to respiratory symptoms. This model accounts for the seemingly contradictory observation that both breathing of CO2 and hyperventilation may precipitate panic attacks. Since caffeine and progesterone are respiratory stim- ulants, the model would explain the complaints of some patients that attacks are more frequent after drinking coffee and during menstrual periods. Indeed, caffeine has been

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shown to produce greater increases in anxiety in patients with panic disorder than in normal persons. 49 If progesterone were a predisposing factor, it could explain the striking sex distribution of the disease.

PANIC DISORDER AND MITRAL VALVE PROLAPSE

The similari ty of symptoms between panic disorder and the mitral valve prolapse syndrome led Wooley 5~ to propose that the two disorders are the same. This proposal is sup- ported by epidemiologic findings as well, since both conditions affect about 5% of the population, both affect women twice as frequently as men, and both are familial with patterns of transmission suggesting mendelian inheritance. Eight studies of mitral prolapse in patients with panic attacks have been reported, and six have found higher rates of prolapse than the population expectation of 5 % . 51-58 The median rate is 39%, but the individual rates vary considerably, with the five earliest studies reporting rates of 38% to 50% and the three more recent ones 0 to 15%. Con- versely, the rate of panic disorder among clinic patients with mitral prolapse was found to be 12.3%, which was greater than that found in heal thy controls (although it was not greater than the rate in cardiac controls). 59

If panic at tacks are associated with mitral prolapse, do they differ from panic at tacks in otherwise healthy persons? Treadmill tests performed on patients with panic disorder with and without mitral prolapse and on heal thy controls revealed that work capacity, as measured by esti- mated maximum oxygen consumption, was impaired in panic disorder patients, but only in those with prolapse. 37 On the other hand, the sodium lactate response is unrelated to the presence or absence of prolapse.6"Likewise, the therapeutic response to imipramine, which suppresses panic attacks, is unaffected by the presence of prolapse. 54 Finally, familial findings and patterns of transmission are the same in families of probands with and without prolapse.31, 61 With the exception of the findings on exercise, the evidence indicates tha t the panic at tacks of patients

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with mitral prolapse are the same as those of patients with panic disorder.

Several explanations have been proposed to explain the association between these two conditions. 62 First, the pro- lapsing valve may cause panic attacks. Conversely, panic attacks may increase the risk of developing mitral prolapse. Another explanation is that panic disorder and mitral prolapse may result from another underlying disorder. Finally, the predisposition to panic disorder may be acti- vated by a variety of physical stresses (e.g., hyperthyroidism, childbirth, etc.), among them mitral prolapse.

The third hypothesis receives some support from findings that patients with mitral prolapse have elevated levels of excretion of epinephrine and norepinephrine in 24-hour urine collections, and that responses to the diving reflex, to a lower body negative pressure, and to phenylephr ine infusion suggest autonomic dysfunction. 6~' ~4 That so many of the symptoms of panic at tack suggest abnormal sympathetic discharge makes the hypothesis of an underlying autonomic dysfunction an attractive one.

Before speculating further about the proposed association, the above findings must be tempered by some recent investigations that question the strength of an association between panic disorder and mitral prolapse. The association studies, it will be remembered, are based on patient populations. These samples are affected by referral patterns and therefore may not be representat ive of the general population. One means of studying an unselected population is to study the relatives of patients with panic disorder and mitral valve prolapse. Since both conditions are familial, relatives should be at risk for them and any association should be found among them. Indeed, families of mitral prolapse patients have a high rate of prolapse, about a third of the first-degree relatives being affected, but no increase in the rate of panic at tacks has been found. 6~ Moreover, when patients with mitral prolapse do have a family history of panic attacks, they usually have panic at tacks themselves. 66

The Framingham study provides another unselected pop-

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ulation, and one in which mitral valve prolapse and some of the symptoms of panic disorder have been assessed. These findings also fail to support an association, for symptoms of chest pain, dyspnea, and syncope were not more frequent among persons with echocardiographically proved mitral prolapse than among normal persons. 67

The evidence suggests that, in unselected populations, the degree of association between mitral valve prolapse and panic disorder, if an association exists, is considerably less than was originally thought on the basis of clinic populations. The findings do not preclude a syndrome of mitral prolapse with panic attacks in a number of individuals, and the possibility of autonomic dysfunction predisposing to both is appealing. In order to fully explore this possibility, autonomic function will need to be examined in unselected samples of patients with mitral prolapse.

NEUROTRANSMITTERS

Evidence from both animal and human work implicates three neurotransmitter systems as playing a role in the mediation of anxiety. The noradrenergic system arises from the locus ceruleus of the pons, from which ascending pathways terminate in the limbic system, upper brain stem, and cerebral and cerebellar cortex. Evidence for a noradrenergic role in anxiety stems from animal studies demonstrating that stimulation of the locus ceruleus produces behavior consistent with a fear response and its de- struction decreases naturally occurring fear reactions. 6s Moreover, in both animals and humans, drugs that increase noradrenergic outflow from the locus ceruleus (e.g., yohimbine) increase anxiety, while those that inhibit noradrenergic ouflow (e.g., clonidine, benzodiazepines, opiates) reduce anxiety. 41' 69

The serotonergic system arises from the midbrain raphe nuclei and the reticular system. Ascending pathways syn- apse in the hypothalamus, the preoptic and septal areas, and the hippocampus, in addition to the basal ganglia and cortex. These pathways are thought to be important in me-

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diating anxiety because animal studies have shown that behavior suppressed by punishment reemerges following either chemical depletion of serotonin or surgical lesions to these pathways. Further evidence comes from observations in humans that the tricyclic and monoamine oxidase-inhibitor antidepressants, both of which suppress panic attacks, block serotonin uptake by neurons and down-regulate serotonin receptors. 7~

The sites of action of both the noradrenergic and the serotonergic system are widespread. The sites that mediate anxiety are not well understood, but the evidence suggests a role for the septo-hippocampal system. 71-73 Recent studies using positron emission tomography demonstrate an asymmetry in blood flow in the parahippocampal gyrus (left less than right) in patients with panic disorder.Tt It is interesting that the asymmetry was found in the resting state, but it was seen only in patients that had responded to a lactate challenge with panic attacks.

Of the various neurotransmitters believed to play a role in anxiety, gamma amino butyric acid (GABA) has led to the most convincing working model of anxiety. The benzodiazepines appear to exert their anxiolytic effect through GABA, an inhibitory neurotransmitter. A major development in the understanding of this system occurred with the discovery of specific benzodiazepine receptors in the mam- malian brain. 75-79

THE BENZODIAZEPINE RECEPTOR

The finding of benzodiazepine receptors within the CNS promises to lead to major advances in our understanding of anxiety. Benzodiazepine binding to these high-affinity receptors is rapid, reversible, saturable, and stereospecific. Most importantly, the affinity of the benzodiazepines for the receptor correlates with their clinical potency, suggesting that these receptors mediate the anxiolytic effect of the drug. Two forms of receptor have been found to exist: the BZl receptor is found diffusely throughout the cortex and probably mediates the anticonvulsant properties of benzo-

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diazepines, while the BZ2 receptor is found in the limbic system, where it may mediate the anxiolytic properties.

Structural ly and functionally, the benzodiazepine receptor is coupled with the GABA receptor and a chloride ionophore (channel). When benzodiazepine binds to the receptor it increases the affinity of GABA for the GABA receptor. The binding of GABA in turn increases the conductance of chloride ions through the chloride ionophore, increasing the depolarization threshold of the neuron.

Evidence implicating the BZ receptor in causing anxiety comes from studies of substances that bind to the receptor. In addition to the benzodiazepines, substances have been found that block benzodiazepine binding but have no in- trinsic activity, while others increase anxiety. These lat ter compounds, the beta-carbolines, produce physiologic responses in monkeys identical to fear responses; moreover, their administration to human volunteers produces severe symptoms of anxiety that are reversed by benzodiazepines.

Recently, an endogenous peptide has been isolated from the CNS that displaces diazepam from the benzodiazepine receptor. This peptide, termed the diazepam binding inhibitor (DBI), acts as an inverse agonist in animal studies. It is hoped that it may prove to be an endogenous ligand for the benzodiazepine receptor, s~

P S Y C H O L O G I C A L F A C T O R S

PERSONALITY

A personali ty vulnerabil i ty to anxiety states appears to exist, al though there has been relatively little study of this area. The premorbid personality of anxious patients, in contrast to that of depressed ones, is characterized by traits of dependency and immaturi ty, sl Histrionic and obsessional t rai ts may also be more common. In addition, patients with anxiety or phobic neuroses seem more likely than those with depressive neurosis to suffer from a personality disorder of the passive-dependent type. s2

The personalities of anxious patients are also character-

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ized by high trai t anxiety, s3 Trait anxiety is a relatively stable reaction tendency. Persons with this t ra i t are highly reactive to their environment and develop anxiety symptoms in response to stressful circumstances. They tend to be apprehensive, worrisome, easily upset, and uneasy in unfamiliar surroundings, s4 High neuroticism scores reflect these tendencies on personality tests, s5 However, because some tests are influenced by symptomatic state they may not accurately reflect premorbid functioning.

EARLY EXPERIENCE

According to psychoanalytic theory, childhood experiences may predispose persons to neurotic illness in adult life. s6 With respect to anxiety and phobic disorders it has been hypothesized that parental overprotection produces anxious dependence, predisposing the child to later illness. Studies of the parental at t i tudes of anxiety and phobic pa- t ients have produced contradictory results, s7 A history of childhood separation anxiety is commonly obtained from adult agoraphobics. As children they report tha t they were clinging, dependent, and intolerant of being alone.14How - ever, this behavior may be a childhood forerunner of the adult disorder, ra ther than a result of abnormal Parental attitudes.

LIFE EVENTS

Although life events are commonly associated with the onset of anxiety disorders, they are unlikely to play a substantial causal role. ss Precipitating events commonly in- volve bereavement, separation, or loss of loved ones. In- deed, events representing danger (e.g., learning that a loved one has cancer) more commonly precede anxiety disorders, whereas events representing loss (e.g., the death of a loved one) are more often associated with depression, s9 Still, events of this kind are part of the normal vicissitudes of life and may have more to do with the t iming than the eventual occurrence of illness.

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SOCIAL FACTORS

The l i terature dealing with neurotic illnesses (a group of disorders including anxiety) and their relationship to environmental factors is extensive but inconclusive. While these disturbances are more prevalent among women and unmarried persons, no association between this broadly defined category and social class was found. 9~ However, data on panic disorder from the Environmental Catchment Area project show that the disorder is more prevalent among women and unmarr ied persons as well as persons of low social class. The prevalence among those in the lowest quartile for social class was five times that among persons in the highest quartile. Studies of social network variables have emphasized perceived satisfaction with social relationships as a factor in neurotic illness. However, there is little evidence that social relationships themselves have any important role in causing neuroses. This is a difficult area of research, and few studies have examined individual disorders.

C L I N I C A L P I C T U R E

Anxiety or panic attacks are the principal feature of panic disorder. These at tacks are characterized by the sudden onset of intense anxiety together with symptoms of autonomic nervous system hyperactivity. Most last from minutes to hours and may vary in their frequency from several daily to a few in the course of a year. Although occasion- ally provoked by strong emotion, excitement, or even physical exertion, most are unrelated to activity or circumstances and strike the patient without warning, even during sleep. Persons having panic at tacks report that they suddenly feel frightened for no reason. They experience tightness or pain in the chest, shortness of breath, and heart pounding or racing. These sensations are commonly accompanied by a feeling of faintness or lighthead- edness. Many patients report weakness, particularly in their legs, and a sense of imbalance or unsteadiness. Sweating and flushing are common, as are hot and cold sensations (Table 6).

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TABLE 6. Frequency of Anxiety Symptoms

ANXIETY SYMPTOMS

% EVER PRESENT

ANXIETY CONTROL SUBJECTS SUBJECTS (N = 112) (S = 110)

Anxiety attacks 88 15 Persisting nervousness 80 16 Fatigue or t iredness 75 22 Palpitations 73 17 Restlessness 71 23 Irritability 69 9 Headaches 69 37 Muscle aching or tension 68 23 Sweating, flushing, or chills 68 17 Dyspnea or choking sensations 64 14 Insomnia 64 14 Abdominal pain or discomfort 63 21 Dizziness or vertigo 63 10 Paresthesias 62 22 Chest pain or discomfort 62 16 Fainting or l ightheadedness 62 9 Trembling or shaking 57 12 Weakness 56 7 Poor concentration 54 12 Nausea or vomiting 53 12 Loss of libido 52 14 Tinnitus 50 13 Dry mouth 44 9 Fear of 'nervous breakdown' 43 6 Fear of death or dying 42 11 Urinary frequency 42 12 Loss of weight 41 6 Blurred vision 40 7 Dysphagia 36 3 Nightmares 33 14

Panic attacks are often accompanied by a feeling of im- pending doom or the thought tha t something terrible is about to happen. Patients often feel tha t some catastrophic accident or illness is imminent (e.g., heart at tack or stroke) or tha t they may lose control of themselves (e.g., faint or

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cry out), causing severe embarrassment . At the height of an at tack patients sometimes feel that they are about to die and hasten to the nearest emergency room in search of lifesaving interventions.

Pat ients are visibly distressed and show obvious physiologic signs of anxiety during attacks. They are often pale, with a fearful wide-eyed expression and a pleading manner. Many are diaphoretic and tremulous with rapid pulse and labored breathing. They may be restless to the point of agitation, and they may have an overpowering impulse to escape from circumstances they perceive as dangerous.

Most patients experience some degree of generalized anxiety between attacks. Thus, they find themselves worried, anxious, and fearful. Many ruminate about unfortunate events that might happen. Others experience tightness or aching in their muscles and restlessness, as well as trembling. They may wear out easily and have difficulty relaxing. Many patients find that they are keyed up and irritable during the day and that at night they have difficulty in gett ing to sleep or sleep restlessly. Some find that their attention or ability to concentrate is poor (see Table 6).

As a consequence of their a t tacks some persons grow fearful of being alone or in public places from which escape might be difficult or help unavailable in the case of sudden incapacitation. They are disturbed by closed or confined places (such as elevators, bridges, tunnels, etc.) and public conveyances (such as buses, trains, planes, etc.). Crowded places, such as stores, restaurants, theaters, and churches are especially disturbing because rapid exit might be difficult or because uncontrolled behavior (e.g., screaming, run- ning out) might result in embarrassment . Pat ients with fears of this kind commonly experience panic at tacks in situations that are disturbing to them.

When the lives of patients become dominated by such fears they are said to have become agoraphobic. Their fears cause them to avoid numerous important activities so that their lives become increasingly restricted. Agoraphobic patients are not only distressed by certain phobic situations but by the anticipation of having to confront them. Thus, a housewife may begin to feel anxious as soon as she thinks

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of going shopping. Pat ients with anticipatory anxiety often grow preoccupied with arranging their activities in order to minimize discomfort and to maximize their sense of control. Some are comforted by the presence of a family member with whom they may go into crowded stores or restaurants.

Associated features include a variety of physiologic dys- functions as well as depressive and depersonalization symptoms. Pat ients with panic disorder commonly experience digestive disturbances including dry mouth, difficult swallowing, nausea, abdominal distress, and diarrhea. An irritable bowel syndrome is commonly diagnosed in these patients. Impairment in sexual functioning is also common. Sexual problems usual ly begin after the onset of anxiety symptoms, suggesting that they are secondary to the disturbance. Where breathing disturbances are prominent, ov- erbreathing may lead to parethesias, faintness, and mus- cular spasms to which the term hyperventi lat ion syndrome is sometimes applied.

Depersonalization is a term applied to an altered percep- tion of one's self or environment that sometimes accompanies anxiety or phobic symptoms and that may be present during panic attacks. Pat ients commonly report feelings of strangeness or unreal i ty that they find hard to describe. It is as though they feel detached from themselves or their surroundings. They may feel empty, as though cut off from their emotions. 91 Hypochondriasis is also reported by some patients.

C O U R S E AND O U T C O M E

ONSET

The onset of panic disorder is often abrupt, al though some patients report a period of gradually increasing anxiety symptoms. A spontaneous panic at tack is often the initial manifestation, and this dramatic and unanticipated event often leaves a lasting and painful impression. The onset is commonly associated with precipitating events or circumstances, s4 Often these are emotionally disturbing

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events, such as the death of a loved one, divorce, financial loss, etc., but physical illness, surgical procedures, and events associated with hormonal change, such as preg- nancy, childbirth, menopause, etc., may also be associated with initial symptoms.

COURSE AND COMPLICATIONS

Panic disorder typically follows a chronic fluctuating course, although remissions and exacerbations are experienced by some patients. Most patients report that their persisting symptoms are reactive to life circumstances and that they are most severe during periods of environmental stress. Symptoms may also be aggravated by physical illness or by the use of caffeine and alcohol. A substantial proportion of these pat ients develop agoraphobic symptoms sometime during the course of their illness. These patients experience a more disabling form of the illness and, as a result, a few become housebound.

The most common complications of panic disorder are depression and alcohol dependence. Depression that begins after the anxiety disorder is well established is called secondary, and this develops in about half of the patients. 92' 93 Such depression is usual ly mild and may be precipitated by distressing events. In some instances, however, it is associated with more severe anxiety symptoms and may be a reaction to worsening symptoms or disability. Depression may explain the increased risk of suicide in panic disorder. 94

Alcohol abuse and dependence may complicate panic disorder, especially if agoraphobic symptoms are present. 95 In fact, a substantial minority of patients with phobic symptoms abuse or become dependent upon alcohol or sedative drugs, including benzodiazepines. 96 Pat ients often claim that they use these substances to reduce their anxiety, only to find themselves increasingly dependent upon them. Sur- veys of alcoholic populations have shown that one third to one half suffer from phobic symptoms. 97' 9s These symptoms usually precede the onset of pathologic drinking, suggesting that phobic disorders play a role in the development of

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alcohol dependence. A proportion of patients who use benzodiazepines to control anxiety find themselves increasing the dose to achieve the same effect or experiencing distressing symptoms when they at tempt to discontinue their u s e . 99

Although the observed association between physical disease and anxiety is subject to a variety of interpretations, physical illness may be a complication of anxiety disorders. A finding of excess mortal i ty in patients with panic disorder followed for 35 years suggests this possibility. 94 A portion of the excess is due to cardiovascular disease in men. Anxiety is frequently identified in patients with physical illnesses such as hypertension and coronary ar tery disease, but the nature of the association remains uncertain. Con- tradictory results have come from follow-up studies of patients with anxiety disorders, i~176 lOl

O U T C O M E

A favorable outcome occurs in half of the psychiatric patients and in two thirds of the general medical patients.S4, 102 Despite a degree of subjective distress associated with continuing symptoms, most patients report little social impairment. Most are able to work, al though some report loss of efficiency as a result of poor concentration or easy fatigability. Some find that worried preoccupation with heal th diverts at tention from pleasurable activities. Once they have developed, agoraphobic symptoms tend to persist, al though there may be relatively few restrictions associated with them.

There have been few predictors of outcome identified for anxiety disorders, al though premorbid personality, precipitating events, and environmental sett ing all are important for neurotic illnesses in general. 1~ The existence of a premorbid personali ty disorder seems to be associated with the less favorable t rea tment outcome, s2 Of course, durat ion of illness is predictive of outcome. Half of the patients who have had symptoms for less than one year can expect to become free of them thereafter, s4 On the other hand, patients who have experienced symptoms continuously for

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more t h a n th ree years are un l ike ly to become free of t h e m la te r on. T r e a t m e n t , a l t hough t e m p o r a r i l y effective, is not cu ra t ive and m a y have l i t t le inf luence on the long- te rm outcome of panic disorder. Because symptoms tend to re- t u r n w h e n medica t ion is wi thdrawn, the long- te rm benefi ts of d rug t r e a t m e n t are uncer ta in . Las t i ng effects of behav io r t h e r a p y ha ve been demons t r a t ed in agoraphobic pat ients .

D I F F E R E N T I A L DIAGNOSIS

PHYSICAL ILLNESS

A v a r i e t y of physical and psychia t r ic i l lnesses are included in the di f ferent ia l diagnosis of panic disorder (Table 7). A n u m b e r of cardiac, endocrine, and neurologic disorders m a y be associated wi th organic anx ie ty syn-

TABLE 7. Physical Conditions in the Differential Diagnosis of Panic Disorder

Cardiovascular :disorders Angina pectoris ~" Paroxysmal atrial tachycardia

�9 Mitral valve prolapse Endocrine disorders

Hyperthyroidism Pheochromocytoma Hypoglycemia Hypoparathyroidism

Neurologic disorders Partial complex seizures Cerebral vascular disorders Multiple sclerosis

Drug intoxication Caffeinism Stimulant intoxication Other drug intoxication

Drug withdrawal Benzodiazepine withdrawal Alcohol withdrawal Other drug withdrawal

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dromes.lO4, lo5 Because an organic cause may be overlooked in patients with anxiety symptoms, the initial workup of such patients should include a physical examination and appropriate laboratory testing. On the other hand, a diagnosis of panic disorder may be missed in patients who have physical symptoms as their chief complaints. 1~ Systematic inquiry about anxiety and psychological symptoms should not be neglected in these patients.

The most common cardiac conditions associated with recurrent anxiety attacks are angina pectoris and cardiac arrhythmias. Angina is characterized by episodes of chest pain or discomfort that may be accompanied by dyspnea and palpitations. It is usually precipitated by exercise or emotional stress. Coronary arteriography may improve the accuracy of diagnosis when symptoms are atypical. A posi- tive response to nitroglycerin may also be of diagnostic value. Cardiac arrhythmias may cause palpitations, chest pain, dyspnea, and faintness. Paroxysmal atrial tachycardia is often distinguished by its abrupt onset and by an association with postural change. The diagnosis of an ar- rhythmia may be made by identifying the abnormal rhythm during an attack and this may be facilitated by a portable monitor.

Mitral valve prolapse may give rise to typical anxiety symptoms including chest pain, palpitations, dyspnea, and faintness. 1~ This minor valvular defect is associated with a midsystolic click followed by a late systolic murmur. Commonly the diagnosis can be made by auscultation. Ech- ocardiography is a noninvasive procedure that may confirm it. Recurrent pulmonary emboli may also be associated with acute anxiety together with dyspnea and hyperventilation. The diagnosis may be difficult to establish from physical examination and x-ray findings, but during acute episodes, a decreased oxygen concentration may be found in the arterial blood. A ventilation profusion lung scan is a noninvasive test, but pulmonary angiography may be necessary to establish the diagnosis.

Endocrine disturbances that produce organic anxiety syndromes include hyperthyroidism and pheochromocytoma. Symptoms of hyperthyroidism include heat intoler-

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ance, excessive sweating, and increased appetite, together with weight loss, palpitations, fatigue, and dyspnea on exertion. Signs include tachycardia, tremor, weight loss, and warm, moist skin. Exophthalmos and a diffuse goiter often are present. The diagnosis is established by tests of thyroid function, and a combination of T4 and T3 resin uptake are sufficient for most cases. Pheochromocytoma is a rare, cate- cholamine-secreting tumor of the adrenal medulla. Head- ache and flushing are prominent symptoms, and sustained hypertension is present in the majority of patients. A urinary metanephrine assay for free catecholamines, metanephrine, and vanillylmandelic acid is usually diagnostic.

Anxiety symptoms are rarely associated with hypoglycemia. l~ This disturbance is usually accompanied by sweating, weakness, tremor, hunger, and headache and is likely to occur three to six hours after a high-carbohydrate meal. The diagnosis may be confirmed by a blood glucose deter- mination during an acute episode. Reactive hypoglycemia may be identified by an oral glucose tolerance test and may be diagnosed if the glucose level falls below 45 mg/dl. At that level typical symptoms should occur. Hypoparathy- roidism may be associated with anxiety symptoms. 1~ Symptoms of this disturbance include muscle cramps, paresthesias of the hands, feet, and mouth. Carpopedal spasm is a useful sign. The diagnosis may be suspected in patients with a history of thyroidectomy. Diagnostic tests include serum calcium and phosphorus levels, as well as parathy- roid hormone levels. Cushing's syndrome may also be associated with anxiety symptoms. 11~

Partial, complex (temporal lobe) seizures often produce anxiety or panic attacks. 11~ This anxiety may be part of the aura or may be the sole manifestation of the seizure disorder. Typically patients experience rising epigastric sensations, as well as olfactory or gustatory hallucinations during attacks. Lip-smacking or chewing movements are also characteristic. The diagnosis may be established by means of an electroencephalogram (EEG), and a sleep recording with nasopharyngeal leads may be important in identifying atypical EEG abnormalities.

Caffeine often produces anxiety symptoms and may do so

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when the daily intake exceeds as little as 250 mg. 112 Brewed coffee contains 90 to 120 mg, tea and instant coffee 70 mg, and cola drinks 20 mg. A number of over-the- counter analgesic preparations contain 30 to 60 mg of caffeine per tablet. The diagnosis is confirmed when symptoms disappear after stopping the drug. However, withdrawal symptoms including headache, nausea, depression, and anxiety may occur 18 hours after the last dose. Other substances that may produce anxiety symptoms include nicotine, cocaine, and alcohol. Symptoms may occur after a relatively brief period of abstinence from alcohol. A pattern of recurring morning anxiety attacks after the previous day's ingestion is not uncommon. Medications that may cause anxiety include ephedrine, aminophylline, amphet- amines, methylphenidate, phenmetrazine, levodopa, anti- histamines, indomethacin, and thyroid preparations.

Benzodiazepine withdrawal may be associated with rebound anxiety as well as a withdrawal syndrome of the type associated with sedative hypnotic drugs. 113 Rebound refers to anxiety that is more severe than original symptoms and that appears temporarily after the drug is withdrawn. An abstinence syndrome is more likely following the abrupt withdrawal of benzodiazepines taken in high doses for long periods of time. However, abrupt withdrawal of therapeutic doses after a year can be expected to produce a syndrome of anxiety, insomnia, loss of appetite, nausea, trembling, sweating, muscle aching, hypersensitivity to light and sound, and a variety of perceptual distortions. Depending on the half-life of the drug, these symptoms may appear in one to three days and may persist for several days to weeks. In addition to benzodiazepines, withdrawal from barbiturates, sedative hypnotics, and opiates may be associated with anxiety symptoms.

PSYCHIATRIC ILLNESS

Anxiety symptoms may accompany almost any psychiatric disorder, but they are most commonly associated with generalized anxiety disorder, simple and social phobias, obsessive-compulsive disorder, and post-traumatic stress dis-

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order. Generalized anxiety disorder is characterized by generalized, persistent anxiety of a chronic nature. Symp- toms of the disorder include muscle aching, trembling, apprehension, poor concentration, difficulty sleeping, irritability, sweating, palpitations, etc. Patients with this disorder do not experience anxiety or panic attacks. 1 Sim- ple phobics are distinguished by having little anxiety out- side of feared situations. Patients with social phobia may have panic attacks, but their illness is distinguished by their fear of social situations such as public speaking, eat- ing in public, or using public toilets. Because of their fear of embarrassment in such situations they avoid them and their lives are restricted. In obsessive-compulsive disorders anxiety is associated with obsessions and compulsions. Anxiety symptoms are prominent in post-traumatic stress disorders that follow life-threatening civilian accidents as well as military experiences. Emotionally traumatic events are associated with the onset of these disorders and form their mental content) 14 The diagnosis depends upon estab- lishing a connection between a traumatic event and the en- suing disturbance.

Anxiety symptoms are often prominent in patients with depression and this makes the differential diagnosis difficult. Roughly 20% of patients with depression report panic attacks. Anxiety disorders have an earlier onset, and when anxiety symptoms appear for the first time after age 40 they are commonly part of a depressive syndrome. Most anxiety disorders are chronic, and a history of discrete episodes suggests depression. Also, a family history of depression suggests the diagnosis of an affective disorder.

T R E A T M E N T

MEDICAL MANAGEMENT

Effective treatment of panic disorder depends upon es- tablishing and communicating the diagnosis. Unfortu- nately, many patients are convinced that they are physi- cally ill, despite evidence to the contrary. Consequently they resist the idea that their problem may be psychiatric.

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Other patients reject the diagnosis of panic disorder because it suggests to them weakness or responsibility for symptoms. Too often, to avoid unpleasant confrontation, patients are told simply that they have no physical disease. Although reassuring, this gives them little information about their illness or its t reatment .

Of course, reexamination and reassurance are important initial steps when patients exhibit acute symptoms. These measures not only rule out more serious disease, but have an important anxiety-relieving function. In the face of persisting symptoms, education becomes important, and discussion of diagnosis and prognosis forms a basis for understanding and accepting the condition. Books wri t ten for patients may be helpful, including those by David Sheehan 115 and Isaac Marks. 11~ Those with agoraphobic symptoms may obtain helpful suggestions about how to cope with them from Claire Weekes. 117 Emotional support is important and may come from meeting and sharing experiences with patients who have similar disorders. Ago- raphobia self-help groups that provide opportunities for this kind of sharing exist in many communities.

The t rea tment of panic disorder, with or without agoraphobia, is effective but not curative (Table 8). The risks and benefits of t rea tment measures including medication should be weighed and dependence upon medical care minimized. The physician-patient relationship should be one of cooperation, and patient responsibility should be encouraged. The goal should be one of helping patients to control symptoms and live with their disorder. They should be encouraged to continue employment and rewarding social activities. Healthful habits should be encouraged. Regular exercise and rest will often diminish symptoms, while excessive alcohol or caffeine may increase them.

DRUG THERAPY

Patients with panic disorder should be considered for drug t rea tment except in the mildest cases. Drugs may provide temporary control of acute symptoms and long-term reduction of chronic ones. The goal is control of symptoms

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TABLE 8. Treatment Options for Panic Disorder

Drug therapy Benzodiazepines Tricyclic antidepressants Monoamine-oxidase inhibitors Beta-adrenergic blocking agents Azospirodecanediones

Behavior therapy Exposure in vivo Systematic desensitization

Psychotherapy Supportive psychotherapy Intensive psychotherapy Marital or family counseling

Self-regulation therapy Progressive muscle relaxation Electromyographic feedback Transcendental meditation

Cognitive therapy Cognitive therapy Paradoxical intention

Social skills training Social skills training Assertiveness training

rather than permanent relief of them, and one of the draw- backs to this type of treatment is the high relapse rate after effective drug therapy is withdrawn. 1Is Useful drugs be- long to five different classes: the benzodiazepines, tricyclic antidepressants, monoamine-oxidase inhibitors, beta-adrenergic blocking agents, and azospirodecanediones. 119

Benzodiazepines are the most widely prescribed drugs in the United States. Although commonly prescribed for general and stress-related anxiety, they are effective for reduc- ing panic attacks as well. 12~ Because of their prompt onset of action, they are ideal agents for the relief of acute symptoms. Diazepam has long been the standard among a host of similar drugs. A dose of 10 to 40 mg daily may be prescribed, and once control of symptoms has been established the dose may be reduced and the drug treatment gradually

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discontinued after a period of weeks to a few months. Drowsiness and tiredness are the most common dose-limit- ing side effects, and mild intoxication may occur at~higher doses. Because of these effects, pat ients should be cau- tioned about driving or performing tasks requiring alertness and coordination, and they should be warned that diazepam enhances the effects of alcohol.

Although the benzodiazepines are well tolerated, two problems associated with their use are a cause for concern and caution in prescribing them. Even though many pa- t ients report continuing benefit from the use of benzodiazepines, others report tha t they seem less effective over t ime or tha t they have to increase the dose to maintain the benefit they receive. At this point it is unclear how clinically important the development of tolerance may be. Depen- dence, both physical and psychological, may develop with the benzodiazepines, and withdrawal phenomena including abstinence syndromes, deliria, and seizures have been doc- umented in a proportion of patients. TM The risks of dependence may be minimized by not prescribing benzodiazepines for patients who abuse alcohol or drugs or who have serious personality disorders. Certain pharmacokinetic properties may make dependence on certain benzodiazepines less likely. Drugs that are more slowly absorbed and longer acting, such as prazepam, fall into this category. In prescribing these drugs physicians should alert patients to the potential risk of dependence and set limits on the amount of drug prescribed. They should also consider other drugs and alternative nondrug t reatments .

A tricyclic antidepressant, imipramine, has become a standard antianxiety drug and may be the drug of choice for long-term administration. Klein and Fink 122 were the first to report beneficial effects of this drug in blocking panic attacks. A series of controlled studies has clearly demonstrated its superiority over placebo. 119 It blocks panic attacks, but may have less effect on other manifestations of the illness such as agoraphobic symptoms. The dose range is similar to that used for depression: 150 mg to 300 mg daily in a single bedtime dose. As with depression, anxiety symptoms are relieved gradually, and maximal im-

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provement may not be achieved for six or more weeks. Some patients are sensitive to side effects of the drug, and for this reason it is wise to s tar t with a 25 mg dose, increasing that by 25 mg every three days. Some patients have an overst imulatory response to imipramine consisting of feeling keyed up, j i t tery, or irritable, and may have difficulty sleeping. However, tolerance may develop to this, as well as to the anticholinergic side effects of the drug, and those who can tolerate only small doses nevertheless benefit from it. Common side effects include dry mouth, constipation, postural hypotension, tremor, and blurred vision.

Patients who respond to imipramine may gradually reduce the dose to a maintenance level where improvement is sustained. After six months the drug t rea tment may be gradually discontinued to assess continuing need. A proportion of patients will experience a re turn of symptoms and may elect to continue taking the drug. Other tricyclics may also be effective, and more sedative drugs, such as doxepin and amitriptyline, have ant ianxiety effects in low doses. Imipramine appears to be a relatively safe drug for long-term administration, although the complications of such administration are not completely known. The risk of cardiac arrhythmias is minimal in patients without heart disease. The risk of cardiovascular complications, including arrhythmias and blood pressure effects, seems to be minimal. Even so, a number of patients gain weight while taking these drugs, and an overdose taken in a suicide a t tempt may be life-threatening. This may be a serious considera- tion in patients with an increased risk of suicide. 94

The monoamine-oxidase inhibitor, phenelzine, is also effective in patients with panic disorder with or without the complication of agoraphobia. Sargant and Dally 123 were the first to report that patients with phobic anxiety had responded to phenelzine. Since then a series of controlled trials has proved the drug's superiority to placebo. 119 Like imipramine, this drug is capable of blocking panic at tacks as well as other features of the disorder. The recommended dose is 60 to 90 mg daily. Pat ients are required to eliminate foods containing tyramine (e.g., red wine, cheese, etc.)

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from their diet. Tyramine, if ingested in sufficient quantity, may interact with the drug to produce a hypertensive crisis. Such crises may have serious consequences, but do not commonly occur if the diet is followed. Pat ients who are not likely to follow the diet or who abuse alcohol should not receive the drug. Other monoamine-oxidase inhibitors may also be effective in panic disorder. However, these drugs are associated with a greater risk and, owing to di- etary restrictions, are less well accepted by patients. Side effects of phenelzine include postural hypotension, dizziness, tremor, diarrhea, and fatigue.

Beta-adrenergic blocking drugs, such as propranolol, have also been shown to have ant ianxiety properties. Gran- ville-Grossman and Turner 124 were the first to show the beneficial effects in patients with anxiety disorders, and subsequently a series of controlled studies has demonstrated the superiority of this and other beta-blocking drugs over placebo. These drugs are not as effective as benzodiazepines, but patients with p rominen t somatic symptoms of anxiety may respond.~25- Palpitat ions and tremor are part icularly suitable target symptoms. The recommended dose range for propranolol is 80 to 320 mg daily in divided doses. Beta-adrenergic blockade is associated with a fall in resting heart rate, and this provides a means for monitoring the drug's activity. Side effects include dizziness, nausea, and fatigue. Propranolol is a well-tolerated drug and is apparently free of potential for psychological dependence. Providing it is not given to patients with asthma or hear t disease it is a relatively safe drug. Other beta-blocking drugs may also be effective, and atenolol may have the advantages of once-daily administrat ion and fewer CNS side effects.

The azospirodecanedione, buspirone, is the first of a new class of promising antianxiety agents. 126 Unlike the benzodiazepines, buspirone does not interact with CNS depres- sants such as alcohol and lacks sedative, anticonvulsant, and muscle relaxant properties. Clinically, the drug appears to have a number of advantages. It is minimally se- dating, has little effect on cognitive or motor performance,

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and appears to be without abuse potential. 127 A series of controlled studies has shown the drug to be comparable to a benzodiazepine in relieving anxiety symptoms in a dose that is roughly equivalent to that of diazepam. Side effects include dizziness and headaches, and at higher doses some patients experience dysphoria. This drug, while unique among ant ianxiety drugs and while showing considerable promise, remains a ra ther unknown quantity. It is not known what side effects may appear with more widespread use. At this writing, approval by the Food and Drug Ad- ministrat ion is pending.

BEHAVIOR THERAPY

Pat ients with agoraphobic symptoms may benefit from behavior therapy. Behavior therapy is simply a systematic method of exposing persons to phobic situations until they lose their fear of them. This therapy follows a principle first put forth by Freud, s6 who noted that it was necessary for phobic patients to expose themselves to the object of their fears if they were to overcome them. In its simplest form this therapy involves instructions to patients to challenge their fears and to expose themselves to progressively more difficult situations. This, accompanied by physician encouragement, is by itself a surprisingly effective technique.

The most effective technique for agoraphobia is exposure in vivo or flooding, s7 This is based on the principle of sudden confrontation in real life, as opposed to systematic desensitization, which at tempts to extinguish the phobic response by pairing it with relaxation. With therapist encouragement patients go into crowded stores or travel dis- tances and remain in these situations until their anxiety subsides. Exposure may be done in groups. This allows patients to support one another and conserves therapist time. Psychologists are commonly trained in these techniques, and other professionals may learn them. Follow-up studies have shown that benefits of behavior therapy may be lasting. 12s

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PSYCHOTHERAPY

Patients with panic disorder may benefit from supportive psychotherapy. As has been mentioned, reassurance about the meaning of symptoms and education about the nature of the illness often bring considerable relief. A sympathetic physician may, through such measures, restore morale and self-confidence. Beyond this, an exploration of the circumstances surrounding the onset of symptoms may reveal factors of importance to their development that can be modified. Marital or family counseling may be important where disturbed marital or family interactions are contributing to symptoms.

As has been observed, many patients with this disorder are dependent and avoid difficult situations. As a result of chronic anxiety symptoms, some patients cope ineffectively with interpersonal difficulties. Because they are dependent and unassertive they may drift into emotionally unhealthy relationships. According to Andrews, 129 the successful therapist initially responds to demands for protection and guid- ance and subsequently uses his influence to persuade patients to confront anxiety-producing situations. With emotional support patients may recognize maladaptive patterns and find ways to change them. Where personality difficulties are associated with panic disorder, intensive therapy designed to produce personality change may be recommended.

SELF-REGULATION THERAPIES

Anxiety symptoms may be reduced through the use of relaxation, biofeedback, and meditation. 13~ The method of progressive muscle relaxation was introduced by Jacob- son. TM This method depends on systematically tensing and relaxing muscle groups. In addition to changes in muscles, relaxation reduces sympathetic nervous system activity. Muscle relaxation may be facilitated by electromyographic feedback, which provides patients with information about the electrical potentials of certain muscle groups. In the treatment of anxiety symptoms it is usually the frontalis

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muscle that is monitored. Although this technique has proved effective, the mechanism of anxiety reduction is uncertain and controlled studies have yet to demonstrate unique superiority.

Transcendental meditation is the most widely practiced method of altering consciousness. The basic principles of this technique may be learned in one or two sessions, although mastery requires extended practice. A physiologic state of restful alertness, different from sleep or wakeful- ness, is produced by transcendental meditation and is associated with reduced oxygen consumption. This physiologic state is similar to that associated with muscle relaxation. Benson 132 called this the ~relaxation response" and described a technique for achieving it. Self-regulatory techniques are useful adjuncts, but are probably not ade- quate treatment in themselves for most chronically anxious patients.

COGNITIVE THERAPY

Cognitive therapy is based on the cognitive model of anxiety. According to this model, anxiety-provoking thoughts and images are the primary disturbance. 133 A theme of per- sonal danger is central to these cognitions. Anxious patients systematically misinterpret innocuous situations and exaggerate the possibilities of physical or psychological harm. The cognitive therapist elicits unrealistic cognitions, analyzes their faulty logic, and explores with the patient alternative ways of thinking. Special techniques have been developed for work with phobic patients. TM There have been few studies of the value of this therapy in anxiety and phobic disorders, although it has been found useful in depression.

Paradoxical intention is a technique designed to reduce symptoms by seeking to increase them. According to this procedure, patients are asked to attempt to realize their worst fears. ~a5 For example, a patient with a fear of fainting might attempt to faint when symptoms of lightheaded- ness occur. When these efforts fail the fear may disappear.

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The essential ingredient in this technique appears to be a reversal of attitude toward symptoms. Few studies have examined its effectiveness.

SOCIAL SKILLS TRAINING

Patients with panic disorder, especially those with agoraphobic symptoms, often find it difficult to express their feelings adequately or to assert themselves. This may reflect premorbid personality or an effect of the anxiety disorder on personality function. Assertiveness training is a technique that involves discussion of social situations in which patients behave timidly. Alternative behaviors are considered and training is undertaken through therapist modeling and rehearsal. This training may produce not only more direct expression, but less phobic avoidance. It often serves to enhance self-confidence and self-reliance, which are important treatment goals for these patients.

PSYCHOSURGERY

Prior to the introduction of effective drug and behavior therapies, a number of patients with agoraphobic symptoms were treated by leukotomy. 136 Presently there is little reason to resort to this treatment, although there is evidence that it reduces anxiety and phobias without causing great changes in personality. The improvement following leukotomy re- sembles that resulting from drugs, where a rapid reduction in anxiety is followed by a more gradual improvement in phobias as feared situations are confronted.

CONCLUSION

Panic disorder is an outstanding example of applying the medical approach to a psychiatric problem to the benefit of patients through better diagnosis and treatment. Al- though panic disorder is considered a psychiatric illness, it, like other medical illnesses, has a clearly defined epidemiology, symptom picture, and course. More importantly,

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effective medical treatment enables the majority of patients to be treated by nonspecialists. Thus, clinicians are now in a position to provide considerable help to these patients, both in treating their symptoms and in relieving their concern about the nature of the illness.

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SELF-ASSESSMENT ANSWERS

1. Panic disorder occurs in 1.4% of the population, and agoraphobia in 6.1%. Women are affected twice as frequently as men with panic disorder, and 3 times as frequently with agoraphobia. The transmission of this disorder in families, as well as a greater concordance rate in monozygotic than dizygotic twins, suggests tha t the disease is genetic.

2. Panic disorder usually begins abrupt ly with recurring panic at tacks and follows a chronic course in 85% of patients. Many will develop a fear of having panic at tacks away from the safety of their home and avoid such situations as crowds, highways, and bridges, a reaction re- ferred to as agoraphobia.

3. Some of the more common considerations in the differential diagnosis should include paroxysmal atrial tachycardia, mitral valve prolapse syndrome, reactive hypoglycemia, s t imulant drug intoxication, and sedative- hypnotic drug and alcohol withdrawal.

4. Five classes of drugs have been used to treat panic disorder. Benzodiazepines are effective in relieving panic attacks, but the potential for dependency should not be overlooked. Tricyclic and monoamineoxydase inhibitor antidepressants have both been shown effective in sup- pressing panic attacks. Beta-adrenergic blocking agents, and a new anxiolytic, buspirone, have both been used to

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treat panic disorder, but less is known about their effectiveness than the other agents.

5. Panic attacks typically began abruptly, can occur in the absence of precipitating stress, and last from minutes to hours, usually leaving the patient fatigued after they subside. The typical signs and symptoms are presented in Table 1 and in Table 6.

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Panic disorder and agoraphobia