OVERVIEW OF PANIC DISORDER

JAMES C. BALLENGER
CHARLESTON, SOUTH CAROLINA

I. INTRODUCTION Once considered rare (1), carefully documented studies have demonstrated that panic disorder (PD) is a common condition affecting at least 1-2% of the general population in any 6-month period. This understanding has stimulated vigorous study of this disorder over the last decade, resulting in increased knowledge and enhanced ability to more accurately diagnose and effectively treat PD. This paper reviews prevalence, etiology, and genetic studies. Diagnostic issues are reviewed, including changes made by the American Psychiatric Association in the Diagnostic and Statistical Manual-IV. Differential diagnosis is addressed and conditions which closely mimic PD are outlined. In addition, data on co-existing disorders such as substance abuse and depression are reviewed. Treatment modalities, including both psychopharmacological and behavioral therapies, are described. Classes of drugs, dosage, duration of treatment, and issues surrounding medication discontinuation are covered as well. Reviews of pertinent clinical trials are included providing a comprehensive overview of those issues critical to the recognition and treatment of PD. II. EPIDEMIOLOGY It has now been clearly established that PD, once considered rare, is actually a common disorder. Data from the NIMH Epidemiologic Catchment Area (ECA) Survey, a study of 18,000 subjects at five sites in the United States, confirmed that panic symptoms are extremely common, affecting 10% of adults at some point during their lives. Although the number of individuals fulfilling frill diagnostic criteria for PD is less common, 6-month and 1-year prevalence is about 1-2% of
Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina. Much of this paper has been previously published in the ASEAN Journal of Psychiatry, Vol. 2, # 1, March 1992, pp. 13-27. Please address reprint requests to: James C. Ballenger, MD, Chairman and Professor, Dept. of Psychiatry and Behavioral Sciences, Medical University of South Carolina, 171 Ashley Avenue, Charleston, South Carolina 29425.
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the population. Agoraphobia is seen more frequently with a 6-month prevalence between 2-5% (1). When all the anxiety disorders are combined, the figures increase, with a 6-month prevalence of 8.9% and lifetime prevalence of 14.6% (2). Data from the ECA Survey and other studies show that women are affected about 2-4 times more frequently than men (1). In addition, PD tends to occur more frequently in individuals between the ages of 25-44 and in those either separated or divorced (1). The ECA Study also showed average age of onset at mid to late 30's, with no correlation between race or education. Weissman et al. (3) demonstrated that in many patients PD can develop into an extremely severe condition with higher morbidity than even the affective disorders. In the ECA community PD sample, 20% had attempted suicide, 27% were on welfare or disability support, and 27% misused/abused alcohol (4).

Genetics Data from multiple studies clearly show a significantly higher incidence of PD within families of probands with PD, with relatives of PD patients having about a 20-50% chance of developing PD during their lifetime (5-7, 8). Torgersen's study of PD twins (9) demonstrated that monozygotic (MZ) twins had a 31% concordance rate for Panic Attacks (PAs), versus no concordance for dizygotic (DZ) twins. Additionally, he examined 318 twin probands; 29 of whom had PD or agoraphobia with PA. Of the panic-disordered sample, 13 were MZ and 16 were DZ twins (10). Two of the 13 MZ twins and none of the DZ twins showed concordance for PD or agoraphobia with PA. Although linkage studies are currently in progress, there is no firm proof of the genetic hereditability of PD.
III. DIAGNOSIS The onset of PD, generally in early adulthood, is marked by the unexpected occurrence of severe anxiety manifest by the development of PAs. Because of the intensity of their symptoms, patients are often convinced they are having a heart attack or are suffering from some other serious and potentially life-threatening physical illness. As this disorder progresses, many patients become fearful of situations in which they might have difficulty escaping or obtaining help. Patients begin to avoid situations where they have previously experienced PAs, hoping to prevent their recurrence, and varying degrees of agoraphobic avoidance can result. If left untreated, approximately 5% of these patients actually become housebound (11).

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Criteria developed by the American Psychiatric Association (12) first recognized PD in 1980 as a separate diagnostic entity, and these criteria were further refined in the DSM-III-R (13). These diagnostic schema have helped to clarify diagnostic issues and have facilitated a more accurate understanding of PD. The recently adopted DSM-IV has further improved the diagnostic criteria, to more accurately describe the typical PD patient, thereby increasing diagnostic reliability. To achieve a diagnosis of PD, the DSM-IV criteria requires the occurrence of unexpected PAs in which at least one of the attacks is followed by a month or more of 1 of 3 conditions: persistent concern about having additional attacks, worry about the implications of the attack or its consequences (such as losing control, having a heart attack, or "going crazy"), or a significant change in behavior related to the attacks (14).

IV. PRESENTATION TO MEDICAL SETTINGS OTHER THAN PSYCHIATRY The PD patient may suffer from some or all of the frightening physiological symptoms associated with this disorder, including chest pain, shortness of breath, choking, hot flashes or chills, lightheadedness, dizziness, numbness and a tingling sensation, gastrointestinal distress including nausea and diarrhea, sweating, and or trembling. These symptoms are frequently accompanied by a feeling of impending doom or dread, as well as a fear of losing control, either of body functions or of their mental state. Despite repeated medical procedures for which results are normal, patients remain convinced that they suffer from a serious, life-threatening condition and present numerous times to the emergency room or other medical settings (15). Because of the somatic nature of this illness, these patients are often seen for long periods of time in medical practices other than psychiatry, resulting in improper diagnosis and incorrect and/or inadequate treatment. It has been estimated that 6-10% of patients seen by primary care or family practice physicians and 10-14% seen by cardiologists actually suffer from PD (16). Katon and colleagues (17) reconfirmed this in a study of 195 primary care patients where 6.5% met diagnostic criteria for PD with another 6.5% having PD with major depression. These findings have been confirmed by a number of other investigators (18-19). Recent studies also show a high percentage of patients in cardiology practices who suffer from PD. Beitman et al studied patients who presented to cardiology with chest pain but who subsequently had unremarkable medical workups. However, %3 of these patients met

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diagnostic criteria for PD (20). An outpatient study by this group showed that 15% of their patients with angina-like pain and evidence of coronary artery disease also suffered from PD, and 44% of the patients with pain but no clinical evidence of coronary disease had PD (20). Once PD has been recognized, the clinician should be careful not to overlook other conditions which often accompany PD and which may require treatment. Many PD patients also suffer from substance abuse disorders (21). Also clearly documented is the frequent co-occurrence of PD and depression. Some studies report that over 60% of PD patients suffer from depression (22-25). Uhde et al. (26), however, reported much lower rates (about 14%). All of these issues must be considered when diagnosing and treating the PD patient. If all factors are recognized and appropriately addressed, response to treatment can be very positive.
V. PHARMACOLOGICAL TREATMENT Early pharmacological treatments were largely ineffective, leaving 75% of patients unimproved (27). Clinical evidence acquired over the past 25 years, however, clearly demonstrates the effectiveness of current pharmacotherapy of PD. The medicines used today fall into basically three categories; the tricyclic (TCAs) and monoamine oxidase inhibitor (MAOI) antidepressants and the benzodiazepines (BZs). Attention is also being given to the newer selective serotonin-reuptake inhibitors (SSRIs). TCAs: The TCA most frequently studied is imipramine, which has been proven clearly superior to placebo in over a dozen double-blind, placebo-controlled trials (28-30) and a number of open trials (31-35). With imipramine, improvement generally requires at least 4-6 weeks, but may take as long as 12-24 weeks of treatment. Generally 70-90% of the patients experience moderate or marked improvement (36). A definite relationship between dose and improvement was demonstrated in a study by Mavissakalian and Perel (37). Patients maintained on doses less than 150 mg/day showed little to no improvement, equivalent to that seen in patients receiving placebo, compared to those who received greater than 150 mg/day of imipramine and who demonstrated a significantly higher rate of improvement. Both open and controlled studies have further documented the efficacy of clomipramine (38-39). A double-blind trial comparing fluvoxamine and clomipramine (40), showed both medications to have efficacy in the treatment of PD. Other TCAs which have proved useful for PD include maprotiline (41); nortriptyline, amitriptyline, and dox-

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epin (42). Evans et al (43) studied zimelidine, and preliminary evidence indicated its superiority to placebo in the treatment of PD. Fluoxetine has also been shown to be effective (44). A trial conducted by Sheehan et al (45) showed bupropion to be ineffective in the treatment of PD. Trazodone has been studied with conflicting results. Mavissakalian et al. (46) found it effective in a small trial; however, Charney and colleagues (47) reported less positive results. The TCAs have proven efficacy in the treatment of PD. Disadvantages include delayed onset of action, generally 4-12 weeks (or longer), and side effects, particularly the hyperstimulatory response often experienced by patients when beginning treatment. Long-term treatment is often associated with significant weight gain in at least a third of patients (48). If the TCA has been administered for several months and is suddenly stopped, the patient may develop gastrointestinal distress, a rebound effect of the medication (49). Taylor et al. (50) observed mild elevations in blood pressure, although the significance of this is uncertain. MAOIs: The MAOIs, like the TCAs, have been extensively studied and shown to be comparably effective in the treatment of PD. The first studies of the MAOIs were undertaken in Australia, England, and Canada in the early 1960s, about the same time that imipramine was being studied in the US and demonstrated their usefulness in the treatment of PD (51-54). The MAOI most frequently studied is phenelzine. Five placebo-controlled trials with phenelzine (28-29, 55-58) demonstrated significant results in the treatment of PD. However, because of the smaller numbers of subjects, relatively low doses, and the mixed diagnoses of patients studied, these trials provide less definitive results than those conducted with the TCAs. Of the five, the study performed by Ballenger and Sheehan (28-29) provides the most definitive results. Phenelzine, 45 mg/day, and imipramine, 150 mg/day, were compared to placebo in agoraphobic patients who suffered from PAs in a 12-week trial. In addition to medication or placebo, patients also received self-exposure instructions and group therapy. Both drugs were shown to be more effective than placebo combined with group therapy, and the patients in both the drug groups reported greater reduction in phobic anxiety and fears, general anxiety, agoraphobic avoidance, and work and social disability. However, the phenelzine-treated patients showed significantly greater improvement on the physician and patient-rated behavioral scales which assessed severity of phobic and avoidance symptoms as well as performance in work and social situations than the imipramine-treated patients. About 75% of the phenelzine patients experienced clinically significant

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results with dramatic improvement in or alleviation of symptoms. Some patients on drug continued to improve after study completion when their medication doses were increased making it unclear whether the phenelzine/imipramine difference observed was dose-related. Following these early studies, three open trials subsequently demonstrated phenelzine's efficacy. Buiges and Vallejo (59) studied PD patients, both with and without PAs. Phenelzine at a mean dose of 55 mg/day was extremely effective, with almost total relief from panic symptomatology. Ballenger and colleagues studied patients who were administered either phenelzine, mean dose 53 mg/day, or lorazepam, alprazolam, and imipramine with self-exposure homework for 12 weeks, and reported excellent results, again with marginal superiority for phenelzine (60-61). Sheehan compared patients receiving either alprazolam, imipramine, phenelzine, or placebo, and all of the medications were associated with positive outcome, at roughly equivalent rates of response (62). Iproniazid has also been shown to be significantly more effective than placebo in decreasing anxiety, but not phobic avoidance (63). Although there is compelling evidence which points to the usefulness of the MAOIs, additional controlled studies are needed. Disadvantages of the MAOIs include the strict dietary restrictions necessary to minimize the chances of a tyramine-induced hypertensive episode. Foods that must be avoided include some cheeses, aged meats, red wine, and caffeine products, as well as many other common foods and medicines. Research is currently underway to study two new reversible MAOIs, which should not require dietary restrictions because of an expected low risk of this hypertensive tyramine reaction. Other common side effects include insomnia and weight gain. Like the TCA's, onset of action generally requires 4-8 weeks to achieve improvement (28, 60). Benzodiazepines: More recently, work has been performed with the high potency benzodiazepines (BZs), particularly alprazolam, which has been demonstrated to be effective in the treatment of PD. To date, twelve controlled trials have replicated the initial positive findings of Chouinard et al. (64), nine of which were placebo controlled. Three studies compared alprazolam to placebo alone (64-66). The Cross-National Phase I Trial conducted by Ballenger et al. (67) studied 526 PD patients treated with alprazolam or placebo, without concomitant behavioral treatment. This study demonstrated marked improvement in approximately 50% of the alprazolam patients, with an additional 40% having moderate improvement (67). Alprazolam was effective in reducing both spontaneous and situational PAs, with approximately 60% of patients experiencing complete cessation of PAs at the end of the 8-week trial. Alprazolam was also effective in significantly reducing phobias, phobic anxiety, anticipatory anxiety,

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and reduced work, family, and social disabilities to near normal levels by study end. When alprazolam was reduced over the next 6 months, improvement was sustained without loss of efficacy. Recent studies indicate that 6 mg is more effective than 2 mg for complete resolution of PAs and for reduction of phobic behavior (68-69). However, the lower dose was effective in a smaller percentage of patients, and again, reduced all of psychopathological features of the PDs, although to a somewhat lesser degree. The Cross National Phase II study essentially replicated the findings of the initial trial (70). In this study, alprazolam, imipramine, and placebo were compared in 1168 patients. Alprazolam was again effective, and results were seen in the first week of treatment. Significant effects with imipramine were not seen until week 4 of treatment. By week 8, however, both alprazolam and imipramine were essentially equal in effectiveness. Two additional open studies further document the efficacy of alprazolam. Liebowitz et al. (71) studied 30 patients treated with alprazolam for 12 weeks, with clinical improvement seen in 65%. Alexander and Alexander (65) treated 27 patients with alprazolam, mean dose 2.2 mg/day, and 85% experienced complete resolution of PAs. Additionally, 21 of 23 PD patients who also had agoraphobia, experienced resolution of their phobic avoidance behavior. All of these studies have confirmed that alprazolam is effective in the treatment of PD, comparable to the TCAs and MAOIs. It has the advantages of being better tolerated with a quicker onset of action. Recent work has demonstrated efficacy with the use of clonazepam in PD. Tesar and Rosenbaum (72) administered clonazepam to 10 PD patients who had been unsuccessfully treated with other commonly used agents including alprazolam. In this group, 70% became completely asymptomatic, with the remaining 30% achieving some degree of relief. A subsequent retrospective study by Tesar (73) of 50 clonazepam-treated PD patients, again, many of whom were previously treated unsuccessfully with other agents, demonstrated that 78% had a positive response to clonazepam. At one-year follow-up of those patients who continued treatment with clonazepam, 90% indicated efficacy similar to other antipanic medicines prescribed for long-term treatment (74). Tesar and colleagues (75-76) then treated 72 patients with PD, with or without agoraphobia, with alprazolam, clonazepam, or placebo in a 6-week trial. Both drugs were comparable in efficacy, with significant improvement beginning in the first week of treatment and continuing throughout the medication trial. The most frequently reported side effects were sedation and ataxia, but they were not severe enough to interfere with treatment results, and by the end of the study had for the most part resolved.

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Other BZs studied include diazepam which when administered at high dosages, roughly 10 times that used with alprazolam, was effective (77). Lorazepam has also been demonstrated effective in open studies (61, 78-79). Charney and Woods conducted a double-blind, placebo-controlled study comparing lorazepam to alprazolam, utilizing behavioral therapy as well as medication treatment. Both drugs were comparable in efficacy and significantly improved the panic symptomatology of the patients studied. However, the patients treated with alprazolam tended to rate themselves as more improved (80). Other BZs with reported efficacy in the treatment of PD include bromazepam (81) and oxazepam (82). Advantages to using BZs include their ability to provide rapid relief of symptoms, generally within the first week of treatment. They are tolerated well and provide significant relief from both anticipatory anxiety and PAs. One minor disadvantage is the need for multiple daily dosing. Some patients experience sedation, but compared to the other drugs currently used to treat PD, the BZs seem to have the fewest side effects. Another disadvantage is the withdrawal syndromes observed on discontinuation in some patients (see below). Medication Discontinuation: There are several phenomena that may occur when medication discontinuation is attempted. First, the patient may remain well. However, many patients experience relapse, a withdrawal syndrome, or rebound. Recent studies have found that 30-45% of the patients treated with current psychopharmacological agents remain well after medication discontinuation (83). Relapse rates among the different medicines seem comparable (48, 62, 84). However the time course when relapse occurs varies among the medicines and correlates with the amount of time required to achieve initial clinical improvement. Withdrawal involves symptoms similar to those experienced pretreatment as well as some new ones (e.g., insomnia, GI symptoms). However, withdrawal symptoms usually become less intense about a week after discontinuation, and generally resolve completely by the end of the second week. Current data indicate that 7-90% (83) of patients experience withdrawal symptoms. The physician can help the patient through this symptomatic period with conservative treatment and reassurance that the symptoms are usually mild and transient. Some patients experience rebound with symptoms more intense than those prior to treatment. If the BZ is discontinued too quickly, the chances of experiencing rebound increase. However, again, the physician can help the patient with the reassurance that rebound is shortlived and is not dangerous. Symptoms generally become less severe by

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the end of the first medication-free week, with complete resolution by day 14. The simultaneous presentation of withdrawal, relapse, and rebound can be difficult for the clinician to differentiate. All of these conditions can take place within the first week following BZ discontinuation. A good guideline is that if symptoms continue after the second week, it is safe to assume that they are symptoms of relapse. Every effort should be taken to prevent these conditions from occurring, and this is best insured by a gradual tapering process. It is generally recommended that the BZs, TCAs, and MAOIs be tapered slowly and gradually over a 2-4 month period. However, in the event that one or more of these syndromes does occur, it is helpful for the patient and physician to know that all of these conditions can be managed. Many times all that is needed is reassurance that the symptoms are not dangerous and will clear within a few days. If insomnia becomes intolerable, a non-benzodiazepine hypnotic to assist with sleep is often extremely helpful. If needed, there are medications which can be used during the taper process. Most recently, carbamazepine has been shown to be helpful (85-86). Long-term Outcomes: There exist relatively little data about the patient's long-range outcome following medication discontinuation. In one of the few published studies addressing this issue, Nagy et al. (87) followed 60 PD patients after discharge from a 4-month trial of alprazolam and behavior therapy. The follow-up period ranged from 1.7 to 4 years (mean 2.5 years) and results indicated that 30% were totally off medication at follow-up. Frequency of PAs continued to be reduced and improvement was maintained in 11 of 14 other areas. The percentage of patients in remission had risen from 33% at the end of the trial to 43% at follow-up. Two hundred twenty patients were followed up by Katschnig et al. (84) 3-6 years after a two-month treatment trial with imipramine, alprazolam, or placebo in the Phase II Trial of the Cross-National Collaborative Panic Study. In this group 25% had been maintained on medication continuously for the entire 3-6 year period. At the time of follow-up, only 55% were taking medicines. The largest group was taking benzodiazepines (25%), with the remainder taking antidepressants (12%), a combination of the two (9%), or other medications (11%) (84). About 33% of this group became well, either during or after the study, and stayed well, although treatment (or lack of it) during the follow-up period is unknown. Half of the subjects had mild symptomatology, and half of this group experienced some periods ofbeing well. However, almost one-fifth of all patients did not have a positive clinical response and remained severely symptomatic both during the study and afterwards.

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VI. BEHAVIORAL TREATMENT In addition to psychopharmacological agents, PD is often successfully treated with some form of behavioral treatment or a combination of the two. Currently, one of the most frequently utilized and most effective behavioral therapies is a combination approach utilizing interoceptive exposure with cognitive therapy and breathing retraining. Panic control treatment (PCT) was studied by Barlow and colleagues (88) in 41 PD patients. The four treatment groups were comprised of patients who were either provided instruction for progressive muscle relaxation (PMR); PCT; a combination of PMR and PCT; or were placed on a wait-list to serve as controls for the study. At the end of the treatment period, 75% of patients in both PCT and combination therapy groups, compared to 40% of the subjects in the PMR group and 33% of the controls were panic-free. Subjects in the three active treatment groups were then followed for 2 years. At the end of the 2-year follow-up, 81% of the PCT group were panic-free compared to 55.6% of the PMR group and 60% of the combination group (89). In another trial PCT was compared with alprazolam and placebo where 87% of the PCT patients compared to 50% of those receiving alprazolam, 36% on placebo, and 33% of the wait-list controls were panic-free by the end of the study (90). In addition, early reports showed reductions in panic symptomatology after receiving cognitive training (91-95). Beck et al. (96) compared 33 patients treated with either cognitive therapy or brief supportive therapy and found that by the end of the study 94% of the patients in the cognitive therapy group were without PAs, and 83% maintained their panic-free status at follow-up. Another group compared cognitive therapy with applied relaxation or imipramine. Clark and colleagues (94) studied 64 PD patients and determined that at the end of the 3-month trial, 90% of the patients in the cognitive therapy group were panic-free compared to 50% of the subjects who received applied relaxation, 55% of the imipramine group, and 7% of the waitlist controls. At 15-month follow-up, 80% of the cognitive therapy group versus 47% of the applied relaxation and 50% of the imipramine group were panic free. Margraf and Schneider (95) compared 80 PD patients who received either behavior therapy only, cognitive treatment, or were placed on a wait-list as controls. All groups improved, with the most improvement seen in the cognitive therapy group (86%). Exposure: Exposure to the phobically feared situation is an effective form of behavioral therapy for treating PD. The clinician prescribes a series of exercises designed to gradually expose the patient to, or place

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the patient in, situations or locations where they have previously experienced PAs. Through this technique, a patient becomes increasingly able to tolerate a situation he previously avoided because of its potential for causing PAs. Exposure has been effective in dealing with phobias (96). However, its utility for decreasing or eliminating PAs has not been fully determined. There is some evidence, however, that individual in vivo exposure may be useful for treating both PAs and agoraphobia (97-98). Breathing Training: Another method of behavior therapy currently receiving attention emanated from the theory that the symptoms involved with a PA are extreme and create such fear in the patient, that the fear actually increases anxiety, leading to a full-blown PA (99-100). With this method of treatment, the patient exercises or hyperventilates to a state which produces PA-like symptoms (101-102). The patient is gradually desensitized to these anxiety and hyperventilation cues and taught to control the rate of breathing as a method of dealing with and overcoming PAs. Multicomponent Therapy: Relaxation has also been reported to have good results in the treatment of PD. In a sample of 11 patients treated with educational intervention, relaxation, assertiveness training, in vivo exposure, and diaphragmatic breathing, Gitlin et al. (103) reported that 10 of the patients were symptom-free by the end of treatment. Shear et al. (104) treated 17 PD patients for an average of 17 sessions. At study termination, 87% experienced complete resolution of symptoms, and all of the sample enjoyed a reduction in symptomatology. Other studies have demonstrated the superiority of multicomponent behavioral therapy over untreated control groups (105).
VII. EDUCATION Education about the disorder is also an important component in all forms of treatment. Understanding what the disease is, that it is not life-threatening, and that it can be successfully treated is extremely useful to the PD patient.
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27. Doctor RM. Major results of a large-scale pre-treatment survey of agoraphobics. In Phobia: A Comprehensive Summary of Modern Treatments. Edited by DuPont RL. New York, Bruner/Mazel, 1982 28. Sheehan DV, Ballenger J, Jacobsen G: Treatment of endogenous anxiety with phobic, hysterical and hypochondriacal symptoms. Arch Gen Psychiatry 1980;37: 51-59 29. Ballenger JC, Sheehan DV, Jacobsen G. Antidepressant treatment of severe phobic anxiety. In Abstracts of the Scientific Proceedings of the 130th Annual Meeting of the American Psychiatric Association, Toronto, May, 1977 30. Zitrin CM, Klein DF, Woerner MG, et al. Treatment of phobias. I. Comparison of imipramine hydrochloride and placebo. Arch Gen Psychiatry 1983;40:125-138 31. Ballenger JC, Peterson GA, Laraia M et al. A study of plasma catecholamines in agoraphobia and the relationship of serum tricyclic levels to treatment response. In Biology of Agoraphobia. Edited by Ballenger JC. Washington DC, APA Press, 1984 32. Lydiard RB, Ballenger JC. Panic-related disorders: evidence for efficacy of the antidepressants. J Anxiety Dis 1988;2:77-94 33. Mavissakalian M, Michelson L. Agoraphobia: Behavioral and pharmacological treatment, preliminary outcome, and process findings. Psychopharmacol Bull 1982;18:91-103 34. Mavissakalian M, Michelson L, Dealy RS. Pharmacological treatment of agoraphobia. Imipramine versus imipramine with programmed practice. Br J Psychiatry 1983;143:348-355 35. McNair DM, Kahn RJ. Imipramine compared with a benzodiazepine for agoraphobia. In Anxiety: New Research and Changing Concepts. Edited by Klein DF, Rabkin JG. New York, Raven Press, 1981 36. Ballenger JC: Biological aspects of panic disorder. Am J Psychiatry 1986; 143(4):516-518 37. Mavissakalian M, Perel J. Imipramine in the treatment of agoraphobia: Doseresponse relationship. Am J Psychiatry 1985;142:1032-1036 38. Beaumont G. A large open multicentre trial of clomipramine (Anafranil) in the management of phobic disorders. J Int Med Res 1977;5:116-123 39. Carey MS, Hawkinson R, Kornhaber A et al. The use of clomipramine in phobic patients: Preliminary research report. Curr Ther Res 1975;17:107-110 40. Den Boer JA, Westenberg HGM, Kamerbeek WDF et al. Effect of serotonin uptake inhibitors in anxiety disorders: A double-blind comparison of clomipramine and fluvoxamine. International Clin Psychopharmacol 1987;2:21-32 41. Lydiard RB. Successful utilization of maprotoline in a patient intolerant of tricyclics. J Clin Psychopharmacol 1987;7:113-114 42. Lydiard RB, Ballenger JC. Antidepressants in panic disorder and agoraphobia. J Affective Dis 1987;13:153-168 43. Evans L, Kenardy J, Schneider P et al. Effect of a selective serotonin uptake inhibitor in agoraphobia with panic attacks: A double-blind comparison of zimelidine, imipramine and placebo. Acta Psychiatrica Scandinavica 1986;73:49-53 44. Gorman J, Liebowitz MR, Fyer AJ et al. An open trial of fluoxetine in the treatment of panic attacks. J Clin Psychopharmacol 1987;7:329-332 45. Sheehan DV, Davidson J. Manschreck T et al. Lack of efficacy of a new antidepressant (Bupropion) in the treatment of panic disorder with phobias. J Clin Psychopharmacol 1983;3:28-31 46. Mavissakalian M, Perel J, Bowler K et al. Trazodone in the treatment of panic disorder and agoraphobia with panic attacks. Amer J Psychiatry 1987;144:785-787

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47. Charney DS, Woods SW, Goodman WK et al. Drug treatment of panic disorder: The comparative efficacy of imipramine, alprazolam, and trazodone. J Clin Psychiatry 1986;47:580 48. Noyes R Jr, Garvey MJ, Cook BL et al. Problems with tricyclic antidepressant use in patients with panic disorder or agoraphobia: Results of a naturalistic follow-up study. J Clin Psychiatry 1989;50:163-169 49. Shatzberg AF, Ballenger JC. Decisions for the clinician in the treatment of panic disorder: When to treat, which treatment to use, and how long to treat. J Clin Psychiatry 1991;52(2):26-32 50. Taylor CB, Hayward C, King R et al. Cardiovascular and symptomatic reduction effects of alprazolam and imipramine in patients with panic disorder: Results of a double-blind, placebo-controlled trial. J Clin Psychopharmacol 1990;10:112-118 51. Kelly D, Guirguis W, Frommer E et al. Treatment of phobic states with antidepressants. A retrospective study of 246 patients. Br J Psychiatry 1970;116:387-398 52. King A. Phenelzine treatment of Roth's calamity syndrome. Med J Aust 1962;1: 879-883 53. Sargant W. The treatment of anxiety states and atypical depressions by the monoamine oxidase inhibitor drugs. J Neuropsychiatry 1962;3:96-103 54. West ED, Dally PJ. Effects of iproniazid in depressive syndromes. Br Med J 1959;1:1491-1494 55. Mountjoy CQ, Roth M, Garside RF et al. A clinical trial of phenelzine in anxiety depressive and phobic neuroses. Br J Psychiatry 1977;131:486-492 56. Solyom L, Heseltine GFD, McClure DJ et al. Behavior therapy versus drug therapy in the treatment of phobic neurosis. Can Psychiatric Assoc J 1973;18:25-32 57. Solyom C, Solyom L, LaPierre Y et al. Phenelzine and exposure in the treatment of phobias. Biol Psychiatry 1981;16:239-247 58. Tyrer P, Candy J, Kelly D. A study of the clinical effects of phenelzine and placebo in the treatment of phobic anxiety. Psychopharmacologia 1973;32:237-254 59. Buijes J, Vallejo J. Therapeutic response to phenelzine in patients with panic disorder and agoraphobia with panic attacks. J Clin Psychiatry 1987;48:55-59 60. Ballenger JC, Howell EF, Laraia M, Lydiard RB. Comparison of Four Medicines in Panic Disorder. Presented at 140th Annual Meeting of the American Psychiatric Association, Chicago, May 14, 1987 61. Howell EF, Laraia MT, Ballenger JC, Lydiard RB. Lorazepam treatment of panic disorder. Presented at the 140th Annual Meeting of the American Psychiatric Association, Chicago, IL, 5/9-15, 1987 62. Sheehan DV. Tricyclic antidepressants in the treatment of panic and anxiety disorders. Psychosomatics 1986;27(S):10-16 63. Lipsedge MS, HajioffJ, Huggins P, Napier L, Pearce J, Pike DF, Rich M. The management of severe agoraphobia: A comparison of iproniazid and systematic desensitization. Psychopharmacologia 1973;32:67-80 64. Chouinard G, Annable L, Fontaine R et al. Alprazolam in the treatment of generalized anxiety and panic disorders: A double-blind, placebo-controlled study. Psychopharmacology 1982;77:229-233 65. Alexander PE, Alexander DD. Alprazolam treatment for panic disorders. J Clin Psychiatry 1986;47:301-304 66. Sheehan DV. Current views on the treatment of panic and phobic disorders. Drug Therapy 1982;12:74-93 67. Ballenger JC, Burrow GD, DuPont RL Jr. et al. Alprazolam in panic disorder and agoraphobia: Results from a multicenter trial. I: Efficacy in short-term treatment. Arch Gen Psychiatry 1988;45:413-422

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68. Lydiard RB, Lesser, Ballenger, Rubin RT, Laraia M, DuPont R. A fixed-dose study of 2 mg alprazolam, 6 mg alprazolam and placebo in panic disorder. J Clin Psychopharmacol 1992;12:96-103 69. Uhlenhuth EH, Matuzas W, Glass RM et al. Response of panic disorder to fixed dose of alprazolam or imipramine. J Aff Disorders 1989;17:261-270 70. Cross National Collaborative Panic Study, Second Phase Investigators. Drug treatment of panic disorder: Comparative efficacy of alprazolam, imipramine and placebo. Br J Psychiatry 1992;160:191-202 71. Liebowitz MR, Fyer AJ, Gorman JM et al. Alprazolam in the treatment of panic disorders. J Clin Psychopharmacol 1986;6:13-20 72. Tesar GE, Rosenbaum JF. Successful use of clonazepam in patients with treatment-resistant panic disorder. J Nerv Ment Dis 1986;174:477-482 73. Tesar GE. High-potency benzodiazepines for short-term management of panic disorder: The US experience. J Clin Psychiatry 1990;51(5 suppl):4-10 74. Pollack MH, Tesar GE, Rosenbaum JF et al. Clonazepam in the treatment of panic disorder and agoraphobia: A one year follow-up. J Clin Psychopharmacol 1986; 6:302-304 75. Tesar GE, Rosenbaum JF, Pollack MH et al. Clonazepam versus alprazolam in the treatment of panic disorder: interim analysis of data from a prospective doubleblind, placebo-controlled trial. J Clin Psychiatry 1987;48(10 suppl):16-19 76. Tesar GE, Rosenbaum JF, Pollack MH. Unpublished data 77. Dunner DL, Ishiki D, Avery DH et al. Effect of alprazolam and diazepam on anxiety and panic attacks in panic disorder: A controlled study. J Clin Psychiatry 1986;47:458-460 78. Rickels K, Schweizer EE. Benzodiazepines for treatment of panic attacks: A new look. Psychopharmacol Bull 1986;22:93-99 79. Schweizer EE, Fox I, Case WG et al. Alprazolam versus lorazepam in the treatment of panic disorder. Presented at the New Clinical Drug Evaluation Unit meeting, May 1987; Key Biscayne, Fl 80. Charney DS, Woods SW. Benzodiazepine treatment of panic disorder: A comparison of alprazolam and lorazepam. J Clin Psychiatry 1989;50:418-423 81. Beaudry P, Fontaine R, Chouinard G. Bromazepam, another high potency benzodiazepine for panic attacks (letter). Am J Psychiatry 1984;141:464-465 82. Fogelson DL. Lorazepam and oxazepam in the treatment of panic disorder (letter). J Clin Psychopharmacol 1988;8:150 83. Ballenger JC, Pecknold J, Rickels K, Sellers EM. Medication discontinuation in panic disorder. J Clin Psychiatry 1993;54(10S):1-7 84. Katschnig H, Stolk J, Kierman GL et al. Discontinuation experience and long-term treatment follow-up of participants in a clinical drug trial for panic disorders. In: Racagni G, Brunellon, Fukuda T, eds. Biol Psy Int Congress, Series 968, Vol. 1, New York: Elsevier, 1991:657-660 85. Ballenger JC, Lydiard RB, Laraia MT, Fossey MD, Zealberg JJ. Use of carbamezepine in alprazolam discontinuation. Presented at Benzodiazepine Discontinuation, at the 144th Annual Meeting of the American Psychiatric Association, New Orleans, LA, May 14, 1991 86. Klein E, Uhde TW, Post RM. Preliminary evidence for the utility of carbamazepine in alprazolam withdrawal. Am J Psychiatry 1986;143:235-236 87. Nagy LM, Krystal JH, Woods SW, Charney DS. Clinical and medication outcome after short-term alprazolam and behavioral group treatment in panic disorder: 2.5 year naturalistic follow-up study. Arch Gen Psychiatry 1989;46(11):993-999

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88. Barlow DH, Craske MG, Cerny JA, Klosko JS. Behavioural treatment of panic disorder. Behavior Therapy 1989;20:261-282 89. Craske MG, Brown TA, Barlow DH. Behavioral treatment in panic disorder: A twoyear follow-up. Behavior Therapy 1991;22:289-304 90. Klosko JS, Barlow DH, Tassinari R, Cerny JA. A comparison of alprazolam and behavior therapy in treatment of panic disorder. J Consult Clin Psychol 1990;58:7-84 91. Sokol L, Beck AT, Greenberg RL, Wright FD, Berchick RJ. Cognitive therapy of panic disorder: A non-pharmacological alternative. J Nerv Ment Dis 1989; 177:711-716 92. Michelson L, Marchione K, Greenwald M, Glanz L, Testa S, Marchione M. Panic disorder: Cognitive-behavioral treatment. Behav Res Ther 1990;28:141-153 93. Clark DM. A cognitive approach to panic. Behavior Research and Therapy 1986a;24:461-470 94. Clark DM. Cognitive therapy for anxiety. Behavior Psychother 1986b;14:283-294 95. Margraf J, Schneider S. Outcome and active ingredients of cognitive-behavioral treatments for panic disorder. Paper presented at the Annual Conference of the Association for Advancement of Behaviour Therapy, New York, 1991 96. Beck AT, Sokol L, Clark DA, Berchick B, Wright F. Focused cognitive therapy of panic disorder: A crossover design and one-year follow-up, submitted for publication (1991) 97. Marks IM. Fears, Phobias, and Rituals: Panic. University Press, 1987, 190-191 98. Marks IM, Horder J. Phobias and their Management. Br Med J 1987;295:689-691 99. Rapee RM. A case of panic disorder treated with breathing retraining. J Behav Ther Exp Psy 1985;10:63-65 100. Rappee RM, Barlow DH. Panic Disorder: Cognitive-behavioral treatment. Psy Annals 1988;18:473-477 101. Clark DM, Gelder MG, Salkovskis PM, Clalkley AJ. Respiratory control as a treatment for panic attacks. J Behav Ther Exp Psychiatry 1985;16:23-30 102. Salkovskis PM, Jones DRO, Clark DM. Respiratory control in the treatment of panic attacks: Replication and extension with concurrent measurement of behavior and pCO2. Br J Psychiatry 1986;148:526-532 103. Gitlin B, Martin M, Shear et al. Behavior therapy for panic disorder. J Nerv Ment Dis 1985;173:742-743 104. Shear MK. Cognitive behavior therapy efficacy for panic disorder. Paper presented at American Association for Behavioral Therapy, Boston, 1987 105. Barlow DH, Cohen AS, Waddell MT et al. Panic and generalized anxiety disorders: Nature and treatment. Behav Ther 1984;15:431-449

DISCUSSION
Dr. Billings, Baton Rouge: Jim, how do you differentiate panic disorder clinically from a pheochromocytoma? As one looks at the blood, how does one differentiate one from another? Does one find pheochromosomal-type compounds within the blood? Also, do beta blockers play a role in attenuating these attacks or in treating them once they occur? Dr. Ballenger: Great questions and not surprising ones. The most important thing I would actually encourage you to take away from this talk is that in my entire career of 25 years of seeing panic disorder, I have never seen a pheo. I have looked for hundreds but never even found one. Nor have my colleagues. Although I am not really going to be able to explain it very well, the symptom pattern doesn't overlap very much. Panic disorder is quite common, pheos are incredibly rare. The things that we can say about how

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you could potentially tell them apart is that the pheo attack is more precipitous, but what can be more precipitous than panic attacks? In some ways it feels that with the pheo there's more flushing and there's more dizziness, but flushing and dizziness are very common symptoms in panic disorder as well. When we look in the urine or in the blood, sometimes one finds increases in norepinephrine indices in panic disorder, but they are generally modest and certainly not in the pheo range. Panic disorder patients are generally young, healthy females, which is some help, and they are healthy and, of course, normotensive. Beta blockers are helpful in a minor way in that they lower the heart rate. Tachycardia is very frightening to most people with panic disorder. However, when they are put head-to-head against really effective medicines in this syndrome, such as the antidepressants and medicines, like alprazalam, they are nowhere near as effective. Dr. Bransome, Augusta: A quick comment and a question. If there is any confusion with a pheochromocytoma, a clonidine suppression test will readily differentiate the two problems. The question relates to Barlow's syndrome. We've seen a striking coincidence of Barlow's syndrome of prolapsing mitral valve and panic disorder. There is a common element with mitral valve prolapse with at least some of Barlow's patients of sympathetic nervous system hyperactivation. Would you comment? Dr. Ballenger: I'd love to. That's a very complex area and the studies of the incidence of mitral valve prolapse and panic disorder range from 0% to 50%, bordering around 35% of panic disorder patients who also have prolapse. We did a study, which I can't help but believe and, in fact, found that 15% of the panic disorder patients had what we would call true prolapse. They also had a click and murmur and had prolapse of about 4 or 5 mm on echocardiography. We also found that 25% more had just echo criteria of more than 2 or 3 mm prolapse, but no click or murmur. We thought that was interesting, and that maybe there were two kinds of prolapse. However, for the first time we had an adequate control group. We took young, thin normal women with a short AP diameter who were extremely healthy. They all had passed Bruce's exercise stress tests. They were asymptomatic, etc. When we broke the blind, we were astounded to discover that 5% of them had click, murmur and prolapse greater than 5 mm and 30% more had prolapse on the echo of 2 to 3 mm but no click-murmur. The 5% and 15% figures were not statistically different. This suggested to us that there may be some greater incidence, but that maybe what we are seeing in this syndrome that accounts for 35% to 40% is actually a phenomenon of the sensitivity of the echo. Maybe these people's hearts are beating harder and faster perhaps from a sympathetic overdrive that is associated with the illness. Dr. Wooley who initially described mitral valve prolapse said at a symposium with me that maybe both of these things come from a common genetic stem. Maybe they have a common etiology and they just look different. It's a very interesting and somewhat unsolved field, obviously. Dr. Schreiner, Georgetown: Jim, that was a very effective presentation. Ifyou really do regularly take three or six hours for a talk like this, you're exceeding the cost-benefit ratio for your other audiences. I noticed that you got total resolution of physical disease in one of your examples. How many of the ones who had a physical disorder and panic disorder cleared it when you resolved the physical syndromes? Dr. Ballenger: Resolved the "symptoms?" Dr. Schreiner, Georgetown: No, the actual disease. Suppose you have panic disorder associated with angina and you have a successful balloon angioplasty. Does the panic disorder disappear? In how many people with both panic disorder and organic disease was the disease involved in the genesis of the panic disorder? Dr. Ballenger: Unfortunately, I can't answer that. I wish I could. We haven't even studied the bigger group, the group that doesn't have demonstrable coronary artery disease. What happens to them when they are treated psychiatrically? Although the work

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that has been done suggests they do better, still they don't do as well as the patients who never went that route and became convinced in their own mind that they had a cardiac illness. Part of what I believe, is that this represents the "cardiac cripple" notion that we have been thinking about for years. These are people who come to see a cardiologist, get studied or are told they have normal coronary arteries and have no illness. As you know, 50% of them never go back to work, 80% of them keep looking for a doctor. I think a lot of them have panic disorder. We haven't even studied them adequately, much less the patient who clearly has angina and who has the coronary artery lesions cleared, and then see what happens to the panic disorder. My guess is that it would get better, but that there would be a lot of residual because one of the most difficult things I've ever seen in clinical medicine personally, is to try to change somebody's mind who is convinced he has coronary artery disease. Even when you tell them that their coronaries are normal, they still have these very, very frightening panic and cardiovascular symptoms, and they stay very fixed on the idea that they really do have coronary disease.