Antidepressants in panic disorder and agoraphobia

Journal of Affectwe Disorders, 13 (1987) 153 168

153

Elsevier JAD 00488

Antidepressants in panic disorder and agoraphobia R. Bruce Lydiard and James C. Ballenger Department of PsTchiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, U.S.A.

(Received December 1986) (Accepted 16 June 1987)

Summary A survey of the literature on the use of antidepressants for treating patients with panic disorder and agoraphobia with panic attacks suggests that both tricyclic antidepressants and monoamine oxidase inhibitors have efficacy in blocking panic attacks. While we have witnessed dramatic progress in the pharmacological treatment of panic-related disorders over the past 20 years, m a n y unresolved questions remain. Further understanding of dose-response relationships, optimal duration of treatment and predictors of relapse are needed to optimize pharmacological treatment of panic-related disorders. Studies comparing the relative efficacy and side effects spectrum of various effective medications are needed. It is not presently possible to specify which patients will require medication or behavioral treatment alone, and studies to date have incompletely examined this murky issue. Further prospective studies directly comparing the pharmacological and behavioral treatments will help further elucidate the relative contribution of each treatment and possibly clarify which patients require both treatments. Controlled studies in the future which standardize dosage and duration of treatment and use comparable, objective outcome variables promise to provide important theoretical and clinical information regarding the pharmacological treatment of panic-related disorders.

Key words: Tricyclic antidepressant; Monoamine oxidase inhibitor; Panic disorder; Agoraphobia

Introduction Descriptions of the syndrome of panic attacks with or without phobic avoidance behavior have appeared in the medical literature for centuries. Examples of the diagnostic labels attached to panAddress for correspondence: Dr. R.B. Lydiard, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425, U.S.A.

ic-related disorder include neurasthenia, Da Costa's syndrome, irritable heart, phobic anxiety, depersonalization syndrome, anxiety hysteria and many others. Effective medical treatments for these syndromes were lacking until the early 1960s when open trials and some controlled studies indicated that monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) were effective in blocking panic attacks and reducing phobias (West and Dally 1959; King 1967; Sargant 1967; Klein and Fink 1962; Klein 1964). These discoveries

0165-0327/87/$03.50 © 1987 Elsevier Science Publishers B.V. (Biomedical Division)

154 began a new era in our ability to treat these patients pharmacologically. Over the past two decades, and particularly over the past several years, substantial advances have been made in our ability to treat panic-related syndromes. Considerable evidence indicates that the presence of spontaneous panic attacks is an indication for very specific pharmacological agents which block their recurrence and, secondarily, their behavioral sequelae. This review will examine the current status of the therapeutic use of antidepressants for treating panic-related disorders. Pertinent studies for each pharmacological class will be reviewed and discussed, and practical guidelines for the clinical use of these agents will be outlined. Finally, remaining clinical questions and directions for future research will be addressed briefly.

Panic disorder and agoraphobia with panic attacks Individuals with panic disorder experience spontaneous and situationally bound attacks of profound anxiety characterized by a feeling of impending doom or imminent death, associated with symptoms of autonomic arousal such as palpitations, dyspnea, sweating, tremulousness, etc. In most, but not all, of such affected patients, anticipatory fear of having more panic attacks occurs, followed by avoidance of various situations in which the individual might feel vulnerable if such an attack were to recur. The recent revision of the DSM-III anxiety disorders category gives central importance to the presence or absence of panic attacks (American Psychiatric Association 1987). Accordingly in DSM-III-Revised, patients who experience panic attacks but do not develop avoidance behavior are given the diagnosis of panic disorder (PD) - uncomplicated. Those who develop only a few associated avoidance behaviors will receive the diagnosis of PD with agoraphobia (with limited phobic avoidance), and those developing significant, pervasive avoidance patterns will receive the diagnosis of PD with agoraphobia (with extensive phobic avoidance). Individuals who exhibit characteristic avoidance behavior but either never have or no longer experience panic attacks will retain the diagnosis of agoraphobia without panic attacks; it is not known whether the pharmacotherapy of this

latter group of patients is different from that of patients with current panic attacks.

Mechanism of antipanic action of antidepressants Much accumulated evidence indicates that increased central and peripheral noradrenergic activity is associated with anxiety states (Rubin et al. 1970; Sweeney et al. 1978; Ko et al. 1983; Ballenger et al. 1984a, b; Charney and Heninger 1985, 1986; Nesse et al. 1985; Lydiard et al. 1986). Redmond and colleagues have suggested that the locus ceruleus (LC), a midbrain noradrenergic nucleus which contains approximately 50% of brain noradrenergic neurons, may mediate the fear/arousal response in primates (Huang et al. 1977: Redmond 1979; Redmond and Huang 1979). If the LC is electrically stimulated, primates exhibit the same fear response as when threatened in the wild. Pharmacological studies have shown that agents which increase the rate of LC firing can cause anxiety of even panic proportions in humans (Holmberg and Gershon 1961; Boulenger et al. 1984; Charney et al. 1984) while agents which reduce LC firing rates are anxiolytic (Nyback et al. 1975; Aghajanian 1978; Svensson 1980; Grant et al. 1980). Although this remains a controversial area, reduction in LC activity may well be an important component of the clinical antipanic effect of the TCAs and MAOIs. The following sections will examine clinical aspects of the use of antidepressants in panic-related disorders.

Tricyclic antidepressants

Panic attack blocking effects Several placebo-controlled studies have compared the efficacy of imipramine and placebo in blocking panic attacks (Klein 1964, 1967; Ballenger et al. 1977; Sheehan et al. 1980; Zitrin et al. 1980, 1983; Marks et al. 1983; Telch et al. 1985; Evans et al. 1986; Matuzas et al. 1986; Mavissakalian and Michelson 1986). The majority of the investigators reported a statistically significant difference favoring imipramine over placebo. In some of these studies actual panic frequency was not presented, but panic blocking effects were reported (Klein 1964, 1967; Ballenger et al. 1977; Sheehan et al. 1980; Matuzas 1986). The three placebo-controlled studies utilizing clomipramine

155 included patients with obsessive-compulsive disorder and social phobia (Escobar and Landbloom 1976; Amin et al. 1977; Karabanow 1977). While patients with agoraphobia improved more with clomipramine treatment than with placebo, effects on panic were not specified. Several open trials support the contention that TCAs including imipramine (Mavissakalian and Michelson 1983; Ballenger et al. 1984a; Garakani et al. 1984; Munjack et al. 1985; Charney et al. 1986) and clomipramine (Carey et al. 1975; Colgan 1975; Waxman 1975; Beaumont 1977; Gloger et al. 1981; Grunhaus et al. 1984) and desipramine (Lydiard 1987a) have antipanic efficacy. Several studies used medication alone, but many employed concomitant behavioral therapy or psychotherapy, thus obscuring the relative contributions of each treatment to the panic attack blocking effects reported. Overall, the data support the efficacy of the TCAs, particularly imipramine, as effective panic attack blocking agents. Combined medication and behavioral therapy As noted, many controlled studies used active drug versus placebo plus various behavioral treatments for all patients, thus obscuring the relative contribution of each treatment. A few studies have attempted to examine systematically the question of the contributions of medication alone or behavior therapy alone. Mavissakalian et al. (1983) treated a group of agoraphobics with imipramine alone (mean 125 m g / d a y ) and imipramine and self-exposure homework for 12 weeks and found relatively little difference in panic measures at the end of the study. However, they noted significant differences favoring the combined treatment on overall symptom severity, phobic anxiety and depression measures. Telch et al. (1985) reported a carefully conducted study in which patients were given (a) imipramine with instruction to avoid exposure to anxiety evoking situations for the first 8 study weeks; (b) imipramine plus 5 weeks' antiexposure treatment followed by intensive therapist-aided exposure and subsequent behavioral instructions; or (c) placebo plus the above behavioral treatments. Both the imipramine-no exposure group and placebo-exposure groups improved on several measures but only the combined treatment experienced a reduction in panic attack

frequency. In contrast, Mavissakalian and Michelson (1986a) reported definite antipanic effects from behavioral treatment alone. In their study, behavioral treatment (self-instruction plus flooding exposure) plus placebo treatment proved to be quite effective in reducing panic frequency. The corresponding group, which received identical behavioral treatment plus imipramine, showed statistically and clinically significant differences favoring the combined treatments. Marks et al. (1983) utilized behavioral treatment plus imipramine or placebo, and reported no differences between treatments in this study. However, reanalysis of these data suggested that imipramine plus behavioral therapy was superior to placebo plus behavior therapy on some measures (Raskin 1983) and suggested that an enhancement of improvement may occur with the combined treatments. However, a medication-no exposure treatment control group was not included in this study, so firm conclusions cannot be made. Klein et al. (1987) recently reanalyzed data from two earlier studies (Zitrin et al. 1980, 1983). They suggest that exposure affects avoidance behavior but not panic frequency. Imipramine was shown to affect panic initially and reduce avoidance subsequently. These investigators concluded that adding imipramine to exposure therapy is necessary for panic control and that medication would 'substantially improve exposure and exposure maintenance'. Despite theoretical differences noted among various investigators, the evidence to date indicates that overall improvement and perhaps specific antipanic effects may result from either medication or behavioral therapy. However, the combination is more likely to result in a more rapid and more complete level of improvement than either treatment alone. More clarification will emerge as further studies systematically examine this controversial issue. Imipramlne versus other medications To date, only three studies have directly compared imipramine with another medication under double-blind, placebo-controlled conditions. One study (Ballenger et al. 1977; Sheehan et al. 1980) reported the results of a study utilizing imipramine (150 mg/day), phenelzine (45 m g / d a y ) or placebo plus biweekly group supportive therapy and self-exposure homework for a group of phobic

156 patients, most of whom had panic attacks and agoraphobia. At the end of 12 weeks, both active medication groups were significantly more improved than the placebo-treated group. Phenelzine-treated patients showed a statistically significantly greater improvement in global ratings than the imipramine-treated group. Evans et al. (1986) recently studied imipramine, zimelidine, and placebo and found no difference between imipramine and placebo, but found a significant effect favoring zimelidine over both treatments. Matuzas et al. (1986) reported preliminary findings from an 8-week study using a fixed dose (225 m g / d a y ) of imipramine versus alprazolam (2 or 6 m g / d a y ) in patients with panic disorder. Imipramine and 6 mg alprazolam were roughly comparable for patients completing the study; alprazolam had a faster onset of antipanic effect. Two other double-blind studies have compared imipramine to benzodiazepines. Kahn et al. (1981) found imipramine (mean 132 rag/day) was superior to chlordiazepoxide (55 m g / d a y ) in blocking panic attacks and alleviating depression in a group of agoraphobics. Rizley et al. (1986) combined imipramine (mean 132.5 m g / d a y ) or alprazolam (mean 2.8 m g / d a y ) with supportive treatment in a 12-week study of patients with PD, agoraphobia or panic attacks with mixed phobias. Both medications were shown to be efficacious in reducing various anxiety measures to a comparable degree by study end, but alprazolam had a faster onset of action. Munjack et al. (1985) compared imipramine with propranolol in a crossover study using a single-blind design and found that both propranolol and imipramine had approximately equal efficacy in reducing panic attack frequency in 23 PD patients. Charney et al, (1986) conducted an open study comparing imipramine, alprazolam, and trazodone. They reported that imipramine and alprazolam were approximately equally efficacious while trazodone was relatively less effective in blocking panic attacks. In summary, the limited data available suggest that imipramine and alprazolam are roughly comparable, although alprazolam appears to have a more rapid onset of therapeutic effect. The only study directly comparing a tricyclic and a MAOI suggested a slight edge for phenelzine over imipramine (Ballenger et al. 1977; Sheehan et al. 1980). Clearly, further studies

comparing imipramine with other antidepressants and benzodiazepines under controlled conditions are indicated.

Dose-response relationships There are five studies which have examined the relationship between plasma levels and clinical response to TCAs. Ballenger et al. (1984a) studied 36 agoraphobics who received imipramine and 12 weeks of self-exposure instruction in a group setting. Half the patients received doses of imipramine which maintained plasma levels at 100-150 n g / m l (imipramine plus desipramine) and the other half received doses sufficient to maintain plasma levels at 200-250 ng/ml. Both groups improved substantially and no important differences were discerned, suggesting approximately equal efficacy for each of the plasma levels. In contrast, Mavissakalian et al. (1984) found a correlation between clinical response and imipramine (but not desipramine) levels in a small group (n = 15) of agoraphobics. In two studies, no relationship was found between imipramine plus desipramine plasma levels and clinical response (Marks et al. 1983; Nesse et al. 1984b). Lydiard (1987a) recently reported PD patients receiving desipramine for 12-16 weeks fared better if plasma levels were greater than 125 ng/ml. Patients with plasma levels below this range responded after an increase in dosage sufficient to achieve a plasma level of over 150 n g / m l in this study. Mavissakalian and Perel (1985) reported that patients receiving less than 150 r a g / d a y orally of imipramine did no better than placebo-treated patients, suggesting that a lower limit of effectiveness may exist for imipramine. Overall, the data are conflicting. What positive results there are suggest a threshold for antipanic efficacy for imipramine and desipramine. Clearly, more studies utilizing a fixed dose or stratified plasma level design will be helpful in elucidating possible dose-response relationships for the TCAs. These data also raise the possibility that a number of patients in the placebo-controlled imipramine studies (Table 1) may have been undertreated.

Negative studies Three placebo-controlled studies of the efficacy of TCAs have reported a lack of beneficial effects

157 TABLE 1 D O U B L E - B L I N D STUDIES C O M P A R I N G I M I P R A M I N E A N D PLACEBO IN P A N I C - R E L A T E D D I S O R D E R S Investigator (year)

Patient sample

Medication treatment daily dosage (mean dosage) + other treatment

Klein (1964)

Inpatients with panic

IMI a up to 300 mg Pbo b

Klein (1967)

Inpatients with phobic anxiety reactions

Zitrin et al. (1980)

n

Duration (weeks)

Results

Comments

7 6

5

IMI >> Pbo in blocking panic

Small sample. Panic frequency not specified

IMI up to 300 m g Pbo

9 10

6

IMI > Pbo on global ratings on anxiety and panic

Retrospective diagnosis in part of sample

Female outpatients with agoraphobia

IMI up to 300 m g + BT ~ or supportive therapy Pbo + BT

41

26

IMI > Pbo on panic frequency, phobia and global outcome ratings

BT or supportive therapy given to all patients

Sheehan et al. (1980)

Outpatients with panic attacks and phobias

IMI 150 mg + BT Pbo + BT

18 22

12

IMI > Pbo on SCL-90 (phobic anxiety) and Symptom Severity and Avoidance, Work and Social Disability Scales

BT given to all patients. IMI dosage modest. Panic frequency not specified

Marks et al. (1983)

Outpatients with agoraphobia

IMI up to 200 mg (mean 110 at week 26) + BT or relaxation Pbo + BT or relaxation

23

28

N o differences in IMI vs. Pbo groups

IMI dosage modest to low by end of study. All patients received BT homework

Outpatients with agoraphobia and mixed phobia

IMI up to 300 mg (mean 204 mg) + BT or supportive therapy Pbo + BT

23

26

IM1 > Pbo in reducing panic frequency in agoraphobics and mixed phobics; no differences in simple phobias noted

All patients received concomitant BT or psychotherapy

Outpatients with agoraphobia

IMI up to 300 mg (mean 179 mg) IMI up to 300 mg (mean 181 mg) + BT Pbo + BT

12

26

IMI + BT > Pbo + BT > IMI alone, No antipanic effect for IMI apparent

Small samples. 'Anti-exposure' instructions given initially

IMI up to 200 mg (mean 130 mg) + BT, flooding or both Pbo + BT, flooding, or both

31

12

IMI > Pbo on phobia and depression ratings

BT or flooding given to all patients. IMI dosage modest

IMI 150 mg Pbo

16 7

6

IMI = Pbo on anxiety and depression ratings

Small samples. Short treatment period. IMI dose modest. Panic frequency not specified

Zitrin et al. (1983)

Telch et al. (1985)

Mavissakalian and Michelson (1986a)

Outpatients with agoraphobia

Evans et al. (1986)

Outpatients with agoraphobia

35

22

24

13 12

31

a IMI = imipramine; b Pbo = placebo; ~ BT = behavioral therapy.

158 in patients with panic-related disorders. Marks et al. (1983), as noted above, found no benefit from imipramine treatment. However, reanalysis of these data indicated that imipramine was superior to placebo on some measures (Raskin 1983). Telch et al. (1985) reported no apparent effect in panic blocking effect from imipramine, although most measures (total phobia, unaccompanied excursions from home, and some depression ratings) showed improvement. The authors noted the treatment groups were small (10 or less by study end). Unlike other studies, these investigators instructed their imipramine-no exposure patients not to expose themselves to anxiety-provoking stimuli. Replication of these findings would be of considerable clinical and theoretical interest. The most recent negative study with imipramine by Evans et al. (1986) was a study comparing imipramine, zimelidine and placebo which was terminated early due to safety concerns regarding zimelidine. Study duration (6 weeks) was relatively short, groups were small, and lack of information about concurrent behavioral therapy or psychotherapy and panic frequency make this study difficult to compare to others.

Response of simple phobics Controlled studies utilizing TCAs indicate that the phobic patients who respond are those with agoraphobia or mixed phobias (i.e., all of whom experienced panic attacks) versus an apparent lack of effect in patients with specific (i.e., simple) phobias (Ballenger et al. 1977; Sheehan et al. 1980; Zitrin et al. 1983). This suggests the antiphobic effectiveness is most apparent in, and is likely specific to, phobic patients who experience panic attacks.

Mavissakalian and Michelson 1986a) but not in others (Ballenger et al. 1977, 1984a; Sheehan et al. 1980). Also, the outcome measures reported across studies were variable. For example, not all studies measured panic attack frequency, but instead reported global outcome measures such as phobic anxiety and avoidance behavior. It is now generally accepted that both avoidance behavior and panic frequency should be measured simultaneously in order to more accurately assess treatment outcome. Clearly, there is a need for standardization of measures of diagnosis, medication dosage (preferably with standardized plasma levels), concomitant behavioral treatment and duration of treatment, avoidance behavior, panic attack frequency and depression (see below) in order to meaningfully compare studies in the future. Despite the limitations of the studies, there is ample evidence that the TCAs, particularly imipramine, are quite effective in treating panic-related disorders. Monoamine oxidase inhibitors

Early clinical trials suggested that monoamine oxidase inhibitors (MAOIs) were effective in treating phobic disorders (King, 1962; Sargant 1962; West and Dally 1969; Kelly et al. 1970). The placebo-controlled studies utilizing MAOIs are shown in Table 2 (Tyrer et al. 1973; Lipsedge et al. 1973; Solyom et al. 1973, 1981; Ballenger et al. 1977; Sheehan et al. 1980; Mountjoy et al. 1977). Five of the six studies employed phenelzine; one employed iproniazid. In general, evidence supporting the efficacy for the MAOIs is somewhat less compelling than for the TCAs but strongly suggests that they are also effective in treating the panic-related disorders.

Comment Diagnostic heterogeneity in the patient samples studied in the TCA studies may have contributed to variations in outcome measures. Mixed groups of phobic patients were studied in several instances. Some studies included only patients with agoraphobic levels of avoidance, others studied inpatients (more likely to be severely ill), and still others studied patients with variable levels of phobic avoidance. Patients with depression were excluded in some studies (Marks et al. 1973;

Panic attack blocking effects None of the placebo-controlled studies in Table 2 report the effects of MAOIs on the actual frequency of panic attacks, although one group (Ballenger et al. 1977; Sheehan et al. 1980) indicated that patients receiving phenelzine or imipramine experienced a reduction in spontaneous panic. In a retrospective study, Kelly et al. (1970) reported that 58% of 74 phobic patients receiving phenelzine for one year were free of panic attacks.

159 with an average of 55 mg/day of phenelzine, documenting that it blocks panic attacks. Our group (Howell et al. 1987) recently reported an

Buiges and Vallejo (1987) recently reported that 16 of 16 PD patients and 18 of 19 agoraphobics were panic-free after 6 months of open treatment

TABLE 2 DOUBLE-BLIND STUDIES C O M P A R I N G MAOIs A N D PLACEBO IN PANIC-RELATED DISORDERS Investigator (year)

Patient sample

Medication treatment daily dosage (mean dosage) + other treatment

n

Tyrer et al (1973)

Outpatients with agoraphobia and social phobia

Phen ~ up to 90 mg (mean 38.5 mg) Pbo b

16

Outpatients with agoraphobia, social phobia, or specific phobia

Phen up to 45 mg and brief psychotherapy Pbo + brief psychotherapy (flooding alone also studied)

10

Lipsedge et al. (1973)

Housebound agoraphobics

Iproniazid up to 150 mg Pbo (Methohexitone-assisted or standard BT c or no BT used with each drug treatment)

32 28

Mountjoy et al. (1977)

Inpatients and outpatients with anxiety neurosis and phobic neurosis

Phen up to 45 m g + diazepam 11 5 mg t.i.d. Pbo + diazepam 5 mg t.i.d. 19

Sheehan et al. (1980)

Outpatients with panic attacks and phobias

Pben 45 mg + BT Pbo + BT

17 22

12

Solyom et al. (1981)

Outpatients with agoraphobia or social phobia

Phen up to 45 mg with or without BT Pbo with or without BT

20

8

Solyom et al. (1973)

Duration (weeks)

Results

Comments

Phen > Pbo on secondary phobia, phobia, anxiety, depression and global outcome

Marginal drug effect. Mixed sample. Low Phen dosage. Panic symptoms not specifled.

Phen > Pbo in reducing WolpeLange, phobia, neuroticism and social maladjustment measures. Flooding > Phen Wolpe-Lange rating improvement

Mixed sample. Panic symptoms not specifled. Patients received psychotherapy

8

Iproniazid > Pbo in reducing anxiety but not avoidance

21 of 60 patients had previous MAOI treatment. Panic symptoms not detailed. Concomitant behavioral treatment given

4

Phen + diazepam > Pbo + diazepam on social phobia, but not on 6 other measures for phobic group. Pbo + diazepam > Phen + diazepam on anxiety for anxiety neurotics

Mixed sample. Concomitant benzodiazepine treatment. Short treatment duration. Panic symptoms not specified

Phen > Pbo in reducing phobic anxiety, avoidance and disability ratings

All patients received concomitant BT. Modest dosage of Phen, Panic frequency not specified

No treatment difference between BT and Phen. Phen > Pbo in controlling exposurerelated anxiety

Mixed sample. Small n (10) in each cell. Modest dosage. Panic symptoms not specified.

8

16

12

10

20

a Phen = phenelzine; b Pbo = placebo; c BT = behavioral therapy.

160 open study in which phenelzine (mean 53.5 m g / day) significantly reduced panic attack frequency in agoraphobics over a 12-week period. To date, no placebo-controlled studies have examined this issue adequately, but the available data strongly suggest a panic attack blocking effect for phenelzine. Information regarding other MAOIs is lacking with respect to antipanic efficacy.

Effects of combining behavioral treatment and MAOIs Solyom et al. (1973) used 'brief psychotherapy' and phenelzine (mean 38.5 rag/day) versus placebo plus brief psychotherapy and found that the combined treatment group fared slightly better on several ratings than did the placebo plus psychotherapy group. Sheehan et al. (1980) noted that phenelzine (45 m g / d a y ) plus group behavioral treatment resulted in significantly more improvement after 12 weeks' treatment than patients receiving similar group therapy with placebo. Solyom et al. (1981) used phenelzine (up to 45 m g / d a y ) and found that the phenelzine plus behavioral therapy group fared better overall than did the phenelzine-no behavioral therapy group. No apparent enhancement of behavioral therapy by phenelzine was evident, except that these patients experienced less exposure-related anxiety. The data are clearly insufficient in this area. What evidence there is generally indicates that as with TCAs, the combination of medication plus behavioral therapy is superior to medication alone. Phenelzine versus other drugs Only one placebo-controlled study has reported the comparative effects of MAOIs and other medications. Ballenger et al (1977) and Sheehan et al. (1980) measured 12-week outcomes in agoraphobics receiving fixed dosages of phenelzine (45 m g / d a y ) and imipramine (150 m g / d a y ) or placebo. In this study, phenelzine treatment was significantly better on global outcome at 12 weeks than was imipramine treatment. Recently, Howell et al. (1987) reported the results of a 12-week study utilizing phenelzine (mean 53.5 rag/day) and lorazepam (mean 3.5 m g / d a y ) with weekly group self-exposure instruction. At the end of 12 weeks' treatment both groups had improved to a significant and comparable extent.

Dose-response relationship The dosage of phenelzine or other MAOIs required for successful treatment of panic-related disorders is unknown. The usual recommendation for phenelzine treatment for depression is 1 mg/kg. Robinson et al. (1977) noted that the degree of MAO inhibition may be a crucial variable for the therapeutic effect of phenelzine in depressed patients. If 1 m g / k g phenelzine is also required to block panic, it is possible that many patients in the placebo-controlled studies utilizing phenelzine (Table 2) may have been undertreated. Negative studies Most of the placebo-controlled studies showed some advantage of MAOIs over placebo but a few showed little or no effect relative to placebo. In the study by Mountjoy et al. (1977), the investigators noted a minimal effect of phenelzine relative to placebo. However, in this study they also treated the placebo group with 15 mg of diazepam per day, possibly obscuring a phenelzine effect. Solyom et al. (1981) studied small groups ( n = 10) of mixed agoraphobics and social phobics and found no enhancement of flooding by phenelzine. These negative studies have significant design flaws as noted above. Clearly, methodological standardization is required in order to clarify important therapeutic issues (see below). Response of simple phobics In the study by Ballenger et al. (1977) and Sheehan et al. (1980) the authors noted that simple phobics tended not to improve with either imipramine or phenelzine relative to placebo. Kelly et al. (1970) included simple phobics in a retrospective report of MAOI treatment of phobic patients, but did not specify their outcome results. Thus, the very limited data suggest that beneficial effects occur primarily in phobic patients with panic attacks. Comments The difficulties in interpreting the studies with MAOIs are similar to those pertaining to the TCA studies. Several studies included mixed patient samples and failed to report the outcomes of these groups separately. Dosages may have been subtherapeutic in a number of patients receiving

161 phenelzine. As in the TCA studies, nearly all studies employed concomitant behavioral therapy or psychotherapy, thus obscuring a possible effect attributable to drug alone. Methods of evaluation varied across studies, as did duration of treatment. Importantly, the frequency and severity of panic attacks was frequently not reported. Despite these methodological flaws, the bulk of the evidence suggests that the MAOIs are effective in treating patients with panic attacks and phobic anxiety and that they are at least equal (and in one study superior) in efficacy to the TCAs. Clear delineation of therapeutic effects of MAOIs will require careful attention to numerous factors including the composition of the patient populations, dosage (and perhaps percentage of MAO inhibition achieved), duration of treatment, avoidance behavior, panic attack frequency and severity, depression, and the use of concomitant behavioral or psychotherapy.

Other antidepressants Data from controlled studies regarding the efficacy of other antidepressants in the treatment of panic-related disorders are scanty. In one controlled trial, bupropion failed to demonstrate efficacy as an antipanic agent (Sheehan et al. 1983b). Trazodone has been reported to be an effective antipanic and antiphobic treatment (Sheehan 1982; Mavissakalian et al. 1987), but this has not been a consistent finding (Charney et al. 1986). Zimelidine, a serotonin re-uptake blocker, has been reported in two open studies and one placebo-controlled study to be an effective treatment for phobic anxiety (Evans and Moore 1981; Koczkas et al. 1981; Evans et al. 1986). Desipramine (Rifkin et al. 1981; Lydiard 1987a), notriptyline (Muskin and Fyer 1981), and maprotiline (Sheehan 1982; Lydiard 1987b) have all been said to be effective antipanic agents. In our clinical experience, doxepin and amitriptyline also have efficacy as antipanic agents. However, controlled studies have not yet been reported for most of these agents.

Relapse after medication withdrawal There is relatively little information regarding the rate of relapse after discontinuation of antide-

pressant treatment in patients. In a follow-up study, Zitrin et al. (1978) noted that of 94 patients achieving marked to moderate improvement on imipramine, 30% had relapsed one year after the end of treatment versus 14% of placebo-treated patients. In a later study, these authors noted a 27% rate of relapse 6 months after discontinuation of drug treatment versus 7% in the placebo-treated group (Zitrin et al. 1980). A recent preliminary report (Zitrin et al. 1987) of 5-year follow-up from a previous study of phobic patients treated with imipramine or placebo plus behavioral or supportive psychotherapy (Zitrin et al. 1983) revealed nearly identical rates of relapse for agoraphobics (17.5%), mixed phobics (22.7%), and simple phobics (18.5%). Relapse was based on therapists' global evaluation of patient progress and specific outcome criteria were not included in this report. Cohen and co-workers (1984) followed their patients for 2 years after discontinuing imipramine treatment. At one year, about one-third of both the placebo- and imipramine-treated patients had contacted a therapist for further treatment. After 2 years about two-thirds of each group had maintained substantial improvement, although it was not clear whether these were the same patients who were improved at one year. Also, some patients received medication treatment during the follow-up period, and it was unclear if all were off medication at the follow-up evaluation. Finally, all patients had received behavioral treatment, possibly making any medication effects more difficult to detect at follow-up. Mavissakalian and Michelson (1986b) reported a carefully conducted 2-year outcome study of 62 agoraphobic patients who had received imipramine or placebo, flooding, or a combination of these. Follow-up data were collected systematically for 2 years. For approximately two-thirds of the patients, agoraphobia was no longer a problem 2 years after treatment. Approximately 30% of the patients had had interim treatment specifically for agoraphobia; these were patients who had generally done poorly initially. No treatment groups were disproportionately represented in the 30% receiving subsequent treatment. Patients who had received imipramine initially tended to show some reversals at 6 months post treatment, possibly as a function of high end-study improvement levels.

162 Solyom and associates (1973) reported that 100% of phenelzine-treated patients relapsed versus 10% of placebo-treated patients at 2-year follow-up. Tyrer and Steinberg (1975) followed 26 patients in a continued blind fashion for an average of one year after treatment with either phenelzine or placebo. Patients were allowed further drug or behavior therapy, but those patients who had received placebo were not allowed to receive MAOIs. Placebo-treated patients required more treatment in the follow-up period than patients receiving phenelzine. Furthermore, withdrawal of phenelzine frequently resulted in relapse if the patients had been treated for less than 6 months. In a large open study, Kelly and associates (1970) reported that 30% of patients who were well for one year were able to discontinue MAOIs, while 36% relapsed after discontinuation. The remaining patients (34%) in this study were advised not to discontinue medication. In a recent report, Sheehan (1986) reported the results of an uncontrolled clinical study of PD patients in which high rates of relapse after discontinuation of phenelzine (71% of 21 patients) or imipramine (86% of 14 patients) occurred, following and 8- to 12-month individually optimized treatment program. It appears that a significant proportion of patients who respond to medication treatment experience a recurrence of symptoms after discontinuation of MAOIs or TCAs, and they may relapse at a higher rate than patients who receive behavioral treatment. Our understanding of this phenomenon is currently inadequate. It has been suggested that part of this difficulty is that criteria for relapse have not been specific, and that evaluation of the recurrence of spontaneous panic attacks might be one way to objectify this important issue (Pohl et al. 1982). Also, initial differences among studies as to severity of anxiety symptoms and depression as well as length of medication treatment may be critical variables. Extent of improvement also should be considered, since some evidence suggests differing patterns of improvement between pharmacological and behavioral treatments - - especially that medication treatment may result in a higher percentage of patients becoming asymptomatic. To date there is only one published prospective study (Mavissakalian and

Michelson 1986a, b) which directly compares behavioral and pharmacological treatment with such specific criteria for improvement and relapse. Accordingly, any firm conclusions about differential relapse rates should be deferred until further studies are completed. At present, identification of those patients who can sustain improvement after withdrawal of medication is currently an important but open question requiring further investigation.

Depression, panic disorder and antidepressants Since the TCAs and MAOIs exert both antidepressant and antipanic effects, there has been speculation that panic disorder and agoraphobia with panic attacks are simply variants or subtypes of depressive illness. The majority of patients with PD experience major depression at some point in time. Anxiety and depression may occur either simultaneously or at different times within the same individual (Leckmann et al. 1983; Breier et al. 1984; Uhde et al. 1985). Several lines of evidence argue against the unitary illness hypothesis. Bupropion, an effective antidepressant, does not block panic attacks (Sheehan et al. 1983b). Individual reports indicate that in some patients panic symptoms, but not depression, may respond to imipramine (Nurnberg and Coccaro 1982). Our clinical experience similarly suggests that panic attacks and depression can respond differentially to pharmacological treatment (Lydiard et al. 1987). Additionally, antidepressants can block panic attack symptoms in non-depressed individuals with agoraphobia with panic attacks and in illnesses such as social phobia or obsessive-compulsive disorder. Controlled studies further support the contention that improvement of panic attacks is not necessarily correlated with depression. Sheehan et al. (1980) found no correlation between the level of depression at baseline and clinical outcome. Zitrin and co-workers (1980) reported that the more severely depressed agoraphobic women in their study actually responded less well to imipramine than did less depressed patients. In a study by Ballenger et al. (1984a) agoraphobic patients with moderately high Hamilton Depression Scale ratings (>_ 18) did as well as did 'non-de-

163 pressed' agoraphobics with scores below this level. In fact, patients who had greater self-rating depression scores (Beck Depression Scale and Symptom Check List-90) actually experienced less improvement in phobic symptoms and disability ratings. Neuroendocrine and sleep studies in patients with PD have provided further evidence that PD and depression are not simply one disorder (Lieberman et al. 1983; Sheehan et al. 1983a; Reynolds and Kupfer 1984; Uhde et al. 1984; Peterson et al. 1985; Lesser in press; Roy-Byrne et al. in press).

Treatment guidelines Therapeutic alliance The vast majority of patients with PD who present for treatment have been ill for many years (averaging 8-13 years) and have received a variety of diagnoses and ineffective treatments (Doctor 1982). The patients, treating physicians, and frustrated family members often feel as though they have run out of options. Some patients have been sent to psychiatrists for treatment as a 'last resort' in order to learn how to cope with their various ill-defined physical and emotional complaints. They often feel that they (or their physicians) are responsible for their failure to improve on prior treatments, and many patients feel humiliation, shame and guilt over their crippling illness. Patients often worry that they are 'crazy'. Understandably, these patients are often demoralized and angry. They have often given up hope for improvement and exhibit extensive dependence and avoidance behaviors (Klein 1981). At the point that the diagnosis is correctly made and definitive treatment planned, it is important to help the patient see the illness from a new perspective. We attempt to convey to the patient that the anticipatory anxiety and avoidance behavior can be understood as a normal response to their terrifying panic attacks. Discussion of the genetic predisposition to PD (Crowe et al. 1983; Torgersen 1983) can allow the patient to begin to conceptualize it as a medical problem. Once the burden of perceived responsibility is lifted from the patient, and they achieve some sense that effective treatment for their illness is possible, a working alliance with the treating clinician can begin.

The use of medication to block the panic attacks is introduced as a logical first step toward reducing the disabling anticipatory anxiety and avoidance behavior which develop secondary to panic attacks. The recovery process should be outlined briefly, and the patient cautioned that recovery has a gradual, variable course. In particular, the lag period between diminution of panic attacks and full behavioral recovery should be emphasized. The possible need for adjunctive behavioral treatment also should be introduced. Based on their generally disappointing previous treatment experiences, patients may require repeated assurances that they can in fact improve. In the critical early stage of treatment, the clinician should make every effort to be available in person or by phone to answer questions, provide moral support, and encourage cautious optimism.

Medical and laboratory evaluation In completing a medical evaluation, attention should be given to medical conditions which mimic or exaggerate anxiety symptoms. Reviewing current prescription and non-prescription medication is also important. In particular, the use of caffeine or other stimulants, alcohol and other sedative hypnotics should be reviewed. A physical examination and routine laboratory evaluation should be completed prior to beginning treatment to rule out any previously undetected medical conditions which might mimic PD. Many patients are taking benzodiazepines with some relief of symptoms and are reluctant to give them up. Assuring the patient that co-administration of antidepressants and modest doses of benzodiazepines is safe and often helpful early in treatment is our usual practice.

Prescribing medication The current antidepressant drugs of choice for PD are imipramine and phenelzine. While there is limited evidence that phenelzine may be more effective than imipramine overall in treating panic-related syndromes (Ballenger et al. 1977; Sheehan et al. 1980), MAOIs require dietary restrictions which often engender further anxiety in already phobic patients. Accordingly, TCAs are generally the first-line antidepressants utilized for PD. Several TCAs are probably effective, but

164 placebo-controlled studies are available only for imipramine and clomipramine (which is not available in the U.S.A.). The guidelines which follow apply specifically to imipramine, but probably apply to most TCAs.

Dosage of TCA (imipramine) Treatment should be initiated with very low dosages because patients are often apprehensive about medication and exquisitely sensitive to side effects. We usually begin with imipramine, 10 mg, preferably administered in the doctor's office to provide the often needed reassurance that the medication is safe. Dosage is then increased by 10 r a g / d a y as tolerated. After a dosage of 50 m g / d a y is reached, increases of 25 mg every 2 - 4 days to a level of 150-200 mg can usually be achieved. While some patients will respond at extremely low dosages (5-25 mg), most require 150-200 mg and others may require 300-400 m g / d a y for a satisfactory response. The relationship between plasma levels and clinical response is not well defined, and the range of effective plasma levels seems to be broad. Therefore, clinical response is currently the best guide to dosage requirements. As a general rule, however, we expect to reach at least 150 m g / d a y in most patients. TCA side effects These patients are often quite sensitive to new physical sensations, especially those which mimic anxiety symptoms. Anticholinergic effects (tachycardia, blurred vision, and dry mouth) and antia-adrenergic symptoms (postural dizziness) should be explained in advance as routine, expectable and transient. Stimulatory side effects are unfortunately common (20%) (Zitrin et al. 1978) and at times dramatic, particularly during the first several weeks of treatment. These include tachycardia, activation, restlessness, insomnia, tremulousness, and even apparent intensification of the anxiety symptoms in some patients. Patients need reassurance that these are predictable symptoms which, in most cases, will pass in 1-3 weeks. Temporarily holding or lowering the level of medication may be necessary for some patients. Occasionally divided dosages may reduce peak activating effects. We have utilized/3-blockers or benzodiazepines to manage these transient symptoms because patients

can refuse further TCA treatment as a result of their anxiety concerning these symptoms.

Dosage of MA OI Phenelzine is the most well studied and widely prescribed MAOI for panic-related disorders, although several are thought to be effective. The usual beginning dose of phenelzine is 15 mg/day, increasing by 15 r a g / d a y every 3-4 days until a dosage of 60 m g / d a y in divided dosages is achieved. Because of activating effects, the dosage is often given in the morning and early afternoon to avoid insomnia. Some patients respond to dosages of 45 mg/day, but many require 60 r a g / day to achieve full efficacy, and some require 75 or 90 mg. MA Ol side effects The unwanted effects produced by the MAOIs are similar to those of the TCAs (Ballenger et al. 1977; Sheehan et al. 1980; Kronig et al. 1983; Rabkin et al. 1985) and include tachycardia, activation, antiadrenergic (postural hypotension) and anticholinergic effects. Anticholinergic effects of the MAOIs are usually less troublesome than with TCAs; however, the postural effects of the MAOIs are frequently more pronounced. One report noted pyridoxine (vitamin B6) deficiency in several patients who were receiving phenelzine (Stewart et al. 1984). Symptoms reported included numbness, paresthesias, edema and 'shock-like' sensations, most of which remitted with 150-300 mg of pyridoxine per day. While prophylactic pyridoxine is not yet indicated, consideration of pyridoxine deficiency and a trial of supplementation may be helpful for patients who develop symptoms suggestive of pyridoxine deficiency. Treatment course The antipanic effects of the antidepressants are often observable after 2 - 4 weeks at an effective dosage level, but 6-12 weeks are often required for substantial improvement. Continued gradual reduction of the frequency and severity of panic attacks may be observed over several months while reduction in avoidance behavior continues for 6-12 months. Once a significant antipanic effect is achieved, patients can often benefit greatly from the addition of behavioral desensitization in order

165 to reduce residual phobic avoidance behavior. Exposure therapy, either self-exposure or therapistaided exposure, for treating agoraphobia has been reviewed comprehensively (Mavissakalian 1984). Basically, the elements of repetition and in vivo exposure over time seem to be critical. While the majority of patients treated with behavioral therapy alone report some improvement, some reports suggest that perhaps only 20% become asymptomatic (Dupont 1982). In contrast, generally 60-95% of patients experience dramatic improvement with the combination of antidepressants and behavioral therapy. At the present time, therefore, it seems most prudent to employ a combination of treatments which are individualized to the particular needs of the patient. Particularly during the early stages of treatment, patients may benefit from concomitant benzodiazepine treatment, both to treat anticipatory anxiety between attacks and to reduce anxiety symptoms if an unexpected panic attack occurs. The need for concomitant benzodiazepine administration usually lessens as symptoms are controlled by antidepressant medication and behavioral treatment. The optimal length of treatment with antidepressants is unknown, as was discussed earlier. The usual period of medication treatment is 6 months to one year, after which the medication generally is tapered. If patients experience a return of symptoms, medication can be reinstated and recovery to the previous level of improvement is usually rapid. After an additional 3 - 6 months, a second attempt to taper medication can be made. Using this strategy, many patients can be tapered off medication during the second year of treatment. An unknown percentage of patients, however, will require extended, possibly indefinite treatment with medication to avoid recurrence of symptoms. In conclusion, this review has attempted to highlight both recent advances and remaining gaps in our knowledge of optimal use of antidepressants for treating panic-related disorders. There are many important clinical and theoretical questions which remain unresolved. Over the next decade we should anticipate continued progress in diagnosis and treatment of panic-related disorders.

Acknowledgements The authors thank Vicki Brumbelow, Roberta Richards, Annette Spivey, and Pam Thompson for their assistance in preparing the manuscript.

References Aghajanian, G.K., Tolerance of locus coeruleus neurons to morphine and suppression of withdrawal response by clonidine, Nature 276 (1978) 186-188. American Psychiatric Association, Diagnostic and Statistic Manual of Mental Disorders, Revised, American Psychiatric Association, Washington, DC, 1987. Amin, M.M., Ban, T.A., Pecknold, J.C. and Klingner, A., Clomipramine (Anafranil) and behavior therapy in obsessive-compulsive and phobic disorders, J. Int. Med. Res., 5 (Suppl. 5) (1977) 33-37. Ballenger, J.C., Sheehan, D.V. and Jacobson, 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. Ballenger, J.C., Peterson, G.A., Laraia, M., Hucek, A., Lake, C.R., Jimerson, D., Cox, D., Trockman, C., Shipe, J.R. and Wilkinson, C., A study of plasma catecholamines in agoraphobia and the relationship of serum tricyclic levels to treatment response. In: J.C. Ballenger (Ed.), Biology of Agoraphobia, American Psychiatric Press, Washington, DC, 1984a, pp. 28-63. Ballenger, J.C., Post, R.M., Jimerson, D.C., Lake, C.R. and Zuckerman, M., Neurobiological correlates of depression and anxiety in normal individuals. In: R.M. Post and J.C. Ballenger (Eds.), Neurobiology of Mood Disorders, Williams and Wilkins, Baltimore, MA, 1984b, pp. 481-501. Beaumont, G., A large open multicentre trial of clomipramine (Anafranil) in the management of phobic disorders, J. Int. Med. Res., 5 (Suppl. 5) (1977) 116-123. Boulenger, J.P., Uhde, T.W., Wolff, III, E.A. and Post, R.M., Increased sensitivity to caffeine in patients with panic disorders: preliminary evidence, Arch. Gen. Psychiatry, 41 (1984) 1067-1071. Breier, A., Charney, D.S. and Heninger, G.R., Major depression in patients with panic disorder, Arch. Gen. Psychiatry, 41 (1984) 1129-1135. Buiges, J. and Vallejo, J., Therapeutic response to phenelzine in patients with panic disorder and agoraphobia with panic attacks, J. Clin. Psychiatry, 48 (1987) 55-59. Carey, M.S., Hawkinson, R., Kornhaber, A. and WeUish, C.S., The use of clomipramine in phobic patients - - Preliminary research report, Curr. Ther. Res., 17 (1975) 107-110. Charney, D.S. and Heninger, G.R., Noradrenergic function and the mechanism of action of antianxiety treatment, Arch. Gen. Psychiatry, 42 (1985) 473-481. Charney, D.S. and Heninger, G.R., Abnormal regulation of noradrenergic function in panic disorders, Arch. Gen. Psychiatry, 43 (1986) 1042-1054.

166 Charney, D.S., Heninger, G.R. and Breier, A., Noradrenergic function in panic anxiety, Arch. Gen. Psychiatry, 41 (1984) 751-763. Charney, D.S., Woods, S.W., Goodman, W.K., Rifkin, B., Kinch, M., Aiken, B., Quadrino, L.M. and Heninger, G.R., Drug treatment of panic disorder: the comparative efficacy of imipramine, alprazolam, and trazodone, J. Clin. Psychiatry, 47 (1986) 580-586. Cohen, S.D., Montiero, W. and Marks, I.M., Two-year followup of agoraphobia after exposure and imipramine, Br. J. Psychiatry, 144 (1984) 276 281. Colgan, A., A pilot study of Anafranil in the treatment of phobic states, Scott. Med. J., 20 (Suppl. 1) (1975) 55 60. Crowe, R.R., Noyes, R. and Pauls, D.L., A family study of panic disorder, Arch. Gen. Psychiatry, 40 (1983) 1065-1069. Doctor, R.M., Major results of a large-scale pretreatment survey of agoraphobics. In: R.L. Dupont (Ed.), Phobia: A Comprehensive Summary of Modern Treatments, Brunner/Mazel, New York, 1982. Dupont, R.L, Profile of a phobia treatment program: two year follow-up. In: R.L. Dupont (Ed.), Phobia: A Comprehensive Summary of Modern Treatments, Brunner/Mazel. New York, 1982. Escobar, J.I. and Landbloom, R.P., Treatment of phobic neurosis with clomipramine: a controlled clinical trial, Curr. Ther. Res., 20 (1976) 680-685. Evans, D.L., Davidson, J.S. and Raft, D.S., Early and late side effects of phenelzine, J. Clin. Psychopharmacol., 2 (1982) 208 210. Evans, L. and Moore, G., The treatment of phobic anxiety by zimelidine, Acta Psychiatr. Scand., 63 (Suppl. 290) (1981) 342-345. Evans, L., Kenardy, J., Schneider, P. and Hoey, H., Effect of a selective serotonin uptake inhibitor in agoraphobia with panic attacks: a double-blind comparison of zimelidine, imipramine and placebo, Acta Psychiatr. Scand., 73 (1986) 49 53. Garakani, H., Zitrin, C.M. and Klein, D.F., Treatment of panic disorder with imipramine alone, Am. J. Psychiatry, 141 (1984) 446-448. Gloger, S., Grunhaus, L., Birmacher, B. and Troudart, T., Treatment of spontaneous panic attacks with clomipramine, Am. J. Psychiatry, 138 (1981) 1215 1217. Grant, S.J., Huang, Y.H. and Redmond, Jr., D.E., Benzodiazepines attenuate single unit activity in the locus coeruleus, Life Sci., 27 (1980) 2231-2236. Grunhaus, L., Gloger, S. and Birmacher, B., Clomipramine for panic attacks in patients with mitral valve prolapse, J. Clin. Psychiatry, 45 (1984) 25-27. Holmberg, G. and Gershon, S., Autonomic and psychic effects of yohimbine hydrochloride, Psychopharmacologia, 2 ( 1961 ) 93 106. Howell, E.F., Laraia, M.T., Ballenger, J.C. and Lydiard, R.B., Lorazepam treatment of panic disorder, Presented at the 140th Annual Meeting of the American Psychiatric Association, Chicago, IL, May 9-15, 1987. Huang, H.Y., Maas, J.W. and Redmond, Jr., D.E., Evidence for noradrenergic specificity of behavioral effects of electrical stimulation of the nucleus locus coeruleus, Neurosci. Abstr., 3 (1977) 251.

Karabanow, O., Double-blind controlled study in phobias and obsessions, J. Int. Med. Res., 5 (Suppl. 5) (1977) 42 48. Kelly, D., Guirguis, W., Frommer, E., Mitchell-Heggs, N. and Sargant, W., Treatment of phobic states with antidepressants, Br. J. Psychiatry, 116 (1970) 387-398. King, A., Phenelzine treatment of Roth's calamity syndrome, Med. J. Aust., 1 (1962) 879-883. Klein, D.F., Delineation of two drug-responsive anxiety syndromes, Psychopharmacologia, 53 (1964) 397-408. Klein, D.F., Importance of psychiatric diagnosis in prediction of clinical drug effects, Arch. Gen. Psychiatry, 16 (1967) 118-125. Klein, D.F., Anxiety reconceptualized. In: D.F. Klein and J.G. Rabkin (Eds.), Anxiety: New Research and Changing Concept, Raven Press, New York, 1981. Klein, D.F. and Fink, M., Psychiatric reaction patterns to imipramine, Am. J. Psychiatry, 119 (1962) 432-438. Klein, D.F., Ross, D.C. and Cohen, P., Panic and avoidance in agoraphobia, application of path analysis to treatment studies, Arch. Gen. Psychiatry, 44 (1987) 377 385. Ko, G.N.~ Elsworth, J.D., Roth, R.H., Rifkin, B.G., Leigh, H. and Redmond, E., Panic-induced elevation of plasma MHPG levels in phobic-anxious patients, Arch. Gen. Psychiatry, 40 (1983) 425-430. Koczkas, S., Holmberg, G. and Wedin, L., A pilot study of the effect of the 5-HT-uptake inhibitor, zimelidine, on phobic anxiety, Acta Psychiatr. Scand., 63 (Suppl. 290) (1981) 328 341. Kronig, M.H., Roose, S.P., Walsh, T.B., Woodrings, S. and Glassman, A.H., Blood pressure effects of phenelzine, J. Clin. Psychopharmacol., 3 (1983) 307-310. Leckmann, J.F., Weissman, M.M., Merikangas, K., Pauls, D.L. and Prusoff, B.A., Panic disorder and major depression, Arch. Gen. Psychiatry, 40 (1983) 1055-1060. Lesser, I.M., The relationship between panic disorder and depression, J. Anx. Disord., in press. Lieberman, J.A., Brenner, R., Lesser, M., Coccaro, E., Borenstein, M. and Kane, J.M., Dexamethasone suppression test in patients with panic disorder, Am. J. Psychiatry, 140 (1983) 917-919. Lipman, R.S., Coil, L. and Shapiro, A.K., The Hopkins Symptom Checklist (HSCL), J. Affect. Disord., 1 (1979) 9-24. Lipsedge, M.S., Hajioff, J., Huggins, P., Napier, L., Pearce, J., Pike, D.F. and Rich M., The management of severe agoraphobia: a comparison of iproniazid and systematic desensitization, Psychopharmacologia, 32 (1973) 67 80. Lydiard, R.B., Desipramine in panic disorder: preliminary results from an open, fixed-dose study, Psychopharmacol. Bull., 23 (1987a) 139-140. Lydiard, R.B., Successful utilization of maprotiline in a patient intolerant of tricyclics, J. Clin. Psychopharmacol.. 7 (1987b) 113-114. Lydiard, R.B., Ballenger, J.C., Laraia, M.T., Howell, E.F., Potter, W.Z. and Lake, C.R., Noradrenergic increases in agoraphobic and panic disorders. Presented at the 139th Annual Meeting of the American Psychiatric Association, Washington, DC, May 10-16, 1986. Lydiard, R.B., Laraia, M.T., Howell, E.F. and Ballenger, J.C., Emergence of depressive symptoms in patients receiving

167 alprazolam for panic disorder, Am. J. Psychiatry, 144 (1987) 664-665. Marks, I.M., Gray, S., Cohen, D., Hill, R., Mawson, D., Ramm, L. and Stern, R.S., Imipramine and brief therapistaided exposure in agoraphobics having self-exposure homework, Arch. Gen. Psychiatry, 40 (1983) 153-162. Matuzas, W., Uhlenhuth, E.H., Glass, R.M., Javaid, J. and Davis, J.M., Alprazolam and imipramine in panic disorder A life table analysis, Presented at the 25th Annual Meeting of the America College of Neuropsychopharmacology, Washington, DC, December 8-12, 1986. Mavissakalian, M., Exposure treatment of agoraphobia. In: L. Grinspoon (Ed.), Psychiatry Update - - The American Psychiatric Association Annual Review Vol. III, American Psychiatric Association Press, Washington DC, 1984, pp. 448-460. Mavissakalian, M. and Michelson, L., Agoraphobia: relative and combined effectiveness of therapist-assisted in vivo exposure and imipramine, J. Clin. Psychiatry, 47 (1986a) 117-122. Mavissakalian, M. and Michelson, L., Two year follow-up of exposure and imipramine treatment of agoraphobia, Am. J. Psychiatry, 143 (1986b) 1106-1112. Mavissakalian, M. and Perel, J., Imipramine in the treatment of agoraphobia: dose-response relationships, Am. J. Psychiatry, 142 (1985) 1032-1036. Mavissakalian, M., Michelson, L. and Dealy, R.S., Pharmacological treatment of agoraphobia: imipramine versus imipramine with programmed practice, Br. J. Psychiatry, 143 (1983) 348-355. Mavissakalian, M., Perel, J. and Michelson, L., The relationship of plasma imipramine and N-desmethylimipramine to improvement in agoraphobia, J. Clin. Psychopharmacol., 4 (1984) 36-40. Mavissakalian, M., Perel, J., Bowler, K. and Dealy, R.S., Trazodone in the treatment of panic disorder and agoraphobia with panic attacks, Am. J. Psychiatry, 144 (1987) 785-787. McNair, D.M. and Kahn, R.J., Imipramine compared with a benzodiazepine for agoraphobia. In: D.F. Klein and J.G. Rabkin (Eds.), Anxiety: New Research and Changing Concepts, Raven Press, New York 1981, pp. 69-80. Mountjoy, C.Q., Roth, M., Garside, R.F. and Leitch, I.M., A clinical trial of phenelzine in anxiety depressive and phobic neuroses, Br. J. Psychiatry, 131 (1977) 486-492. Munjack, D.J., Rebal, R., Shaner, R., Staples, F., Braun, R. and Leonard, M., Imipramine versus propranolol for the treatment of panic attacks: a pilot study, Compr. Psychiatry, 26 (1985) 80-89. Muskin, P.R. and Fyer, A.J., Treatment of panic disorder, J. Clin. Psychopharmacol., 1 (1981) 81-90. Nesse, R.M., Cameron, O.G., Buda, A.J., McCann, D.S. and Huber-Smith, M.J., Urinary catecholamines and mitral valve prolapse in panic-anxiety patients, Psychiatry Res., 14 (1984a) 67-74. Nesse, R.M., Cameron, O.G., Curtis, G.C., McCann, D.S. and Huber-Smith, M.J., Adrenergic function in patients with panic anxiety, Arch. Gen. Psychiatry, 41 (1984b) 771-776. -

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Nurnberg, H.G. and Coccaro, E.F., Response of panic disorder and resistance of depression to imipramine, Am. J. Psychiatry, 8 (1982) 1060-1062. Nyback, H., Walters, J.R., Aghajanian, G.K. and Roth, R.H., Tricyclic antidepressants: effects on the firing rate of brain noradrenergic neurons, Eur. J. Pharmacol., 32 (1975) 302-312. Peterson, G.A., Ballenger, J.C., Cox, D.P., Hucek, A., Lydiard, R.B., Laraia, M.T. and Trockman, C., The dexamethasone suppression test in agoraphobia, J. Clin. Psychopharmacol., 5 (1985) 100-102. Pohl, R., Berchou, R. and Rainey, J.M., Tricyclic antidepressants and monoamine oxidase inhibitors in the treatment of agoraphobia, J. Clin. Psychopharmacol., 2 (1982) 399-407. Rabkin, J., Quitkin, F.M., McGrath, P., Harrison, W. and Tricamo, E., Adverse reactions to monoamine oxidase inhibitors. II. Treatment correlates and clinical management, J. Clin. Psychopharmacol., 5 (1985) 2-9. Raskin, A., The influence of depression on the antipanic effects of antidepressant drugs. Presented at Biological Considerations in the Etiology and Treatment of Panic-Related Anxiety Disorder, Boston, MA, November 4-6, 1983. Redmond, Jr., D.E., New and old evidence for the involvement of a brain norepinephrine system in anxiety. In: W.E. Fann and I. Karacan (Eds.), Phenomenology and Treatment of Anxiety, Spectrum, New York, 1979, pp. 153-203. Redmond, Jr., D.E. and Huang, Y., Current concepts. If. New evidence for a locus coeruleus-norepinephrine connection with anxiety, Life Sci., 25 (1979) 2149-2162. Reynolds, C.F. and Kupfer, D.J., Sleep EEG comparison of anxiety and depression. Presented at the 137th Annual Meeting of the American Psychiatric Association, Los Angeles, CA, May 5-11, 1984. Rifkin, A., Klein, D.F., Dillon, D. and Levitt, M., Blockade by imipramine or desipramine of panic induced by sodium lactate, Am.J. Psychiatry, 138 (1981) 676-677. Rizley, R., Kahn, R.S., McNair, D.M. and Frankenthaler, L.M., A comparison of alprazolam and imipramine in the treatment of agoraphobia and panic disorder, Psychopharm. Bull., 22 (1986) 167-172. Robinson, D.S., Nies, A., Ravaris, L.L., Ives, J. and Barlett, D., Clinical pharmacology of phenelzine, Arch. Gen. Psychiatry, 35 (1978) 629-635. Roy-Byrne, P.P., Mellman, T. and Uhde, T.W., Biologic findings in panic disorder: a focus on neuroendocrine and sleep-related abnormalities, J. Anx. Disord., in press. Rubin, R.T., Miller, R.G., Clark, B.R., Poland, R.F. and Arthur, R.J., The stress of aircraft carrier landings, lI. 3-methoxy-4-hydroxy-phenylethylene glycol excretion in naval aviators, Psychosom. Med., 32 (1970) 589-597. Sargant, W., The treatment of anxiety states and atypical depressions by the monoamine oxidase inhibitor drugs, J. Neuropsychiatry, 3 (Suppl. 1) (1962) 96-103. Sheehan, D.V., Current views on the treatment of panic and phobic disorders, Drug Ther. Hosp., October (1982) 74-93. Sheehan, D.V., Tricyclic antidepressants in the treatment of anxiety disorders. Presented at the 139th Annual Meeting

168 of the American Psychiatric Association, Washington, DC, May, 1986. Sheehan, D.V., Ballenger, J.C. and Jacobson, G., Treatment of endogenous anxiety with phobic, hysterical, and hypochondriacal symptoms, Arch. Gen. Psychiatry, 37 (1980) 51-59. Sheehan, D.V., Claycomb, J.B., Surman, O.S., Baer, L., Coleman, J. and Gelles, L., Panic attacks and the dexamethasone suppression test, Am. J. Psychiatry, 140 (1983a) 1063-1064. Sheehan, D.V., Davidson, J., Manschreck, T. and Van Wyck Fleet, J., Lack of efficacy of a new antidepressant (bupropion) in the treatment of panic disorder with phobias, J. Clin. Psychopharmacol., 3 (1983b) 28-31. Solyom, L., Heseltine, G.F.D., McClure, D.J., Solyom, C., Ledwidge, B. and Steinberg, G., Behavior therapy versus drug therapy in the treatment of phobic neurosis, Can. Psychiatr. Assoc. J., 18 (1973) 25-32. Solyom, C., Solyom, L., LaPierre, Y., Pecknold, J. and Morton, L., Phenelzine and exposure in the treatment of phobias, Biol. Psychiatry, 16 (1981) 239-247. Stewart, J.W., Harrison, W., Quitkin, F. and Liebowitz, M.R., Phenelzine-induced pyridoxine deficiency, J. Clin. Psychopharmacol., 4 (1984) 225-226. Svensson, T.H., Effect of chronic treatment with tricyclic antidepressant drugs on identified brain noradrenergic and serotonergic neurons, Acta Psychiatr. Scand., (Suppl. 280) (1980) 121-131. Sweeney, D.R., Maas, J.W. and Heninger, G.R., State anxiety, physical anxiety, and urinary 3-methoxy-4-hydroxy-phenylethylene glycol excretion, Arch. Gen. Psychiatry, 34 (1978) 1418-1423. Telch, M.J., Agras, W.S., Taylor, B., Roth, W.T. and Gallen, C.C., Combined pharmacological and behavioral treatment for agoraphobia, Behav. Res. Ther., 23 (1985) 325-335.

Torgersen, S., Genetic factors in anxiety disorders, Arch. Gen. Psychiatry, 40 (1983) 1085-1089. Tyrer, P. and Steinberg, D., Symptomatic treatment of agoraphobia and social phobias: a follow-up study, Br. J. Psychiatry, 127 (1975) 163-168. Tyrer, P., Candy, J. and Kelly, D., A study of the clinical effects of phenelzine and placebo in the treatment of phobic anxiety, Psychopharmacology, 32 (1973) 237-254. Uhde, T.W., Roy-Byrne, P., Gillin, J.C., Mendelson, W., Boulenger, J.P., Vittone, B.J. and Post, R.M., The sleep of patients with panic disorder: a preliminary report, J. Psychiatr. Res., 12 (1984) 251-259. Uhde, T.W., Boulenger, J.P., Roy-Byrne, P.P., Gerall, M.F.. Vittone, B.J. and Post, R.M., Longitudinal course of panic disorder: clinical and biological considerations, Prog. Neuropsychopharmacol. Biol. Psychiatry, 9 (1985) 39-51. Waxman, D., An investigation into the use of Anafranil in phobic and obsessional disorders, Scott. Med. J., 20 (Suppl. 1) (1975) 61-66. West, E.D. and Dally, P.J., Effects of iproniazid in depressive syndromes, Br. Med. J., 1 (1959) 1491-1494. Zitrin, C.M., Klein, D.F. and Woerner, M.G., Behavior therapy, supportive psychotherapy, imipramine and phobias, Arch. Gen. Psychiatry, 35 (1978) 307-316. Zitrin, C.M., Klein, D.F. and Woerner, M.G., Treatment of agoraphobia with group exposure in vivo and imipramine, Arch. Gen. Psychiatry, 37 (1980) 63 72. Zitrin, C.M., Klein, D.F., Woerner, M.G. and Ross, D.C., Treatment of phobias. I. Comparison of imipramine hydrochloride and placebo, Arch. Gen. Psychiatry, 40 (1983) 125-138. Zitrin, C.M., Juliano, M. and Kahen, M., Five year relapse rate after phobia treatment. Presented at the 140th Annual Meeting of the American Psychiatric Association, Chicago, IL, May 9-14, 1987.