Panic-related disorders:

Journal of A,we,yv Duorderr. Vol. 2. pp. 77-94. Printed in the USA. All nghts reserved.

IYXE Copynghl

0887.6185!88 53.00 - .M) C 1988 Pergamon Journal\. Ltd.

Panic-Related Disorders: Evidence for Efficacy of the Antidepressants R. BRUCE LYDIARD, PH.D.,

AND JAMES C. BALLENGER,

M.D.

Medico1 University

M.D.

ofSouth Carolina

Abstract-Literature examining the efficacy of antidepressants for treating patients with panic-related disorders is reviewed. The majority of studies support their effectiveness in treating patients with panic attacks and phobic avoidance behavior. While significant advances have been made, important questions remain. Optimal duration of treatment. predictors of relapse upon withdrawal of medication, dose-response relationships, and relative effects of pharmacological and behavioral treatments have yet to be ascertained. The need for standardization of studies including dosage and duration of treatment variables and use of comparable outcome measures are indicated to enhance our understanding of the optimal use of antidepressants in panic-related disorders.

INTRODUCTION Early studies indicating the effectiveness of the monoamine oxidase inhibitors (MAOIs) (King 1962; West & Dally, 1959) and tricyclic antidepressants (TCAs) (Klein, 1964; Klein & Fink, 1962) began a new era in our ability to treat patients with panic-related disorders. Considerable evidence has accumulated to suggest that patients who experience spontaneous panic attacks can benefit greatly from treatment with TCAs or MAOIs with a subsequent reduction in these attacks and their consequences. This review will examine evidence for the efficacy of the antidepressants in treating panic-related disorders (American Psychiatric Association, 1987) as well as suggesting treatment guidelines for their clinical use. Additionally, unresolved questions and directions for future research will be outlined briefly. MECHANISM

OF ACTION IN PANIC-RELATED

DISORDERS

Redmond and colleagues have reported data suggesting that the locus coeruleus (LC), a midbrain noradrenergic nucleus containing a substanAddress correspondence and reprint requests to R. Bruce Lydiard. Ph.D., IM.D., Medical University of South Carolina, Department of Psychiatry and Behavioral Sciences, 171 Ashley Avenue, Charleston, SC 29425. 77

78

R. B. LYDIARD

AND I. C. BALLENGER

tial proportion of brain noradrenergic neurons, may, in part, mediate fear and arousal responses in primates (Redmond, 1979). Various studies indicate that increased central and peripheral nonadrenergic activity may be associated with anxiety symptoms (Ballenger, Post, Jimerson, Lake. & Zuckerman, 1984: Charney & Heninger, 1985, 1986; Charney. Heninger, & Breier, 1984). Pharmacological studies indicate that agents which increase the rate of LC firing are anxiogenic (Boulenger, Uhde, Wolff, & Post, 1984: Holmberg & Gershon, 1961; Woods, Goodman, & Charney, 1986) and that agents which reduce LC firing rates are anxiolytic (Grant, Huang, & Redmond, 1980; Nyback, Walters, Aghajanian, & Roth, 1975; Svensson, 1980). It is currently thought that reduction in LC firing may be, at least in part, an important aspect of the clinical antipanic effects of the TCAs and MAOIs. TRICYCLIC ANTIDEPRESSANTS Imipramine

The 11 double-blind, placebo controlled studies comparing the efficacy of imipramine and placebo in treating panic-related disorders are shown in Table 1. In eight of these, imipramine was reported to be superior to placebo. Klein’s early reports (1964, 1967) indicated that imipramine was more effective in blocking spontaneous panic attacks than was placebo treatment, but was not particularly effective in alleviating anticipatory anxiety. Klein, Zitrin, and colleagues subsequently employed in vivo exposure therapy with imipramine and placebo in 76 agoraphobic women, and noted a statistically significant drug-placebo difference on primary phobia, spontaneous panic, and global improvement measures (Zitrin, Klein, & Woerner, 1980). They reported similar findings in a sample of patients with mixed phobias and agoraphobia but found no drug-placebo difference in patients with simple phobia (Zitrin, Klein, Woerner, & Ross, 1983). Ballenger, Sheehan, and co-workers (Ballenger, Sheehan, & Jacobson, 1977; Sheehan, Ballenger, & Jacobson, 1980) treated a group of patients with panic attacks and agoraphobia with bi-weekly supportive psychotherapy and self-exposure homework combined with either imipramine, phenelzine, or placebo. Both drug groups showed more improvement in reducing phobic anxiety, anxiety, and phobic avoidance behavior than did the placebo group. The authors also noted that patients with simple phobias derived no apparent medication benefit. Mavissakalian and Michelson (1986a) reported results from a 12 week, placebo-controlled double-blind study in which 62 agoraphobics received imipramine or placebo combined with either self-exposure instruction, therapistaided in vivo exposure (flooding), or both. They reported statistical and clinical trends on several measures favoring the imipramine-treated group and a statistically significant difference favoring imipramine on measures of phobia and depression. Matuzas, Uhlenhuth, Glass, Javaid, and Davis (1986) reported preliminary findings from an S-week, fixed-dose study

0 % A

Sheehan et al. (1987)

al. (19X6)

et al. (19X6)

M:~tuzaset

Evans

and

(1986a)

Michelson

(outpatients)

Panic disorder

(outpatients)

agoraphobia

Panic disorder

(oulpdlients)

Agoraphobia

(outpatients)

Agoraphobia

?

PbO

IMI

PbO

IMI

PbO

IMI

(mean 292 mg)

225 (fixed dose)

I50 mg

both

or

flooding,

flooding,

PbO + BT,

both

+ BT,

(mean 130 mg)

(year)

Mavissakalian

(mean dosage) + other treatment

Patient

Diagnosis

Investigalor

IMI

treatmen!

daily dosage

Mediation ‘

or

8 8

IX

X

6

12

Weeks

Duration,

IX

20

20

7

16

31

31

N

TABLE I -Continued

IMI

dropout

not

rate

and panic frequency

but not

anxiety depression

phobias,

main

> PbO in reducing panic intensity.

IMI

measures

other anxiety

dose (75 mg)

High

specilied

dose

treatment Panic

IMI frequency

modest.

period.

Small 1, Short

global improvement

or

dosage. UT

due to large initial

> PbO in antipanic

IMI

given 10 all palients

Modest

Comments

effect, but not on

IMI

ratings

= PbO on anxiety,

depression

IMI

ratings

> PbO on phobia,

depression

IMI

Results

PANIC-RELATED

DISORDERS

81

comparing imipramine. alprazolam, and placebo. In this study, imipramine (225 mg/day) had significantly greater effect in blocking panic attacks than placebo. Sheehan and colleagues recently reported the results of a study comparing imipramine (mean 292 mg/day), buspirone, and placebo (Sheehan, Raj, Soto, & Harnett-Sheehan, 1987). In that study, imipramine was significantly better than placebo and buspirone (which were not different) in reducing panic intensity (but not frequency), main phobia, and global improvement measures. Three negative studies have been reported to date. Marks and colleagues reported no apparent effect attributable to imipramine in a group of patients receiving behavioral treatment combined with either imipramine or placebo (Marks et al., 1983). However, reanalysis of these data indicates that imipramine treatment was superior to placebo on several measures (Raskin, 1983). Another negative study (Telch, Agras, Taylor, Roth, & Gallen, 1985) reported no apparent panic attack-blocking effect from imipramine, although most measures (total phobia, unaccompanied excursions from home, and some depressions ratings) showed some improvement. In this study, treatment groups were small (less than IO by study end). Additionally, the authors initially advised their subjects to avoid exposing themselves to anxiety-provoking stimuli. Most recently, Evans, Kenardy, Schneider, and Hoey (1986) compared imipramine, zimelidine, and placebo and found no benefit for imipramine treatment. In this study, which was terminated early due to safety concerns regarding zimelidine, the duration of treatment (6 weeks) was relatively short and treatment groups were small; insufficient information about concurrent behavioral therapy or psychotherapy and panic frequency make this study difficult to compare with others. Further studies will help clarify the magnitude and breadth of response to TCAs. However, the preponderance of evidence clearly documents that they have significant effects in this illness. Two studies have addressed the question of whether imipramine alone is effective in treating patients with panic-related disorders. Mavissakalian, Michelson, and Dealy (1983) treated a group of agoraphobics with imipramine alone (mean dosage 125 mg/day) or with imipramine plus self-exposure homework over 12 weeks. They found relatively minor group differences in panic and anxiety symptoms at the end of the study but noted significant differences favoring the combined treatment. Garakani, Zitrin, and Klein (1984) reported that 8 of 10 patients with panic disorder without phobic avoidance experienced a cessation of panic attacks after taking medication for at least 3 weeks; the four patients who took medication for more than 5 months were dramatically improved. There are five studies regarding dose-response relationships for imipramine. In one study, a group of 36 agoraphobics received imipramine and 12 weeks of self-exposure instruction in a group setting as well as exposure homework. Half of the patients received dosages of imipramine sufficient to maintain plasma levels (imipramine plus desmethyl imipramine combined) in the 100-150 r&ml range and the other half received dosages which resulted in plasma levels in the 200-250 ngiml range. Both

82

R. B. LYDIARD

AND J. C. BALLENGER

groups achieved significant and comparable benefits with essentially equal efficacy for both plasma levels (Balienger, Peterson et al., 1984). Mark et al. (1983), Nesse, Cameron, Curtis, McCann, and Huber-Smith (1984), and Aronson (1987) found no relationship between plasma imipramine plus desipramine concentration and clinical response. In contrast, Mavissakalian, Perei, and Michelson (1984) reported a relationship between plasma imipramine but not desipramine levels and clinical improvement in 15 agoraphobics. The same group reported that oral dosage of at least 150 mg daily was associated with substantial clinical improvement in a group of agoraphobics, while patients who took less than 1.50 mg daily fared as a group no better than their placebo-treated counterparts (Mavissakalian & Perei, 1985). Clomipramine Three placebo-controlled studies have demonstrated clomipramine to be more effective than placebo in a heterogenous group of patients with anxiety disorders, some of whom were agoraphobics (Amin, Ban, Pecknoid, & Klinger, 1977; Escobar & Landbloom, 1976; Karabanow. 1977). However, these studies also included patients with social and simple phobias, depression, and obsessive-compulsive disorder. A recent double-blind comparative study of ciomipramine vs. fluvoxamine in patients with anxiety disorders including panic also suggested efficacy for ciomipramine (DenBoer, Westenberg, Kamerbeek, Verhoeven, & Kahn, 1987). Further studies comparing ciomipramine with other antipanic medications in panic disorder patients. under placebo-controlled, doubieblind conditions would be of great interest. Comment The controlled studies in general suggest that imipramine and ciomipramine are significantly more effective than placebo in blocking panic attacks. It also appears that TCAs are effective primarily in agoraphobics or mixed phobics (i.e., who have panic) and not in simple phobic patients. This suggests, but does not prove, that the antiphobic and antipanic effects of TCAs are closely associated. However, many studies also employed concomitant behavioral therapy for phobic avoidance behavior, making it somewhat difficult to assess a specific contribution of medication treatment. In those studies in which it is possible to discriminate these effects, it seems that combined treatments are more effective overall than either behavior or medication treatment alone. There is also some limited evidence that the TCAs have direct antiphobic efficacy not necessarily related to their antipanic effects. The dosage of TCAs used in a number of the imipramine studies averaged at or below 1.50 mg in several instances (see Table 1). This raises the possibility that some patients receiving imipramine in these studies were undertreated and possible

PANIC-REL.ATED

DISORDERS

83

drug effects may have been underestimated. Diagnostic heterogeneity in patient samples studied may also have contributed to variable outcome results. For example, mixed groups of phobic (i.e., social and simple phobics) patients were included in several studies. Some included only patients with agoraphobic levels of avoidance, others included inpatients (likely to be more ill) and still others studied patients with variable levels of phobic avoidance. Some studies excluded depressed patients (Marks et al., 1983); others did not (Ballenger et al., 1977; Sheehan et al., 1980). Also, outcome measures reported were variable. Not all studies measured panic 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 most accurately assess treatment outcome. These studies point to the need for a standardization of measures including diagnosis, medication dosage (preferably with plasma levels), use of concomitant behavioral treatments and duration of treatment, measures of avoidance behavior, panic attack frequency, and presence or absence of depression in order to meaningfully compare studies in the future. Despite these numerous limitations, there is ample evidence supporting the antipanic efficacy of TC,4s, particularly imipramine. MONOAMINE

OXIDASE INHIBITORS

Six placebo-controlled studies have been reported to date (see Table 2). Five of the six studies employed phenelzine and one employed iproniazid. In general, evidence supporting efficacy for the MAOIs is less complete than for the TCAs but strongly suggests that the MAOIs are effective in treating panic-related disorders. Tyrer, Candy. and Kelly (1973) treated a mixed group of patients suffering from agoraphobia and social phobia with phenelzine, up to 90 mgiday, or placebo. After 8 weeks treatment, the phenelzine group had improved more than the placebo on secondary phobia and psychiatrist-rated global outcome measures, but not on a variety of other measures. Solyom et al. (1973) treated a mixed sample of patients with agoraphobia, social phobia, and specific phobias with flooding alone vs. either phenelzine (up to 45 mg/day) or placebo combined with brief psychotherapy. Phenelzine treatment was superior to placebo in improvement in Wolpe-Lange Fear survey ratings, phobia reduction, neurotic symptoms, and social maladjustment scores. In this study, flooding was superior to placebo treatment in reducing WolpeLange scores. Lipsedge et al. (1973) compared iproniazid (up to 150 mg/ day) and placebo alone with either methohexitone-assisted systematic desensitization or standard systematic desensitization. After 8 weeks, the iproniazid-treated group was rated as being less anxious than the placebo group but did not differ in avoidance behavior. Mountjoy, Roth, Garside, and Leitch (1977) prescribed either phenelzine (up to 75 me/day) plus diazepam (15 mg/day) or placebo plus diazepam for patients with anxiety

et al. (1973)

et ill. (1977)

Lipsedge

Mountjoy

et al. (1973)

or social

neurosis

outpatients)

(inpatirnls

nnd

phobic neurosis

Anxiety

(outpatients)

Agoraphobia

;md

up to I50 mg

H’I“ or no

used with each

I’bO

t t

IS mg

I5 mg

diazepam

diazcp;ml

Phen up to 45 mg

treatment)

BT

or standard

(Methohexitone-assisted

PbO

lproniazid

studied)

alone also

+ psychotherapy

(flooding

PbO

+ psychotherapy

phobia (outpatients)

Phen up to 45 mg

social

PBOb

Phena (mean 38.5 mg)

phobia or specific

Agoraphobia,

phobia (outpatients)

Agoraphobia

(mean dosage) + other treatment

Ihtienl

2

I9

II

28

32

IO

IO

I6

I6

N

4

8

I2

8

Weeks

Kesults

DISORDERS

depression

and

sample.

> Phen on fear

+ di;ir.cp;im

phobic group.

PbO

not other measures

for

on social phobia, but

> I’bO

Phen + diazepam

not avoidance

but

> PbO in

improvement

reducing anxiety

Iproniazid

ruling

Flooding

measures

BT

not

treatment

treatment.

Mixed

duration

not

given.

Short

brnzodiazpine

Concomitant

Mixed s;m~ple.

detailed

Panic symptoms

Concomilant

specified

symptoms

Panic

sample.

received

not

neuroticism

Patients

specitied

symptoms

psychotherapy.

maladjustment

Low Phen dosage. Panic

Mixed

Drug effecl minimal.

Comments

fear, phobia, and social

Phen > PbO in reducing

global outcome

anxiety

Phen > PbO on phobia,

IN PANIC-RELATED

Duration,

AND PLACEUO

treatment

Diagnosis

et al. (1973)

Solyom

Tyrer

TABLE MAOls

daily dosage

Medkxtion

COMPARING

(year)

STU~)IES

Investigator

DOUBLE-BLIND

treatment

et aI. (1980)

Solyom et al. (1981)

Sheehan

(cont’d)

et al. (1977)

or social

phobia (outpatients)

Agoraphobia

phobias (outpatients)

Pimic iItI;lcks ;IIKI -6 U’I

PbO

r

UT

Phen up to 45 mg 2 BT

PbO

Phen 45 mg + I31

(year)

Mountjoy

(mean dosage) + other treatment

Patient

Diagnosis

Investigator

20

20

22

I7

N

~-CONI~IIII~~

daily dosage

Medication

TABLE

8

I2

Weeks

Duration,

> Phen

for anxiety

on

specilied

symptoms

not

dosage. related anxiety

exposure-

Modest

Panic

Small 11 controlling

sample.

not

each cell.

Mixed

specified

Panic

IIT.

not

received dosage. frequency

Modest

All patients

(IO) in

ratings

avoid-

specified

Panic symptoms

Comments

Phen > PbO in

No Phen elTect

and disability

phobic anxiety,

Phen > PhO in reducing

neurotics

anxiety

+ diazepam

+ diazepam

Results

86

R. B. LYDIARD

AND J. C. BALLENGER

neurosis (most had panic-like symptoms) or phobic neurosis (probably agoraphobia). The phenelzine-treated patients experienced a significantly greater reduction in social phobia ratings than placebo-treated patients, while placebo-treated anxiety neurotics exhibited greater reduction in Hamilton Anxiety Ratings than did their phenelzine-treated counterparts. No differences were found on a variety of measures including agoraphobia, anxiety, and global outcome. Ballenger, Sheehan and co-workers (Ballenger et al., 1977; Sheehan et al., 1980) compared phenelzine (45 mg/day), imipramine (150 mg/day), and placebo in patients with panic attacks and agoraphobia. Patients also received self-exposure instruction and bi-weekly supportive therapy over 12 weeks. While both medication groups were rated as significantly more improved than the placebotreated group on the two principal behavioral measures, the phenelzinetreated group showed a consistent trend toward greater improvement than the imipramine-treated group. This was statistically significant at I2 weeks. Solyom, Solyom, LaPierre. Pecknold, and Morton (1981) prescribed phenelzine (up to 45 mgiday) and placebo with or without exposure instruction. Patients with specific phobias or depression were excluded. Only the group receiving placebo without exposure failed to improve significantly, while all other groups were improved on psychiatrist rating scales and phobia self-rating scales. In this study no effect for phenelzine enhancement of exposure treatment was apparent, except that the group reported less subjective anxiety during exposure. Two recent open studies have utilized phenelzine. Sixteen of 16 panic disorder patients and I8 of I9 agoraphobics were free of panic attacks after 6 months of open treatment with phenelzine (mean 55 mg/day) (Buiges & Vallejo. 1987). Howell, Laraia, Ballenger, and Lydiard (1987) also reported significant panic attack-blocking effects from phenelzine treatment in a group of agoraphobics receiving phenelzine (mean 53.5 mg/day) or lorazepam plus self-exposure homework during a 12-week study. Comment Difficulties in comparing studies assessing specific effects of the MAOIs are similar to those described for the TCA studies. For example, no placebo-controlled study employing MAOIs has reported panic attack frequency, although several authors noted that patients reported cessation of panic. Studies assessed mixed patient samples and often failed to report outcomes of these groups separately. Although there are no data regarding specific dose-response relationships of phenelzine or other MAOIs in panic disorder, there is some evidence that a degree of MAO1 inhibition may be critical for the therapeutic antidepressant effects of phenelzine (Robinson, Nies, Ravaris, Ives, & Barlett, 1978). The typical dose of 1 mg/kg phenelzine is recommended for depression; if this is also required to block panic, the dosage of phenelzine employed may have

PANIC-RELATED

DISORDERS

87

been subtherapeutic for a number of patients. Methods of evaluation varied between studies, as did duration of treatment. Despite these methodological flaws, the bulk of the evidence suggests that the lMAOIs are also effective in treating patients with panic attacks and phobic anxiety. Clearly, delineation of the therapeutic effects of MAOIs in this condition will require attention to numerous factors including composition of patient samples, dosage, duration of treatment, measurements of avoidance and panic attack frequency, concurrent depression, and use of concomitant behavioral therapy or psychotherapy. OTHER ANTIDEPRESSANTS There are few data from controlled studies regarding the efficacy of other antidepressants in the treatment of panic-related disorders. In one controlled study, bupropion failed to demonstrate efficacy as an antipanic agent (Sheehan, Davidson, Manschreck, & Van Wyck Fleet, 1983). Fluvoxamine, a selective serotonin up-take inhibitor, has been reported in one double-blind study to have antipanic efficacy (DenBoer et al., 1987). Trazodone has been reported by one group to be highly effective (Mavissakalian, Perel, Bowler, & Dealy, 1987) and by another to be relatively ineffective (Charney et al., 1986) in blocking panic attacks. Zimelidine has been reported to have some efficacy (Evans et al., 1986). Lydiard (1987a) conducted a fixed-dose study of desipramine and found evidence suggesting that a plasma level greater than 150 ng/ml is associated with a greater probability of positive response. Additionally, nortriptyline (Muskin & Fyer, 1981; Rifkin, Klein, Dillon, & Levitt, 1981) and maprotiline (Lydiard, 1987b; Muskin & Fyer, 1981) have been anecdotally reported to be effective antipanic agents. In our experience doxepin and amitriptyline also have efficacy as antipanic agents, but these have not yet been studied under controlled conditions. While the data are largely anecdotal, it appears that several tricyclic and other cyclic antidepressants are likely to be effective, but double-blind, placebo-controlled studies must be completed in order to confirm these clinical impressions. RELAPSE AFTER MEDICATION

WITHDRAWAL

There are few data regarding the recurrence of panic attacks and phobias after withdrawal of medication treatment. Zitrin, Klein, and Woerner (1978) followed 94 patients who achieved marked to moderate improvement. Thirty percent of imipramine-treated patients and 14% of placebo-treated patients had relapsed within one year after the end of treatment. These authors noted a similarly higher rate of relapse (27%) in patients who had received imipramine vs. placebo (7%) at six months after discontinuation of treatment in another study (Zitrin et al., 1980). In a preliminary report of S-year follow-up of patients from an earlier study (Zitrin et al., 1983), phobic patients who received either imipramine or

88

R.

B.

LYDIARD

AND

J.

C.

BALLENGER

placebo plus behavioral or supportive psychotherapy showed similar relapse rates of about 20% across groups, as estimated by therapists’ global ratings (Zitrin. Juliano, & Kahen, 1987). In a two year followup study, Cohen, Montiero, and Marks (1984) found that about two-thirds of both placebo- and imipramine-treated patients had maintained substantial improvement, but some patients had received medication treatment during this follow-up period. It was unclear whether all patients were off medication at this follow-up evaluation. The most carefully conducted prospective study of outcome after discontinuation of treatment has been reported by Mavissakalian and Michelson (1986b). Approximately twothirds of patients reported that agoraphobia was no longer a problem two years after treatment with imipramine, placebo, flooding, or a combination of these. Approximately 30% of patients had received interim treatment for agoraphobia; these were mainly the patients who had initially done poorly. No disproportionate relapse among patients receiving various treatments was noted, although patients who had received imipramine initially tended to show some reversals at six months post-treatment. The authors noted that this was possibly a function of high endstudy improvement levels in this group. Relapse following discontinuation of MAOIs has been even less well studied. Solyom et al. (1973) reported 100% relapse in 10 phenelzinetreated patients versus 10% of placebo-treated patients at two-year follow-up. Tyrer and Steinberg (197.5) followed patients for an average of one year after treatment with either phenelzine or placebo. Placebotreated patients required more treatment in the follow-up period than did their pheneizine-treated counterparts. Withdrawal of phenelzine frequently was noted to result in relapse if patients had received it for less than six months. Kelly, Guirguis, Fommer, Mitchel-Haggs, and Sargant (1970) studied a large group of patients in an open fashion and noted that 36% of patients who had been well for one year relapsed after discontinuation of phenelzine. Most recently, Sheehan (1986) reported the results of a clinical study of panic disorder patients in which high overall rates of relapse were observed. After an S-12 month individually optimized treatment program, relapse rates with phenelzine (71% of 21 patients) or imipramine (86% of 14 patients) were reported. The data accrued to date suggest that patients relapse at a high rate after discontinuation of antidepressant medication treatment. Additionally, it appears that they may relapse at a higher rate than patients who received behavioral treatment alone. It has been suggested that part of this discrepancy is that criteria for relapse have been nonspecific and that evaluation of the recurrence of spontaneous panic may be an important way to objectify this issue (Pohl, Berchou, & Rainey, 1982). Extent of improvement should also be considered, since some evidence suggests different patterns of improvement between pharmacological and behavioral treatments, with higher percentages of patients who have received medication becoming asymptomatic. The only published prospective study directly examining this question (Mavissakalian & Michelson 1986a, 1986b) found no difference in long-term outcome for patients

PANIC-RELATED

DISORDERS

89

treated with medication, behavioral treatment, or the combination. Our understanding of this important question is currently inadequate, and firm conclusions about differential relapse rates must be deferred until further information becomes available. Currently, identification of patients who can maintain improvement without continuing medication is an important but unanswered question which requires further study. DEPRESSION

AND PANIC-RELATED

DISORDERS

There has been some speculation that the effects of antidepressants in panic-related disorders are primarily mediated via improvement in mood or that panic disorder itself is a variant of affective illness. These issues are discussed in detail elsewhere (see Lesser, and Roy-Byrne, Mellman & Uhde, this issue). Several lines of evidence argue against these hypotheses. Buproprion is an effective antidepressant which has no effect on panic attacks (Sheehan et al., 1983). Additionally, there is some evidence that panic and depressive symptoms may respond differentially to pharmacological treatment (Lydiard, Laraia, Ballenger, & Howell, 1987; Nurnberg & Coccaro, 1982). Controlled studies provide further evidence that improvement in panic is not necessarily related to depression. Ballenger, Sheehan and colleagues (Ballenger et al., 1977; Sheehan et al., 1980) reported that there was no correlation between baseline levels of depression and clinical outcome. Zitrin et al. (1980) found that more severely depressed agoraphobics tended to respond less well to imipramine. Ballenger, Peterson and colleagues (1984) reported that patients with higher depression rating scales did approximately as well as patients with lower depression ratings after 12 weeks of imipramine treatment. Finally, Mavissakalian (1987) has analyzed data from a placebo-controlled study and reports that a greater response to imipramine 150-200 mg/day was observed in agoraphobics with relatively lower initial depression scores. In summary, evidence for panic as a distinct entity and the independence of antidepressant and anti-panic effects of antidepressants are supported in general by the data accumulated to date. TREATMENT

CONSIDERATIONS

Following a thorough medical evaluation (see Goldberg, this issue), and if the diagnosis is clear, the clinician is left with the decision of which medication to choose. Many patients may be taking benzodiazepines with some relief of symptoms and be reluctant to stop them. Co-administration of antidepressants and benzodiazepines in modest dosages is safe and often helpful in early stages of treatment. If treatment with anti-depressant medication is chosen, the current antidepressant drugs of choice for panic disorder appear to be imipramine and phenelzine. Since phobic patients often express concern about dietary restrictions required with MAO1 treatment, TCAs are generally first recommended. Treatment with TCAs is generally initiated with extremely low doses

90

R.

B.

LYDIARD

AND

J. C.

BALLENGER

so as to avoid activating side effects. With imipramine, 10 mg as the initial dose is often better tolerated than higher doses, with increments by 10 mg/day as tolerated to a dosage of approximately 50 mgiday. This is followed by increases of 2.5 mg between every 2 and 7 days to a level of 1.50-200 mg. Some patients respond at very low levels while others may require 300-400 mg/day. Until plasma level/clinical response relationships are better defined, clinical response remains the best guide to treatment. While anticholinergic effects are bothersome, TCA-related activation can be a limiting adverse effect (Lydiard, 1987a; Zitrin et al., 1978). Treatment of activating side effects with reassurance, perhaps supplemented by benzodiazepines or beta blockers, particularly early in treatment, often helps maximize compliance. Additionally, it is our experience that warning patients about these symptoms ahead of time, as well as indicating that their occurrence suggests a likelihood of correct diagnosis and subsequent good response to treatment, allows most patients to remain in treatment. Phenelzine is the most commonly recommended MAO1 for panic disorder. The usual starting dose is I5 mg, increasing by 1.5 mg every 3-4 days to a dosage of 60 mg; occasional patients respond to a lower dose or require higher doses (e.g., 75-90 mg/day). Since phenelzine and other MAOIs may cause insomnia, the dosage is often given in divided fashion in the morning and early afternoon. Adverse effects induced by MAOIs include tachycardia, hyposomnia, postural hypotension, and usually mild anticholinergic effects. Of these, the postural effects seem to be the most frequently bothersome. Stewart, Harrison, Quitkin, and Liebowitz (1984) reported that some patients receiving phenelzine exhibit symptoms resembling pyridoxine deficiency (numbness, parasthesias, and “shocklike” sensations), most of which remitted after the administration of 150-300 mg of pyridoxine per day. There is no current indication for pyridoxine prophylaxis, but a trial of pyridoxine in patients with symptoms suggestive of pyridoxine deficiency may be helpful. Treatment

Course

The onset of the antipanic effects of antidepressants is gradual; occasionally patients are distinctly better within a few weeks after beginning treatment, but 6-12 weeks at the effective dosage is often required for meaningful improvement. The usual response consists of a gradual diminuition of intensity and frequency of the spontaneous and later situationally-bound attacks. Reduction in avoidance behavior follows and is usually proportional to improvement in panic symptoms. Once a significant antipanic effect is apparent, patients often benefit greatly from the addition of behavioral treatment. The usual period of medication treatment for panic-related disorders is between 6 months and 1 year, after which medication is gradually tapered. The optimal duration of treatment has not been determined in any systematic fashion. However, if patients experience a return of symptoms after medication has been tapered,

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DISORDERS

91

rapid recovery usually results from reinstitution of medication and behavioral treatments. If patients relapse after withdrawal from medication treatment, an additional 6 months of treatment is usually followed by a second attempt to taper the medication. As noted above, the actual percentage of patients who can be successfully weaned off of medication indefinitely is, as yet, unknown. It appears that a small proportion of patients require chronic treatment in order to remain free of panic symptoms. In the 25 years since Klein’s initial description of the usefulness of imipramine in treating spontaneous panic attacks, our ability to treat panic-related disorders has improved substantially. This review has summarized the literature regarding the efficacy of antidepressants in panicrelated disorders. It is apparent that considerable information has been gathered and also that important questions remain unanswered. The next decade should provide important information which will further enhance our ability to treat these serious and potentially crippling disorders.

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