Antidepressants in the treatment of agoraphobia and obsessive-compulsive disorder

Antidepressants in the Treatment of Agoraphobia and Obsessive-Compulsive Disorder Matig Mavissakalian

A

GORAPHOBIA and obsessive-compulsive disorder share many similarities, not the least of which is their response to behavioral and pharmacological treatments. The mechanism of action of antidepressants in these complex anxiety disorders is not known. The question as to whether they possess antiphobic/antiobsessional properties, independent of their antidepressant effect, is controversial and unlikely to be solved on symptomatic grounds alone. A fruitful approach is indicated by recent biochemical findings that link their obsessional effect to the serotonergic neurotransmitter system. The use of agents with more specific biochemical action should permit a more accurate differentiation of antiphobic/antiobsessional and antidepressant effects. Furthermore, the exploration of the role of neurotransmitter systems in agoraphobia and obsessive-compulsive disorder might further elucidate the relationship between depressive disorders and anxiety disorders. INTRODUCTION

Agoraphobia and obsessive-compulsive disorder are both classified under anxiety disorders’ and thus explicitly share the prominence of symptomatic anxiety as a major clinical feature. Indeed, recent evidence from genetic’ and psychophysiological studies3s4 suggest that anxiety-proneness, as measured by increased basal autonomic arousal, characterizes anxiety-neurotics, agoraphobics, and obsessive-compulsive patients and differentiates them from “normals” and simple phobics. Agoraphobia and obsessive-compulsive disorder also have an intimate relationship to depression which has interested and baffled many clinicians and investigators.5-9 What seems to be almost certain is that the presence of agoraphobia or obsessive-compulsive disorder may indicate liability to depressive disorder and, indeed, several recent studies have shown that one-third to one-half of anxiety neurotics develop secondary depression.“-‘* Another close parallel between agoraphobia and obsessive-compulsive disorder is the successful application of behavioral treatments based on prolonged exposure and response prevention.13 The fate of the often accompanying depressive symptomatology, however, is uncertain as some centers have shown that the usual mild to moderate depressive symptomatology continues unchanged while others have shown concurrent improvement in depression as we11.‘4-‘6 From the Department of Psychiatry, University of Pittsburgh. School of Medicine. Pittsburgh, Pa.. and Western Psychiatric Institute and Clinic, Pittsburgh. Pa. Matig Mavissakalian, M.D.: Associate Professor of Psychiatry, Department of Psychiatry. University of Pittsburgh School of Medicine; Western Psychiatric Institute and Clinic. Address reprint reqlcests to Matig Mavissakalian, M.D., Western Psychiatric Institute und Clinic, 3811 O’Hara Street, Pittsburgh, Pa. 15213. @ 1983 by Grune & Stratton. Inc. 0010_440X/8312403/00I1i$1.~l0

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The recognition that antidepressants are effective in the treatment of agoraphobia and obsessive-compulsive disorder has underscored the close relationship between them. Moreover, the study of their antidepressant and antiphobic-antiobsessional effects, has the potential of elucidating the relationship between depressive disorder and anxiety disorders. TREATMENT

WITH ANTIDEPRESSANTS

In the treatment of agoraphobia, phenelzine’7-22 and imipramine23-27 have been the drugs most studied, whereas in the case of obsessive-compulsive disorder, a relatively new tricyclic antidepressant, clomipramine,28-30 has been the single most drug investigated. From the relatively large number of clinical studies referred to, and which have been reviewed in greater detail elsewhere,3’ one gains the impression that the pharmacotherapy of these disorders is not only effective, but bears an uncanny similarity to the exposure based treatments. Very few studies have looked at the comparative effectiveness of the different antidepressants in these disorders. Sheehan et a1.32compared phenelzine, imipramine, and placebo in a group of 87 neurotic patients with prominent panic attacks, phobic anxiety, and depersonalization akin to agoraphobia. They demonstrated the superiority of the active medications over placebo and their measures slightly favored phenelzine to imipramine. Ananth and van den Steed3 compared clomipramine with doxepin in 20 obsessive-compulsive patients and found clomipramine to be superior. Seventy percent of the patients treated with this drug improved on extensive self-report measures as compared to 55% of the patients on doxepin. More recently, Thoren et a1.34compared clomipramine to nortriptyline and placebo in a 5-wk randomized double-blind trial. The results showed that clomipramine effected a significantly greater reduction in obsessive-compulsive symptomatology than placebo and that nortriptyline did not differ significantly from either clomipramine or placebo. In the ensuing open phase of the study, 22 patients were treated with clomipramine, 50% of whom responded clinically to the drug. A major problem with the use of antidepressants is the high drop-out rate which can be as high as 30% in agoraphobics. 27,32 Drop-out does not seem to be as high in obsessive-compulsive patients.30-34 Zitrin et al.” have reported that approximately 20% of agoraphobics respond to even small doses of imipramine with insomnia, jitteriness, irritability, and exacerbation of panic attacks. This particular oversensitivity might explain the high dropout rates in this group. However, drop-out rates do not seem to differ between agoraphobics assigned to placebo or active drugs,32 suggesting that dropping out of pharmacologic treatment in this group of patients, might be a nonspecific reaction due to pill taking rather than to the pharmacologic effects of the drugs. Another major problem with the drug treatments remains the relatively high relapse, approximately 25%, following cessation of treatment. This contrasts with the maintenance of gains following behavioral treatments. Klein and his associates23-2s have repeatedly observed that agoraphobics who relapse following imipramine are those who do not make the effort to enter their phobic situations e.g., practice exposure. Marks3’ found that clomipramine enhances

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compliance in behavior therapy and exposure practices with obsessivecompulsive patients. It is conceivable, therefore, that combining exposure treatments and pharmacotherapy might reduce relapse rate. However, Zitrin et al.” reported that 27% of patients receiving combined imipramine/flooding treatment relapsed as compared to 6% in the flooding group, suggesting that combination treatments might not necessarily be the solution for high relapse rates. Tyrer and Steinberg” reported that relapse following phenelzine was particularly high in agoraphobics if treatment lasted less than 6 mo. Zitrin et al.“’ reported major gains in the second half of a 26wk-long trial with imipramine of agoraphobics which reinforces the need for longer durations of treatment. Moreover, the literature consistently reports improvement following the reinstatement of medication in relapsed patients, clearly indicating that a period of maintenance on the drugs seems necessary, although what constitutes an optimal length of treatment awaits determination. MECHANISM

OF ACTION

OF ANTIDEPRESSANTS

The most commmon question investigators have assessed is whether antidepressants possess antiphobiciantiobsessional effects that are independent of their antidepressant properties. King” as early as 1962 was impressed by the effectiveness of phenelzine in treating agoraphobia and suggested that monoamine oxidase (MAO) inhibitors should not be classified as antidepressants. Many workers since have noted that the presence of depression at pretreatment made no significant difference in the outcome of treatment. This was the case in the treatment of phobic states with MAO inhibitors,‘s.32 agoraphobia with imipramine,26.27,32and obsessive-compulsive disorder with clomipramine.32 Indeed, Zitrin2’ and her associates noted that the presence of high scores of depression was associated with a poor outcome on several measures. Marks et a1.30 are the only investigators who found that improvement in obsessive-compulsive disorder with clomipramine was greater in those patients who showed marked depression as compared to those with little depression. Recently, Marks35 has reanalyzed the existing literature and has found support for his contention that antidepressants lack independent antiphobic/ antiobsessional effect. The general conclusion he draws is that these drugs have a global patholytic effect on depressive, phobic obsessional as well as anxiety symptoms. In a recent study, however, McNair and Kahn36 found evidence to support that improvement in panic attacks was independent of depression, but they also observed that improvement in phobic ratings was associated with depression. Thus, they tentatively proposed a dual mechanism of imipramine’s action in agoraphobia according to which the drug’s antipanic effect would be independent of its antidepressive effect, whereas its beneficial antiphobic effect would be mediated through its antidepressive action. This is an interesting hypothesis that fully deserves confirmatory testing. Reports that both MAO inhibitors3’ and imipramine3’ can block anxiety attacks experimentally induced via lactate infusion constitute the most direct suggestive evidence for a specific antipanic effect.

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It is generally accepted that the common active ingredient in the effective behavioral treatments is exposure to phobic stimuli.39 Mathews et aL40 have investigated a behavioral treatment based on systematic instructions to practice in vivo exposure and have found it to be of comparative effectiveness to therapist-assisted treatments. Such instructions reportedly have been given to patients in most pharmacologic trials of agoraphobia26.27,3zand therefore present an important difficulty in determining the pharmacologic effect of the drugs and studying their possible differential antiphobic and antidepressant properties. Solyom et aL4’ have investigated this very issue by studying 40 agoraphobic and socially phobic patients in a 2 by 2 factorial design. The subjects were treated with phenelzine and exposure, either alone or in combination, and the results revealed that phenelzine did not differ significantly from placebo, whereas exposure either alone or with phenelzine seemed to be the most effective treatment. Although the authors, rightly, consider the relatively low daily dosage of phenelzine used (45 mg) to be responsible for their negative results, the findings stand in sharp contrast to the significant improvements reported by Sheehan et a1.32 who used the same dosage. The major factor accounting for the differences between these two studies seems to be that in Sheehan’s study improvement was assessed by measures of general psychopathology and symptom ratings, whereas Solyom reported improvement in terms of specific changes in phobias. Because of the scantness of the data reported and the lack of comprehensive standardized assessments, it is impossible to assess the clinical signiticance of the findings of Solyoms et al. Nevertheless, their results indicate absence of antiphobic effect due to the drug. Furthermore, they underscore the need for instructional controls as well as the importance of measuring change in targeted behaviors in future research studying the mode of action of antidepressants in agoraphobia. Recent findings in obsessive-compulsive disorder are more revealing in this respect. Thoren et al.” compared the effectiveness of clomipramine in a 5-wk randomized double-blind trial and found that clomipramine (which is a potent serotonin uptake blocker) was more effective than nortriptyline which is a more specifically noradrenergic antidepressant. More importantly, they found that improvement in obsessive-compulsive symptoms was associated with the reduction of CSF 5-HIAA (5-hydroxyindoleacetic acid) but not to levels of MHPG (4-hydroxy-3-methoxyphenyl glycol). They thus provided compelling evidence in favor of the hypothesis that clomipramine’s antiobsessional effect could be mediated through its serotonergic action. In another study, Stern et a1.43 observed that plasma clomipramine concentration was related to improvement in rituals, whereas plasma N-Desmethylclomipramine level was related to outcome of depression. They speculated “whether these discrepancies related to the differential chemistry of the two compounds (clomipramine inhibiting serotonin reuptake and N-Desmethylclomipramine inhibiting noradThese studies, therefore, confer a prominent role to reneline reuptake).” serotonin in mediating improvement of obsessive-compulsive disorder and suggest a biochemical differentiation between the antiobsessional and antidepressive effects of clomipramine. That the serotonergic system may also play a central role in agoraphobia is

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suggested by the close clinical phenomenologic similarities between obsessive-compulsive disorder and agoraphobia. Furthermore, there have been encouraging reports of successful treatment of agoraphobia with clomipramineHm4’ and two recent reports with zimelidine (a specific serotonin reuptake blocker) point in the same direction. In a pilot study, Evans and associates4* treated seven patients with zimelidine for a period of 5 wk with doses of up to 300 mg/day and reported remarkable improvement in five of the six patients completing the trial. In a second open tria1,4913 patients suffering from phobic anxiety states were treated with zimelidine (dosage range 200 to 300 mg/day) for a period of 12 wk. Six patients were considered nonresponders at the 6-wk mark. The other seven showed remarkable improvement, accompanied by increased working ability, improved social functioning, and reduced need for anxiolytics. CONCLUSION

In summary, antidepressants can be effective in the treatment of agoraphobia and obsessive-compulsive disorder with improvement rates centering around 70% of treated patients. Relapse following discontinuation of drugs is high and represents a major challenge for future clinical research. The elucidation of the mechanism of action of these drugs in these disorders has just begun. The sole reliance on symptom ratings of depression, phobic anxiety, and obsessive-compulsive symptoms has not been very rewarding in determining whether antidepressants possess specific antiphobic/antiobsession effect independent of their antidepressant properties. Future research studying the differential effect of drugs across the behavioral and mood dimensions (depression, fears, obsessions) might prove more fruitful in this regard. Recent evidence has implicated the serotonergic system in obsessivecompulsive and agoraphobic disorders. A more accurate investigation of the role of neurotransmitter systems in these disorders is now possible by the use of drugs selectively affecting the serotonergic or the noradrenergic systems. The neurobiochemical effects of both imipramine and clomipramine are controlled by pharmacokinetic effects, i.e., the parent compounds are serotonergic whereas their desmethyl metabolites are mostly noradrenergic. Drugs with greater pharmacologic specificity (e.g., zimelidine, maprotiline) thus circumvent these pharmacokinetic problems and provide an excellent opportunity for the pharmacologic dissection of antidepressants’ effect in these disorders. Biochemical investigations of agoraphobia and obsessive-compulsive disorder are likely to elucidate further the relationship of anxiety disorders and depressive disorders in view of the recent identification of two biochemical subtypes in affective disorders; one related to reduced functional serotonergic activity, the other to reduced noradrenergic activity.So-52 One can only speculate if the suggested prominence of serotonin metabolism in obsessivecompulsive disorder (and agoraphobia) could mean a closer affinity to the serotonin-deficient subtype of depression. What is clearly needed, however, is the application and extension of gains made in pharmacologic and biochemical research of depressive disorder to these complex anxiety disorders.

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