881

AgoraphobiaAT a time when caution is being urged in the

prescription of anxiolytic drugs for chronic anxietydisorders, it may be surprising to read reports from theUnited States of treatment for agoraphobia with highdoses of a new benzodiazepine.1 These reportswarrant attention because they describe studies thatoriginate from a controversial theory about the causeof agoraphobia. In this view, the most importantsymptoms of agoraphobia are the spontaneous panicattacks, which are thought to arise from a basic

"biological" disorder;2 the more obvious symptoms ofsituational anxiety and avoidance behaviour are

regarded as secondary elaborations of this disorder,probably results of conditioning. It is also suggestedthat the basic disorder is identical with that in panicdisorder, a syndrome in which there are frequentspontaneous panic attacks but no avoidance. A

consequence of this theory is that agoraphobia shouldbe treated with drugs to correct the biologicalaberration-ie, behavioural treatment is deemed

capable of reversing the secondary changes caused byconditioning but not of righting the underlyingproblem.

1 Klerman GL. Overview of the Cross-national Collaborative Panic Study. Arch GenPsychiatry 1988; 45: 407-12.

2 Carr DB, Sheehan DV. Panic anxiety: anew biological model. J Clin Psychiatry 1984;45: 323-30.

For many years, drugs have been used in thetreatment of agoraphobia. Originally barbiturateswere prescribed. Then in Britain, phenelzine, a

monoamine oxidase inhibitor, was advocated for thetreatment of these cases,3 whereas in the United Statesimipramine, a tricyclic antidepressant, was

recommended for the same purposed Two otherantidepressants, clomipramine5 and desipramine 6have lately been found to be effective. When

benzodiazepines were introduced, there was a clinicalimpression that they were not as beneficial in thetreatment of agoraphobia as in generalised anxietydisorders. Consequently, there was considerableinterest in reports that a new triazolobenzodiazepine,alprazolam, produced rapid improvement in

agoraphobia (and also in panic disorder).Initial assessment of the value of new psychotropic

drugs is often difficult because individual clinical trialsare carried out with small numbers of patients anddifferent trials seldom use the same methods ofassessment. The makers of aprazolam deserve credit,therefore, for arranging a large multicentre trial withaltogether 1700 patients, conducted by leadingresearch workers from several countries. The trial wasin two stages. The first stage with 600 patients showedthat alprazolam is more effective than placebo intreating agoraphobia and panic disorder.7 The secondstage, comparing alprazolam with imipramine, has notbeen reported. Comparisons of imipramine withplaceb08 suggest that its therapeutic effect is

comparable to that of alprazolam. However, morepatients drop out from imipramine than from

alprazolam treatment in the early weeks because ofunpleasant side-effects, including restlessness andinsomnia.9Do these findings mean that alprazolam has a

special therapeutic effect not shared by other

benzodiazepines? Probably not because, in these

trials, alprazolam was given in large doses (equivalentto about 60 mg of diazepam10 a day), and there arereports that large doses of diazepam and clonazepamllhave similar therapeutic effects. Should alprazolam oranother benzodiazepine be preferred to an

antidepressant as a drug treatment for agoraphobia?

3 Sargant W, Dally PJ. Treatment of anxiety states by antidepressant drugs. Br Med J1962; i: 6-9.

4 Klein DF, Fink M. Psychiatric reaction patterns to imipramine Am J Psychiatry 1962;119: 432-38.

5 Johnson DG, Troyer IE, Whitsett SF. Clomipramine treatment of agoraphobicwomen Arch Gen Psychiatry 1988, 45: 453-59.

6 Lydiard BR. Desipramine in agoraphobia with panic attacks: an open fixed-dosestudy. J Clin Psychopharmacol 1987, 7: 258-60.

7. Ballenger JC, Burrows GD, DuPont RL, et al Alprazolam in panic disorder andagoraphobia. results from a multicenter trial I. Efficacy in short-term treatment.Arch Gen Psychiatry 1988, 45: 413-22.

8. Sheehan DV, Ballenger J, Jacobsen G Treatment of endogenous anxiety with phobichysterical, and hypochondriacal symptoms. Arch Gen Psychiatry 1980; 37: 51-59.

9 Noyes R, DuPont RL, Pecknold JC, et al. Alprazolam in panic disorder and

agoraphobia results from a multicenter trial III Patient acceptance, side-effectsand safety. Arch Gen Psychiatry 1988; 45: 423-28.

10 Dunner DL, Ishiki D, Avery DH, Wilson LG, Hyde TS Effect of alprazolam anddiazepam on anxiety and panic attacks in panic disorder a controlled study J Clin

Psychiatry 1986, 47: 458-6011. Tesar GE, Rosenbaum JF Successful use of clonazepam in patients with treatment

resistant panic disorder J Nerv Ment Dis 1986; 174: 477-82

882

This question is less easy to answer until the results ofthe second phase of the multicentre trial are known.The therapeutic effect of imipramine develops moreslowly than that of alprazolam and, if unpleasantside-effects are to be avoided, it is necesssary to startwith small doses and increase the amount gradually.However, these difficulties in starting treatment withimipramine have to be weighed against the problemsof stopping alprazolam. Withdrawal symptoms canoccur at the end of treatment with alprazolam, evenwhen the dose is reduced very gradually." Theseriousness of this withdrawal syndrome needs to bedetermined, but until there is more reassuringinformation, it may be best to start with imipramineand reserve a benzodiazepine for patients in whomunpleasant side-effects of imipramine make it

necessary to stop the drug.Since agoraphobia can be treated with behavioural

methods, should drugs be used at all? There is goodevidence from clinical trials that behaviouraltreatment can produce substantial and lastingimprovement in agoraphobia, although many patientsare left with minor residual symptoms.13,14 Behaviourtherapy has been shown to enhance the effect ofimipramine in agoraphobia,15 but it is not certainwhether the addition of imipramine to behaviouraltreatment increases the effect16,17 or does not changeit.18 One explanation for the conflicting findings maybe that the beneficial effect of imipramine appearsonly in agoraphobics who have depressive symptoms,and that the proportion of such patients has varied indifferent trials. In view of these uncertainties it isreasonable to start treatment with behaviour therapy ifit is readily available, adding drugs only when thereare pronounced symptoms of depression or if

improvement does not take place within a few weeks. 19If behaviour therapy is not easy to arrange, drugtreatment can be tried first.What do these studies of drugs tell us about the

aetiology of agoraphobia? Probably very little becausethe drugs are as likely to be blocking the expression ofsymptoms as acting on the basic cause of agoraphobia.If there is a biological basis to this condition, it is morelikely to be revealed in genetic studies and

investigations of neurotransmitter function by

12. Pecknold JC, Swinson RP, Kuck K, Lewis CP Alprazolam in panic disorder andagoraphobia results from a multicenter trial III Discontinuation effects. ArchGen Psychiatry 1988; 45: 429-36.

13 Munby M, Johnston D. Agoraphobia: a long-term follow-up of behaviouraltreatment. Br J Psychiatry 1980; 137: 418-27.

14. McPherson FM, Brougham L, McLaren L Maintenance of improvements in

agoraphobic patients treated by behavioural methods in a four year follow-up.Behav Res Ther 1980; 18: 150-52

15. Mavissakalian M, Michelson L, Dealy RS Pharmacological treatment of agoraphobia:imipramine versus imipramine and programmed practice. Br J Psychiatry 1983;143: 348-55,

16. Telch MJ, Agras WS, Taylor CB, Roth WT, Gallen CG Combined pharmacologicaland behavioural treatment for agoraphobia Behav Res Ther 1985, 23: 325-35

17 Zitrin CM, Klein DF Woerner MG. Behavior therapy, supportive psychotherapy,imipramine, and phobias Arch Gen Psychiatry 1978; 35: 307-16.

18 Marks IM, Grey S, Cohen SD, Hill R, Mawson D, Ramm EM, Stem RS.Imipramine and brief therapist aided exposure in agoraphobics having self

exposure homework a controlled trial. Arch Gen Psychiatry 1983, 40: 153-62.19. Zitrin CM. Differential treatment of phobias use of imipramine for panic attacks

J Behav Ther Exp Psychiatry 1983, 14: 11-18

pharmacological challenge tests than by inferringcausation from the therapeutic effects of drugs.Results of these kinds of investigation have not yetproduced wholly convincing evidence of a biologicalbasis for agoraphobia 20 although there are indicationsthat panic disorder may be inherited.21 Other studiessuggest mainly psychological causes for the symptomsof agoraphobia, not only for the avoidance behaviourbut also for some of the apparently spontaneous panicattacks.22 This last result is especially interestingbecause these panic attacks are the centre-piece of thebiological theory of aetiology. It seems improbable,however, that either panic attacks or agoraphobia willturn out to have wholly psychological or whollybiological causes; it is much more likely that the twofactors interact, as they do in other psychiatricdisorders.

Hepatic Haemangioma—A SuitableCase for Treatment?

HAEMANGIOMA is the commonest benign liver

tumour, with necropsy frequency of 2-5 %.1 It hassome hamartomatous features2 and there are few

pathological associations. It is common in patientswith tuberous sclerosis3 and may be associated with

hepatic focal nodular hyperplasia.4 Oestrogenadministration has been linked with rapid growth,sand also with massive recurrence many years afterresection.6 Tumour enlargement has been reported inpregnancy. 7 Increasing use and sensitivity ofultrasound and computerised tomographic (CT)scanning have led to identification of many more ofthese lesions in a symptomless phase, and even inutero.8 Early diagnosis has led to two seriousdilemmas for the clinician: first, how to be certain that

20. Gelder MG. Panic attacks: new approaches to an old problem Br J Psychiatry 1986,149: 346-52.

21. Harris EL, Noyes R, Crowe RR, Chaudtry DR. A family study of agoraphobia reportof a pilot study. Arch Gen Psychiatry 1983; 40: 1061-64.

22. Clark DM, Salkovskis PM, Gelder MG, et al Test of a cognitive theory of panic InWittchen HV, Hand I, eds. Panic and phobia, vol III Munich Springer, 1988

1. Ochsner JL, Halpert B. Cavernous hemangioma of the liver Surgery 1958, 43: 577-822. Kojimahara M. Ultrastructural study of hemangiomas. Acta Pathol Jpn 1986, 36:

1477-85.3. Fleury P, Smits N, Van-Baal S. The incidence of hepatic hamartomas in tuberous

sclerosis evaluation by ultrasonography ROFO 1987; 146: 694-96.4. Wanless IR, Mawdsley C, Adams R. On the pathogenesis of focal nodular hyperplasia

of the liver. Hepatology 1985; 5: 1194-200.5 Morley JE, Myers JB, Sachs FS, et al. Enlargement of cavernous hemangioma

associated with exogenous administration of oestrogens. South Afr Med J 1974, 48:695-97.

6. Conter RL, Longmire WP Jr. Recurrent hepatic hemangiomas. Possible associationwith estrogen therapy. Ann Surg 1988; 207: 115-19.

7. Issa P. Cavernous hemangioma of the liver: the role of radiotherapy Br J Radiol 1968,41: 26-32.

8. Nakamoto SK, Dreilinger A, Dattel B, Mattrey RF, Key TC. The sonographicappearance of hepatic hemangioma in utero. J Ultrasound Med 1983, 2: 239-41