Comment Drug Treatment of Panic Disorder

British Journal of Psychiatry (1993), 162, 795—796

Comment

Drug Treatment of Panic Disorder Further Comment ISAAC M. MARKS, METIN BA$OãLU,HOMA NOSHIRVANI, JOHN GREIST,

RICHARDP. SWINSON and GERALDINEO'SULLIVAN

The late Dr Gerald Kierman was one of the foremost psychiatrists of his day, and his death is a grievous loss to us all. An incisive thinker,

he

did much to help psychiatry become a scientific discipline. His numerous fine contributions included an excellent controlled study (with Myrna Weissman

and Eugene Paykel) of an antidepressant and psycho therapy in depression. As director of ADAMHA he facilitated the launch of two major multicentre studies —¿ the Epidemiologic Catchment Area study and the National Institute of Mental Health's controlled trial contrasting an antidepressant and two psychotherapies in depression —¿ which raised the

standards of psychiatric research. The comments below in no way detract from Dr Kierman's achievements for psychiatry, and are made only to sharpen the scientific issues and to reduce the chance that mistaken inferences could lead patient care to suffer. In Table 1 of Dr Kierman's (1992) reply to our

a week or two which is cited is at best a question able gain from the patient's longer perspective. In their original article, Kierman et al (Cross National Collaborative Panic Study, Second Phase Investigators, 1992, p. 199) stated that studies of various benzodiazepines other than alprazolam “¿have been completed―(our italics). Their Comment claims (p. 469) their article had noted “¿that other benzo diazepines. . - have been subsequently studied and found effective in panic disorders―(our italics). Those crucial last six words were not in the original paper, from which it was difficult to conclude that in panic disorder alprazolam had an effect like that of other benzodiazepines.

“¿The advantage of the placebo-controlled drug design is that it at least attempts to control for bias due to non-blindess.― When the success of such

attempts was tested in several drug studies that were run ‘¿double-blind', the raters were found

in fact

to have guessed the treatment condition correctly own comments on the Cross-National Collaborative (Margraf et a!, 1991). Many behaviour therapy Panic Study, the completer analysis shows no signi studies used independent blind raters just as drug ficant drug effect for “¿b Total panic attacks―either studies do. in the Phase II or in the Phase I study. This makes Kierman et al's reply alleges (p. 468) “¿there is no suspect the idea that alprazolam is an antipanic drug. equivalent of placebo in studies of psychological It is also noteworthy that non-panic measures improved treatment―. Relaxation has been used successfully significantly even without an antipanic effect. The as a placebo treatment in many studies of phobic drug effect on panic in Phase!! was ‘¿significant'only and obsessive—compulsivedisorders. It is credible on endpoint analysis. As noted before, it is uncertain to patients, who do relaxation faithfully, yet it how valid the assumption for endpoint analysis is produces little change in these disorders. that drop-outs would not have improved had they The controlled London/Toronto study (Marks remained in the study. et a!, this issue, pp. 776—787)puts the Phase II On p. 469 Klerman challenges the idea that “¿thereresults in perspective. As in the Phase I and II is no reason to expect the effects [of alprazolam] studies, it found alprazolam had no significant effect to increase beyond eight weeks― by citing an on panic in completers. Nor did alprazolam have a unpublished finding by Curtis that drug effects significant effect on our endpoint analyses, which were sustained over six- to eight-month follow-up. included all patients who had at least three weeks Sustained is different from increased. of treatment, to make that analysis comparable to On p. 468 a ruling by the US Food and Drug the Phase I and II analyses. Administration is cited justifying the four-week The London/Toronto study found an exposure Phase II and I results as a “¿precise estimate of effect at least twice that of alprazolam on most efficacy―. Are patients with problems of five to non-panic measures in the short term which persisted nine years' duration at the time of presentation to 10-month follow-up. The low drop-out rate in being asked to take drugs for years on the basis this study, unlike that in Phases II and I, allowed of four-week trials? A more rapid action within its results to be accepted with some confidence. 795

796

MARKS ET AL

The short-term as well as long-term results were ignored in the Phase II report and in the reply to our comment. Klerman et al write that the full London/Toronto

results had not been published or circulated to them. In fact Dr Klerman: (a) chaired the Upjohn sponsored investigators' meeting in his Department in New York on 22 March 1990 which reviewed the early results that were like the main ones; (b) chaired

the Upjohn-sponsored June 1990 Geneva panic conference where the main results were presented; (c) wrote the Introduction to the September 1990 Journal of Psychiatric Research Supplement which published an abstract of those results; and (d) was at the later Consensus on Panic meeting which discussed those results. A great debt of gratitude

That reply indicates that the Phase II

and I studies were done “¿with the intention of submitting

care. A new treatment

for a chronic condition needs

to be compared with other treatment of enduring efficacy, and to have a controlled withdrawal phase or a naturalistic follow-up. The cost of such well designed trials would be but a small fraction of the huge sums spent on recent multicentre short-term trials funded by drug companies. Large numbers are no substitute for good design. Only when the regulations of the FDA and the UK's Committee on the Safety of Medicines are changed to require better designs can we expect most such controlled trials to meet scientific and patients' needs more than those of the marketplace.

is due to Dr Klerman

for having, as Upjohn's scientific adviser to their series of panic studies, helped to fund, design and execute the London/Toronto study. Klerman et al's reply, however, ignores the implications of its findings.

centre studies. That aim is understandable from a commercial point of view, but should not be confused with the aims of good science and health

a NDA [New Drug Application]

to the

FDA for approval of alprazolam in the ‘¿treatment of panic disorder and related conditions―. The aim of getting FDA approval of a drug's use in particular disorders drives many multi

References CROSS-NATIONALCOLLABORATIVEPANIc STUDY, SECOND PHASE INvEsTIGAToRs (1992) Drug treatment of panic disorder.

Comparative efficacy of aiprazolam, imipramine, and placebo. British Journal of Psychiatry, 160, 191-202. KLERMAN,0. L. (1992) Drug treatment

of panic disorders.

Reply

to comment by Marks and associates. British Journal of Psychiatry, 161, 465—471. MAROW, .1, EHLERS,A., Rom, W. T., eta! (1991) How ‘¿blind' are double-blind studies? Journal of Consulting and Clinical Psychology, 59, 184—187.

lsaac M. Marks, MD,FRCPSyCh, Professor, Institute of Psychiatry, London SES 8AF; Metin Ba@o@lu,MD, Honorary Senior Registrar, Institute of Psychiatry; John Greist, MD,Dean Foundation, Madison, USA; Homa Noshirvani, MRCPsyth,Research Worker, Institute of Psychiatry; Richard P. Swinson, MD,FRCPSYCh, Clinical Director, Clarke Institute, Toronto, Canada; Geraldine O'Sullivan, MRCPsych,Senior Registrar, Institute of Psychiatry Correspondence

The Editor now regards these matters closed to further comment in this journal.