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University of Health Sciences/The Chicago Medical School Department of Psychiatry and Behavioral Sciences

October 10, 1990

Dockets Management Branch
FDA
Room 4-62
5600 Fishers Lane
Rockville MD 20857

Re: 21 CFR Part 882 (Docket No. 82P-0316): Neurological devices; proposed rule to reclassify the electroconvulsive therapy device intended for use in treating severe depression

Gentlemen:

I have the following comments concerning the above-referenced proposed rule, which appeared in the Federal Register, vol. 55, No. 172, pp. 36578-36590, Wednesday, September 5, 1990.

1. Limitation of intended use to severe depression, as defined by DSM-III-R criteria for major depressive episode with melancholia. (section IV, p. 36580)

a. Exclusion of non-melancholic major depressives.

The 5 references cited in support of this proposed limitation are mostly outdated--4 of them appeared between 1953 and 1965--especially in view of the several random-assignment, double-blind, sham ECT-controlled studies demonstrating the efficacy of ECT in depressed patients who do not meet DSM-III-R criteria for major depressive episode with melancholia, as follows.

Freeman, Basson and Crighton (1978) found genuine ECT (N=20) superior to sham ECT (N=20) in patients suffering from "depressive illness", which the authors defined only as a persistent mood change exceeding customary sadness, accompanied by at least one of the symptoms of guilt, insomnia, retardation, or agitation. This definition is substantially less restrictive than that for DSM-III-R major depressive episode with melancholia, which requires a minimum of 10 depressive features: at least 5 for major depressive episode plus at least 5 more for melancholia.

West (1981) demonstrated the superiority of genuine (N=11) over sham (N=11) ECT in patients with "primary depressive illness" diagnosed according to the Feighner criteria, which are substantially less restrictive than those of DSM-III-R for major depressive episode with melancholia because they require only 5 depressive features for a "definite" or 4 for a "probable" diagnosis.

Brandon et al (1984) found an advantage for genuine (N=38) vs. sham (N=31) ECT in patients described only as having "major depression", without any specification as to endogenicity, psychosis, melancholia, or number or type of symptoms required.

Gregory et al (1985) reported an advantage for genuine (N=40) vs. sham (N=20) ECT in patients who met ICD-9 criteria for major depressive disorder (296.2/3), which are very simply and broadly defined as "a widespread depressed mood of gloom and wretchedness with some degree of anxiety", often with reduced activity or agitation and restlessness, and much less restrictive than DSM-III-R criteria for major depressive episode with melancholia.

Moreover, the FDA's own summary of data in support of the proposed reclassification (section IV para. A, p. 36580) relies heavily on the 1976 study of Avery and Winokur (FDA reference #7) to support the claim that ECT exerts more potent antidepressant effects than tricyclic antidepressants. The Avery and Winokur (1976) study, however, employed only a Feighner "probable" diagnosis of depression--that is, at least four depressive symptoms--which is far less restrictive than DSM-III-R requirements for a major depressive episode with melancholia.

Thus, the proposed rule to limit the use of ECT devices in the treatment of major depression to patients who meet DSM-III-R criteria for major depressive episode with melancholia is unjustifiably restrictive, and should be broadened by dropping the "with melancholia" qualifier.

b. Exclusion of patients with schizophrenia.

The FDA's position (p. 36582) that the evidence regarding the efficacy of ECT in schizophrenia is inconclusive because it is based on mainly anecdotal and uncontrolled studies omits consideration of two important double-blind, random assignment, sham-ECT controlled studies:

Bagadia et al (1983) found a course of 6 genuine ECTs plus placebo (N=20) to be therapeutically equal to a course of 6 sham ECTs plus 600 mg/day chlorpromazine (N=18) in a sample of 38 patients who met the stringent Research Diagnostic Criteria for schizophrenia. This study is notable for excluding patients with prominent affective symptoms.

Brandon et al (1985) found a course of 8 genuine ECTs (N=9) significantly more effective than 8 sham ECTs (N=8) in lowering Montgomery-Asherg Schizophrenia Scale scores in a sample of 17 patients diagnosed as schizophrenic according to the PSE-based CATEGO program.

Taken together with the Taylor and Fleminger (1980) sham-ECT controlled study cited by the FDA, these reports provide strong scientific evidence for the efficacy of ECT in schizophrenia.

c. Exclusion of patients with the diagnosis of mania.

In taking the position (p. 36585) that further scientific study is needed to demonstrate the effectiveness of ECT in mania, the FDA notes that it is already aware of the "well-designed prospective study" by J.G. Small et al (1988) . Perhaps because it is the only controlled study on the subject, the FDA apparently decided not to give it much weight; it is necessary, however, to place this study in a perspective that includes the fact that virtually every textbook on ECT, and every clinician experienced with using ECT, agrees that ECT is no less effective in mania than in melancholia. Moreover, the Small et al (1988) study must also be viewed in the context of a series of carefully-conducted retrospective chart review studies drawn from very large patient samples treated over many years (McCabe, 1976; McCabe and Norris, 1977; Thomas and Reddy, 1982; Black, Winokur, and Nasrallah, 1987), that provide compelling if not definitive evidence for a substantial anti-manic effect of ECT--in fact, no contradictory data exist. In this sense, the case was already considered proved by most experts, and lacked only the "formality" of confirmation by a controlled trial such as that of Small et al (1988)

It is further noteworthy that the recent chart review study of Black, Winokur, and Nasrallah (1987), which shows a much greater efficacy of ECT than lithium in the treatment of mania, was done at the same institution and with the same methodology as the study of Avery and Winokur (1976) that is so prominently cited by the FDA in support of the greater efficacy of ECT than antidepressant drugs. Moreover, Avery and Winokur (1976) reported that only 49% of depressives receiving ECT enjoyed "marked improvement", whereas Black, Winokur and Nasrallah (1987) found that 78% of manics who received ECT achieved this degree of improvement.

These considerations all strongly suggest that FDA should include mania as a prime indication for ECT in the proposed labeling requirement.

2. The proposed labeling requirement that the use of ECT should progress from unilateral to bilateral placement, from pulse to sine wave energy, and from subcritical to minimum amount of energy needed to induce seizure activity.

The unfortunate result of this well-intended but antitherapeutic requirement is that all patients must intially receive brief pulse right -unilateral ECT administered with near-threshold dosing, ignoring the elegant study of Sackeim et al (1987) , which conclusively demonstrates that just-above-threshold brief pulse right unilateral ECT lacks significant therapeutic benefit in depression. The requirement also ignores the fact that the only one out of 6 genuine vs. sham ECT studies that failed to show an advantage for genuine ECT (Lambourn & Gill, 1978) employed low- dose (1OJ energy) brief pulse unilateral ECT as the "active" treatment.

Finally, my colleagues and I (Abrams, Swartz and Vedak, Arch. Gen. Psychiat., in press, copy enclosed) have recently demonstrated that high-dose (markedly suprathreshold) brief pulse right unilateral ECT is equal in therapeutic efficacy to bilateral ECT, in contrast to an earlier study at the same site (Abrams et al, 1983) that found conventional-dose unilateral ECT to be much less effective than bilateral ECT.

Sincerely yours,

Richard Abrams, M.D.
Professor of Psychiatry

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