Food and Drug Administration Action Is Required

Arch Gen Psychiatry 2000; 57:445-446
Richard Abrams, MD

SUBSTANTIAL research funds and energy have been expended over several decades in attempts to determine the benefits and risks of bilateral and right unilateral electroconvulsive therapy (ECT). Proponents of each method are divided into opposing camps; having been on both sides of the issue, I believe I can fairly state the arguments for each side as follows.

Those favoring bilateral ECT point to the controlled trials demonstrating its greater efficacy and discount its more pronounced adverse cognitive effects as being transient and not different from those of right unilateral ECT weeks or months after a course of treatment. The very infrequent occurrence of prolonged memory impairment after bilateral ECT is acknowledged, but it is held to be a small price to pay for the reduced patient morbidity and mortality thought to result from the use of bilateral ECT.

Those favoring right unilateral ECT point to the controlled trials showing therapeutic equivalence to bilateral ECT, and to the dramatically lower cognitive effects immediately after a course of treatment. The therapeutic advantage of bilateral ECT in some patients is acknowledged, but attributed to inadequate technique especially inadequate dosage with unilateral ECT. The occasional need to switch from unilateral to bilateral ECT during a course of ECT because of insufficient therapeutic response to right unilateral ECT is said to be a small price to pay for the pronounced cognitive advantages of unilateral ECT. These cognitive advantages are held to substantially dilute the negative image of ECT prevalent among the public, fellow professionals, lawmakers, and the media, thereby increasing patient acceptance of ECT.

The 2 articles published in this issue of ARCHIVES, when examined in light of previously reported data, should help resolve some of the issues that have separated the opposing camps and facilitate a rational conclusion of the controversy.

The article by Sackeim et al(1) compares right unilateral ECT given at 3 different dosage levels (1.5, 2.5, and 6 times seizure threshold) with the criterion standard of high-dose bilateral ECT given at 2.5 times threshold (mean dose, 277 millicoulombs [mC]). High-dose unilateral ECT (6 times threshold; mean dose, 441 mC) was indistinguishable in antidepressant efficacy from high-dose bilateral ECT at both post-ECT assessment intervals: 1 or 2 days and 1 week after the course of treatment (after which both groups were given the physician's choice of treatment). The treatment response for the 2 groups was identical: 80% immediately after the ECT course, falling to 65% several days later.

At all post-ECT assessment intervals, there were greater deficits after bilateral than high-dose unilateral ECT in a variety of memory measures. Notably, 2 months after the treatment course, patients receiving bilateral ECT exhibited greater amnesia for past public and personal events than those receiving high-dose unilateral ECT.

The article by McCall et al (2) compared right unilateral ECT given with either titrated 2.25 times threshold dosing (mean dose, 136 mC) or fixed high dosing (403 mC). Patients receiving fixed high-dose unilateral ECT had a markedly superior therapeutic response at the 1- or 2-day post-ECT assessment: 67% (n=49) vs 39% (n=28) for the titrated moderate-dosage group.

Immediately after unilateral ECT, global cognitive disturbance was worse for those in the high-dosage group; they also recalled a somewhat smaller proportion of autobiographical memory items. Other memory measures, including verbal and figural anterograde tests, and patients' self-ratings of subjective global memory, did not differentiate between the groups.

The antidepressant efficacy of right unilateral ECT in these 2 studies is comparable to that we reported earlier in a comparison of fixed high-dose (378 mC) bilateral and unilateral ECT.(3) In our study, the antidepressant response immediately after the sixth ECT dose was indistinguishable for the 2 methods: 79% for high-dose bilateral ECT vs 68% for high-dose unilateral ECT, employing the same response criterion used in the present studies. We performed no cognitive assessments.

The bilateral vs unilateral ECT controversy may be approaching resolution. Increasing the stimulus dose for unilateral ECT whether as a multiple of seizure threshold or as a fixed dose reliably increases its antidepressant effect to approximate that of bilateral ECT. Why do I hedge? Because the study by McCall and colleagues (2) excluded the most severely ill patients (preferentially assigning them to bilateral ECT at the outset), and because some depressed patients in the study by Sackeim et al (1) who failed high-dose right unilateral ECT responded well when switched to bilateral ECT.

Moreover, sample sizes were small (about 20 per group) in the comparisons of high-dose right unilateral and bilateral ECT the studies by Sackeim et al (1) and Abrams et al (3) suggesting the possibility of insufficient statistical power to demonstrate a real difference between the 2 methods.

Furthermore, optimal dosage levels and stimulus parameters for unilateral ECT remain to be established. Although some excellent results have been demonstrated with 6 times seizure threshold dosing for stimulus titration and 375 mC to 450 mC for fixed dosing, the point of maximal antidepressant response to increasing the dosage with right unilateral ECT has yet to be reached; higher doses may be even more effective. Similarly, the pulse widths employed have been at the higher end of the available range (1.0-1.5 milliseconds), and it is reasonable to predict that shorter pulse widths (eg, in the 0.25- to 0.5-millisecond range) might be more efficacious, either in themselves or via the longer stimulus trains they generally require. (4)

Dosage above the seizure threshold is an important determinant of the antidepressant efficacy of right unilateral ECT. An apparent relationship between absolute stimulus dose and treatment response (4) results from the facts that titrating the stimulus dose to a larger multiple of the seizure threshold yields both higher doses and a better treatment response, and that higher fixed dose produce a greater extent of dose above seizure threshold and thereby a better treatment response. Nevertheless, from a practical perspective, both the studies of McCall et al (2) and Abrams et al (3) show that increasing the absolute stimulus dose for unilateral ECT without consideration of the seizure threshold is a clinically effective strategy.

Finally, the choice of the seizure threshold as the variable on which to base ECT dosage is arbitrary; more useful measures may exist. (4) An individual physiological response, such as the degree of electroencephalographic postictal suppression (ie, a postictal suppression threshold), should provide a more rational guide to stimulus dosage because, unlike the seizure threshold, the degree of postictal suppression has been shown to be related to the antidepressant response.5-7 Other readily obtainable physiological measures (eg, heart rate) are also candidates for thresholds against which to titrate the stimulus dose. (8)

Even when administered at high dosages, unilateral ECT seems to retain important cognitive advantages over bilateral ECT. To date, unilateral ECT regardless of dosage has not been demonstrated to induce persistent amnesia, whereas studies have found detectable retrograde amnesia 2 to 6 months after bilateral ECT. However, because the 2.5 times seizure threshold dosing used in the study by Sackeim et al (1) is higher than required for the usual and expected antidepressant benefit from bilateral ECT, (9) it probably exaggerated the cognitive differences between the 2 methods.

It is time for the Food and Drug Administration to act. The aforementioned dosage considerations are moot for US psychiatrists and their patients in that present Food and Drug Administration regulations do not permit the sale in this country of ECT devices capable of administering, for example, 6 times seizure threshold dosing to all patients (high-dose ECT devices have been available outside the United States for many years). Unless more efficient forms of stimulation (eg, shorter pulse width, longer-duration stimuli) are proven effective at dosages within the range of presently available ECT devices, patients in the United States will be excluded from receiving the most efficacious forms of unilateral ECT. (4, 10)

Author/Article Information

Richard Abrams, MD
Department of Psychiatry and Behavioral Sciences
Chicago Medical School
3333 Green Bay Rd
North Chicago, IL 60064

Dr Abrams is director of Somatics Inc, Lake Bluff, Ill, the manufacturer of the Thymatron Electroconvulsive Therapy device.

I thank Max Fink, MD, and Conrad M. Swartz, PhD, MD, for providing helpful critiques of earlier drafts of this commentary.

REFERENCES

1. Sackeim HA, Prudic J, Devanand DP, Nobler MS, Lisanby SH, Peyser S, Fitzsimons L, Moody BJ, Clark J. A prospective, randomized, double-blind comparison of bilateral and right unilateral electroconvulsive therapy at different stimulus intensities. Arch Gen Psychiatry. 2000;57:425-434.

2. McCall WV, Reboussin DM, Weiner RD, Sackeim HA. Titrated moderately suprathreshold vs fixed high-dose right unilateral electroconvulsive therapy: acute antidepressant and cognitive effects. Arch Gen Psychiatry. 2000;57:438-444.

3. Abrams R, Swartz CM, Vedak C. Antidepressant effects of high-dose right unilateral electroconvulsive therapy. Arch Gen Psychiatry. 1991;48:746-748.

4. Abrams R. Electroconvulsive Therapy. 3rd ed. New York, NY: Oxford University Press; 1997.

5. Krystal AD, Weiner RD, Gassert D, McCall WV, Coffey CE, Sibert T, Holsinger T. The relative ability of three ictal EEG frequency bands to differentiate ECT seizures on the basis of electrode placement, stimulus intensity, and therapeutic response. Convuls Ther. 1996;12:13-24.

6. Nobler MS, Sackeim HA, Solomou M, Luber B, Devanand DP, Prudic J. EEG manifestations during ECT: effects of electrode placement and stimulus intensity. Biol Psychiatry. 1993;34:321-330. MEDLINE

7. Petrides G, Kellner C, Knapp R, Rummans T, O'Connor K, Hussain M, Fink M, Rush AJ, Rasmussen K, Beale M, Bernstein H, Biggs M, Mueller M, Zhao W. Can ictal EEG indices predict response to ECT? Presented as a poster at: the National Clinical Drug Evaluation Unit meeting; May 30-June 2, 2000; Boca Raton, Fla.

8. Swartz CM. Disconnection of EEG, motoric, and cardiac evidence of ECT seizure. Convuls Ther. 1996;12:25-30.

9. Sackeim HA, Prudic J, Devanand DP, Kiersky JE, Fitzsimons L, Moody BJ, McElhiney MC, Coleman EA, Settembrino JM. Effects of stimulus intensity and electrode placement on the efficacy and cognitive effects of electroconvulsive therapy. N Engl J Med. 1993;328:839-846.

10. Sackeim HA. Are ECT devices underpowered? Convuls Ther. 1991;7:233-236.

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