What is an adequate treatment in convulsive therapy? It is with pleasure that I write these notes and recollect the many contributions of Jan-Otto Ottosson, a friend and colleague for more than 40 years. I recall many pleasant and thought-provoking days during his visits to the United States and many meetings in which his thoughts about ECT influenced my work in the clinic and the laboratory. I recall how his ideas influenced the fine work in ECT of d’Elia, Laurell, Raotma, Widepalm and Frederiksen. He supported the launching of the journal Convulsive Therapy and did much to assure its success, despite his obligations as editor of the Acta and the chairmanship at Goteborg. Jan-Otto is the world leader in convulsive therapy, both in practice and research. We owe him much.
Fink M. What is an adequate treatment in convulsive therapy? Acta Psychiatr Scand 1991: 84: 424-427.
The parameters of the induction of an effective electroconvulsive therapy (ECT) treatment are poorly defined. We find variations in outcome, with changes in electrode placement and energy levels, despite measures of motor seizure duration greater than 25 s. To maximize the outcome of ECT, attention is again focused on the electrophysiologic and biochemical features of seizures, much as Ottosson studied them in 1960.
When Ladislas Meduna induced seizures in a catatonic patient with injections of camphor and the patient recovered from a 4-year illness, Meduna was surprised; a surprise that was matched by the rest of the world when he reported his experience with a large number of patients (1). In his neuropathology studies, he had found a shortage of glia in the brains of patients with dementia praecox, and a surfeit of glia in epileptics. He concluded that seizures might ameliorate the symptoms of dementia praecox by inducing gliosis. When this strange idea was fruitful and the symptoms of dementia praecox were indeed relieved by induced seizures, he argued that seizures were essential to improvement in psychosis (2, 3). When Ugo Cerletti and Luigi Bini demonstrated that seizures could be induced by electric currents, and that these were as salutary as those induced by pentylenetetrazol, electroconvulsive therapy replaced pharmacoconvulsive therapy as a much easier and more humane induction of seizures. Cerletti (4) also concluded that induced seizures were essential to the therapeutic process. But others were not so sure and many asked whether it was the seizure, or the electric currents, or the change in milieu that mattered. Treatments were modified by photoconvulsive inductions, by
424
M. Fink Department of Psychiatry and Behavioral Science, SUNY at Stony Brook, Long Island and International Association for Psychiatric Research, Inc., St. James, New York, USA
Key words: convulsive therapy; ECT; seizure Max Fink, M.D., P.O. Box 457, St. James, NY 11780, USA Accepted for publication April 4, 1990
subconvulsive currents, by intensive (regressive) electroshock, by changing current type (brief pulse currents were introduced by Liberson in 1948, for example), and by changing electrode location. The literature of the 1940s is filled with innovative ideas to determine which elements of the treatment were essential and which irrelevant to the treatment process. In the 1950s, the landscape of psychiatry held not only convulsive therapy and its variations, but insulin coma and leucotomy. The claims for clinical success for these interventions clouded our thinking, for we were not sure whether the treatments were effective or sham, whether coma or brain damage effected the changes in behavior, or whether intensive interpersonal care was all that mattered. In this morass of ambiguity, 2 investigators undertook experiments that remain hallmarks of the era. In St. Louis, George Ulett examined the relative merits of ECT and sham ECT. He modified treatments with scopolamine and atropine and found that the interictd seizure patterns (and presumably seizure patterns) were materially altered. These modified treatments were less effective than the unmodified. Ulett concluded that seizures were essential to the treatment process (5,6).
Convulsive therapy
Jan-Otto Ottosson in Stockholm inquired whether blocking electrical seizure activity with lidocaine interfered with clinical efficacy. He injected lidocaine intravenously in doses of 3-4 mg/kg before treatment in patients receiving ECT. In the modified treatments, the duration of the seizure and the postseizure electrical silence were shorter, the EEG was more like that of a petit ma1 than that of a grand ma1 seizure, and clinical results were poorer. He concluded that a full seizure was essential to the therapeutic process (7). We believed Ottosson’s and Ulett’s conclusions on the importance of the seizure. But we were troubled by an inability to determine which aspects of the seizure were in the therapeutic chain and which were responsible for side effects. Had the psychopharmacologic revolution not intervened in the 1950s, we would surely have studied the effects of modified seizures more, and would have come to understand the behavioral effects of seizures better. But new psychoactive substances suddenly appeared in our clinics and dramatically changed our thinking. It was no longer fashionable to use or study convulsive therapy, insulin coma or leucotomy. These somatic treatments were too complex, too labor-intensive, too risky, and in the instance of insulin coma, less effective than its replacement, chlorpromazine (8). These somatic treatments were rapidly replaced by psychoactive drugs. In the 1970s, however, our interest in ECT was reawakened, as much by the anti-psychiatry movements around the world as by our awareness that psychoactive drugs, as useful as they were, still left many hopelessly ill. Numerous evaluations found ECT to be an effective treatment. Indeed, some patients were better treated by ECT than by drug therapies. And our technical skills allowed us to deliver safe and humane inductions, even in the face of associated severe somatic illnesses (9, 10). We studied the role of electrode placement and brief pulse currents, monitored seizure durations, and expanded the indications for the use of ECT. In Great Britain, the belief that the seizure did not matter led some students to assess the relative merits of ECT and sham-ECT. They again concluded that seizure induction affected the clinical efficacy of ECT (1 1). We once believed that all grand ma1 seizures were equivalent, that “a seizure is a seizure”. But experience with electrical and chemical inductions and with different current types, energy levels and electrode placements argued persuasively that the overt manifestations of the seizure in motor activity, duration, generalization and symmetry are inadequate reflections of what must lie at the heart of the therapeutic process. We argued about the relative efficacy of seizures
induced through unilateral and bilateral electrode placements. We found good efficacy and less memory deficits for seizures induced through unilateral placements (9, 12). But efficacywas less, even though the observed seizures were similar in duration and in motor patterns to those induced through bilateral electrode placements (13, 14). These observations were puzzling, for if “a seizure is a seizure”, and a seizure is central to the treatment process, then the clinical results should be the same for both inductions. But it is more difficult to induce seizures through unilateral electrodes, with many more short, aborted, or incomplete seizures (10, 13). The EEG patterns are asymmetric, often with poor development of burst patterns, imprecise end-points, and short isoelectric periods. Interseizure EEG records often show less slow wave activity in asymmetric patterns. These findings are precisely those reported by Ottosson (7) to be associated with poorer clinical results in the lidocaine-treated subjects. Perhaps the difference in efficacy is related to differences in the seizure; if so, are we now to be concerned that “a seizure is not a seizure”, that similar overt motor seizures may have different central neurophysiologic and biochemical substrates? To develop a useful index of an effective treatment, the duration of the seizure was studied. The duration of the motor seizure in a cuffed limb (following the technique of Addersley & Hamilton (15)), epileptic activity in the EEG, and increased heart rate were each used as indices. Motor seizures less than 15 s in duration rarely exhibited tonic and clonic phases, and these seemed to be clinically less effective than longer seizures. Motor seizures with durations greater than 25 s were usually generalized, and this index was taken as a measure of an adequate treatment. (This conclusion was derived by consensus, and was not based on experimental data.) In some elderly patients, the seizure duration for each treatment is less than 25 s and yet the patient improves. The strength and duration of the inducing currents affect treatment efficacy. Higher energy levels are clinically more effective than threshold levels. They induce longer seizures, and even when the total charge is kept constant, longer strains of impulses more often induce longer seizures (16). The relationship between seizure duration and clinical outcome in the treatment of depression is poor. We concluded that seizure duration is too imprecise and unreliable to be a criterion of seizure efficacy. These observations are consistent with the findings of Ottosson. An epileptic grand ma1 seizure is accompanied by the release of prolactin into the blood. Plasma levels are doubled or tripled within 20 min of a grand ma1 seizure. In experimental ECT studies, more pro-
425
Fink
lactin is released with high inducing currents, with bilateral electrode placement, and with the initial seizures in a series (13). If prolactin release reflects the direct effects of the stimulus and the seizure on the brain, then current path and dosage should be reflected in efficacy. And indeed they are. Sackeim and co-workers at Columbia University developed a threshold titration technique for seizure induction (17, 18). When their depressed patients were treated with energies just above threshold through unilateral electrode placements, efficacy was poor, and less than 30% of the patients improved. (Seizure durations were monitored and seizures were shown to be generalized with durations greater than 25 s in motor activity.) The efficacy of the same currents through bilateral electrodes was better. When high-energy currents, defined as 150% above threshold, were applied through unilateral or bilateral electrodes, efficacy was best. Similar findings were reported by Robin & deTissera (19). In their latest study, Abrams et al. (14) describe an experiment in which depressed patients were randomly assigned to bilateral or right unilateral ECT with equal high-energy currents. They report equal treatment results, again arguing that the strength of currents is a factor in the efficacy of seizures. Ottosson (20) recently re-examined the unilateralbilateral ECT controversy, especially the claims for less efficacy with unilateral ECT. He concluded that the studies that reflected less efficacy failed to assure adequate seizures. They usually delivered submaxima1 seizure activity because of short interelectrode distance, barely suprathreshold stimulation, and the concurrent use of benzodiazepine drugs which raised seizure thresholds. For the past decade, to minimize the effects on cognition and largely to keep our critics at bay, we used minimum amounts of energy (threshold currents), brief pulse currents, and unilateral electrode placements to induce seizures in our patients. Was the emphasis on safety at the price of efficacy? Did we encourage clinically inadequate treatments? I believe so, especially when we consider that the principal measure of treatment efficacy was seizure duration, and not any qualitative or quantitative aspect of the seizure (21). We have learned much about the seizure-inducing stimulus and the characteristics of an effective treatment, but we are still unable to answer the question of how best to treat our patients. Will studies like those of Ottosson and Ulett help us develop a better idea of the ECT therapeutic process? I believe they will, and we should undertake such studies in the clinic and the laboratory. In the clinic, we can identify populations of &ectively ill people who show characteristic behavioral 426
improvement with ECT. We can standardize the frequency and numbers of treatments, electrical energy, and pathways in a course. If we measure the electrical characteristics of each seizure and seek relations to clinical outcome, we should better define the electrophysiology of the therapeutic process. Such studies are ongoing in the reports of Abrams, Sackeim, Weiner, and Staton and Brumback. We may seek clues in our present theories. In 1972, we organized an international conference to examine theories of the mode of action of ECT (22). Reviews of the biochemical, cognitive, and electrophysiologic hypotheses found these wanting. Ottosson (23) discussed the systemic biochemical effects of ECT, and concluded that there was little evidence that any biochemical measure was clearly in the therapeutic chain. At the time, de Wied in the Netherlands described the behavioral effects of hypothalamic peptides, and others reported that affectively ill patients exhibited severe neuroendocrine dysregulation. For example, phasic diurnal rhythms in plasma cortisol were lost, basal levels were elevated, and the typical decrease in plasma levels after exogenous steroids could not be elicited. If our patients had evidence of hypothalamic pathology, might the administration of behavioral active peptides not improve behavior and the neuroendocrine pathology? Peptides were administered to affect memory, mood, and thought, and although the results were not sufficient to alter our treatment tactics, we were persuaded that these compounds did have behavioral effects. In 1978, Ottosson again reviewed the evidence for biochemical changes in the therapeutic chain of ECT, specifically in its antidepressant efficacy. His review increased interest in hypothalamic physiology, and led us to combine the data of neuroendocrine challenge tests, behavioral experiments with peptides, and our clinical knowledge to propose a neuroendocrine view of the antidepressant action of ECT (24). In this view, the core defect in affective disorders is seen to be hypothalamic hypofunction, which results in a deficiency of regulatory peptides that are necessary for our wellbeing in mood and thought. Evidence is found in severe neuroendocrine dysregulation, its reversal with treatment, and accompanying behavioral improvement. Recent reviews of the theory find it still viable (25). The most interesting data come from studies of prolactin and of thyrotropin-releasing hormone (TRH). The amount of prolactin released with each seizure varies with treatment parameters and parallels the influence of these parameters on therapeutic outcome (electrode placement and electrical dosage, for example). We now believe that the amount of
Convulsive therapy prolactin released into the blood is an index of the efficacy of a treatment - perhaps the more precise index we have been seeking. Studies of TRH find this peptide to have antidepressant and anticonvulsant effects, making it a model for a peptide with behavior-modifying (antidepressant and antimanic) effects. In our next studies, it may be fruitful to examine variations in seizure induction (as modified by electrode placement or strength of current), seizure efficacy (as reflected in EEG characteristics), with peptide release into CSF and blood. We have learned much. Our attention is again directed at the questions of the 1950s that tantalized Ottosson and Ulett and remain challenges for this decade: What is essential to the ECTprocess? And, how do induced epileptic seizures assure a persistent behavioral change among the severe mentally ill? Neither the catecholamine nor the receptor theories have been helpful in explaining either the effects of drugs or seizures, or the pathophysiology of mental illnesses. Our reliance on the present psychopharmacologic cornucopia has helped many patients, but left as many ill. The remarkable efficacy (and present safety) of modified ECT after more than a half century of use argues for our reexamination of the process, not only for an understanding of it, but for clues as to the classification and pathophysiology of mental illnesses. References 1. MEDUNAL. Die Konvulsionstherapie der Schizophrenie. Haile: Karl Marhold, 1937. 2. MEDUNAL. Autobiography. Part I. Convulsive Ther 1985: 1: 43-57. 3. MEDUNAL. Autobiography. Part 11. Convulsive Ther 1985: 1: 121-35. 4. CERLETTI U. Electroshock therapy. In: MARTI-IBANEZ F, SACKLER AM, SACKLER MD, SACKLER RR ed. The great physiodynamic therapies in psychiatry. New York: HoeberHarper, 1956: 91-100. 5. ULETT GA, SMITHK, GLESERGC. Evaluation of convulsive and subconvulsive shock therapies utilizing a control group. Am J Psychiatry 1956: 112: 795-802.
6. ULETTGA, JOHNSON MW. Effect of atropine and scopolamine upon electroencephalographic changes induced by electroconvulsive therapy. Electroencephalogr Clin Neurophysiol 1957: 9: 217-24. 7. OTTOSSON J-0.Experimental studies of the mode of action of electroconvulsive therapy. Acta Psychiatr Neurol Scand 1960: 35: (SUPPI145) 1-141. 8. FINKM, SHAWR, GROSSG, COLEMAN FS. Comparative study of chlorpromazine and insulin coma in therapy of psychosis. JAMA 1958: 166: 1846-50. 9. American Psychiatric Association. Electroconvulsive therapy. Task Force Report # 14. Washington, DC: APA, 1978. 10. FINKM. Convulsive therapy: theory and practice. New York: Raven Press, 1979. 11. PALMERRL, ed. Electroconvulsive therapy: an appraisal. Oxford: Oxford University Press, 1981. 12. D’ELIAG, RAOTMA H. Is unilateral ECT less effective than bilateral ECT? Br J Psychiatry 1975: 126: 83-9. 13. ABRAMSR. Electroconvulsive therapy. New York: Oxford University Press, 1988. 14. ABRAMS R, SWARTZ CM, VEDAKC. Antidepressant effects of high-dose right unilateral ECT. Am J Psychiatry 1989: 146: 1190-2. DJ, HAMILTON M. Use of succinylcholine in 15. ADDERSLEY ECT. Br Med J 1953: 1: 195-7. 16. SWARTZCM, LARSONG. ECT stimulus duration and its efficacy. Ann Clin Psychiatry 1989: 1: 147-52. 17. MALITZS, SACKEIM HA. Electroconvulsive therapy: clinical and basic research issues. Ann NY Acad Sci 1986: 462: 1-424. 18. SACKEIM HA, DECINA P, PORTNOYS, NEELEYP, MALITZ S. Studies of dosage, seizure threshold, and seizure duration in ECT. Biol Psychiatry 1987: 22: 249-68. 19. ROBINA, DETISSERA S. A double-blind controlled comparison of the therapeutic effects of low and high energy electroconvulsive therapies. Br J Psychiatry 1982: 141: 357-66. 20. OTTOSSON J-0. Is unilateral nondominant ECT as efficient as bilateral ECT? A new look at the evidence. Convulsive Ther 1991: 7: 190-200. 21. FINKM. An adequate treatment? Convulsive Ther 1989: 5: 311-3. 22. FINKM, KETYS, MCGAUGHJ, WILLIAMS T, ed. Psychobiology of convulsive therapy. Washington, DC: V.H. Winston & Sons, 1974. J-0. Systemic biochemical effects of ECT. In: 23. OTTOSSON FINKM, KETYS, MCGAUGHJ, WILLIAMS T, ed. Psychobiology of convulsive therapy. Washington, DC: V.H. Winston & Sons, 1974: 209-20. 24. FINKM, OTTOSSON J-0. A theory of convulsive therapy in endogenous depression: significance of hypothalamic functions. Psychiatry Res 1980: 2: 49-61. 25. FINKM. How does ECT work? Neuropsychopharmacology 1991: 3: 73-82.
421
Fink M. What is an adequate treatment in convulsive therapy? Acta Psychiatr Scand 1991: 84: 424-427.
The parameters of the induction of an effective electroconvulsive therapy (ECT) treatment are poorly defined. We find variations in outcome, with changes in electrode placement and energy levels, despite measures of motor seizure duration greater than 25 s. To maximize the outcome of ECT, attention is again focused on the electrophysiologic and biochemical features of seizures, much as Ottosson studied them in 1960.
When Ladislas Meduna induced seizures in a catatonic patient with injections of camphor and the patient recovered from a 4-year illness, Meduna was surprised; a surprise that was matched by the rest of the world when he reported his experience with a large number of patients (1). In his neuropathology studies, he had found a shortage of glia in the brains of patients with dementia praecox, and a surfeit of glia in epileptics. He concluded that seizures might ameliorate the symptoms of dementia praecox by inducing gliosis. When this strange idea was fruitful and the symptoms of dementia praecox were indeed relieved by induced seizures, he argued that seizures were essential to improvement in psychosis (2, 3). When Ugo Cerletti and Luigi Bini demonstrated that seizures could be induced by electric currents, and that these were as salutary as those induced by pentylenetetrazol, electroconvulsive therapy replaced pharmacoconvulsive therapy as a much easier and more humane induction of seizures. Cerletti (4) also concluded that induced seizures were essential to the therapeutic process. But others were not so sure and many asked whether it was the seizure, or the electric currents, or the change in milieu that mattered. Treatments were modified by photoconvulsive inductions, by
424
M. Fink Department of Psychiatry and Behavioral Science, SUNY at Stony Brook, Long Island and International Association for Psychiatric Research, Inc., St. James, New York, USA
Key words: convulsive therapy; ECT; seizure Max Fink, M.D., P.O. Box 457, St. James, NY 11780, USA Accepted for publication April 4, 1990
subconvulsive currents, by intensive (regressive) electroshock, by changing current type (brief pulse currents were introduced by Liberson in 1948, for example), and by changing electrode location. The literature of the 1940s is filled with innovative ideas to determine which elements of the treatment were essential and which irrelevant to the treatment process. In the 1950s, the landscape of psychiatry held not only convulsive therapy and its variations, but insulin coma and leucotomy. The claims for clinical success for these interventions clouded our thinking, for we were not sure whether the treatments were effective or sham, whether coma or brain damage effected the changes in behavior, or whether intensive interpersonal care was all that mattered. In this morass of ambiguity, 2 investigators undertook experiments that remain hallmarks of the era. In St. Louis, George Ulett examined the relative merits of ECT and sham ECT. He modified treatments with scopolamine and atropine and found that the interictd seizure patterns (and presumably seizure patterns) were materially altered. These modified treatments were less effective than the unmodified. Ulett concluded that seizures were essential to the treatment process (5,6).
Convulsive therapy
Jan-Otto Ottosson in Stockholm inquired whether blocking electrical seizure activity with lidocaine interfered with clinical efficacy. He injected lidocaine intravenously in doses of 3-4 mg/kg before treatment in patients receiving ECT. In the modified treatments, the duration of the seizure and the postseizure electrical silence were shorter, the EEG was more like that of a petit ma1 than that of a grand ma1 seizure, and clinical results were poorer. He concluded that a full seizure was essential to the therapeutic process (7). We believed Ottosson’s and Ulett’s conclusions on the importance of the seizure. But we were troubled by an inability to determine which aspects of the seizure were in the therapeutic chain and which were responsible for side effects. Had the psychopharmacologic revolution not intervened in the 1950s, we would surely have studied the effects of modified seizures more, and would have come to understand the behavioral effects of seizures better. But new psychoactive substances suddenly appeared in our clinics and dramatically changed our thinking. It was no longer fashionable to use or study convulsive therapy, insulin coma or leucotomy. These somatic treatments were too complex, too labor-intensive, too risky, and in the instance of insulin coma, less effective than its replacement, chlorpromazine (8). These somatic treatments were rapidly replaced by psychoactive drugs. In the 1970s, however, our interest in ECT was reawakened, as much by the anti-psychiatry movements around the world as by our awareness that psychoactive drugs, as useful as they were, still left many hopelessly ill. Numerous evaluations found ECT to be an effective treatment. Indeed, some patients were better treated by ECT than by drug therapies. And our technical skills allowed us to deliver safe and humane inductions, even in the face of associated severe somatic illnesses (9, 10). We studied the role of electrode placement and brief pulse currents, monitored seizure durations, and expanded the indications for the use of ECT. In Great Britain, the belief that the seizure did not matter led some students to assess the relative merits of ECT and sham-ECT. They again concluded that seizure induction affected the clinical efficacy of ECT (1 1). We once believed that all grand ma1 seizures were equivalent, that “a seizure is a seizure”. But experience with electrical and chemical inductions and with different current types, energy levels and electrode placements argued persuasively that the overt manifestations of the seizure in motor activity, duration, generalization and symmetry are inadequate reflections of what must lie at the heart of the therapeutic process. We argued about the relative efficacy of seizures
induced through unilateral and bilateral electrode placements. We found good efficacy and less memory deficits for seizures induced through unilateral placements (9, 12). But efficacywas less, even though the observed seizures were similar in duration and in motor patterns to those induced through bilateral electrode placements (13, 14). These observations were puzzling, for if “a seizure is a seizure”, and a seizure is central to the treatment process, then the clinical results should be the same for both inductions. But it is more difficult to induce seizures through unilateral electrodes, with many more short, aborted, or incomplete seizures (10, 13). The EEG patterns are asymmetric, often with poor development of burst patterns, imprecise end-points, and short isoelectric periods. Interseizure EEG records often show less slow wave activity in asymmetric patterns. These findings are precisely those reported by Ottosson (7) to be associated with poorer clinical results in the lidocaine-treated subjects. Perhaps the difference in efficacy is related to differences in the seizure; if so, are we now to be concerned that “a seizure is not a seizure”, that similar overt motor seizures may have different central neurophysiologic and biochemical substrates? To develop a useful index of an effective treatment, the duration of the seizure was studied. The duration of the motor seizure in a cuffed limb (following the technique of Addersley & Hamilton (15)), epileptic activity in the EEG, and increased heart rate were each used as indices. Motor seizures less than 15 s in duration rarely exhibited tonic and clonic phases, and these seemed to be clinically less effective than longer seizures. Motor seizures with durations greater than 25 s were usually generalized, and this index was taken as a measure of an adequate treatment. (This conclusion was derived by consensus, and was not based on experimental data.) In some elderly patients, the seizure duration for each treatment is less than 25 s and yet the patient improves. The strength and duration of the inducing currents affect treatment efficacy. Higher energy levels are clinically more effective than threshold levels. They induce longer seizures, and even when the total charge is kept constant, longer strains of impulses more often induce longer seizures (16). The relationship between seizure duration and clinical outcome in the treatment of depression is poor. We concluded that seizure duration is too imprecise and unreliable to be a criterion of seizure efficacy. These observations are consistent with the findings of Ottosson. An epileptic grand ma1 seizure is accompanied by the release of prolactin into the blood. Plasma levels are doubled or tripled within 20 min of a grand ma1 seizure. In experimental ECT studies, more pro-
425
Fink
lactin is released with high inducing currents, with bilateral electrode placement, and with the initial seizures in a series (13). If prolactin release reflects the direct effects of the stimulus and the seizure on the brain, then current path and dosage should be reflected in efficacy. And indeed they are. Sackeim and co-workers at Columbia University developed a threshold titration technique for seizure induction (17, 18). When their depressed patients were treated with energies just above threshold through unilateral electrode placements, efficacy was poor, and less than 30% of the patients improved. (Seizure durations were monitored and seizures were shown to be generalized with durations greater than 25 s in motor activity.) The efficacy of the same currents through bilateral electrodes was better. When high-energy currents, defined as 150% above threshold, were applied through unilateral or bilateral electrodes, efficacy was best. Similar findings were reported by Robin & deTissera (19). In their latest study, Abrams et al. (14) describe an experiment in which depressed patients were randomly assigned to bilateral or right unilateral ECT with equal high-energy currents. They report equal treatment results, again arguing that the strength of currents is a factor in the efficacy of seizures. Ottosson (20) recently re-examined the unilateralbilateral ECT controversy, especially the claims for less efficacy with unilateral ECT. He concluded that the studies that reflected less efficacy failed to assure adequate seizures. They usually delivered submaxima1 seizure activity because of short interelectrode distance, barely suprathreshold stimulation, and the concurrent use of benzodiazepine drugs which raised seizure thresholds. For the past decade, to minimize the effects on cognition and largely to keep our critics at bay, we used minimum amounts of energy (threshold currents), brief pulse currents, and unilateral electrode placements to induce seizures in our patients. Was the emphasis on safety at the price of efficacy? Did we encourage clinically inadequate treatments? I believe so, especially when we consider that the principal measure of treatment efficacy was seizure duration, and not any qualitative or quantitative aspect of the seizure (21). We have learned much about the seizure-inducing stimulus and the characteristics of an effective treatment, but we are still unable to answer the question of how best to treat our patients. Will studies like those of Ottosson and Ulett help us develop a better idea of the ECT therapeutic process? I believe they will, and we should undertake such studies in the clinic and the laboratory. In the clinic, we can identify populations of &ectively ill people who show characteristic behavioral 426
improvement with ECT. We can standardize the frequency and numbers of treatments, electrical energy, and pathways in a course. If we measure the electrical characteristics of each seizure and seek relations to clinical outcome, we should better define the electrophysiology of the therapeutic process. Such studies are ongoing in the reports of Abrams, Sackeim, Weiner, and Staton and Brumback. We may seek clues in our present theories. In 1972, we organized an international conference to examine theories of the mode of action of ECT (22). Reviews of the biochemical, cognitive, and electrophysiologic hypotheses found these wanting. Ottosson (23) discussed the systemic biochemical effects of ECT, and concluded that there was little evidence that any biochemical measure was clearly in the therapeutic chain. At the time, de Wied in the Netherlands described the behavioral effects of hypothalamic peptides, and others reported that affectively ill patients exhibited severe neuroendocrine dysregulation. For example, phasic diurnal rhythms in plasma cortisol were lost, basal levels were elevated, and the typical decrease in plasma levels after exogenous steroids could not be elicited. If our patients had evidence of hypothalamic pathology, might the administration of behavioral active peptides not improve behavior and the neuroendocrine pathology? Peptides were administered to affect memory, mood, and thought, and although the results were not sufficient to alter our treatment tactics, we were persuaded that these compounds did have behavioral effects. In 1978, Ottosson again reviewed the evidence for biochemical changes in the therapeutic chain of ECT, specifically in its antidepressant efficacy. His review increased interest in hypothalamic physiology, and led us to combine the data of neuroendocrine challenge tests, behavioral experiments with peptides, and our clinical knowledge to propose a neuroendocrine view of the antidepressant action of ECT (24). In this view, the core defect in affective disorders is seen to be hypothalamic hypofunction, which results in a deficiency of regulatory peptides that are necessary for our wellbeing in mood and thought. Evidence is found in severe neuroendocrine dysregulation, its reversal with treatment, and accompanying behavioral improvement. Recent reviews of the theory find it still viable (25). The most interesting data come from studies of prolactin and of thyrotropin-releasing hormone (TRH). The amount of prolactin released with each seizure varies with treatment parameters and parallels the influence of these parameters on therapeutic outcome (electrode placement and electrical dosage, for example). We now believe that the amount of
Convulsive therapy prolactin released into the blood is an index of the efficacy of a treatment - perhaps the more precise index we have been seeking. Studies of TRH find this peptide to have antidepressant and anticonvulsant effects, making it a model for a peptide with behavior-modifying (antidepressant and antimanic) effects. In our next studies, it may be fruitful to examine variations in seizure induction (as modified by electrode placement or strength of current), seizure efficacy (as reflected in EEG characteristics), with peptide release into CSF and blood. We have learned much. Our attention is again directed at the questions of the 1950s that tantalized Ottosson and Ulett and remain challenges for this decade: What is essential to the ECTprocess? And, how do induced epileptic seizures assure a persistent behavioral change among the severe mentally ill? Neither the catecholamine nor the receptor theories have been helpful in explaining either the effects of drugs or seizures, or the pathophysiology of mental illnesses. Our reliance on the present psychopharmacologic cornucopia has helped many patients, but left as many ill. The remarkable efficacy (and present safety) of modified ECT after more than a half century of use argues for our reexamination of the process, not only for an understanding of it, but for clues as to the classification and pathophysiology of mental illnesses. References 1. MEDUNAL. Die Konvulsionstherapie der Schizophrenie. Haile: Karl Marhold, 1937. 2. MEDUNAL. Autobiography. Part I. Convulsive Ther 1985: 1: 43-57. 3. MEDUNAL. Autobiography. Part 11. Convulsive Ther 1985: 1: 121-35. 4. CERLETTI U. Electroshock therapy. In: MARTI-IBANEZ F, SACKLER AM, SACKLER MD, SACKLER RR ed. The great physiodynamic therapies in psychiatry. New York: HoeberHarper, 1956: 91-100. 5. ULETT GA, SMITHK, GLESERGC. Evaluation of convulsive and subconvulsive shock therapies utilizing a control group. Am J Psychiatry 1956: 112: 795-802.
6. ULETTGA, JOHNSON MW. Effect of atropine and scopolamine upon electroencephalographic changes induced by electroconvulsive therapy. Electroencephalogr Clin Neurophysiol 1957: 9: 217-24. 7. OTTOSSON J-0.Experimental studies of the mode of action of electroconvulsive therapy. Acta Psychiatr Neurol Scand 1960: 35: (SUPPI145) 1-141. 8. FINKM, SHAWR, GROSSG, COLEMAN FS. Comparative study of chlorpromazine and insulin coma in therapy of psychosis. JAMA 1958: 166: 1846-50. 9. American Psychiatric Association. Electroconvulsive therapy. Task Force Report # 14. Washington, DC: APA, 1978. 10. FINKM. Convulsive therapy: theory and practice. New York: Raven Press, 1979. 11. PALMERRL, ed. Electroconvulsive therapy: an appraisal. Oxford: Oxford University Press, 1981. 12. D’ELIAG, RAOTMA H. Is unilateral ECT less effective than bilateral ECT? Br J Psychiatry 1975: 126: 83-9. 13. ABRAMSR. Electroconvulsive therapy. New York: Oxford University Press, 1988. 14. ABRAMS R, SWARTZ CM, VEDAKC. Antidepressant effects of high-dose right unilateral ECT. Am J Psychiatry 1989: 146: 1190-2. DJ, HAMILTON M. Use of succinylcholine in 15. ADDERSLEY ECT. Br Med J 1953: 1: 195-7. 16. SWARTZCM, LARSONG. ECT stimulus duration and its efficacy. Ann Clin Psychiatry 1989: 1: 147-52. 17. MALITZS, SACKEIM HA. Electroconvulsive therapy: clinical and basic research issues. Ann NY Acad Sci 1986: 462: 1-424. 18. SACKEIM HA, DECINA P, PORTNOYS, NEELEYP, MALITZ S. Studies of dosage, seizure threshold, and seizure duration in ECT. Biol Psychiatry 1987: 22: 249-68. 19. ROBINA, DETISSERA S. A double-blind controlled comparison of the therapeutic effects of low and high energy electroconvulsive therapies. Br J Psychiatry 1982: 141: 357-66. 20. OTTOSSON J-0. Is unilateral nondominant ECT as efficient as bilateral ECT? A new look at the evidence. Convulsive Ther 1991: 7: 190-200. 21. FINKM. An adequate treatment? Convulsive Ther 1989: 5: 311-3. 22. FINKM, KETYS, MCGAUGHJ, WILLIAMS T, ed. Psychobiology of convulsive therapy. Washington, DC: V.H. Winston & Sons, 1974. J-0. Systemic biochemical effects of ECT. In: 23. OTTOSSON FINKM, KETYS, MCGAUGHJ, WILLIAMS T, ed. Psychobiology of convulsive therapy. Washington, DC: V.H. Winston & Sons, 1974: 209-20. 24. FINKM, OTTOSSON J-0. A theory of convulsive therapy in endogenous depression: significance of hypothalamic functions. Psychiatry Res 1980: 2: 49-61. 25. FINKM. How does ECT work? Neuropsychopharmacology 1991: 3: 73-82.
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