Sidney Malitz

Cognitive consequences of low-dosage electroconvulsive therapy.

Standard electroconvulsive therapy (ECT) procedures, as a consequence of general anesthesia, muscle relaxation, and the elicitation of generalized seizure, result inevitably in loss of consciousness and of spontaneous respiration. Following the ECT-induced seizure, as with spontaneous generalized seizures and most acute brain injuries and head traumas, there is a variable period of disorientation. The duration of the period of disorientation following ECT appears to be exquisitely sensitive to treatment parameters, including modality or electrode placement (unilateral/ bilateral); dosage of electrical stimulation and/or stimulus waveform; cumulative treatment number; and temporal spacing of treatments.- With the recovery of orientation during the acute postictal period, patients manifest a variety of neuropsychological deficits. Retrograde memory, usually operationalized as memory for information presented just prior to the treatment, and anterograde memory, usually operationalized as memory for information presented following seizure elicitation, are often grossly disturbed! Postictal deficits have been reported for other aspects of memory functioning, particularly semantic memory? More broadly, there has been relatively little investigation of possible acute postictal effects of ECT on aspects of perceptual-cognitive functioning other than memory. Nonetheless, there is evidence that ECT may temporarily disrupt basic attentional processes, as assessed by simple cancellation procedures,6 and may alter perceptual thresholds and the localization of sound in space. It appears that the cognitive deficits induced by ECT are typically most intense during the acute postictal period. Repeated testing at time points further removed from the seizure has demonstrated rapid recovery However, with traditional

Effects of depression and ECT on anterograde memory

This study investigated immediate and delayed recognition memory in depressed patients undergoing electroconvulsive therapy (ECT) and in matched, normal controls. At baseline, patients manifested a marked deficit in immediate memory (acquisition), but showed no deficit in delayed memory (retention). When retested 24-36 hr following the seventh ECT, patients showed reductions in both immediate and delayed memory performance. At retesting 4 days, on average, after the ECT course, immediate memory scores returned to baseline levels, but delayed memory performance remained impaired. The findings supported the classic claims that depression is associated with a deficit in the acquisition of information, whereas ECT has a more profound influence on the retention of information. This dissociative pattern could not be viewed as an artifact of task psychometric properties, nor of practice effects in control subjects.

Dosage, Seizure Threshold, and the Antidepressant Efficacy of Electroconvulsive Therapya

In accounting for the mechanisms of action of electroconvulsive therapy (ECT), considerable attention has been paid to the seizure. Generalized tonic-clonic seizures are hypermetabolic states. They result in pronounced electrical discharge and in pronounced increases in cerebral blood flow (CBF), cerebral oxygen, and glucose consumption. These effects are robust and have been observed in studies of spontaneous or induced seizures in epileptic patients,I4 in ECT patients,5 and in animals?. The increase in circulatory and metabolic rates may be on the order of 200 to 300%. CBF will increase markedly, with or without adequate oxygenation, and under conditions of constant cardiac output. As the magnitude of the CBF increase typically exceeds the increased metabolic demands, with modified ECT clinically significant changes are not expected in cerebral arteriovenous (A-V) oxygen pressure (PO,), carbon dioxide pressure (pCOz), and lactate gradients, or in tissue pOz, accumulation of tissue lactate and C02, or hypo~ia.6**~*~ We have suggested that despite the marked neurophysiological changes that accompany the seizure, these are not central to the therapeutic consequences of ECT. Rather, we suggested that the processes that terminate the seizure are more reflective of the state of the brain following ECT and are more critical in accounting for the antidepressant properties of the treatment. Specifically, we suggested that ECT has marked anticonvulsant properties and that these anticonvulsant properties provide the basis for the antidepressant effects of the treatment.** At this point we know that it is not true that the seizure ends because the brain runs out of carbohydrate supplies, or because of acidosis or hypoxia. Such events either do

The Efficacy of Electroconvulsive Therapya

A criticism often raised about electroconvulsive therapy (ECT) is that it, like other somatic treatments in psychiatry, has no rational basis.’ We are ignorant of “how” and “why” ECT is so powerful as an antidepressant agent. In the case of ECT, however, this charge, in important respects, is wrong. Largely following the work of Ottosson: for a quarter century it has been accepted that the elicitation of a generalized seizure is essential to the therapeutic process. In depressed patients, chemical or electrical inductions of generalized seizure appear to be equivalent in producing strong therapeutic results.’-5 Using bilateral ECT, Ottosson reported that there was no difference in rates of therapeutic response when a traditional electrical dosage was compared to a more intense, supramaximal dosage.2 Blockade of the seizure discharge with an anticonvulsant medication or the use of subconvulsive electrical dosage is known to be nontherapeutic.2s68 On the basis of this evidence, the most widely accepted view has been that the elicitation of a generalized seizure provides both the necessary and sufficient conditions for the antidepressant properties of the Furthermore, there have been longstanding indications that electrical dosage and/or waveform characteristics are related to the cognitive side effects of ECT.2*”*’2 Configurations requiring greater electrical intensity are generally associated with more profound side effects.” d’Elia and colleagues recently summarized this view, stating: “An optimal therapeutic effect depends on the Occurrence of a generalized, tonic-clonic seizure. . . . On the other hand, supraliminal stimulation does not enhance the therapeutic effect. The organic

Some observations on psilocybin, a new hallucinogen, in volunteer subjects.

Summary Fourteen paid volunteers, sereened by clinical interviews, received Psilocybin orally over a dosage range of 8 to 36 mg. The perceptual, affective, cognitive, behavioral and autonomic responses observed were qualitatively similar to those previously described with d-LSD-25, but quantitatively, a greater impairment of cognition with Psilocybin was noted which may have been related to dosage or personality differences. EEG findings in four out of eight subjects were similar to those previously reported with d-LSD-25 and mescaline. The use of psychotomimetic drugs as therapeutic agents in an out-patient setting may prove potentially hazardous. Acute states of excitement, depression with suicidal ideation and impairment of judgment may occur with these drugs even in the most carefully supervised in-patient setting. With out-patients, the danger of self-administration and inadequate supervision could compound such occurrences. Further research is indicated regarding the site of action of hallucinogens, the relationship between personality, dosage level and total behavioral pattern, and the possible prognostic value of such drugs in assessing ego strength in specific individuals.

Acute effects of ECT on cardiovascular functioning: relations to patient and treatment variables

ABSTRACT— In 34 patients with primary, major depressive disorder, randomly assigned to bilateral or right unilateral ECT, heart rate (HR) and blood pressure (BP) were assessed prior and following seizure induction at every treatment. In contrast to prior reports, no cumulative pattern was observed in HR or BP changes as a function of treatment number. Generally, treatment variables, including ECT modality (bilateral vs. unilateral), anesthetic agent (methohexital vs. pentothal), and prior subconvulsive stimulation in a session, had no effects on the magnitude of peak postictal increases in HR or BP. The peak changes were also unrelated to the history of cardiac illness, remission of depressive symptomatology, patient seizure threshold and patient seizure duration. Pre‐treatment HR was strongly predictive of peak postictal change in both HR and BP, while pretreatment BP was not. Patients with high pre‐ECT HR had smaller peak postictal HR and BP increases. The findings suggested that low dosage, titrated ECT has HR and BP effects similar to traditional high dosage techniques, and that pre‐treatment HR is the best predictor of these effects.

Effects of ect on the TRH stimulation test

The prognostic value of the TRH stimulation test was evaluated in 23 inpatients with major depressive disorder before and after a trial of ECT. In contrast to previous reports, the peak TSH response to TRH was significantly decreased after treatment compared with before treatment. This effect was consistent across individuals and subgroups (responders/nonresponders; unilateral/bilateral ECT). The particular ECT technique used in the study may account for the discrepancies between these findings and those previously reported by other authors.

Serial dexamethasone suppression tests in initial suppressors and nonsuppressors treated with electroconvulsive therapy

Four different methods of quantifying the 1-mg Dexamethasone Suppression Test (DST) were contrasted with serial testing in endogenous depressives receiving electroconvulsive therapy (ECT). Of three continuous measures in 38 patients with pretreatment DSTs, only the log-transformed value for plasma cortisol was normally distributed, indicating that it possessed superior psychometric properties. Pretreatment Hamilton Depression Rating Scores (HAM-D) correlated positively with pretreatment DST status, with a similar association noted between posttreatment DST status and HAM-D scores. There was no uniform effect of ECT on the DST. Although pretreatment nonsuppressors showed a trend toward decreased postdexamethasone cortisol values, initial suppressors (cutoff: 5 micrograms/dl) evidenced a significant increase in these values, and 35.3% of initial suppressors were nonsuppressors at final DST assessment. These trends were noted in the DST assessment done following the third ECT treatment, suggesting an effect of regression to the mean. The findings highlight the importance of following initial DST suppressors in studies of this type.

Mechanisms of Action

The mechanism of action of convulsive therapy has been questioned and investigated since the first therapeutic use of induced seizures by Meduna in 1935.’ Meduna believed that biological antagonism existed between the process that produces epilepsy and the process that produces schizophrenia. Thus, he thought that an induced convulsion in man would change brain chemistry in a therapeutic manner. When, in 1938, Cerletti and Bini introduced the use of electrically induced convulsions: they believed that the seizure was the fundamental therapeutic factor while the electricity was only the epileptogenic stimulus. In 1960, Ottosson and associates reported on a series of studies in which energy of electrical stimulation and cerebral seizure activity were systematically and independently manipulated experimentally to carefully delineate the specific effects of the electrical stimulation and seizure activity.’ They concluded that the therapeutic and cognitive effects of electroconvulsive therapy (ECT) arise through different mechanisms. The therapeutic effect “is due to seizure activity and not, or only slightly, to the other effects of the c~ r ren t . ”~ The memory disturbance is to a great extent accounted for by the effects of the electrical stimulation other than the seizure. Over the years of extensive ECT usage, a variety of theories or explanations have been forthcoming to attempt to ascribe the therapeutic effect of ECT to other causes including the occurrence of structural brain changes and psychological theories focusing on fear, punishment, amnesia, denial, repression, and ego adaptation.‘ No evidence is available supporting any of these theories. However, primacy of the generalized seizure itself has been confirmed clearly and repeatedly over the last 10 years in a series of controlled clinical trials comparing ECT and sham ECT (simulated ECT in which all elements of the treatment, including general anesthesia and muscle relaxant, are given except for the electrical Contemporary clinical therapy and most research on ECT have been guided by these basic assumptions. In recent years, basic and clinical scientists have intensified research efforts to better understand the mechanism of action of ECT by delineating the specific alterations in brain biological functioning brought about by a series of electrically induced generalized seizures that serve to relieve depression in man. As a result, a wealth of information is available on the effects of ECT on brain biological function from a multitude of vantage points including the neurophysiology, neuroendocrinology, neurochemistry, and neuroreceptorology. Much of this work, which has been presented earlier in this volume, has been based on basic studies employing electroconvulsive shocks in rodents. Human clinical studies attempting to clarify the

Preliminary evaluation of a new phenothiazine derivative, NP207.

Conclusions1.NP207 appears to have definite beneficial effects in the reduction of tension. It seems to diminish anxiety with fewer side effects than chlorpromazine.2.Although an insufficient number of patients received both drugs to make a direct comparison, it is the writers impression that chlorpromazine in equivalent doses is somewhat more effective in reducing anxiety and tension than NP207.3.NP207 and BOL 148 combined did not show a superior action in the reduction of tension over NP207 alone. Higher doses and a larger series with a different patient group might give better results however.4.Because of the development with this drug of symptoms resembling retinitis pigmentosa, further research should be undertaken only with extreme caution.