Titrated moderately suprathreshold vs fixed high-dose right unilateral electroconvulsive therapy: acute antidepressant and cognitive effects.

BACKGROUND: The antidepressant and cognitive side effects of right unilateral (RUL) electroconvulsive therapy (ECT) are reported to depend on the magnitude of the electrical stimulus relative to the seizure threshold. The stimulus doses explored in previous clinical trials of RUL ECT have generally been limited to 1 to 2.5 times the convulsive threshold and the antidepressant efficacy has been low compared with bilateral (BL) ECT. The present study compares the antidepressant and cognitive side effects of 2 RUL dosing strategies: titrated moderately suprathreshold and fixed high dose. METHODS: Seventy-two adult patients with major depression were randomized to either titrated RUL ECT at 2.25 times initial seizure threshold (mean dose, 136 millicoulombes [mC]), or RUL ECT at a fixed dose of 403 mC. Primary outcome measures were antidepressant response and cognitive status 1 or 2 days after the course of ECT. RESULTS: The 2 treatment groups were comparable in demographic and clinical characteristics prior to ECT. Both groups received a mean of 5.7 sessions of RUL ECT. Patients receiving fixed-dose ECT were more likely to have an antidepressant response at the end of the protocol (n = 49 [67%]) compared with those receiving titrated dosing (n = 28 [39%]). Furthermore, the likelihood of both antidepressant response and cognitive deficits increased as stimulus dose increased relative to initial seizure threshold, up through 8 to 12 times the threshold. CONCLUSIONS: The antidepressant efficacy and cognitive side effects of RUL ECT are dependent on the magnitude of the stimulus dose relative to the seizure threshold, and a dose-response relationship extends through at least 12 times the seizure threshold.

Quantitative cerebral anatomy in depression. A controlled magnetic resonance imaging study.

Magnetic resonance imaging was used to examine cerebral anatomy in 48 inpatients with severe depression who were referred for electroconvulsive therapy and in 76 normal control subjects. The magnetic resonance imaging measures included determinations of regional cerebral volumes and ratings of the frequency and severity of cortical atrophy, lateral ventricular enlargement, and subcortical hyperintensity. The mean total frontal lobe volume was found to be 7% smaller in the inpatients with severe depression (235.88 mL) than in the normal control subjects (254.32 mL)--a difference that was statistically significant even after adjusting for the effects of age, sex, education, and intracranial size. No group differences were observed in the volumes of the cerebral hemispheres, the temporal lobes, or the amygdala-hippocampal complex, nor in the frequency of cortical atrophy. Neither did the groups differ with respect to the total volumes of the lateral and third ventricles, nor in the frequency of lateral ventricular enlargement. Patients with depression had a significantly higher frequency of subcortical hyperintensity in the periventricular white matter, with an odds ratio of 5.32.

Brain anatomic effects of electroconvulsive therapy. A prospective magnetic resonance imaging study.

To determine prospectively whether electroconvulsive therapy (ECT) produces structural brain changes, 35 inpatients with depression underwent magnetic resonance imaging before and twice after (at 2 to 3 days and at 6 months) completion of a course of brief-pulse, bilateral ECT. The magnetic resonance images were analyzed blindly for evidence of changes in brain structure using two approaches: measurement of regional brain volumes and a pairwise global comparison. Structural brain abnormalities were present in many patients before ECT. The course of ECT produced no acute or delayed (6-month) change in brain structure as measured by alterations of the total volumes of the lateral ventricles, the third ventricle, the frontal lobes, the temporal lobes, or the amygdala-hippocampal complex. In five subjects, the pairwise global comparisons revealed an apparent increase in subcortical hyperintensity, most likely secondary to progression of ongoing cerebrovascular disease during follow-up. Our results confirm and extend previous imaging studies that also found no relationship between ECT and brain damage.

ECT and seizure threshold: effects of stimulus wave form and electrode placement.

The effects of stimulus parameters and electrode placement upon ECT seizure threshold were investigated in 40 psychiatric inpatients referred for ECT treatment, using EEG monitoring of seizure activity. Overall, brief pulse stimuli were found to require approximately one-third as much stimulus energy as sine wave stimuli in producing equivalent suprathreshold seizures. For brief pulse stimuli, unilateral nondominant electrode placement, utilizing a parieto-frontotemporal arrangement, was associated with a slightly lower seizure threshold than for bilateral electrode placement. For sine wave stimuli, on the other hand, no difference in seizure threshold on the basis of electrode placement was found, although unilateral electrode placement as associated with briefer seizures. The implications of these findings in terms of clinical efficacy and CNS side effects are discussed.

Clozapine-induced electroencephalogram changes as a function of clozapine serum levels.

Specific electroencephalogram (EEG) changes during clozapine therapy were prospectively studied in a cohort of 50 chronic state hospital patients with schizophrenia who were randomly assigned to one of three nonoverlapping clozapine serum level ranges (50-150 ng/mL, 200-300 ng/mL, and 350-450 ng/mL). EEGs were obtained before clozapine was instituted, and after 10 weeks of treatment. Fifty-three percent of patients showed EEG changes during the 10-week study period. We observed three seizures (6%), one in a patient on 900 mg (serum level 320 ng/mL) clozapine, and two in patients with lower clozapine serum levels (200-300 ng/mL) who had prior histories of seizures and inadequate valproate coverage. Thirteen percent of patients developed spikes with no relationship to dose or serum level of clozapine. Fifty-three percent of patients developed slowing on EEG. Compared to plasma levels below 300 ng/mL, a clozapine serum level between 350 and 450 ng/mL led to more frequent and more severe slowing. The EEG slowing correlated with observed sleepiness, although this factor was not sufficient to explain the severity of high-dose effects.

Topographic maps of brain electrical activity--pitfalls and precautions.

Topographic mapping of brain electrical activity is a popular, powerful, and potentially misleading technique. The map lies at the end of a long chain of physiological, technical, electronic, and mathematical processes and is vulnerable to artifact, error, and distortion at many points. Close attention must be paid to data collection parameters, subject cooperation, minimization of artifact, limitations of resolutions, selection, and transformation of parameters for display, and map generation strategy to yield an accurate, physiologically interpretable map. Review of the data at each step of analysis, from the paper electroencephalogram (EEG) to sets of maps on video display, may be necessary for optimum understanding. Development of more sophisticated qualitative and quantitative concepts of "normal" physiology is needed. These improvements in electrophysiological data analysis demand, rather than obviate, sophistication on the part of the user.

The effects of ECT stimulus dose and electrode placement on the ictal electroencephalogram: an intraindividual crossover study.

Recent evidence suggests that electroconvulsive therapy (ECT) efficacy depends upon both electrode placement and the degree to which stimulus dosage exceeds seizure threshold (T), and not simply on surpassing a minimum seizure duration as has been assumed. In light of these findings and studies reporting ictal electroencephalogram (EEG) differences between bilateral and unilateral ECT, we performed this 19-subject intraindividual crossover study of the effects of dose and electrode placement on the ictal EEG. We found ictal EEG evidence of greater seizure intensity with bilateral than unilateral ECT and with higher dosage (2.25 T) compared with barely suprathreshold stimuli. Seizure duration was not longer with bilateral than unilateral ECT and actually decreased with increased dose. A number of ictal EEG variables separated the unilateral 2.25 T and unilateral T conditions, which reportedly differ in efficacy, and therefore, these EEG measures show promise as markers of treatment adequacy.

Convulsive threshold differences in right unilateral and bilateral ECT.

UNLABELLED: This study examines how the convulsive threshold in electroconvulsive therapy (ECT) varies with electrode placement (bilateral [BL] versus right unilateral [RUL]), age, gender, weight, and the nasion-inion measurements of the head. METHOD: Twenty-eight subjects underwent stimulus dose titration to determine the convulsive threshold. Titration was accomplished for each subject with both electrode placements during the first and second ECT in a balanced design. Head measurements were made prior to the first ECT. Results indicated that the convulsive threshold was higher for BL than RUL, higher for men than women, increased with age, and increased with an increasing nasion-inion measurement in women but not in men. We concluded that the convulsive threshold varies according to the choice of electrode placement, gender, and age as has been reported by others. We additionally report that the convulsive threshold increases with increasing head size as reflected in the nasion-inion distance.

Seizure threshold in electroconvulsive therapy (ECT) II. The anticonvulsant effect of ECT.

To measure the anticonvulsant effects of a course of electroconvulsive therapy (ECT), we used a flexible stimulus dosage titration procedure to estimate seizure threshold at the first and sixth ECT treatments in 62 patients with depression who were undergoing a course of brief pulse, constant current ECT given at moderately suprathreshold stimulus intensity. Seizure threshold increased by approximately 47% on average, but only 35 (56%) of the 62 patients showed a rise in seizure threshold. The rise in seizure threshold was associated with increasing age, but not with gender, stimulus electrode placement, or initial seizure threshold. Dynamic impedance decreased by approximately 5% from the first to the sixth ECT treatment, but there was no correlation between the change in dynamic impedance and the rise in seizure threshold. No relation was found between the rise in seizure threshold and either therapeutic response status or speed of response to the ECT treatment course. These findings confirm the anticonvulsant effect of ECT but suggest that such effects are not tightly coupled to the therapeutic efficacy of moderately suprathreshold ECT.

Seizure threshold in electroconvulsive therapy: I. Initial seizure threshold.

We measured initial seizure threshold by means of a structured stimulus dosage titration procedure in a clinical sample of 111 depressed patients undergoing brief-pulse, constant-current electroconvulsive therapy (ECT). Initial seizure threshold was approximately 60 millicoumbs (mc) (10 Joules) on average, but varied widely (6-fold) across patients. Initial seizure threshold was predicted by four variables: electrode placement (higher with bilateral), gender (higher in men), age (higher with increasing age), and dynamic impedance (inverse relationship). Use of neuroleptic medication was associated with a lower seizure threshold. EEG seizure duration was inversely related to initial seizure threshold, but no other relations with seizure duration were found. These findings may have important clinical implications for stimulus dosing strategies in ECT.

The dexamethasone suppression test and quantitative cerebral anatomy in depression.

To determine whether structural brain abnormalities in patients with depression are related to cortisol state, we examined the relationship between the dexamethasone suppression test (DST) and brain magnetic resonance imaging (MRI) in 40 inpatients with severe depression referred for electroconvulsive therapy (ECT). Prior to ECT, 27 (68%) of the patients exhibited nonsuppression on the DST. Frontal lobe volume was negatively correlated with peak post-dexamethasone cortisone (r = -0.37) and was 13% smaller in DST nonsuppressors than suppressors; these findings were no longer significant after adjustments for age, gender, and cranial size. Lateral and third ventricular volumes were also correlated with peak postdexamethasone cortisol (r = 0.34 and 0.33, respectively), but not after adjustments for age, gender, and cranial size. Subcortical hyperintensity was associated with peak postdexamethasone cortisol and was more common in DST nonsuppressors than suppressors. Again these findings were no longer significant after adjustments for age. Finally, longitudinal DST and brain MRI studies in 11 of these patients revealed no changes in regional brain volumes nor in postdexamethasone cortisol up to six months after ECT. However, within individual patients, postdexamethasone cortisol was positively (and significantly) correlated with frontal lobe volume.

Spectral and topographic analysis of EEG in schizophrenic patients.

The authors performed spectral analysis of electroencephalograms (EEG), recorded awake, with eyes closed, in 13 patients with schizophrenia and 9 age-matched individuals without psychiatric diagnosis. We tested several possible parameterizations of the data, and two data-reduction strategies; these yielded similar results. Comparison of the two groups revealed a relative increase in alpha frequency activity in the frontal regions in the patient group. The authors believe that this finding is consistent with data from neuropsychologic tests, metabolic imaging studies, and evoked potential studies that suggest impaired activation of frontal brain areas in patients with schizophrenia.

Leukoencephalopathy in elderly depressed patients referred for ECT.

Using brain magnetic resonance imaging (MRI) and high-resolution computed tomography (CT), we identified changes in the subcortical white matter in 44 of 67 elderly depressed inpatients (66%) referred for electroconvulsive therapy (ECT). This "leukoencephalopathy" was frequently associated with other structural brain changes, including cortical atrophy, lateral ventricular enlargement, and lacunar infarctions of the basal ganglia and thalamus. Many (58%) of the patients had developed late-onset depressive disorders, and the majority (86%) had been refractory to and/or intolerant of antidepressant drug therapy. Nevertheless, all but 1 of the 44 patients subsequently responded to a course of ECT, which in general was well tolerated. Although the precise etiology of the leukoencephalopathy remains unclear, clinical data suggest that it may result from arteriosclerotic disease of the medullary arteries that supply the subcortical brain regions. Several lines of evidence suggest that leukoencephalopathy may have implications for the pathophysiology of depressive illness, at least in some elderly patients.

Cardiovascular response to unilateral electroconvulsive therapy.

Few studies have examined the cardiovascular response to pulse unilateral electroconvulsive therapy (ECT) performed using modern techniques. In this study of 30 patients (mean age 62 years) with major depression, we determined the effects of pulse unilateral ECT on cardiac work load using the rate-pressure product (RPP), a product of pulse and systolic blood pressure. The mean RPP across all ECT treatments increased by an average of 96% from pre-ECT baseline, with the maximal RPP occurring typically during the seizure. The amount of increase in RPP did not differ significantly over the course of treatments. The increase in RPP was significantly and inversely related to baseline RPP, such that subjects with the highest baseline RPPs actually had smaller increases in RPP during the ECT treatments. The mean percent change in RPP was not associated with age, sex, presence of cardiovascular disease, ECT stimulus charge, EEG seizure duration, or amnestic side effects. There was a trend (p = 0.06), however, for the mean increase in RPP to be greater in responders (100% increase, n = 25) than in nonresponders (76% increase, n = 5). The potential relationship of clinical outcome to the increase in RPP suggests that both factors may be manifestations of the physiological intensity of the ECT-induced seizure.

The psychiatric use of electrically induced seizures.

ECT is an effective but also controversial treatment modality in psychiatry. The decision of when to use ECT is predicated on a knowledgeable assessment of anticipated benefits and possible risks as they apply to each individual case. Refinements in ECT technique have minimized risks, but have also increased the methodological complexity. The author presents a clinical review of ECT use with particular emphasis on practical issues related to efficacy, risks, and technique.

ECT-induced status epilepticus and further ECT: a case report.

The author describes an occurrence of ECT-induced status epilepticus in a patient who was psychotically depressed and unresponsive to tricyclic and neuroleptic medication. After an extensive evaluation and further unsuccessful use of treatment alternatives the patient then received a course of specially modified ECT; he had no further sequelae and had a good clinical response.

Use of ECT in the United States in 1975, 1980, and 1986.

OBJECTIVE: The objective was to analyze nationally representative data from the National Institute of Mental Health (NIMH) to update trends in the use of ECT in the United States. METHOD: The data are estimates from the NIMH Sample Survey Program for 1975, 1980, and 1986, which include representative samples of inpatients in psychiatric facilities in the United States. The authors' analyses use trend data from public general hospitals, private general hospitals, private psychiatric hospitals, and state and county mental hospitals. They report on 126,739 patients who received ECT in 1975, 1980, and 1986, focusing on data from 1980 and 1986. RESULTS: In 1986, 36,558 patients received ECT. This represents a decrease from the 1975 figure (58,667 patients) but no change from 1980 (31,514 patients). ECT was used primarily in private general hospitals (64%) and private psychiatric hospitals and much less often in public general hospitals and state and county mental hospitals. In 1986 over 90% of ECT recipients were white, and 84% had an affective disorder diagnosis. Although 71% of the patients who received ECT were women, hospital type and age were more important than gender in predicting ECT use. Individuals 65 years of age and older received ECT out of proportion to their numbers in inpatient care. CONCLUSIONS: The declining use of ECT in the United States ended in the 1980s. Few African Americans receive ECT, and its use is becoming more targeted toward patients with affective disorders. The amount of services research done on this modality is very small. Basic questions have yet to be answered, including who refers patients for ECT and why, and how ECT fits into the overall course of treatment.

Lack of relapse with tryptophan depletion following successful treatment with ECT.

OBJECTIVE: Although the antidepressant mechanism of ECT is unknown, there are considerable data to support serotonergic involvement. The effects of tryptophan depletion were studied in patients with major depression treated successfully with ECT. METHOD: Five patients who had been successfully treated with ECT for major depression were studied in a randomized, double-blind, crossover design comparing tryptophan depletion to a placebo procedure. RESULTS: No effect of tryptophan depletion on mood symptoms was observed despite more than an 85% decrease in total serum tryptophan. CONCLUSIONS: These data suggest that presynaptic serotonin availability may not be necessary for the acute maintenance of an antidepressant response to ECT.

Seizures terminable and interminable with ECT.

The authors discuss the incidence, detection, management, and significance of prolonged seizures with ECT and present a case example. They suggest that the incidence of this phenomenon may be underreported and that its occurrence may be linked to hyperoxygenation, the use of multiple-monitored ECT, and preexisting states of cerebral hyperexcitability. Since prolonged seizures may result in adverse metabolic changes, prompt detection and intervention are essential.

Caffeine augmentation of ECT.

In a randomized, double-blind, placebo-controlled pilot study of 40 depressed inpatients, the authors compared two techniques for maintaining seizure duration during pulse unilateral ECT: pretreatment with intravenous caffeine versus electrical stimulus intensity dosing. Both techniques effectively maintained seizure duration, but with caffeine this was accomplished without any increase in mean stimulus intensity over the course of ECT. There were no differences between the two techniques in therapeutic outcome or cognitive side effects from ECT, and caffeine pretreatment was well tolerated. The authors discuss the clinical and research implications of these findings with respect to strategies for maintaining seizure duration during ECT.