Severity of subcortical gray matter hyperintensity predicts ECT response in geriatric depression.

OBJECTIVE: To determine the effect of subcortical white and gray matter lesions on ECT outcome. METHOD: 41 geriatric psychiatric inpatients underwent an MRI scan during their ECT work-up. Periventricular, deep white matter, and subcortical gray matter hyperintensities were graded. The associations of low versus high hyperintensity ratings and symptom scores, Clinical Global Impression severity (CGS) ratings, Montgomery-Asberg Depression Scale score, and number of treatments were examined using t-tests and repeated measures ANOVA. RESULTS: Patients with more severe subcortical gray hyperintensities (SCG) had significantly less improvement as measured by CGS ratings. CONCLUSIONS: SCG severity may limit the improvement of patients receiving ECT. Further studies are needed to examine differences based on electrode placement and to determine whether patients with severe SCG may require more ECT treatments in an index course.

EEG effects of ECT: implications for rTMS.

Electroconvulsive therapy (ECT) involves the use of electrical stimulation to elicit a series of generalized tonic-clonic seizures for therapeutic purposes and is the most effective treatment known for major depression. These treatments have significant neurophysiologic effects, many of which are manifest in the electroencephalogram (EEG). The relationship between EEG data and the response to ECT has been studied since the 1940s, but for many years no consistent correlates were found. Recent studies indicate that a number of specific EEG features recorded during the induced seizures (ictal EEG) as well as before and after a course of treatment (interictal EEG) are related to both the therapeutic efficacy and cognitive side effects. Similar to ECT, repetitive transcranial magnetic stimulation (rTMS), which involves focal electromagnetic stimulation of cortical neurons, has also been studied as an antidepressant therapy and also appears to have neurophysiologic effects, although these have not been as fully investigated as is the case with ECT. Given the similarity of these treatments, it is natural to consider whether advances in understanding the electrophysiologic correlates of the ECT response might have implications for rTMS. The present article reviews the literature on the EEG effects of ECT and discusses the implications in terms of the likely efficacy and side effects associated with rTMS in specific anatomic locations, the potential for producing an antidepressant response with rTMS without eliciting seizure activity, eliciting focal seizures with rTMS, and the possibility of using rTMS to focally modulate seizure induction and spread with ECT to optimize treatment.

ECT stimulus intensity: are present ECT devices too limited?

OBJECTIVE: The maximum output charge for ECT devices is limited to 576 millicoulombs in the United States, although there are no data ensuring that this limit will allow consistently effective treatments. The authors examined whether this limit has a negative impact on therapeutic response and, therefore, whether a higher stimulus charge should be available. METHOD: They retrospectively reviewed the records of 471 patients who received a clinical index course of ECT at Duke University between 1991 and 1998. These patients received conservative stimulus dosing of 2.25 times seizure threshold for unilateral ECT and 1.5 times seizure threshold for bilateral ECT. RESULTS: Seventy-two (15%) of the 471 patients required the maximum stimulus intensity during their index ECT course. Of these, 24 (5% of the total) had either a short EEG seizure (less than 25 seconds) or had no seizure at the maximum level. Strategies to augment therapeutic response with caffeine, ketamine, or hyperventilation were used in 14 of the 24 patients, and data on therapeutic response were available for 22 of the 24. Only seven (32%) of these 22 patients were considered ECT responders, compared with 242 (66%) of the remaining 364 patients for whom data on response to ECT were available. Older age and pre-ECT course EEG slowing were predictors of requiring the maximum stimulus level. CONCLUSIONS: The maximum available stimulus output was therapeutically insufficient for 5% of the patients studied even when available means to augment response were instituted. This percentage would likely be even larger with the use of a less conservative dosing protocol for unilateral ECT. Increases in maximum stimulus output for ECT devices should be considered as a means to ensure adequate treatment response.

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.

Prediction of the utility of a switch from unilateral to bilateral ECT in the elderly using treatment 2 ictal EEG indices.

BACKGROUND: The choice of whether to administer nondominant unilateral (UL) or bilateral (BL) ECT remains controversial. METHODS: A study in which moderately suprathreshold UL nonresponders at treatment 6 were randomized to UL or BL ECT offered the opportunity to explore whether ictal EEG indices at treatment 2 might predict response to UL ECT, and also which UL ECT nonresponders are likely to respond to BL ECT. RESULTS: We found that less postictal suppression in response to the second UL ECT stimulus was predictive of a poorer subsequent therapeutic response to UL ECT, but of a better therapeutic response if switched to BL ECT. A multivariate ictal EEG model was developed that had a significant capacity to differentiate those who will respond to UL ECT versus those who will not respond to UL ECT, but who will be therapeutic responders when switched to BL ECT. CONCLUSIONS: This study raises the possibility that ictal EEG indices at treatment 2 may identify situations when UL ECT is physiologically and therapeutically inadequate, and when BL ECT is likely to be more effective. The determination of whether such predictive physiologic models are of clinical utility for the prediction of outcome awaits further study.

The development and retrospective testing of an electroencephalographic seizure quality-based stimulus dosing paradigm with ECT.

The optimization of electroconvulsive therapy (ECT) stimulus dosing remains uncertain. Previous work suggests the potential utility of ictal EEG models of seizure adequacy, but such models have never been tested for their ability to improve the clinical dosing of ECT treatments. Using data from 149 depressed patients, the authors developed an ictal electroencephalographic (EEG) model that can discriminate seizures produced by more therapeutically effective and less efficacious types of stimuli. They retrospectively determined how stimulus dosing according to this seizure adequacy-based model would have differed from that actually used in an additional 61 patients who received ECT according to a standard clinical dose-titration and EEG seizure duration-based dosing strategy. Although the model indicated an increase in stimulus intensity at some point during the ECT treatment course in 23 of 61 patients, only 5 of these 23 actually received a clinical increase in stimulus intensity. The patients who did not receive this increase had a significantly diminished therapeutic response compared with the other patients. Conversely, the model also indicated that an increase in stimulus intensity that occurred clinically might have been unnecessary to achieve therapeutic efficacy in 11% of the patients. This study provides preliminary evidence that ictal EEG models have the potential to make clinically relevant seizure adequacy distinctions among ECT treatments. Further prospective work is indicated to determine the clinical utility of such models.

EEG correlates of the response to ECT: a possible antidepressant role of brain-derived neurotrophic factor.

Studies on the relationship of electroencephalographic (EEG) data to the therapeutic response to electroconvulsive therapy (ECT) have been carried out since the 1940s, but for many years they did not yield any consistent correlates. Recent studies, however, are providing a growing body of evidence of relationships between the antidepressant response to ECT and both the ictal (recorded during ECT seizures) and interictal (recorded during waking) EEG. These studies appear to be consistent in pointing to the importance of electrophysiologic changes in the prefrontal cortex as a potential mediator of the antidepressant response to ECT. The available findings are reviewed and discussed in light of recent neurophysiologic and neuropsychiatric research, including that related to neurotrophic factors.

The use of flumazenil in the anxious and benzodiazepine-dependent ECT patient.

Many patients who receive electroconvulsive therapy (ECT) are benzodiazepine dependent or are anxious and require benzodiazepine drugs. Because these agents may diminish the therapeutic effectiveness of ECT, we explored the dosing, safety, and efficacy of pre-ECT flumazenil administration, a benzodiazepine-competitive antagonist, in patients receiving benzodiazepine medications. We report our experience with 35 patients who received both flumazenil and benzodiazepine drugs during their ECT course. We compared seizure duration with and without flumazenil and compared treatment efficacy to 49 patients who received ECT without either of these medications. Flumazenil could be safely administered with ECT. A few subjects taking higher chronic benzodiazepine dosages experienced breakthrough anxiety or withdrawal symptoms, which were well managed by dosing flumazenil immediately before the anesthetic agent and by immediate posttreatment benzodiazepine administration. A dose of 0.4-0.5 mg was adequate for all but those taking the highest benzodiazepine dosages, where 0.8-1.0 mg resulted in a clinically more effective reversal. No differences in efficacy or seizure duration were found as a function of flumazenil administration. Flumazenil offers the promise of safe and effective ECT in patients receiving benzodiazepine drugs. Follow-up outcome investigation on a random assignment basis will be necessary for definitive assessment of the value of flumazenil. In addition, the direct effect of benzodiazepine drugs and the flumazenil/benzodiazepine combination on ECT seizures remains to be determined.

Changes in seizure threshold over the course of electroconvulsive therapy affect therapeutic response and are detected by ictal EEG ratings.

Therapeutic effectiveness of electroconvulsive therapy is influenced by the degree to which the stimulus intensity exceeds the seizure threshold. However, the threshold rises variably over the treatment course, confounding maintenance of desired relative stimulus intensity. In 47 depressed patients, decreases in relative stimulus intensity between treatments 1 and 6 were associated with diminished therapeutic response at treatment 6 for unilateral (UL) ECT. A multivariate model including manual ratings of ictal EEG data predicted whether seizure threshold rose with 82% accuracy. The same EEG variables were also significantly related to therapeutic response. Thus, decreases in relative stimulus intensity over the ECT course affect the therapeutic potency of UL ECT. Further, ictal EEG indices have considerable potential for predicting such stimulus intensity changes and their effect on therapeutic outcome.

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.

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.

The largest Lyapunov exponent of the EEG during ECT seizures as a measure of ECT seizure adequacy.

Attributes of the electroencephalogram (EEG) recorded during electroconvulsive therapy (ECT) seizures appear promising for decreasing the uncertainty that exists about how to define a therapeutically adequate seizure. In the present report we study whether one promising and not yet tested ictal EEG measure, the largest Lyapunov exponent (lambda1), is useful in this regard. We calculated lambda1 from 2 channel ictal EEG data recorded in 25 depressed subjects who received right unilateral ECT. We studied the relationship of lambda1 to treatment therapeutic outcome and to an indirect measure of treatment therapeutic potency, the extent to which the stimulus intensity exceeds the seizure threshold. We found lambda1 could be reliably calculated from ictal EEG data and that the global mean, maximum, and standard deviation of lambda1 were smaller in the more therapeutically potent moderately suprathreshold ECT and in therapeutic responders. These results imply a more predictable or consistent pattern of EEG seizure activity over time in more therapeutically effective ECT seizures. These findings also suggest the promise of lambda1 as a marker of ECT seizure therapeutic adequacy and build on our previous work suggesting that lambda1 may be useful for classifying seizures and for reflecting the relative physiologic impact of seizure activity.

A comparison of EEG signal dynamics in waking, after anesthesia induction and during electroconvulsive therapy seizures.

Evidence suggests that quantitative dynamical measures of electroencephalogram (EEG) signals are more appropriate for characterizing the differences between states in an individual rather than as absolute indices. One such measure, the largest Lyapunov exponent (lambda 1), appears to have potential for identifying seizure activity and for being of clinical utility for characterizing electroconvulsive therapy (ECT) seizures. As a result, we compared lambda 1 for the EEG recorded in 8 depressed subjects in 3 states: (1) during right unilateral ECT seizures, (2) during the pre-ECT waking state, and (3) following anesthesia administration but prior to ECT. Spectral amplitude and autocorrelation were also calculated in these states, allowing a comparison of these measures with lambda 1. We hypothesized that lambda 1 would be lowest during the ECT seizures, suggestive of greater EEG signal predictability over time during the seizures. We found that during the seizures lambda 1 was smaller, while spectral amplitude was larger. Significant inter-state differences were not found for the left temporal and occipital regions suggesting that these measures might serve as markers of the degree of seizure involvement of specific brain regions. Spectral amplitude and lambda 1 were uncorrelated and varied independently in some cases. The autocorrelation time was shortest in the waking EEG, and longest for the post-anesthesia EEG, and did not account for the differences seen in lambda 1. In contrast, the persistence of oscillations in the autocorrelation functions was greater for the ictal EEG than the other two states and may relate to lambda 1.

Serum prolactin, electrode placement, and the convulsive threshold during ECT.

This study examines the relationship of serum prolactin changes (delta PRL) to variations in electrode placement after controlling for differences in the convulsive threshold. Previous studies showing greater release of PRL with bilateral (BL) compared with right unilateral (RUL) electrode placement were conducted without knowledge of the convulsive threshold. Twenty-two patients each received threshold RUL, threshold BL, 2.25 times threshold RUL, and 2.25 times threshold BL ECT. Serum PRL was collected 5 min before and 15 min after each electroconvulsive therapy (ECT). The convulsive threshold was greater for BL than RUL electrode placement. delta PRL was greater with BL than RUL ECT at comparable relative stimulus intensities. delta PRL was not correlated with seizure duration or absolute stimulus dose.

Effect of ECT treatment number on the ictal EEG.

Recent evidence suggests that attributes of the ictal electroencephalogram (EEG) may be clinically useful for estimating the extent to which the electroconvulsive therapy (ECT) stimulus exceeds the seizure threshold (relative stimulus intensity). Such a tool could allow a practitioner, who chose, on the basis of expected therapeutic response and side effect rates, to implement stimulus dosing to maintain relative stimulus intensity over the treatment course, despite the uncertain rise in seizure threshold that occurs. One potential confounding factor is a possible systematic change in the ictal EEG over the treatment course that is not due to changes in seizure threshold. We explored the effect of treatment number by comparing ictal EEG data obtained at treatments across the ECT course that were delivered at the identical relative stimulus intensity. We found that the ictal EEG at treatment 1 was characterized by a greater mid-ictal amplitude and post-ictal suppression (trend) than subsequent treatments for barely suprathreshold unilateral ECT, but not for barely suprathreshold bilateral or moderately suprathreshold unilateral ECT, and that this change may affect therapeutic effectiveness. These findings suggest the importance of treatment-number effects for the clinical application of the ictal EEG and point to possible physiological differences between unilateral and bilateral ECT.

The relative ability of three ictal EEG frequency bands to differentiate ECT seizures on the basis of electrode placement, stimulus intensity, and therapeutic response.

Ictal EEG indices show promise for separating individual ECT seizures on the basis of treatment electrode placement (ELPL), relative stimulus intensity (Dose), and expected therapeutic response. One factor impeding the effective clinical implementation of ictal EEG indices for these purposes is uncertainty as to the relative utility of lower and higher frequency EEG activity. Recent articles are contradictory in this regard, but no data exist addressing this issue. As a result, we reanalyzed data from 44 subjects in two studies and compared the relative ability of ictal EEG data in three frequency bands to differentiate seizures as a function of ELPL, Dose, and therapeutic response. We found that the frequency band that best differentiated these groups depended on the EEG measure used, the temporal portion of the seizure, and whether ELPL, Dose, or therapeutic response was being compared.