Mitchell S. Nobler

Effects of Pulse Width and Electrode Placement on the Efficacy and Cognitive Effects of Electroconvulsive Therapy

BACKGROUND While electroconvulsive therapy (ECT) in major depression is effective, cognitive effects limit its use. Reducing the width of the electrical pulse and using the right unilateral electrode placement may decrease adverse cognitive effects, while preserving efficacy. METHODS In a double-masked study, we randomly assigned 90 depressed patients to right unilateral ECT at 6 times seizure threshold or bilateral ECT at 2.5 times seizure threshold, using either a traditional brief pulse (1.5 ms) or an ultrabrief pulse (0.3 ms). Depressive symptoms and cognition were assessed before, during, and immediately, two, and six months after therapy. Patients who responded were followed for a one-year period. RESULTS The final remission rate for ultrabrief bilateral ECT was 35 percent, compared with 73 percent for ultrabrief unilateral ECT, 65 percent for standard pulse width bilateral ECT, and 59 percent for standard pulse width unilateral ECT (all Ps<0.05 after covariate adjustment). The ultrabrief right unilateral group had less severe cognitive side effects than the other 3 groups in virtually all primary outcome measures assessed in the acute postictal period, and during and immediately following therapy. Both the ultrabrief stimulus and right unilateral electrode placement produced less short- and long-term retrograde amnesia. Patients rated their memory deficits as less severe following ultrabrief right unilateral ECT compared to each of the other three conditions (P<0.001). CONCLUSIONS The use of an ultrabrief stimulus markedly reduces adverse cognitive effects, and when coupled with markedly suprathreshold right unilateral ECT, also preserves efficacy. (ClinicalTrials.gov number, NCT00487500.).

EEG manifestations during ECT: effects of electrode placement and stimulus intensity

This study examined the ictal electroencephalographic (EEG) characteristics of four forms of electroconvulsive therapy (ECT) known to differ in efficacy. Previously, we demonstrated that titrated, low-dose right unilateral ECT reliably produces generalized seizures of adequate duration, but is remarkably weak in antidepressant effects. Using a new rating scale, we found that specific features of the ictal and immediate postictal EEG varied significantly with ECT stimulus intensity and electrode placement. The low-dose right unilateral condition differed from more effective forms of ECT in having the longest polyspike phase duration, averaging twice that of the other conditions; it was also the condition least likely to manifest bioelectric suppression immediately following seizure termination. In contrast, high-dose bilateral ECT--a treatment with particularly rapid antidepressant effects--resulted in the greatest peak slow-wave amplitude in both hemispheres. Total seizure duration did not differ among the four treatment conditions. These findings indicate that seizure duration is not a useful marker of therapeutic efficacy, and instead provide preliminary evidence that other features of the EEG may be more useful markers of treatment adequacy.

Seizure expression during electroconvulsive therapy: relationships with clinical outcome and cognitive side effects.

Since electroconvulsive therapy (ECT) can result in generalized seizures that lack efficacy, physiological markers of treatment adequacy are needed. Specific electroencephalographic (EEG) features differentiate seizures produced with barely suprathreshold right unilateral (RUL) ECT, an ineffective treatment, from effective forms of ECT. This study determined whether EEG features are sensitive to treatment condition using a broad dosing range for RUL ECT, as well as predictive of clinical and cognitive outcomes. Quantitative EEG measures and observer ratings were compared in predictive power. From a larger study, 54 in-patients with major depression were randomized to low (1.5 × seizure threshold (ST)), moderate (2.5 × ST), or high-dose (6 × ST) RUL ECT, or high-dose (2.5 × ST) bilateral (BL) ECT. High dosage RUL and BL ECT were comparable in efficacy, and superior to low and moderate dosage RUL ECT. In the slow frequency bands (δ), BL ECT resulted in greater ictal power, ictal coherence, and postictal suppression than each RUL ECT condition, but the EEG measures failed to discriminate the RUL ECT groups. EEG measures were modestly associated with clinical outcome, with greater ictal power, δ coherence, and postictal suppression positive predictors. None of the EEG measures were associated with cognitive outcomes. Inability to distinguish forms of RUL ECT differing markedly in dosage and efficacy suggests that EEG measures have limited potential as markers of treatment adequacy. Rather than assaying treatment adequacy, the EEG features associated with efficacy may reflect individual differences in the strength of inhibitory processes that terminate the seizure, and can help isolate the biological variability that predisposes to positive or negative clinical response to ECT.

Quantitative Eeg During Seizures Induced by Electroconvulsive Therapy: Relations to Treatment Modality and Clinical Features. I. Global Analyses

This study examined the effects of electroconvulsive therapy (ECT) treatment conditions, patient individual difference factors, and clinical outcome on global electroencephalogram (EEG) power during and immediately following ECT-induced seizures. Sixty-two patients were randomized to ECT conditions differing in electrode placement (right unilateral versus bilateral) and stimulus dosage (just above seizure threshold versus 2.5 times seizure threshold). At the second and penultimate treatments, global total power (1.5–28.5 Hz) and global power in specific frequency bands were quantified in 19-lead EEG recordings of the generalized seizure and the immediate postictal period. Seizures induced with high dosage, and to lesser extent, with bilateral electrode placement, resulted in greater global power. Patient age, initial seizure threshold, and baseline depression severity were inversely related to global power during seizures. While superior clinical outcome following ECT was associated with greater global power during seizures, this effect was small. The factors associated with more robust seizure expression also resulted in greater postictal bioelectric suppression. Associations with treatment parameters and patient variables were stronger at the second than penultimate treatment. We conclude that manipulations of ECT technique strongly determine the magnitude of seizure expression, but relations with clinical outcome are weak. The findings raise doubt about the clinical utility of algorithms based on analysis of EEG features to guide ECT parameter selection.

Electrophysiological correlates of the adverse cognitive effects of electroconvulsive therapy.

Resting state, eyes closed, 19-lead EEG recordings were obtained at pre-ECT baseline and just prior to penultimate treatment and during the week following the ECT course in 59 patients with major depression. Patients had been randomized to ECT conditions that varied in electrode placement and stimulus intensity. The EEG data were submitted to power spectral analysis, and global and topographic effects were characterized for the delta and theta frequency bands. Relations between the EEG changes and scores on three cognitive measures were examined. The period of disorientation immediately following RUL ECT was associated with an accentuation of delta power in anterior frontal and temporal regions. Across the electrode placements, increased theta activity in left frontotemporal regions was associated with longer recovery of orientation. Post-ECT decrements in global cognitive status, as assessed by the modified Mini-Mental State exam, were associated with a greater increase in delta relative to theta power, globally across the cortex. The magnitude of retrograde amnesia for autobiographical events correlated with increased theta activity in left frontotemporal regions. The findings suggest that distinct neurophysiological changes subserve the therapeutic and adverse cognitive effects of ECT. Postictal disorientation and post-ECT retrograde amnesia appear to share a common physiological substrate.

Ect in the Treatment of Status Epilepticus

Introduction Owing to its potent anticonvulsant actions, electroconvulsive therapy (ECT) has been proposed as an intervention for treatment-resistant seizure disorders. Method We review the literature on the use of ECT in treatment-resistant epilepsy and status epilepticus (SE) and present a case of a patient who was in nonconvulsive SE for 26 days and then treated with ECT after all standard pharmacological strategies were exhausted. Because of skull defects, a novel electrode placement was used. Results Owing to massively elevated seizure threshold attributable to concomitant anticonvulsant medications, extraordinarily high electrical dosage was needed for ECT to elicit generalized seizures. Status was terminated after three successful ECT-induced seizures. However, the long-term functional outcome of the patient was poor. Discussion The role of ECT in the treatment algorithm for SE is discussed.

Regional Cerebral Blood Flow in Mood Disorders, V.: Effects of Antidepressant Medication in Late-Life Depression

Twenty elderly outpatients with major depression were treated with either nortriptyline or sertraline. Resting regional cerebral blood flow (rCBF) was assessed by the planar (133)Xenon inhalation technique after a medication washout and following 6- 9 weeks of antidepressant treatment. At baseline, the depressed sample had reduced rCBF in frontal cortical regions when compared with 20 matched normal-control subjects. After treatment, Responders and Nonresponders differed in the expression of a specific topographic alteration, with Responders manifesting reduced perfusion in frontal regions. These findings are consistent with this groups previous report of reduced rCBF after response to electroconvulsive therapy (ECT) and suggest a common mechanism of action.

Personality Disorders in Elderly Patients With Dysthymic Disorder

The authors evaluated personality disorders in elderly patients with DSM-IV dysthymic disorder (DD) to identify prevalent personality disorders and their clinical correlates. Outpatients (>/=60 years; N=76) with DD were evaluated; most were male (65.8%) and had late age at onset (>50 years: 60.5%). Axis II disorders were present in 31.2% of patients, with obsessive-compulsive personality disorder (OCD; 17.1%) and avoidant personality disorder (11.8%) being the most common. Personality disorders were associated with an earlier age at onset of depressive illness, greater lifetime history of comorbid Axis I disorders, greater severity of depressive symptoms, and lower socioeconomic status. Personality disorders occurred in a minority of elderly patients with DD and mainly comprised the obsessive-compulsive and avoidant subtypes, similar to reports of personality disorders in elderly patients with major depression. In contrast, young adults with DD have been shown consistently to have personality disorders at high frequency. Together with the predominance of late onset and the lack of psychiatric comorbidity, the current findings on personality disorders reinforce our view that DD in elderly patients is typically a different disorder from DD in young adults.

New developments in electroconvulsive therapy and magnetic seizure therapy.

New findings regarding the mechanisms of action of electro-convulsive therapy (ECT) have led to novel developments in treatment technique to further improve this highly effective treatment for major depression. These new approaches include novel placements, optimization of electrical stimulus parameters, and new methods for inducing more targeted seizures(eg, magnetic seizure therapy [MST]). MST is the use of transcranial magnetic stimulation to induce a seizure. Magnetic fields pass through tissue unimpeded, providing more control over the site and extent of stimulation than can be achieved with ECT. This enhanced control represents a means of focusing the treatment on target cortical structures thought to be essential to antidepressant response and reducing spread to medial temporal regions implicated in the cognitive side effects of ECT. MST is at an early stage of development. Preliminary results suggest that MST may have some advantages over ECT in terms of subjective side effects and acute cognitive functioning. Studies designed to address the antidepressant efficacy of MST are underway. As with all attempts to improve convulsive therapy technique, the clinical value of MST will need to be established through controlled clinical trials. This article reviews the experience to date with MST, and places this work in the broader context of other means of optimizing convulsive therapy in the treatment of depression.

Serotonin, cerebral blood flow, and cerebral metabolic rate in geriatric major depression and normal aging.

While there is substantial evidence for abnormalities in serotonin (5-HT) neurotransmission in major depressive disorder (MDD), almost all of the findings derive from studies of young adults. Moreover, relatively little research has assessed brain 5-HT transmission in vivo. Neuroendocrine studies do not permit evaluation of a range of brain regions, but only the limited circuitry associated with hormone release. Data from autopsy studies are limited by the difficulties of assessment of the acute clinical picture before death, and by post-mortem artifacts. In vivo neuroimaging techniques overcome many of the methodological limitations of both these approaches. There is a large body of imaging data indicating regional cerebral blood flow (rCBF) and cerebral metabolic rate (rCMR) decrements both with aging and in patients with MDD. While the physiological bases for these phenomena are largely unknown, changes in brain 5-HT function may be involved. Neuroanatomical studies have revealed an intricate network of 5-HT-containing neurons within the cerebral microvasculature, with physiological evidence for serotonergic control of both rCBF and rCMR. Acute pharmacological challenges are available to probe brain 5-HT function. Such paradigms, using neuroendocrine responses as endpoints, have been of some utility in predicting outcome with antidepressant treatment. The role of 5-HT dysregulation in geriatric MDD takes on more importance given concerns regarding putative reduced efficacy of serotonin-specific reuptake inhibitors (SSRIs) in this population. If this is due to diminished responsivity of 5-HT systems, then the ability to identify antidepressant nonresponders via 5-HT challenge in combination with neuroimaging measures may have important clinical utility.