Cognitive effects of brief and ultrabrief pulse bitemporal electroconvulsive therapy: a randomised controlled proof-of-concept trial.

BACKGROUND: Reduction of the pulse width has been reported to improve ECT outcomes with unilateral ECT (similar efficacy, fewer cognitive side effects), but has been minimally studied for bitemporal ECT. The only study comparing brief and ultrabrief pulse bitemporal ECT found reduced efficacy for bitemporal ultrabrief compared to bitemporal brief pulse stimulation. This randomised controlled trial (RCT) aimed to test if ultrabrief pulse bitemporal ECT results in fewer cognitive side effects than brief pulse bitemporal ECT, when given at doses adjusted with the aim of achieving comparable efficacy. METHODS: Thirty-six participants were randomly assigned to receive ultrabrief (at 3 times seizure threshold) or brief (at 1.5 times seizure threshold) pulse bitemporal ECT given 3 times a week in a double-blind, controlled proof-of-concept trial. Blinded raters assessed mood and cognitive functioning over the ECT course. RESULTS: Efficacy and cognitive outcomes did not differ significantly between the two treatment groups over the ECT course. The ultrabrief pulse group performed better on a test of visual memory assessed acutely after an ECT treatment. CONCLUSIONS: This study suggests there may be a small cognitive advantage in giving bitemporal ECT with an ultrabrief pulse when dosage is increased to match the efficacy of brief pulse bitemporal ECT, but the study was underpowered to fully examine this issue.Clinical Trials Registration: www.clinicaltrials.gov, NCT00870805.

Effects of COMT, DRD2, BDNF, and APOE Genotypic Variation on Treatment Efficacy and Cognitive Side Effects of Electroconvulsive Therapy.

OBJECTIVES: The aim of this study was to explore the main and interaction effects of the COMT Val158Met, DRD2 C957T, BDNF Val66Met, and APOE polymorphisms on treatment efficacy and cognitive side effects of electroconvulsive therapy (ECT). METHODS: A total of 117 adult inpatients with a diagnosis of major depressive disorder recruited from 3 hospitals were administered the Montgomery-Äsberg Depression Rating Scale and a cognitive battery assessing global cognition, anterograde memory, executive function, speed and concentration, as well as retrograde memory at baseline and after ECT treatment. RESULTS: DRD2 C957T heterozygotes had 3.7 (95% confidence interval, 1.13-12.25; P = 0.032) greater odds of remission compared with CC homozygotes. Among the men, COMT Val/Val carriers had greater depressive symptom reduction compared with Met/Met carriers (Montgomery-Äsberg Depression Rating Scale percentage of reduction, 76% vs 35%; P = 0.020) but not among the women (P = 0.903) after ECT. For cognitive outcomes, an interaction effect on anterograde memory was observed between the DRD2 and BDNF polymorphisms (P = 0.016), in which carriers of the DRD2 TT and BDNF Val/Val genotypes had significantly less decline in anterograde performance than those that carried the TC and Met-allele (P = 0.001) or CC and Met-allele (P = 0.003) genotypes. However, no results withstood correction for multiple comparisons. CONCLUSIONS: These observations provide preliminary evidence supporting an association between common functional genotypic variation and ECT efficacy as well as anterograde memory side effects after ECT. Validation of these findings is required before firm conclusions can be made and clinical utility can be assessed.

A randomized controlled trial of brief and ultrabrief pulse right unilateral electroconvulsive therapy.

BACKGROUND: Some studies suggest better overall outcomes when right unilateral electroconvulsive therapy (RUL ECT) is given with an ultrabrief, rather than brief, pulse width. METHODS: The aim of the study was to test if ultrabrief-pulse RUL ECT results in less cognitive side effects than brief- pulse RUL ECT, when given at doses which achieve comparable efficacy. One hundred and two participants were assigned to receive ultrabrief (at 8 times seizure threshold) or brief (at 5 times seizure threshold) pulse RUL ECT in a double-blind, randomized controlled trial. Blinded raters assessed mood and cognitive functioning over the ECT course. RESULTS: Efficacy outcomes were not found to be significantly different. The ultrabrief group showed less cognitive impairment immediately after a single session of ECT, and over the treatment course (autobiographical memory, orientation). CONCLUSIONS: In summary, when ultrabrief RUL ECT was given at a higher dosage than brief RUL ECT (8 versus 5 times seizure threshold), efficacy was comparable while cognitive impairment was less.

Speed of response in ultrabrief and brief pulse width right unilateral ECT.

Ultrabrief pulse width stimulation electroconvulsive therapy (ECT) results in less cognitive side-effects than brief pulse ECT, but recent work suggests that more treatment sessions may be required to achieve similar efficacy. In this retrospective analysis of subjects pooled from three research studies, time to improvement was analysed in 150 depressed subjects who received right unilateral ECT with a brief pulse width (at five times seizure threshold) or ultrabrief pulse width (at six times seizure threshold). Multivariate Cox regression analyses compared the number of treatments required for 50% reduction in depression scores (i.e. speed of response) in these two samples. The analyses controlled for clinical, demographic and treatment variables that differed between the samples or that were found to be significant predictors of speed of response in univariate analyses. In the multivariate analysis, older age predicted faster speed of response. There was a non-significant trend for faster time to 50% improvement with brief pulse ECT (p = 0.067). Remission rates were higher after brief pulse ECT than ultrabrief pulse ECT (p = 0.007) but response rates were similar. This study, the largest of its kind reported to date, suggests that fewer treatments may be needed to attain response with brief than ultrabrief pulse ECT and that remission rates are higher with brief pulse ECT. Further research with a larger randomized and blinded study is recommended.

Ketamine as a new treatment for depression: a review of its efficacy and adverse effects.

OBJECTIVE: Narrative review of the literature on the efficacy and safety of subanaesthetic doses of ketamine for the treatment of depression. METHOD: Medline and PubMed databases were searched up to October 2012 using appropriate keywords. RESULTS: The studies consistently report substantial efficacy with high response and remission rates from 4 to 72 hours (averages 77% and 43%, respectively) from single doses, though not all patients respond to ketamine. Early relapse is common. While the usual procedure involves the administration of intravenous ketamine at a dose of 0.5 mg/kg over 40 minutes, some preliminary evidence suggests other dosing regimens and routes of administration may be useful or even better. Repeated doses and maintenance pharmacological treatments have been investigated in order to prolong the antidepressant effects, with only modest success. CONCLUSIONS: Current research on the antidepressant effects of ketamine has consistently shown rapid and substantial improvement in mood in the majority of patients. However, these effects have often been found to be short-lived. Future research should focus on identifying predictors of response (e.g. clinical, genetic, pharmacokinetic, environmental), examining different dosing regimens and routes of administration, and strategies to maintain the antidepressant response.

Pilot dose-response trial of i.v. ketamine in treatment-resistant depression.

OBJECTIVES: Research studies have reported impressive antidepressant effects with ketamine but significant knowledge gaps remain over the best method of administering ketamine, and the relationships between dose, antidepressant response and adverse effects. METHODS: In this pilot dose-finding study, the efficacy and tolerability of ketamine given by rapid intravenous (i.v.) infusion were assessed in a double-blind, placebo-controlled, crossover design, in four subjects with treatment- resistant depression. Each subject received up to four i.v. doses of ketamine (0.1, 0.2, 0.3, 0.4 mg/kg), given over 2-5 min, 1 week apart, and one randomly inserted placebo treatment. RESULTS: Three of four subjects achieved antidepressant response (≥ 50% decrease in Montgomery-Asberg Depression Rating Scale scores), two at the minimum 0.1 mg/kg dose, though all relapsed within a week. For two subjects, the greatest improvement occurred at the highest dose received. Rapid infusion over 2 min led to significant adverse psychotomimetic effects which also increased proportionately with ketamine dosage. CONCLUSIONS: This is the first trial to present dose-response data of ketamine efficacy and psychomimetic effects in depressed subjects. Antidepressant efficacy may be dose-related. Psychotomimetic effects were dose-related. Rapid infusion over 2 min may not be a feasible clinical approach to treatment, given poor tolerability.

A new early cognitive screening measure to detect cognitive side-effects of electroconvulsive therapy?

Cognitive side-effects from electroconvulsive therapy (ECT) can be distressing for patients and early detection may have an important role in guiding treatment decisions over the ECT course. This prospective study examined the utility of an early cognitive screening battery for predicting cognitive side-effects which develop later in the ECT course. The screening battery, together with the Mini Mental Status Examination (MMSE), was administered to 123 patients at baseline and after 3 ECT treatments. A more detailed cognitive battery was administered at baseline, after six treatments (post ECT 6) and after the last ECT treatment (post treatment) to assess cognitive side-effects across several domains: global cognition, anterograde memory, executive function, speed and concentration, and retrograde memory. Multivariate analyses examined the predictive utility of change on items from the screening battery for later cognitive changes at post ECT 6 and post treatment. Results showed that changes on a combination of items from the screening battery were predictive of later cognitive changes at post treatment, particularly for anterograde memory (p < 0.01), after controlling for patient and treatment factors. Change on the MMSE predicted cognitive changes at post ECT 6 but not at post treatment. A scoring method for the new screening battery was tested for discriminative ability in a sub-sample of patients. This study provides preliminary evidence that a simple and easy-to-administer measure may potentially be used to help guide clinical treatment decisions to optimise efficacy and cognitive outcomes. Further development of this measure and validation in a more representative ECT clinical population is required.

A review of ultrabrief pulse width electroconvulsive therapy.

The effect of shortening the pulse width of the electrical stimulus when administering electroconvulsive therapy (ECT) has recently been systematically studied with promising results. This review examines reported outcomes from three randomized controlled trials which compared ultrabrief (≤0.3 ms) with brief (0.5-1.5 ms) pulse width ECT, and other recent clinical trials of ultrabrief pulse width ECT. The emerging evidence for ultrabrief pulse right unilateral (RUL) ECT suggests clinically meaningful efficacy and substantially reduced neuropsychological side effects compared with standard (brief) pulse ECT; this may represent a generational advance in the ECT technique. However, it is unclear if patients receiving ultrabrief pulse RUL ECT may have a slower speed of response and require additional treatments compared with brief pulse ECT. Therefore, until further data are available, clinicians may be well advised to use brief pulse ECT in situations requiring an urgent clinical response. The evidence base for ultrabrief bilateral ECT is limited, with findings that efficacy may be reduced compared with brief pulse width ECT. Thus ultrabrief bilateral ECT should not be used outside the research setting.

Neuropsychological and mood effects of ketamine in electroconvulsive therapy: a randomised controlled trial.

BACKGROUND: Preliminary evidence suggests that the use of ketamine during electroconvulsive therapy (ECT) may be neuroprotective against cognitive impairment and have synergistic antidepressant effects. This study tested whether the addition of ketamine reduced cognitive impairment and enhanced efficacy over a course of ECT, in a randomised, placebo-controlled, double-blind study. METHODS: Fifty-one depressed patients treated with ultrabrief pulse-width right unilateral ECT were randomised to receive either ketamine (0.5mg/kg) or placebo (saline) in addition to thiopentone during anaesthesia for ECT. Neuropsychological outcomes (measured before ECT, after six treatments, and after the final ECT treatment) and mood outcomes (measured before ECT, and weekly after every three ECT treatments) were measured by a rater blinded to treatment condition. RESULTS: Neuropsychological outcomes did not differ between groups. The ECT-ketamine group had a slightly greater improvement in depressive symptoms over the first week of treatment and at one-week follow up, though there was no overall difference in efficacy at the end of the ECT course. No psychomimetic effects were detected. LIMITATIONS: The study was conducted in a clinical setting, so not all aspects of ECT treatment were fully controlled. Thiopentone doses differed slightly between groups, in order to accommodate the addition of ketamine to the anaesthetic. CONCLUSIONS: The addition of ketamine did not decrease cognitive impairment in patients having ultrabrief pulse-width right unilateral ECT, but was safe and slightly improved efficacy in the first week of treatment and at one-week follow up. CLINICAL TRIALS REGISTRATION: Clinicaltrials.gov ID: NCT00680433. Ketamine as an anaesthetic agent in electroconvulsive therapy (ECT). www.clinicaltrials.gov.

Physical treatments for bipolar disorder: a review of electroconvulsive therapy, stereotactic surgery and other brain stimulation techniques.

BACKGROUND: Despite pharmacological advances, bipolar disorder continues to be difficult to treat. This article reviews the evidence base for the use of electroconvulsive therapy (ECT) and other brain stimulation therapies in bipolar disorder. METHODS: The evidence base for the efficacy of ECT and transcranial magnetic stimulation in the treatment of mania, bipolar depression and mixed affective states was reviewed. Reports on the use of vagus nerve stimulation, stereotaxic surgery, deep brain stimulation, magnetic seizure therapy and transcranial direct current stimulation in treating depression, as well as bipolar disorder were also reviewed. Studies were identified from Medline and Embase database searches. RESULTS: There are a few randomized controlled trials of ECT in mania and bipolar depression, and none in mixed affective states. Nevertheless, such studies consistently reported clinically meaningful efficacy, with a majority of pharmacotherapy resistant patients responding to ECT. Evidence for the use of other brain stimulation therapies in treating bipolar mood states is preliminary and limited. CONCLUSIONS: ECT is an effective treatment for acute mania, bipolar depression and mixed affective states and has useful efficacy even in pharmacotherapy-resistant patients. Other brain stimulation techniques may have potential for the treatment of bipolar disorder and should be further researched.

Predictors of response to ultrabrief right unilateral electroconvulsive therapy.

BACKGROUND: Recent trials have demonstrated clinically meaningful efficacy and minimal cognitive side effects with ultrabrief pulsewidth right unilateral (RUL) ECT. In many countries it is gradually being adopted into clinical practice and further information on predictors of response is needed. METHODS: Data collected from 75 depressed patients who received ultrabrief RUL ECT in a prospective research trial were analysed for predictors of response. Mood improvement was assessed with the Montgomery-Asberg Depression Rating Scale. Improvement in unipolar versus bipolar depression was analysed. RESULTS: Sixty-one percent of patients met the criteria for response and 36% met the criteria for remission. Logistic regression identified index episode duration ≥one year (OR=10.50, p=.006), fewer failed antidepressant treatments (OR=0.46, p=.003), previous ECT course (OR=7.33, p=.01), and absence of concurrent antidepressant (OR=0.09, p=.005) as predictors of response. Psychotic features (OR=7.18, p=.032) and baseline depression severity (OR=0.90, p=.017) were predictors of remission. There was a trend towards greater improvement in bipolar than unipolar depression in the first week of treatment (p=0.077). LIMITATIONS: Data were obtained from a prospective but non-randomised clinical trial which was designed to evaluate efficacy rather than to examine predictors of response. Treatment decisions (concurrent medication, switching to other types of ECT) were made on clinical grounds. CONCLUSIONS: This preliminary study suggests that predictors of response for ultrabrief RUL ECT are similar to those identified for other types of ECT previously studied.