Relapse following bitemporal and high-dose right unilateral electroconvulsive therapy for major depression.

OBJECTIVE: Electroconvulsive therapy (ECT) is an effective acute treatment for severe and/or medication-resistant depression but maintaining remission following completion of a course remains a clinical challenge. METHODS: EFFECT-Dep Trial (ISRCTN23577151) participants with a DSM-IV major depressive episode who met remission criteria after a randomly assigned course of twice-weekly brief-pulse bitemporal (1.5 × seizure threshold) or high-dose (6 × seizure threshold) right unilateral ECT were monitored for relapse for 12 months. In line with the pragmatic trial design, all patients received treatment-as-usual individualised pharmacotherapy during and after ECT; no remitter received continuation ECT. RESULTS: Of 61 remitters, 24 (39.3%) relapsed, one (1.6%) withdrew from the study while in remission and the remaining 36 (59.0%) stayed well for a year. Most relapses occurred within the first six months, resulting in a cumulative six-month relapse rate of 31.1%. In a multivariable Cox proportional hazards regression model, older age (p = 0.039) and psychotic features at pre-ECT baseline (p = 0.037) were associated with a more favourable long-term prognosis while a greater number of previous depressive episodes (p = 0.028) and bipolar II (but not bipolar I) diagnosis (p = 0.030) were associated with a worse long-term outcome. Electrode placement and medication resistance prior to ECT had no effect on relapse. Adjusting for covariates, fewer patients treated with lithium relapsed in the overall group (p = 0.008) and in the unipolar depression subgroup (p = 0.027). CONCLUSION: Long-term outcome following high-dose right unilateral ECT does not differ from bitemporal ECT. Prognosis is particularly favourable in older adults, psychotic depression and patients maintained on lithium.

Peripheral blood E2F1 mRNA in depression and following electroconvulsive therapy.

The E2F transcription factors are a group of proteins that bind to the promotor region of the adenovirus E2 gene. E2F1, the first family member to be cloned, is linked to functions including cell proliferation and apoptosis, DNA repair, cell senescence and metabolism. We recently performed a deep sequencing study of micro-RNA changes in whole blood following ECT. Two micro-RNAs (miR-126-3p and miR-106a-5p) were identified and gene targeting analysis identified E2F1 as a shared target of these miRNAs. To our knowledge, no studies have examined E2F1 mRNA levels in patients with depression. Peripheral blood E2F1 mRNA levels were therefore examined in patients with depression, compared to healthy controls, and the effects of a course of ECT on peripheral blood E2F1 mRNA was investigated. Depressed patient and healthy control groups were balanced on the basis of age and sex. E2F1 mRNA levels were significantly lower in depressed patients in comparison to controls (p = .009) but did not change with ECT. There was no relationship between baseline E2F1 levels and depression severity, response to treatment, presence of psychosis or polarity of depression. There were no significant correlations between E2F1 levels and mood scores based on the HAM-D24. These results indicate that reduced peripheral blood E2F1 mRNA could be a trait feature of depression.

Peripheral blood SIRT1 mRNA levels in depression and treatment with electroconvulsive therapy.

Sirtuins are a family of nicotinamide adenine dinucleotide (NAD+) dependent enzymes that regulate cellular functions through deacetylation of protein targets. They have roles in both the periphery and central nervous system and have been implicated in depression biology. A recent genome-wide association study has identified a locus for major depression in the Sirtuin1 gene (SIRT1) and lower blood levels of SIRT1 mRNA in patients with depression have also been observed in two studies. To our knowledge, no studies have examined the effect of treatment on SIRT1 levels in patients with depression. We therefore examined SIRT1 mRNA levels in a well characterised group of patients with depression, compared to healthy controls, and characterised the effects of a course of electroconvulsive therapy (ECT) on peripheral blood SIRT1 mRNA. Depressed patients (n = 91) were matched to healthy controls (n = 85) on the basis of age and sex. In line with previous studies, blood SIRT1 mRNA levels were lower in depressed patients in comparison to controls (p = 0.005). However, ECT had no effect on SIRT1 levels (p = 0.67). There was no relationship between baseline pre-ECT SIRT1 levels and depression severity, change in mood scores, suicidality, depression polarity, presence of psychosis, or response to treatment. There was a trend for a negative association between an increase in SIRT1 mRNA and a decrease in HAM-D24 scores in ECT responders and remitters. These results indicate that reduced peripheral blood SIRT1 mRNA could be a trait feature of depression.

Bitemporal Versus High-Dose Unilateral Twice-Weekly Electroconvulsive Therapy for Depression (EFFECT-Dep): A Pragmatic, Randomized, Non-Inferiority Trial.

OBJECTIVE: ECT is the most effective treatment for severe depression. Previous efficacy studies, using thrice-weekly brief-pulse ECT, reported that high-dose (6× seizure threshold) right unilateral ECT is similar to bitemporal ECT but may have fewer cognitive side effects. The authors aimed to assess the effectiveness and cognitive side effects of twice-weekly moderate-dose (1.5× seizure threshold) bitemporal ECT with high-dose unilateral ECT in real-world practice. METHOD: This was a pragmatic, patient- and rater-blinded, noninferiority trial of patients with major depression (N=138; 63% female; age=56.7 years [SD=14.8]) in a national ECT service with a 6-month follow-up. Participants were independently randomly assigned to bitemporal or high-dose unilateral ECT. The primary outcome was change in the 24-item Hamilton Depression Rating Scale (HAM-D) score after the ECT course; the prespecified noninferiority margin was 4.0 points. Secondary outcomes included response and remission rates, relapse status after 6 months, and cognition. RESULTS: Of the eligible patients, 69 were assigned to bitemporal ECT and 69 to unilateral ECT. High-dose unilateral ECT was noninferior to bitemporal ECT regarding the 24-item HAM-D scores after the ECT course (mean difference=1.08 points in favor of unilateral ECT [95% CI=-1.67 to 3.84]). There were no significant differences for response and remission or 6-month relapse status. Recovery of orientation was quicker following unilateral ECT (median=19.1 minutes versus 26.4 minutes). Bitemporal ECT was associated with a lower percent recall of autobiographical information (odds ratio=0.66) that persisted for 6 months. CONCLUSIONS: Twice-weekly high-dose unilateral ECT is not inferior to bitemporal ECT for depression and may be preferable because of its better cognitive side-effect profile.

Epigenetics and depression: return of the repressed.

INTRODUCTION: Epigenetics has recently emerged as a potential mechanism by which adverse environmental stimuli can result in persistent changes in gene expression. Epigenetic mechanisms function alongside the DNA sequence to modulate gene expression and ultimately influence protein production. The current review provides an introduction and overview of epigenetics with a particular focus on preclinical and clinical studies relevant to major depressive disorder (MDD). METHODS: PubMed and Web of Science databases were interrogated from January 1995 up to December 2012 using combinations of search terms, including "epigenetic", "microRNA" and "DNA methylation" cross referenced with "depression", "early life stress" and "antidepressant". RESULTS: There is an association between adverse environmental stimuli, such as early life stress, and epigenetic modification of gene expression. Epigenetic changes have been reported in humans with MDD and may serve as biomarkers to improve diagnosis. Antidepressant treatments appear to reverse or initiate compensatory epigenetic alterations that may be relevant to their mechanism of action. LIMITATIONS: As a narrative review, the current report was interpretive and qualitative in nature. CONCLUSION: Epigenetic modification of gene expression provides a mechanism for understanding the link between long-term effects of adverse life events and the changes in gene expression that are associated with depression. Although still a developing field, in the future, epigenetic modifications of gene expression may provide novel biomarkers to predict future susceptibility and/or onset of MDD, improve diagnosis, and aid in the development of epigenetics-based therapies for depression.

Relapse following successful electroconvulsive therapy for major depression: a meta-analysis.

High rates of early relapse following electroconvulsive therapy (ECT) are typically reported in the literature. Current treatment guidelines offer little information to clinicians on the optimal nature of maintenance therapy following ECT. The aim of this study was to provide a systematic overview of the existing evidence regarding post-ECT relapse. A keyword search of electronic databases was performed for studies appearing in the peer-reviewed literature before January 2013 reporting on relapse rates in responders to an acute course of ECT administered for a major depressive episode. Meta-analyses were performed where appropriate. Thirty-two studies with up to 2 years' duration of follow-up were included. In modern era studies of continuation pharmacotherapy, 51.1% (95% CI=44.7-57.4%) of patients relapsed by 12 months following successful initial treatment with ECT, with the majority (37.7%, 95% CI=30.7-45.2%) relapsing within the first 6 months. The 6-month relapse rate was similar in patients treated with continuation ECT (37.2%, 95% CI=23.4-53.5%). In randomized controlled trials, antidepressant medication halved the risk of relapse compared with placebo in the first 6 months (risk ratio=0.49, 95% CI=0.39-0.62, p<0.0001, number needed to treat=3.3). Despite continuation therapy, the risk of relapse within the first year following ECT is substantial, with the period of greatest risk being the first 6 months. The largest evidence base for efficacy in post-ECT relapse prevention exists for tricyclic antidepressants. Published evidence is limited or non-existent for commonly used newer antidepressants or popular augmentation strategies. Maintenance of well-being following successful ECT needs to be improved.

Antidepressant augmentation and combination in unipolar depression: strong guidance, weak foundations.

Depression will be the second leading contributor to the global burden of disease by 2020. In Ireland, in 2009, 6061 people were hospitalised with depressive disorders. This represents a significant economic and social burden. There is growing awareness of the difficulty in treating depression with medications alone. The likelihood that a patient will achieve remission with the first antidepressant tried is around 30%, and the rates are similar for the second antidepressant tried. This falls to around 15% after three trials. Many patients are exposed to pharmacotherapy for extended periods of time with little beneficial effect, but often with side-effects. Patients are therefore in great need of clear information with regard to their chance of success. Clinicians are in need of clear guidance on prescribing strategies which have proven efficacy. However, this guidance often discusses treatment strategies based on varying levels of evidence. Guiding bodies may approach the problem from varying perspectives. The UK National Institute for Health and Clinical Excellence (NICE) has a clear government mandate with regard to provision of not only effective but cost-effective treatments. The British Association of Psychopharmacology (BAP) is an independent body of interested researchers and therefore may discuss prescribing options from the point of view of tertiary care institutions, and university centres. The South London and Maudsley NHS Foundation Trust publish the popular Maudsley guidelines. These are perhaps more pragmatic in nature, but include very low levels of evidence, including case series. The American Psychiatric Association (APA) is an independent member association which also publishes guidelines. These are published in the American Journal of Psychiatry and the latest guidelines were published in October 2010. All these bodies attempt to weigh their advice according to the level of evidence available and aim to provide clinical guidance in difficult situations. The burden on guiding organisations is to provide some direction and clarity in areas that are often unclear or controversial. Clinical guidelines are one method of providing support and guidance to busy clinicians. However, this clinician-centered approach has limitations. The onus is on the authors of the guidance to provide ever-more treatment options. This may mean that conclusions about the efficacy of medications is overstated or the limitations of the literature not fully explored in explanatory notes.