Bitemporal v. high-dose right unilateral electroconvulsive therapy for depression: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Brief-pulse electroconvulsive therapy (ECT) is the most acutely effective treatment for severe depression though concerns persist about cognitive side-effects. While bitemporal electrode placement is the most commonly used form worldwide, right unilateral ECT causes less cognitive side-effects though historically it has been deemed less effective. Several randomized trials have now compared high-dose (>5× seizure threshold) unilateral ECT with moderate-dose (1.0-2.5× seizure threshold) bitemporal ECT to investigate if it is as effective as bitemporal ECT but still has less cognitive side-effects. We aimed to systematically review these trials and meta-analyse clinical and cognitive outcomes where appropriate. METHOD: We searched PubMed, PsycINFO, Web of Science, Cochrane Library and EMBASE for randomized trials comparing these forms of ECT using the terms 'electroconvulsive' OR 'electroshock' AND 'trial'. RESULTS: Seven trials (n = 792) met inclusion criteria. Bitemporal ECT did not differ from high-dose unilateral ECT on depression rating change scores [Hedges's g = -0.03, 95% confidence interval (CI) -0.17 to 0.11], remission (RR 1.06, 95% CI 0.93-1.20), or relapse at 12 months (RR 1.42, 95% CI 0.90-2.23). There was an advantage for unilateral ECT on reorientation time after individual ECT sessions (mean difference in minutes = -8.28, 95% CI -12.86 to -3.70) and retrograde autobiographical memory (Hedges's g = -0.46, 95% CI -0.87 to -0.04) after completing an ECT course. There were no differences for general cognition, category fluency and delayed visual and verbal memory. CONCLUSIONS: High-dose unilateral ECT does not differ from moderate-dose bitemporal ECT in antidepressant efficacy but has some cognitive advantages.

Peripheral blood microRNA and VEGFA mRNA changes following electroconvulsive therapy: implications for psychotic depression.

OBJECTIVE: MicroRNAs are short, non-coding molecules that regulate gene expression. Here, we investigate the role of microRNAs in depression and electroconvulsive therapy (ECT). METHODS: We performed three studies: a deep sequencing discovery-phase study of miRNA changes in whole blood following ECT (n = 16), followed by a validation study in a separate cohort of patients pre-/post-ECT (n = 37) and matched healthy controls (n = 34). Changes in an experimentally validated gene target (VEGFA) were then analysed in patients pre-/post-ECT (n = 97) and in matched healthy controls (n = 53). RESULTS: In the discovery-phase study, we found no statistically significant differences in miRNA expression from baseline to end of treatment in the group as a whole, but post hoc analysis indicated a difference in patients with psychotic depression (n = 3). In a follow-up validation study, patients with psychotic depression (n = 7) had elevated baseline levels of miR-126-3p (t = 3.015, P = 0.006) and miR-106a-5p (t = 2.598, P = 0.025) compared to healthy controls. Following ECT, these differences disappeared. Baseline VEGFA levels were significantly higher in depressed patients compared to healthy controls (F(1,144) = 27.688, P = <0.001). Following ECT, there was a significant change in VEGFA levels in the psychotic group only (t = 2.915, P = 0.010). CONCLUSION: Molecular differences (miRNA and VEGFA) may exist between psychotic and non-psychotic depression treated with ECT.

When less is more--microRNAs and psychiatric disorders.

OBJECTIVE: MicroRNAs are small non-coding RNA molecules that regulate gene expression, including genes involved in neuronal function and plasticity that have relevance for brain function and mental health. We therefore performed a systematic review of miRNAs in general adult psychiatric disorders. METHOD: Systematic searches in PubMed/MEDLINE and Web of Science were conducted to identify published clinical articles on microRNAs in general adult psychiatric disorders. We also reviewed references from included articles. RESULTS: There is mounting evidence of microRNAs' regulatory roles in a number of central nervous system processes, including neurogenesis and synaptic plasticity. The majority of clinical studies of microRNAs in psychiatric disorders are in schizophrenia, where a number of specific microRNAs have been identified in separate studies. There is some evidence of marked downregulation of some microRNAs in affective disorders. Treatment with antidepressants appears to upregulate microRNA levels. There is currently little evidence from human studies in anxiety, addiction or other psychiatric disorders. CONCLUSION: MicroRNA research in psychiatry is currently in a nascent period, but represents an emerging and exciting area, with the potential to clarify molecular mechanisms of disease and identify novel biomarkers and therapeutic agents.

A critique of narrative reviews of the evidence-base for ECT in depression.

There has been recent debate regarding the efficacy of electroconvulsive therapy in the treatment of depression. This has been based on narrative reviews that contradict existing systematic reviews and meta-analyses. In this special article, we highlight the mistakes that occur when interpreting evidence using narrative reviews, as opposed to conventional systematic reviews and meta-analyses.

Regional variation in electroconvulsive therapy use.

Although electroconvulsive therapy (ECT) is the most powerful treatment for depression, substantial variability in use has been described in Ireland. The Mental Health Commission collects usage data from approved centres but does not include home addresses or independent sector patients. Therefore, estimates of regional variation cannot be accurate, e.g. 145 (35% of total) independent sector patients were omitted from their 2008 analysis. When public and independent sector patients are combined inter-regional variation for 2008 is more than halved (chi-squared decreased from 83 to 30), with Western region contributing most to variation (chi-squared = 43). Ratio of ECT programmes to depressed admissions correlated negatively with rate for depressed admissions (r = -0.53, p = 0.01), while depressed admission numbers correlated with acute beds per area (r = 0.68, p = 0.001). Regional variation in ECT is less than previously reported; service factors probably account for much of this with smaller centres admitting severely ill patients more likely to require ECT.

From Molecules to Mind: Mechanisms of Action of Electroconvulsive Therapy.

(Reprinted with permission from Acta Psychatrica Scandinavica (John Wiley & Sons, Ltd.); ©John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Acta Psychiatrica Scandinavica 2018: 138:177-179).

Kynurenine pathway metabolism and the neurobiology of treatment-resistant depression: Comparison of multiple ketamine infusions and electroconvulsive therapy.

Current first-line antidepressants can take weeks or months to decrease depressive symptoms. Low dose ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, shows potential for a more rapid antidepressant effect, with efficacy also evident in previously treatment-resistant populations. However, a greater understanding of the physiological mechanisms underlying such effects is required. We assessed the potential impact of ketamine infusion on neurobiological drivers of kynurenine pathway metabolism in major depression (HPA axis hyperactivity, inflammation) in patients with treatment-resistant depression compared to gender-matched healthy controls. Furthermore, we assessed these biomarkers before and after electroconvulsive therapy (ECT), which is currently the gold standard for management of treatment-resistant depression. As previously demonstrated, treatment with ketamine and ECT was associated with improved depressive symptoms in patients. At baseline, waking cortisol output was greater in the ECT cohort, kynurenine was greater in the ketamine cohort, and kynurenic acid was lower in patients compared to healthy controls, although inflammatory markers (IL-6, IL-8, IL-10 or IFN-γ) were similar in patients and controls. Furthermore, in patients who responded to ECT, the cortisol awakening response was decreased following treatment. Despite a trend towards reduced kynurenine concentrations in those who responded to ketamine, ketamine was not associated with significant alterations in any of the biomarkers assessed.

The clinical effectiveness and cost of repetitive transcranial magnetic stimulation versus electroconvulsive therapy in severe depression: a multicentre pragmatic randomised controlled trial and economic analysis.

OBJECTIVE: To investigate if repetitive transcranial magnetic stimulation (rTMS) was as effective as electroconvulsive therapy (ECT) in treating major depressive episodes and to perform a cost-effectiveness analysis. DESIGN: A single-blind pragmatic multicentre randomised controlled trial (RCT) with 6 months of follow-up to test equivalence of rTMS with ECT. SETTING: The South London and Maudsley NHS Trust and Pembury Hospital in the Invicta Mental Health Trust in Kent. PARTICIPANTS: Right-handed adult patients referred for ECT for treatment of a major depressive episode (DSM-IV) were assessed. During the 2.5-year trial period, 260 patients were referred for ECT, of whom 46 entered the trial. The main reason for not entering the trial was not consenting to ECT while being formally treated under the UK Mental Health Act 1983. INTERVENTIONS: Patients were randomised to receive a 15-day course of rTMS of the left dorsolateral prefrontal cortex (n = 24) or a course of ECT (n = 22). MAIN OUTCOME MEASURES: Patients were assessed before randomisation, at end of treatment and at the 6-month follow-up. Primary outcome measures were the 17-item Hamilton Rating Scale for Depression (HRSD) and proportion of remitters (defined as HRSD score

Clinical predictors of involuntary detention among voluntary inpatients in St Patrick's University Hospital (SPUH).

BACKGROUND: Few studies have described clinical characteristics of patients subject to an involuntary detention in an Irish context. The Irish Mental Health Act 2001 makes provision under Section 23(1), whereby a person who has voluntary admission status can be detained. Aims This study aimed to describe all involuntary admissions to St Patrick's University Hospital (SPUH) (2011-2013) and to evaluate clinical characteristics of voluntary patients who underwent Mental Health Act assessment during 2011 to determine differences in those who had involuntary admission orders completed and those who did not. METHODS: All uses of Mental Health Act 2001 within SPUH 2011-2013 were identified. All uses of Section 23(1) during 2011 were reviewed and relevant documents/case-notes examined using a pro forma covering clinical data, factors recognized to influence involuntary admissions and validated scales were used to determine diagnoses, insight, suicide and violence risk. RESULTS: Over 2011-2013, 2.5-3.8% of all admissions were involuntary with more detained after use of Section 23(1) than Section 14(2). The majority of initiations of Section 23(1) did not result in an involuntary admission (72%), occurred out of hours (52%) and many occurred early after admission (<1 week, 43%). Initiation of Section 23(1) by a consultant psychiatrist (p=0.001), suicide risk (p=0.03) and lack of patient insight into treatment (p=0.007) predicted conversion to involuntary admission. CONCLUSION: This study predicts a role for patient insight, suicide risk and consultant psychiatrist decision making in the initiation of Mental Health Act assessment of voluntary patients. Further data describing the involuntary admissions process in an Irish setting are needed.

Electroconvulsive therapy modulates plasma pigment epithelium-derived factor in depression: a proteomics study.

Electroconvulsive therapy (ECT) is the most effective treatment for severe depression, yet its mechanism of action is not fully understood. Peripheral blood proteomic analyses may offer insights into the molecular mechanisms of ECT. Patients with a major depressive episode were recruited as part of the EFFECT-Dep trial (enhancing the effectiveness of electroconvulsive therapy in severe depression; ISRCTN23577151) along with healthy controls. As a discovery-phase study, patient plasma pre-/post-ECT (n=30) was analyzed using 2-dimensional difference in gel electrophoresis and mass spectrometry. Identified proteins were selected for confirmation studies using immunodetection methods. Samples from a separate group of patients (pre-/post-ECT; n=57) and matched healthy controls (n=43) were then used to validate confirmed changes. Target protein mRNA levels were also assessed in rat brain and blood following electroconvulsive stimulation (ECS), the animal model of ECT. We found that ECT significantly altered 121 protein spots with 36 proteins identified by mass spectrometry. Confirmation studies identified a post-ECT increase (P<0.01) in the antiangiogenic and neuroprotective mediator pigment epithelium-derived factor (PEDF). Validation work showed an increase (P<0.001) in plasma PEDF in depressed patients compared with the controls that was further increased post-ECT (P=0.03). PEDF levels were not associated with mood scores. Chronic, but not acute, ECS increased PEDF mRNA in rat hippocampus (P=0.02) and dentate gyrus (P=0.03). This study identified alterations in blood levels of PEDF in depressed patients and further alterations following ECT, as well as in an animal model of ECT. These findings implicate PEDF in the biological response to ECT for depression.

The clinical, occupational and financial outcomes associated with a bespoke specialist clinic for military aircrew-a cohort study.

OBJECTIVES: To assess the clinical, occupational and financial outcomes of a new Clinical Aviation Medicine Service (CAMS) for UK military personnel. METHODS: Consecutive patients over a 2 year period were included. Predictors of flying restrictions at referral and final outcome following consultation were modelled using logistic regression. National Health Service (NHS) Payment by Results tariffs and Defence capitation data were used to assess the financial impact of the service. RESULTS: Eight hundred and sixteen new referrals (94.5% male, median age 45 years (range 19-75)) were received and 1025 consultations performed. Cardiovascular disease was the commonest reason for referral. CAMS clinical activity cost at NHS tariff was £453 310 representing a saving of £316 173 (£137 137 delivery cost). In total, 310/816 (38%) patients had employment restrictions on referral and 49.0% of this group returned to full employment following their initial consultation. Compared with cardiology, general medicine and respiratory patients were more likely to have been occupationally restricted prior to referral (50 vs. 35%, OR 1.81; 95% CI 1.18-2.76, P values=0.006 and 53 vs. 35%, OR 2.12; 95% CI 1.15-3.90, P values = 0.016, respectively). Overall 581/816 (71.2%) of patients returned to unrestricted employment while 98/816 (12.0%) were unable to continue in any aircrew role. The service saved 7000 lost working days per year at an estimated occupational saving of ∼£1 million per annum. CONCLUSIONS: This bespoke service has allowed rapid, occupationally relevant clinical care to be delivered with both time and financial savings. The model may have significant occupational and financial relevance for other environmental and occupational medical organizations.

MicroRNAs as biomarkers for major depression: a role for let-7b and let-7c.

There is a growing emphasis in the field of psychiatry on the need to identify candidate biomarkers to aid in diagnosis and clinical management of depression, particularly with respect to predicting response to specific therapeutic strategies. MicroRNAs are small nucleotide sequences with the ability to regulate gene expression at the transcriptomic level and emerging evidence from a range of studies has highlighted their biomarker potential. Here we compared healthy controls (n=20) with patients diagnosed with major depression (n=40) and who were treatment-resistant to identify peripheral microRNA biomarkers, which could be used for diagnosis and to predict response to electroconvulsive therapy (ECT) and ketamine (KET) infusions, treatments that have previously shown to be effective in treatment-resistant depression (TRD). At baseline and after treatment, blood samples were taken and symptom severity scores rated using the Hamilton Depression Rating Scale (HDRS). Samples were analyzed for microRNA expression using microarray and validated using quantitative PCR. As expected, both treatments reduced HDRS scores. Compared with controls, the baseline expression of the microRNA let-7b was less by ~40% in TRD patients compared with controls. The baseline expression of let-7c was also lower by ~50% in TRD patients who received ECT. Bioinformatic analysis revealed that let-7b and let-7c regulates the expression of 27 genes in the PI3k-Akt-mTOR signaling pathway, which has previously been reported to be dysfunctional in depression. The expression of miR-16, miR-182, miR-451 and miR-223 were similar to that in controls. Baseline microRNA expression could not predict treatment response and microRNAs were unaffected by treatment. Taken together, we have identified let-7b and let-7c as candidate biomarkers of major depression.

Bilirubin inhibition of enzymes involved in the mitochondrial malate-aspartate shuttle.

The effect of increasing bilirubin concentrations upon the catalytic activity of a series of dehydrogenases and aminotransferases was examined. The particular enzymes were chosen to examine the effect of bilirubin upon the activity of enzymes responsible for the indirect transfer of reducing equivalents across the inner mitochondrial membrane. Malate dehydrogenase was inhibited at very low concentrations of bilirubin and showed competitive inhibition with respect to coenzyme of 2 microM, while the cytosolic form of this enzyme exhibited a 15 microM inhibition constant. Cytosolic glycerol-3-phosphate dehydrogenase was not appreciably inhibited by bilirubin. Both the mitochondrial and cytosolic forms of aspartate aminotransferase showed moderate competitive bilirubin inhibition with respect to substrates with a Ki of 30 microM with respect to 2-oxoglutarate and a Ki of 80 microM with respect to aspartate. Preincubation studies indicated that inhibition was reversible for all enzymes examined. These results are interpreted in terms of the inhibition of the malate-aspartate shuttle by relatively low concentrations of bilirubin.

Purification and properties of the major isozymic form of cytoplasmic glycerol-3-phosphate dehydrogenase from rabbit liver.

The major isozymic form of sn-glycerol-3-phosphate dehydrogenase (sn-glycerol-3-phosphate:NAD+ 2-oxidoreductase, EC 1.1.1.8) has been purified from rabbit liver using a simplified three-step chromatographic procedure involving an ion exchange and two affinity chromatography steps. The 1200-fold purified enzyme is electrophoretically homogeneous, nucleotide-free, and possesses a specific activity of 295 units/mg and an isoelectric point of 6.5. A steady-state kinetic analysis was applied to both the forward and reverse reactions. The NADH oxidation reaction was found to adhere to Michaelis-Menten behavior with Km values of 22 micrometer and 75 micrometer for NADH and dihydroxyacetone phosphate, respectively. In the NAD reduction reaction, sigmoidal kinetic patterns were observed when NAD was the variable substrate whereas with sn-glycerol-3-phosphate as the variable substrate, strictly hyperbolic kinetics were observed. The apparent Km values for NAD and glycerol-3-phosphate were 83 and 909 micrometer, respectively. By comparison with published reports, these results demonstrate that the rabbit muscle and liver isozymes of sn-glycerol-3-phosphate dehydrogenase have different kinetic properties and suggest that the liver isozyme is better adapted to participation in glyconeogenesis in vivo.

The interaction of fatty acids with rabbit liver and muscle glycerol-3-phosphate dehydrogenase.

Various fatty acids containing 10--22 carbons and including unsaturated derivatives were found to be inhibitors of rabbit liver and skeletal muscle sn-glycerol-3-phosphate dehydrogenase (sn-glycerol-3-phosphate:NAD+ 2-oxidoreductase, EC 1.1.1.8). For the liver enzyme, the logarithm of the inhibition constant was linearly related to the number of carbon atoms in the saturated fatty acids whereas the muscle enzyme, which was generally more strongly inhibited, showed a nonlinear dependence. The liver and muscle enzymes also interacted differently with a series of unsaturated fatty acids for which a high degree of specificity was exhibited which was related to the position, configuration, and number of double bonds in the compound. A steady-state kinetic analysis shows that under some conditions, the kinetics of the NADH reduction of dihydroxyacetone phosphate by NADH in the presence of stearic acid do not follow simple Michaelis-Menten behavior but rather the velocity shows a sigmoidal dependence on fatty acid concentration and strong substrate inhibition. Stearic acid is a much poorer inhibitor of the NAD-dependent oxidation of glycerol-3-phosphate. At low substrate concentrations stearic acid is competitive with respect to NAD with an inhibition constant of 24 micrometer for stearic acid. In addition to the effect of fatty acids on the initial velocities of the enzyme-catalyzed reactions, preincubation of the enzyme with fatty acid leads to a slow, time-dependent irreversible inactivation of the enzyme which is prevented by the presence of NADH. The results are discussed in terms of the differences in the conformations of the hydrophobic binding sites on the two enzymes.

The role of mesenchyme in thymus development.

We have reviewed the evidence that thymic mesenchymal cells and their progeny thymic fibroblasts play an important role in early T-cell development. Although it is possible that mesenchyme plays an inductive role in thymic epithelial morphogenesis, we have presented evidence to suggest that there is a direct effect of mesenchyme and fibroblasts on T-cell development. Moreover the association of these cell types with an ECM raises the possibility that the latter might be important in integrin and/or cytokine presentation especially during the CD4(-)8- phase of T-cell development.