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.

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.

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.

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.

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.

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.

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.

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.

Serum BDNF as a peripheral biomarker of treatment-resistant depression and the rapid antidepressant response: A comparison of ketamine and ECT.

BACKGROUND: Ketamine is associated with rapid antidepressant efficacy but the biological mechanisms underpinning this effect are unclear. Serum brain-derived neurotrophic factor (sBDNF) is a potential circulating biomarker of treatment-resistant depression (TRD) and ketamine response but it is unclear if this is a common target of both ketamine and electroconvulsive therapy (ECT), the current gold standard for TRD. Moreover, the impact of multiple ketamine infusions on sBDNF has not yet been established. METHODS: Thirty five TRD patients with a current DSM-IV diagnosis of recurrent depressive disorder received up to 12 ECT sessions (N=17) or up to three intravenous infusions of low-dose (0.5mg/kg) ketamine (N=18). Blood samples were taken over the course of the study for assessment of sBDNF. Symptom severity and response were monitored using the 17-item Hamilton Depression Rating Scale (HDRS). sBDNF was assessed in 20 healthy controls to allow comparison with TRD patients. RESULTS: As expected, sBDNF was lower in TRD patients at baseline compared to healthy controls. Ketamine and ECT treatment were both associated with significant reductions in depressive symptoms. However, sBDNF was significantly elevated only at one week following the first ketamine infusion in those classified as responders one week later. sBDNF was not elevated following subsequent infusions. ECT reduced depressive symptoms, as expected, but was not associated with an enhancement in BDNF. LIMITATIONS: Patients continued with their psychotropic medications throughout this trial. CONCLUSIONS: SBDNF normalisation does not appear to be a prerequisite for symptomatic improvement in TRD following ketamine or ECT treatment.

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.

Use of codeine-containing medicines by Irish psychiatric inpatients before and after regulatory limitations on their supply.

BACKGROUND: In recent years, concerns have been highlighted in several jurisdictions, including Ireland, regarding abuse of over-the-counter codeine-containing medicines. On the 1st of August 2010, national regulatory guidelines aimed at limiting the supply of these medicines in Ireland came into force. Aims To study the effects of the new regulations on the use of non-prescribed codeine-containing medicines by psychiatric patients admitted to an Irish university teaching hospital before (n = 117) the regulations came into effect and 6 months afterwards (n = 126). METHODS: Participants completed a brief self-administered survey questionnaire about their use of over-the-counter codeine-containing medicines in the preceding 3 months. RESULTS: Compared with before the introduction of the new regulations, there was a large decline in the reported 'often' or 'regular' use of codeine-containing medicines in the 3 months before admission (33.3% v. 17.4%, χ 2 = 6.354, p = 0.01) and there was a reduction in the proportion of patients for whom others had expressed concerns about their frequency of use of such medications (15.5% v. 4.8%, χ 2 = 7.29, p = 0.03). There was also a decline in the proportion of patients who stated that they would use codeine-containing medicines for either a 'feel-good' effect or to curb cravings (15.9% v. 1.9%, p < 0.01, two-tailed Fisher's exact test). CONCLUSION: We conclude that tight regulations on the supply of non-prescription codeine-containing medicines have the potential to reduce the use and abuse of such medicines in patient populations availing of admission to psychiatry hospitals.

Reduced expression of glucocorticoid-inducible genes GILZ and SGK-1: high IL-6 levels are associated with reduced hippocampal volumes in major depressive disorder.

Neuroplasticity may have a core role in the pathophysiology of major depressive disorder (MDD), a concept supported by experimental studies that found that excessive cortisol secretion and/or excessive production of inflammatory cytokines impairs neuronal plasticity and neurogenesis in the hippocampus. The objective of this study was to examine how changes in the glucocorticoid and inflammatory systems may affect hippocampal volumes in MDD. A multimodal approach with structural neuroimaging of hippocampus and amygdala, measurement of peripheral inflammatory proteins interleukin (IL)-6 and C-reactive protein (CRP), glucocorticoid receptor (GR) mRNA expression, and expression of glucocorticoid-inducible genes (glucocorticoid-inducible genes Leucin Zipper (GILZ) and glucocorticoid-inducible kinase-1 (SGK-1)) was used in 40 patients with MDD and 43 healthy controls (HC). Patients with MDD showed smaller hippocampal volumes and increased inflammatory proteins IL-6 and CRP compared with HC. Childhood maltreatment was associated with increased CRP. Patients with MDD, who had less expression of the glucocorticoid-inducible genes GILZ or SGK-1 had smaller hippocampal volumes. Regression analysis showed a strong positive effect of GILZ and SGK-1 mRNA expression, and further inverse effects of IL-6 concentration, on hippocampal volumes. These findings suggest that childhood maltreatment, peripheral inflammatory and glucocorticoid markers and hippocampal volume are interrelated factors in the pathophysiology of MDD. Glucocorticoid-inducible genes GILZ and SGK-1 might be promising candidate markers for hippocampal volume changes relevant for diseases like MDD. Further studies need to explore the possible clinical usefulness of such a blood biomarker, for example, for diagnosis or prediction of therapy response.

Lemur tyrosine kinase-2 signalling regulates kinesin-1 light chain-2 phosphorylation and binding of Smad2 cargo.

A recent genome-wide association study identified the gene encoding lemur tyrosine kinase-2 (LMTK2) as a susceptibility gene for prostate cancer. The identified genetic alteration is within intron 9, but the mechanisms by which LMTK2 may impact upon prostate cancer are not clear because the functions of LMTK2 are poorly understood. Here, we show that LMTK2 regulates a known pathway that controls phosphorylation of kinesin-1 light chain-2 (KLC2) by glycogen synthase kinase-3ß (GSK3ß). KLC2 phosphorylation by GSK3ß induces the release of cargo from KLC2. LMTK2 signals via protein phosphatase-1C (PP1C) to increase inhibitory phosphorylation of GSK3ß on serine-9 that reduces KLC2 phosphorylation and promotes binding of the known KLC2 cargo Smad2. Smad2 signals to the nucleus in response to transforming growth factor-ß (TGFß) receptor stimulation and transport of Smad2 by kinesin-1 is required for this signalling. We show that small interfering RNA loss of LMTK2 not only reduces binding of Smad2 to KLC2, but also inhibits TGFß-induced Smad2 signalling. Thus, LMTK2 may regulate the activity of kinesin-1 motor function and Smad2 signalling.

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.

Amyotrophic lateral sclerosis mutant vesicle-associated membrane protein-associated protein-B transgenic mice develop TAR-DNA-binding protein-43 pathology.

Cytoplasmic ubiquitin-positive inclusions containing TAR-DNA-binding protein-43 (TDP-43) within motor neurons are the hallmark pathology of sporadic amyotrophic lateral sclerosis (ALS). TDP-43 is a nuclear protein and the mechanisms by which it becomes mislocalized and aggregated in ALS are not properly understood. A mutation in the vesicle-associated membrane protein-associated protein-B (VAPB) involving a proline to serine substitution at position 56 (VAPBP56S) is the cause of familial ALS type-8. To gain insight into the molecular mechanisms by which VAPBP56S induces disease, we created transgenic mice that express either wild-type VAPB (VAPBwt) or VAPBP56S in the nervous system. Analyses of both sets of mice revealed no overt motor phenotype nor alterations in survival. However, VAPBP56S but not VAPBwt transgenic mice develop cytoplasmic TDP-43 accumulations within spinal cord motor neurons that were first detected at 18 months of age. Our results suggest a link between abnormal VAPBP56S function and TDP-43 mislocalization.