Comparative efficacy, cognitive effects and acceptability of electroconvulsive therapies for the treatment of depression: Protocol for a systematic review and network meta-analysis

Introduction There have been important advances in the use of electroconvulsive therapy (ECT) to treat major depressive episodes. These include variations to the type of stimulus the brain regions stimulated, and the stimulus parameters (eg, stimulus duration/pulse width). Our aim is to investigate ECT types using a network meta-analysis (NMA) approach and report on comparative treatment efficacy, cognitive side effects and acceptability. Method We will conduct a systematic review to identify randomised controlled trials that compared two or more ECT protocols to treat depression. This will be done using the following databases: Embase, MEDLINE PubMed, Web of Science, Scopus, PsycINFO, Cochrane CENTRAL and will be supplemented by personal contacts with researchers in the field. All authors will be contacted to provide missing information. Primary outcomes will be symptom severity on a validated continuous clinician-rated scale of depression, cognitive functioning measured using anterograde verbal recall, and acceptability calculated using all-cause drop-outs. Secondary outcomes will include response and remission rates, autobiographical memory following a course of ECT, and anterograde visuospatial recall. Bayesian random effects hierarchical models will compare ECT types. Additional meta-regressions may be conducted to determine the impact of effect modifiers and patient-specific prognostic factors if sufficient data are available. Discussion This NMA will facilitate clinician decision making and allow more sophisticated selection of ECT type according to the balance of efficacy, cognitive side effects and acceptability. Ethics This systematic review and NMA does not require research ethics approval as it will use published aggregate data and will not collect nor disclose individually identifiable participant data. PROSPERO registration number CRD42022357098

Transient Cognitive Impairment and White Matter Hyperintensities in Severely Depressed Older Patients Treated With Electroconvulsive Therapy

BACKGROUND: Although electroconvulsive therapy (ECT) is a safe and effective treatment for patients with severe late life depression (LLD), transient cognitive impairment can be a reason to discontinue the treatment. The aim of the current study was to evaluate the association between structural brain characteristics and general cognitive function during and after ECT. METHODS: A total of 80 patients with LLD from the prospective naturalistic follow-up Mood Disorders in Elderly treated with Electroconvulsive Therapy study were examined. Magnetic resonance imaging scans were acquired before ECT. Overall brain morphology (white and grey matter) was evaluated using visual rating scales. Cognitive functioning before, during, and after ECT was measured using the Mini Mental State Examination (MMSE). A linear mixed-model analysis was performed to analyze the association between structural brain alterations and cognitive functioning over time. RESULTS: Patients with moderate to severe white matter hyperintensities (WMH) showed significantly lower MMSE scores than patients without severe WMH (F(1,75.54) = 5.42, p = 0.02) before, during, and post-ECT, however their trajectory of cognitive functioning was similar as no time × WMH interaction effect was observed (F(4,65.85) = 1.9, p = 0.25). Transient cognitive impairment was not associated with medial temporal or global cortical atrophy (MTA, GCA). CONCLUSION: All patients showed a significant drop in cognitive functioning during ECT, which however recovered above baseline levels post-ECT and remained stable until at least 6 months post-ECT, independently of severity of WMH, GCA, or MTA. Therefore, clinicians should not be reluctant to start or continue ECT in patients with severe structural brain alterations

Physical play - How do we inspire and motivate young children to be physically active through play? An international analysis of twelve countries’ national early years curriculum policies and practices for physical activity and physical play

Lifelong movement and physical activity (PA) patterns develop during early childhood. Therefore, educators (teachers and practitioners) in early childhood education and care (ECEC) should provide opportunities to support children’s play, PA, and movement development. The World Health Organization (2019) offers new recommendations for PA, for children under five years. The guidelines do not specify the ways ECEC staff can support PA through play. Therefore, this paper investigates, how physical play (PP) is enacted globally. An international policy and practice analysis of twelve countries, (Australia [Victoria], Belgium [Flanders], Canada [Alberta], China, Finland, Ireland, Italy, Portugal, Spain, Sweden, UK [England] and USA) was completed by analyzing the ECEC curricula and their implementation in different cultural contexts. A content analysis was undertaken by AIESEP Early Years SIG experts revealing that PP was not clearly defined. When defined, it was described as PA, and important for children’s holistic development. The majority of curricula did not state the length/time for PP. Three main strategies for implementing PP were found: a) pedagogical framework; b) active learning methods; and c) motor development. This international analysis highlights the global need for better ECEC staff support in acknowledging and implementing PP to aid children’s overall development, PA and wellbeing

Are Apathy and Depressive Symptoms Related to Vascular White Matter Hyperintensities in Severe Late Life Depression?

OBJECTIVE: Apathy symptoms are defined as a lack of interest and motivation. Patients with late-life depression (LLD) also suffer from lack of interest and motivation and previous studies have linked apathy to vascular white matter hyperintensities (WMH) of the brain in depressed and nondepressed patients. The aim of this study was to investigate the relationship between apathy symptoms, depressive symptoms, and WMH in LLD. We hypothesize that late-onset depression (LOD; first episode of depression after 55 years of age) is associated with WMH and apathy symptoms. METHODS: Apathy scores were collected for 87 inpatients diagnosed with LLD. Eighty patients underwent brain magnetic resonance imaging. Associations between depressive and apathy symptoms and WMH were analyzed using linear regression. RESULTS: All 3 subdomains of the 10-item Montgomery–Åsberg Depression Rating Scale correlated significantly with the apathy scale score (all P < .05). In the total sample, apathy nor depressive symptoms were related to specific WMH. In LOD only, periventricular WMH were associated with depression severity (β = 5.21, P = .04), while WMH in the left infratentorial region were associated with apathy symptoms (β coefficient = 5.89, P = .03). CONCLUSION: Apathy and depressive symptoms are highly overlapping in the current cohort of older patients with severe LLD, leading to the hypothesis that apathy symptoms are part of depressive symptoms in the symptom profile of older patients with severe LLD. Neither apathy nor depressive symptoms were related to WMH, suggesting that radiological markers of cerebrovascular disease, such as WMH, may not be useful in predicting these symptoms in severe LLD

The Global ECT-MRI Research Collaboration (GEMRIC): Establishing a multi-site investigation of the neural mechanisms underlying response to electroconvulsive therapy.

Major depression, currently the world's primary cause of disability, leads to profound personal suffering and increased risk of suicide. Unfortunately, the success of antidepressant treatment varies amongst individuals and can take weeks to months in those who respond. Electroconvulsive therapy (ECT), generally prescribed for the most severely depressed and when standard treatments fail, produces a more rapid response and remains the most effective intervention for severe depression. Exploring the neurobiological effects of ECT is thus an ideal approach to better understand the mechanisms of successful therapeutic response. Though several recent neuroimaging studies show structural and functional changes associated with ECT, not all brain changes associate with clinical outcome. Larger studies that can address individual differences in clinical and treatment parameters may better target biological factors relating to or predictive of ECT-related therapeutic response. We have thus formed the Global ECT-MRI Research Collaboration (GEMRIC) that aims to combine longitudinal neuroimaging as well as clinical, behavioral and other physiological data across multiple independent sites. Here, we summarize the ECT sample characteristics from currently participating sites, and the common data-repository and standardized image analysis pipeline developed for this initiative. This includes data harmonization across sites and MRI platforms, and a method for obtaining unbiased estimates of structural change based on longitudinal measurements with serial MRI scans. The optimized analysis pipeline, together with the large and heterogeneous combined GEMRIC dataset, will provide new opportunities to elucidate the mechanisms of ECT response and the factors mediating and predictive of clinical outcomes, which may ultimately lead to more effective personalized treatment approaches

Effective resting-state connectivity in severe unipolar depression before and after electroconvulsive therapy

Background Electroconvulsive therapy (ECT) is one of the most effective treatments for severe depressive disorders. A recent multi-center study found no consistent changes in correlation-based (undirected) resting-state connectivity after ECT. Effective (directed) connectivity may provide more insight into the working mechanism of ECT. Objective We investigated whether there are consistent changes in effective resting-state connectivity. Methods This multi-center study included data from 189 patients suffering from severe unipolar depression and 59 healthy control participants. Longitudinal data were available for 81 patients and 24 healthy controls. We used dynamic causal modeling for resting-state functional magnetic resonance imaging to determine effective connectivity in the default mode, salience and central executive networks before and after a course of ECT. Bayesian general linear models were used to examine differences in baseline and longitudinal effective connectivity effects associated with ECT and its effectiveness. Results Compared to controls, depressed patients showed many differences in effective connectivity at baseline, which varied according to the presence of psychotic features and later treatment outcome. Additionally, effective connectivity changed after ECT, which was related to ECT effectiveness. Notably, treatment effectiveness was associated with decreasing and increasing effective connectivity from the posterior default mode network to the left and right insula, respectively. No effects were found using correlation-based (undirected) connectivity. Conclusions A beneficial response to ECT may depend on how brain regions influence each other in networks important for emotion and cognition. These findings further elucidate the working mechanisms of ECT and may provide directions for future non-invasive brain stimulation research.publishedVersio

Effective resting-state connectivity in severe unipolar depression before and after electroconvulsive therapy

BACKGROUND: Electroconvulsive therapy (ECT) is one of the most effective treatments for severe depressive disorders. A recent multi-center study found no consistent changes in correlation-based (undirected) resting-state connectivity after ECT. Effective (directed) connectivity may provide more insight into the working mechanism of ECT. OBJECTIVE: We investigated whether there are consistent changes in effective resting-state connectivity. METHODS: This multi-center study included data from 189 patients suffering from severe unipolar depression and 59 healthy control participants. Longitudinal data were available for 81 patients and 24 healthy controls. We used dynamic causal modeling for resting-state functional magnetic resonance imaging to determine effective connectivity in the default mode, salience and central executive networks before and after a course of ECT. Bayesian general linear models were used to examine differences in baseline and longitudinal effective connectivity effects associated with ECT and its effectiveness. RESULTS: Compared to controls, depressed patients showed many differences in effective connectivity at baseline, which varied according to the presence of psychotic features and later treatment outcome. Additionally, effective connectivity changed after ECT, which was related to ECT effectiveness. Notably, treatment effectiveness was associated with decreasing and increasing effective connectivity from the posterior default mode network to the left and right insula, respectively. No effects were found using correlation-based (undirected) connectivity. CONCLUSIONS: A beneficial response to ECT may depend on how brain regions influence each other in networks important for emotion and cognition. These findings further elucidate the working mechanisms of ECT and may provide directions for future non-invasive brain stimulation research

The thymidine phosphorylase inhibitor 5′-O-tritylinosine (KIN59) is an antiangiogenic multitarget fibroblast growth factor-2 antagonist

5′-O-Tritylinosine (KIN59) is an allosteric inhibitor of the angiogenic enzyme thymidine phosphorylase. Previous observations showed the capacity of KIN59 to abrogate thymidine phosphorylase-induced as well as developmental angiogenesis in the chicken chorioallantoic membrane (CAM) assay. Here, we show that KIN59 also inhibits the angiogenic response triggered by fibroblast growth factor-2 (FGF2) but not by VEGF in the CAM assay. Immunohistochemical and reverse transcriptase PCR analyses revealed that the expression of laminin, the major proteoglycan of the basement membrane of blood vessels, is downregulated by KIN59 administration in control as well as in thymidine phosphorylase- or FGF2-treated CAMs, but not in CAMs treated with VEGF. Also, KIN59 abrogated FGF2-induced endothelial cell proliferation, FGF receptor activation, and Akt signaling in vitro with no effect on VEGF-stimulated biologic responses. Accordingly, KIN59 inhibited the binding of FGF2 to FGF receptor-1 (FGFR1), thus preventing the formation of productive heparan sulphate proteoglycan/FGF2/FGFR1 ternary complexes, without affecting heparin interaction. In keeping with these observations, systemic administration of KIN59 inhibited the growth and neovascularization of subcutaneous tumors induced by FGF2-transformed endothelial cells injected in immunodeficient nude mice. Taken together, the data indicate that the thymidine phosphorylase inhibitor KIN59 is endowed with a significant FGF2 antagonist activity, thus representing a promising lead compound for the design of multi-targeted antiangiogenic cancer drugs. ©2012 AACR.Peer Reviewe

Exploring resting state connectivity in patients with psychotic depression

BACKGROUND: Severe depression is associated with high morbidity and mortality. Neural network dysfunction may contribute to disease mechanisms underlying different clinical subtypes. Here, we apply resting-state functional magnetic resonance imaging based measures of brain connectivity to investigate network dysfunction in severely depressed in-patients with and without psychotic symptoms. METHODS: A cohort study was performed at two sites. Older patients with major depressive disorder with or without psychotic symptoms were included (n = 23 at site one, n = 26 at site two). Resting state 3-Tesla functional MRI scans, with eyes closed, were obtained and Montgomery-Åsberg Depression Rating Scales were completed. We denoised data and calculated resting state networks in the two groups separately. We selected five networks of interest (1. bilateral frontoparietal, 2.left lateralized frontoparietal, 3.right lateralized frontoparietal, 4.default mode network (DMN) and 5.bilateral basal ganglia and insula network) and performed regression analyses with severity of depression, as well as presence or absence of psychotic symptoms. RESULTS: The functional connectivity (FC) patterns did not correlate with severity of depression. Depressed patients with psychotic symptoms (n = 14, 61%) compared with patients without psychotic symptoms (n = 9, 39%) from site one showed significantly decreased FC in the right part of the bilateral frontoparietal network (p = 0.002). This result was not replicated when comparing patients with (n = 9, 35%) and without (n = 17, 65%) psychotic symptoms from site two. CONCLUSION: Psychotic depression may be associated with decreased FC of the frontoparietal network, which is involved in cognitive control processes, such as attention and emotion regulation. These findings suggest that FC in the frontoparietal network may be related to the subtype of depression, i.e. presence of psychotic symptoms, rather than severity of depression. Since the findings could not be replicated in the 2nd sample, replication is needed before drawing definite conclusions