Implementing a psychosocial intervention DIALOG+ for patients with psychotic disorders in low and middle income countries in South Eastern Europe: protocol for a hybrid effectiveness-implementation cluster randomized clinical trial (IMPULSE)

Psychotic disorders have large treatment gap in low- and middle-income countries (LMICs) in South-Eastern Europe, where up to 45% of affected people do not receive care for their condition. This study will assess the implementation of a generic psychosocial intervention called DIALOG+ in mental health care services and its effectiveness at improving patients’ clinical and social outcomes.This is a protocol for a multi-country, pragmatic, hybrid effectiveness–implementation, cluster-randomised, clinical trial. The trial aims to recruit 80 clinicians and 400 patients across 5 South-Eastern European LMICs: Bosnia and Herzegovina, Kosovo*, Montenegro, Republic of North Macedonia and Serbia. Clusters are clinicians working with patients with psychosis, and each clinician will deliver the intervention to five patients. After patient baseline assessments, clinicians will be randomly assigned to either the DIALOG+ intervention or treatment as usual, with an allocation ratio of 1:1. The intervention will be delivered six times over 12 months during routine clinical meetings. TThe primary outcome measure is the quality of life at 12 months [Manchester Short Assessment of Quality of Life (MANSA)]; the secondary outcomes include mental health symptoms [Brief Psychiatric Rating Scale (BPRS), Clinical Assessment Interview for Negative Symptoms (CAINS), Brief Symptom Inventory (BSI)], satisfaction with services [Client Satisfaction Questionnaire (CSQ-8)] and economic costs at 12 months [based on Client Service Receipt Inventory (CSRI), EQ-5D-5L and Recovering Quality of Life (ReQOL-10)]. The study will assess the intervention fidelity and the experience of clinicians and patients’ about implementing DIALOG+ in real-life mental health care settings. In the health economic assessment, the incremental cost-effectiveness ratio is calculated with effectiveness measured by quality-adjusted life year. Data will also be collected on sustainability and reach to inform guidelines for potentially scaling up and implementing the intervention widely. Conclusion: The study is expected to generate new scientific knowledge on the treatment of people with psychosis in health care systems with limited resources. The learning from LMICs could potentially help other countries to expand the access to care and alleviate the suffering of patients with psychosis and their families. Trial registration: ISRCTN 11913964This study has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779334

Electroconvulsive therapy practice in Serbia today

This is the first survey of the practice of electroconvulsive therapy (ECT) in the Republic of Serbia. A retrospective chart review was undertaken including all patients having received ECT in Serbia in 2012. Only one center in Serbia offered ECT in 2012 to a total of 54 patients (54% women). Thirty-six (36) patients received acute ECT treatment and eighteen (18) patients maintenance ECT, yielding a ECT utilization rate of 0.05/100.000 population. ECT was delivered with a modern square-wave (brief pulse) machine with EEG and ECG monitoring. In all cases the electrode placement was bifrontal and treatment modified (with anesthesia). The most frequent indication was recurrent depressive disorder (66.7%) for both acute and maintenance treatment. The limited availability of ECT in Serbia raises serious concerns. Provision of updated and effective treatment modalities for severe psychiatric disorders is crucial and the need for additional ECT services in Serbia is urgent

Terminating the replication helicase.

A feature of the cell cycle is that the events of one cycle must be reset before the next one begins. A study now shows that the replication machinery is removed from fully replicated DNA by a conserved ubiquitin- and CDC48 (also known as p97)-dependent pathway. This explains how eukaryotic chromosomes are returned to the unreplicated state

High-Pass Filtering of Input Signals by the Ih Current in a Non-Spiking Neuron, the Retinal Rod Bipolar Cell

Hyperpolarization–activated cyclic nucleotide–sensitive (HCN) channels mediate the If current in heart and Ih throughout the nervous system. In spiking neurons Ih participates primarily in different forms of rhythmic activity. Little is known, however, about its role in neurons operating with graded potentials as in the retina, where all four channel isoforms are expressed. Intriguing evidence for an involvement of Ih in early visual processing are the side effects reported, in dim light or darkness, by cardiac patients treated with HCN inhibitors. Moreover, electroretinographic recordings indicate that these drugs affect temporal processing in the outer retina. Here we analyzed the functional role of HCN channels in rod bipolar cells (RBCs) of the mouse. Perforated–patch recordings in the dark–adapted slice found that RBCs exhibit Ih, and that this is sensitive to the specific blocker ZD7288. RBC input impedance, explored by sinusoidal frequency–modulated current stimuli (0.1–30 Hz), displays band–pass behavior in the range of Ih activation. Theoretical modeling and pharmacological blockade demonstrate that high–pass filtering of input signals by Ih, in combination with low–pass filtering by passive properties, fully accounts for this frequency–tuning. Correcting for the depolarization introduced by shunting through the pipette–membrane seal, leads to predict that in darkness Ih is tonically active in RBCs and quickens their responses to dim light stimuli. Immunohistochemistry targeting candidate subunit isoforms HCN1–2, in combination with markers of RBCs (PKC) and rod–RBC synaptic contacts (bassoon, mGluR6, Kv1.3), suggests that RBCs express HCN2 on the tip of their dendrites. The functional properties conferred by Ih onto RBCs may contribute to shape the retina's light response and explain the visual side effects of HCN inhibitors

Cognitive functioning throughout adulthood and illness stages in individuals with psychotic disorders and their unaffected siblings

Important questions remain about the profile of cognitive impairment in psychotic disorders across adulthood and illness stages. The age-associated profile of familial impairments also remains unclear, as well as the effect of factors, such as symptoms, functioning, and medication. Using cross-sectional data from the EU-GEI and GROUP studies, comprising 8455 participants aged 18 to 65, we examined cognitive functioning across adulthood in patients with psychotic disorders (n = 2883), and their unaffected siblings (n = 2271), compared to controls (n = 3301). An abbreviated WAIS-III measured verbal knowledge, working memory, visuospatial processing, processing speed, and IQ. Patients showed medium to large deficits across all functions (ES range = –0.45 to –0.73, p < 0.001), while siblings showed small deficits on IQ, verbal knowledge, and working memory (ES = –0.14 to –0.33, p < 0.001). Magnitude of impairment was not associated with participant age, such that the size of impairment in older and younger patients did not significantly differ. However, first-episode patients performed worse than prodromal patients (ES range = –0.88 to –0.60, p < 0.001). Adjusting for cannabis use, symptom severity, and global functioning attenuated impairments in siblings, while deficits in patients remained statistically significant, albeit reduced by half (ES range = –0.13 to –0.38, p < 0.01). Antipsychotic medication also accounted for around half of the impairment in patients (ES range = –0.21 to –0.43, p < 0.01). Deficits in verbal knowledge, and working memory may specifically index familial, i.e., shared genetic and/or shared environmental, liability for psychotic disorders. Nevertheless, potentially modifiable illness-related factors account for a significant portion of the cognitive impairment in psychotic disorders