An online evidence-based dictionary of common adverse events of antidepressants: a new tool to empower patients and clinicians in their shared decision-making process.

BACKGROUND: Adverse events (AEs) are commonly reported in clinical studies using the Medical Dictionary for Regulatory Activities (MedDRA), an international standard for drug safety monitoring. However, the technical language of MedDRA makes it challenging for patients and clinicians to share understanding and therefore to make shared decisions about medical interventions. In this project, people with lived experience of depression and antidepressant treatment worked with clinicians and researchers to co-design an online dictionary of AEs associated with antidepressants, taking into account its ease of use and applicability to real-world settings. METHODS: Through a pre-defined literature search, we identified MedDRA-coded AEs from randomised controlled trials of antidepressants used in the treatment of depression. In collaboration with the McPin Foundation, four co-design workshops with a lived experience advisory panel (LEAP) and one independent focus group (FG) were conducted to produce user-friendly translations of AE terms. Guiding principles for translation were co-designed with McPin/LEAP members and defined before the finalisation of Clinical Codes (CCs, or non-technical terms to represent specific AE concepts). FG results were thematically analysed using the Framework Method. RESULTS: Starting from 522 trials identified by the search, 736 MedDRA-coded AE terms were translated into 187 CCs, which balanced key factors identified as important to the LEAP and FG (namely, breadth, specificity, generalisability, patient-understandability and acceptability). Work with the LEAP showed that a user-friendly language of AEs should aim to mitigate stigma, acknowledge the multiple levels of comprehension in 'lay' language and balance the need for semantic accuracy with user-friendliness. Guided by these principles, an online dictionary of AEs was co-designed and made freely available ( https://thesymptomglossary.com ). The digital tool was perceived by the LEAP and FG as a resource which could feasibly improve antidepressant treatment by facilitating the accurate, meaningful expression of preferences about potential harms through a shared decision-making process. CONCLUSIONS: This dictionary was developed in English around AEs from antidepressants in depression but it can be adapted to different languages and cultural contexts, and can also become a model for other interventions and disorders (i.e., antipsychotics in schizophrenia). Co-designed digital resources may improve the patient experience by helping to deliver personalised information on potential benefits and harms in an evidence-based, preference-sensitive way.

Digital Mental Health for Schizophrenia and Other Severe Mental Illnesses: An International Consensus on Current Challenges and Potential Solutions.

BACKGROUND: Digital approaches may be helpful in augmenting care to address unmet mental health needs, particularly for schizophrenia and severe mental illness (SMI). OBJECTIVE: An international multidisciplinary group was convened to reach a consensus on the challenges and potential solutions regarding collecting data, delivering treatment, and the ethical challenges in digital mental health approaches for schizophrenia and SMI. METHODS: The consensus development panel method was used, with an in-person meeting of 2 groups: the expert group and the panel. Membership was multidisciplinary including those with lived experience, with equal participation at all stages and coproduction of the consensus outputs and summary. Relevant literature was shared in advance of the meeting, and a systematic search of the recent literature on digital mental health interventions for schizophrenia and psychosis was completed to ensure that the panel was informed before the meeting with the expert group. RESULTS: Four broad areas of challenge and proposed solutions were identified: (1) user involvement for real coproduction; (2) new approaches to methodology in digital mental health, including agreed standards, data sharing, measuring harms, prevention strategies, and mechanistic research; (3) regulation and funding issues; and (4) implementation in real-world settings (including multidisciplinary collaboration, training, augmenting existing service provision, and social and population-focused approaches). Examples are provided with more detail on human-centered research design, lived experience perspectives, and biomedical ethics in digital mental health approaches for SMI. CONCLUSIONS: The group agreed by consensus on a number of recommendations: (1) a new and improved approach to digital mental health research (with agreed reporting standards, data sharing, and shared protocols), (2) equal emphasis on social and population research as well as biological and psychological approaches, (3) meaningful collaborations across varied disciplines that have previously not worked closely together, (4) increased focus on the business model and product with planning and new funding structures across the whole development pathway, (5) increased focus and reporting on ethical issues and potential harms, and (6) organizational changes to allow for true communication and coproduction with those with lived experience of SMI. This study approach, combining an international expert meeting with patient and public involvement and engagement throughout the process, consensus methodology, discussion, and publication, is a helpful way to identify directions for future research and clinical implementation in rapidly evolving areas and can be combined with measurements of real-world clinical impact over time. Similar initiatives will be helpful in other areas of digital mental health and similarly fast-evolving fields to focus research and organizational change and effect improved real-world clinical implementation.

TRPM2 and CaMKII Signaling Drives Excessive GABAergic Synaptic Inhibition Following Ischemia.

Excitotoxicity and the concurrent loss of inhibition are well-defined mechanisms driving acute elevation in excitatory/inhibitory (E/I) balance and neuronal cell death following an ischemic insult to the brain. Despite the high prevalence of long-term disability in survivors of global cerebral ischemia (GCI) as a consequence of cardiac arrest, it remains unclear whether E/I imbalance persists beyond the acute phase and negatively affects functional recovery. We previously demonstrated sustained impairment of long-term potentiation (LTP) in hippocampal CA1 neurons correlating with deficits in learning and memory tasks in a murine model of cardiac arrest/cardiopulmonary resuscitation (CA/CPR). Here, we use CA/CPR and an in vitro ischemia model to elucidate mechanisms by which E/I imbalance contributes to ongoing hippocampal dysfunction in male mice. We reveal increased postsynaptic GABAA receptor (GABAAR) clustering and function in the CA1 region of the hippocampus that reduces the E/I ratio. Importantly, reduced GABAAR clustering observed in the first 24 h rebounds to an elevation of GABAergic clustering by 3 d postischemia. This increase in GABAergic inhibition required activation of the Ca2+-permeable ion channel transient receptor potential melastatin-2 (TRPM2), previously implicated in persistent LTP and memory deficits following CA/CPR. Furthermore, we find Ca2+-signaling, likely downstream of TRPM2 activation, upregulates Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity, thereby driving the elevation of postsynaptic inhibitory function. Thus, we propose a novel mechanism by which inhibitory synaptic strength is upregulated in the context of ischemia and identify TRPM2 and CaMKII as potential pharmacological targets to restore perturbed synaptic plasticity and ameliorate cognitive function.

Assessing the Impact of Evidence-Based Mental Health Guidance During the COVID-19 Pandemic: Systematic Review and Qualitative Evaluation.

BACKGROUND: During the COVID-19 pandemic, the Oxford Precision Psychiatry Lab (OxPPL) developed open-access web-based summaries of mental health care guidelines (OxPPL guidance) in key areas such as digital approaches and telepsychiatry, suicide and self-harm, domestic violence and abuse, perinatal care, and vaccine hesitancy and prioritization in the context of mental illness, to inform timely clinical decision-making. OBJECTIVE: This study aimed to evaluate the practice of creating evidence-based health guidelines during health emergencies using the OxPPL guidance as an example. An international network of clinical sites and colleagues (in Australia, New Zealand, and the United Kingdom) including clinicians, researchers, and experts by experience aimed to (1) evaluate the clinical impact of the OxPPL guidance, as an example of an evidence-based summary of guidelines; (2) review the literature for other evidence-based summaries of COVID-19 guidelines regarding mental health care; and (3) produce a framework for response to future global health emergencies. METHODS: The impact and clinical utility of the OxPPL guidance were assessed using clinicians' feedback via an international survey and focus groups. A systematic review (protocol registered on Open Science Framework) identified summaries or syntheses of guidelines for mental health care during and after the COVID-19 pandemic and assessed the accuracy of the methods used in the OxPPL guidance by identifying any resources that the guidance had not included. RESULTS: Overall, 80.2% (146/182) of the clinicians agreed or strongly agreed that the OxPPL guidance answered important clinical questions, 73.1% (133/182) stated that the guidance was relevant to their service, 59.3% (108/182) said that the guidelines had or would have a positive impact on their clinical practice, 42.9% (78/182) that they had shared or would share the guidance, and 80.2% (146/182) stated that the methodology could be used during future health crises. The focus groups found that the combination of evidence-based knowledge, clinical viewpoint, and visibility was crucial for clinical implementation. The systematic review identified 2543 records, of which 2 syntheses of guidelines met all the inclusion criteria, but only 1 (the OxPPL guidance) used evidence-based methodology. The review showed that the OxPPL guidance had included the majority of eligible guidelines, but 6 were identified that had not been included. CONCLUSIONS: The study identified an unmet need for web-based, evidence-based mental health care guidance during the COVID-19 pandemic. The OxPPL guidance was evaluated by clinicians as having a real-world clinical impact. Robust evidence-based methodology and expertise in mental health are necessary, but easy accessibility is also needed, and digital technology can materially help. Further health emergencies are inevitable and now is the ideal time to prepare, including addressing the training needs of clinicians, patients, and carers, especially in areas such as telepsychiatry and digital mental health. For future planning, guidance should be widely disseminated on an international platform, with allocated resources to support adaptive updates.

Acute reorganization of postsynaptic GABAA receptors reveals the functional impact of molecular nanoarchitecture at inhibitory synapses.

Neurotransmitter receptors partition into nanometer-scale subdomains within the postsynaptic membrane that are precisely aligned with presynaptic neurotransmitter release sites. While spatial coordination between pre- and postsynaptic elements is observed at both excitatory and inhibitory synapses, the functional significance of this molecular architecture has been challenging to evaluate experimentally. Here we utilized an optogenetic clustering approach to acutely alter the nanoscale organization of the postsynaptic inhibitory scaffold gephyrin while monitoring synaptic function. Gephyrin clustering rapidly enlarged postsynaptic area, laterally displacing GABAA receptors from their normally precise apposition with presynaptic active zones. Receptor displacement was accompanied by decreased synaptic GABAA receptor currents even though presynaptic release probability and the overall abundance and function of synaptic GABAA receptors remained unperturbed. Thus, acutely repositioning neurotransmitter receptors within the postsynaptic membrane profoundly influences synaptic efficacy, establishing the functional importance of precision pre-/postsynaptic molecular coordination at inhibitory synapses.

Distinct mechanisms drive sequential internalization and degradation of GABAARs during global ischemia and reperfusion injury.

Synaptic inhibition is critical for controlling neuronal excitability and function. During global cerebral ischemia (GCI), inhibitory synapses are rapidly eliminated, causing hyper-excitability which contributes to cell-death and the pathophysiology of disease. Sequential disassembly of inhibitory synapses begins within minutes of ischemia onset: GABAARs are rapidly trafficked away from the synapse, the gephyrin scaffold is removed, followed by loss of the presynaptic terminal. GABAARs are endocytosed during GCI, but how this process accompanies synapse disassembly remains unclear. Here, we define the precise trafficking itinerary of GABAARs during the initial stages of GCI, placing them in the context of rapid synapse elimination. Ischemia-induced GABAAR internalization quickly follows their initial dispersal from the synapse, and is controlled by PP1α signaling. During reperfusion injury, GABAARs are then trafficked to lysosomes for degradation, leading to permanent removal of synaptic GABAARs and contributing to the profound reduction in synaptic inhibition observed hours following ischemia onset.

AMPA and GABAA receptor nanodomains assemble in the absence of synaptic neurotransmitter release.

Postsynaptic neurotransmitter receptors and their associated scaffolding proteins assemble into discrete, nanometer-scale subsynaptic domains (SSDs) within the postsynaptic membrane at both excitatory and inhibitory synapses. Intriguingly, postsynaptic receptor SSDs are mirrored by closely apposed presynaptic active zones. These trans-synaptic molecular assemblies are thought to be important for efficient neurotransmission because they concentrate postsynaptic receptors near sites of presynaptic neurotransmitter release. While previous studies have characterized the role of synaptic activity in sculpting the number, size, and distribution of postsynaptic SSDs at established synapses, it remains unknown whether neurotransmitter signaling is required for their initial assembly during synapse development. Here, we evaluated synaptic nano-architecture under conditions where presynaptic neurotransmitter release was blocked prior to, and throughout synaptogenesis with tetanus neurotoxin (TeNT). In agreement with previous work, neurotransmitter release was not required for the formation of excitatory or inhibitory synapses. The overall size of the postsynaptic specialization at both excitatory and inhibitory synapses was reduced at chronically silenced synapses. However, both AMPARs and GABAARs still coalesced into SSDs, along with their respective scaffold proteins. Presynaptic active zone assemblies, defined by RIM1, were smaller and more numerous at silenced synapses, but maintained alignment with postsynaptic AMPAR SSDs. Thus, basic features of synaptic nano-architecture, including assembly of receptors and scaffolds into trans-synaptically aligned structures, are intrinsic properties that can be further regulated by subsequent activity-dependent mechanisms.

Evaluation of telepsychiatry during the COVID-19 pandemic across service users, carers and clinicians: an international mixed-methods study.

BACKGROUND: Worldwide uptake of telepsychiatry accelerated during the COVID-19 pandemic. OBJECTIVE: To conduct an evaluation of the opinions, preferences and attitudes to telepsychiatry from service users, carers and clinicians in order to understand how telepsychiatry can be best used in the peri/post-COVID-19 era. METHODS: This mixed-methods, multicentre, international study of telepsychiatry was set in two sites in England and two in Italy. Survey questionnaires and focus group topic guides were co-produced for each participant group (service users, carers and clinicians). FINDINGS: In the UK, 906 service users, 117 carers and 483 clinicians, and in Italy, 164 service users, 56 carers and 72 clinicians completed the surveys. In all, 17 service users/carers and 14 clinicians participated in focus groups. Overall, telepsychiatry was seen as convenient in follow-ups with a specific purpose such as medication reviews; however, it was perceived as less effective for establishing a therapeutic relationship or for assessing acutely disturbed mental states. In contrast to clinicians, most service users and carers indicated that telepsychiatry had not improved during the COVID-19 pandemic. Most service users and carers reported that the choice of appointment modality was most often determined by the service or clinician. CONCLUSION AND RELEVANCE: There were circumstances in which telepsychiatry was seen as more suitable than others and clear differences in clinician, carer and service user perspectives on telepsychiatry. CLINICAL IMPLICATIONS: All stakeholders should be actively engaged in determining a hybrid model of care according to clinical features and service user and carer preferences. Clinicians should be engaged in training programmes on telepsychiatry.

Digital mental health: challenges and next steps.

Digital innovations in mental health offer great potential, but present unique challenges. Using a consensus development panel approach, an expert, international, cross-disciplinary panel met to provide a framework to conceptualise digital mental health innovations, research into mechanisms and effectiveness and approaches for clinical implementation. Key questions and outputs from the group were agreed by consensus, and are presented and discussed in the text and supported by case examples in an accompanying appendix. A number of key themes emerged. (1) Digital approaches may work best across traditional diagnostic systems: we do not have effective ontologies of mental illness and transdiagnostic/symptom-based approaches may be more fruitful. (2) Approaches in clinical implementation of digital tools/interventions need to be creative and require organisational change: not only do clinicians and patients need training and education to be more confident and skilled in using digital technologies to support shared care decision-making, but traditional roles need to be extended, with clinicians working alongside digital navigators and non-clinicians who are delivering protocolised treatments. (3) Designing appropriate studies to measure the effectiveness of implementation is also key: including digital data raises unique ethical issues, and measurement of potential harms is only just beginning. (4) Accessibility and codesign are needed to ensure innovations are long lasting. (5) Standardised guidelines for reporting would ensure effective synthesis of the evidence to inform clinical implementation. COVID-19 and the transition to virtual consultations have shown us the potential for digital innovations to improve access and quality of care in mental health: now is the ideal time to act.

Palmitoylation controls the stability of 190 kDa ankyrin-G in dendritic spines and is regulated by ZDHHC8 and lithium.

Introduction: AnkG, encoded by the ANK3 gene, is a multifunctional scaffold protein with complex isoform expression: the 480 and 270 kDa isoforms have roles at the axon initial segment and node of Ranvier, whereas the 190 kDa isoform (AnkG-190) has an emerging role in the dendritic shaft and spine heads. All isoforms of AnkG undergo palmitoylation, a post-translational modification regulating protein attachment to lipid membranes. However, palmitoylation of AnkG-190 has not been investigated in dendritic spines. The ANK3 gene and altered expression of AnkG proteins are associated with a variety of neuropsychiatric and neurodevelopmental disorders including bipolar disorder and are implicated in the lithium response, a commonly used mood stabilizer for bipolar disorder patients, although the precise mechanisms involved are unknown. Result: Here, we showed that Cys70 palmitoylation stabilizes the localization of AnkG-190 in spine heads and at dendritic plasma membrane nanodomains. Mutation of Cys70 impairs AnkG-190 function in dendritic spines and alters PSD-95 scaffolding. Interestingly, we find that lithium reduces AnkG-190 palmitoylation thereby increasing its mobility in dendritic spines. Finally, we demonstrate that the palmitoyl acyl transferase ZDHHC8, but not ZDHHC5, increases AnkG-190 stability in spine heads and is inhibited by lithium. Discussion: Together, our data reveal that palmitoylation is critical for AnkG-190 localization and function and a potential ZDHHC8/AnkG-190 mechanism linking AnkG-190 mobility to the neuronal effects of lithium.

Explainable artificial intelligence for mental health through transparency and interpretability for understandability.

The literature on artificial intelligence (AI) or machine learning (ML) in mental health and psychiatry lacks consensus on what "explainability" means. In the more general XAI (eXplainable AI) literature, there has been some convergence on explainability meaning model-agnostic techniques that augment a complex model (with internal mechanics intractable for human understanding) with a simpler model argued to deliver results that humans can comprehend. Given the differing usage and intended meaning of the term "explainability" in AI and ML, we propose instead to approximate model/algorithm explainability by understandability defined as a function of transparency and interpretability. These concepts are easier to articulate, to "ground" in our understanding of how algorithms and models operate and are used more consistently in the literature. We describe the TIFU (Transparency and Interpretability For Understandability) framework and examine how this applies to the landscape of AI/ML in mental health research. We argue that the need for understandablity is heightened in psychiatry because data describing the syndromes, outcomes, disorders and signs/symptoms possess probabilistic relationships to each other-as do the tentative aetiologies and multifactorial social- and psychological-determinants of disorders. If we develop and deploy AI/ML models, ensuring human understandability of the inputs, processes and outputs of these models is essential to develop trustworthy systems fit for deployment.

Perinatal mental health and COVID-19: Navigating a way forward.

The COVID-19 pandemic and its aftermath have increased pre-existing inequalities and risk factors for mental disorders in general, but perinatal mental disorders are of particular concern. They are already underdiagnosed and undertreated, and this has been magnified by the pandemic. Access to services (both psychiatric and obstetric) has been reduced, and in-person contact has been restricted because of the increased risks. Rates of perinatal anxiety and depressive symptoms have increased. In the face of these challenges, clear guidance in perinatal mental health is needed for patients and clinicians. However, a systematic search of the available resources showed only a small amount of guidance from a few countries, with a focus on the acute phase of the pandemic rather than the challenges of new variants and variable rates of infection. Telepsychiatry offers advantages during times of restricted social contact and also as an additional route for accessing a wide range of digital technologies. While there is a strong evidence base for general telepsychiatry, the particular issues in perinatal mental health need further examination. Clinicians will need expertise and training to navigate a hybrid model, flexibly combining in person and remote assessments according to risk, clinical need and individual patient preferences. There are also wider issues of care planning in the context of varying infection rates, restrictions and vaccination access in different countries. Clinicians will need to focus on prevention, treatment, risk assessment and symptom monitoring, but there will also need to be an urgent and coordinated focus on guidance and planning across all organisations involved in perinatal mental health care.

Lithium rescues dendritic abnormalities in Ank3 deficiency models through the synergic effects of GSK3ß and cyclic AMP signaling pathways.

Bipolar disorder (BD) is a highly heritable mood disorder with intermittent episodes of mania and depression. Lithium is the first-in-line medication to treat BD, but it is only effective in a subset of individuals. Large-scale human genomic studies have repeatedly linked the ANK3 gene (encoding ankyrin-G, AnkG) to BD. Ank3 knockout mouse models mimic BD behavioral features and respond positively to lithium treatment. We investigated cellular phenotypes associated with BD, including dendritic arborization of pyramidal neurons and spine morphology in two models: (1) a conditional knockout mouse model which disrupts Ank3 expression in adult forebrain pyramidal neurons, and (2) an AnkG knockdown model in cortical neuron cultures. We observed a decrease in dendrite complexity and a reduction of dendritic spine number in both models, reminiscent of reports in BD. We showed that lithium treatment corrected dendrite and spine deficits in vitro and in vivo. We targeted two signaling pathways known to be affected by lithium using a highly selective GSK3ß inhibitor (CHIR99021) and an adenylate cyclase activator (forskolin). In our cortical neuron culture model, CHIR99021 rescues the spine morphology defects caused by AnkG knockdown, whereas forskolin rescued the dendrite complexity deficit. Interestingly, a synergistic action of both drugs was required to rescue dendrite and spine density defects in AnkG knockdown neurons. Altogether, our results suggest that dendritic abnormalities observed in loss of function ANK3 variants and BD patients may be rescued by lithium treatment. Additionally, drugs selectively targeting GSK3ß and cAMP pathways could be beneficial in BD.

miRNA-mediated control of gephyrin synthesis drives sustained inhibitory synaptic plasticity.

Activity-dependent protein synthesis is crucial for many long-lasting forms of synaptic plasticity. However, our understanding of the translational mechanisms controlling inhibitory synapses is limited. One distinct form of inhibitory long-term potentiation (iLTP) enhances postsynaptic clusters of GABAARs and the primary inhibitory scaffold, gephyrin, to promote sustained synaptic strengthening. While we previously found that persistent iLTP requires mRNA translation, the precise mechanisms controlling gephyrin translation during this process remain unknown. Here, we identify miR153 as a novel regulator of Gphn mRNA translation which controls gephyrin protein levels and synaptic clustering, ultimately impacting GABAergic synaptic structure and function. We find that iLTP induction downregulates miR153, reversing its translational suppression of Gphn mRNA and allowing for increased de novo gephyrin protein synthesis and synaptic clustering during iLTP. Finally, we find that reduced miR153 expression during iLTP is driven by an excitation-transcription coupling pathway involving calcineurin, NFAT and HDACs, which also controls the miRNA-dependent upregulation of GABAARs. Overall, this work delineates a miRNA-dependent post-transcriptional mechanism that controls the expression of the key synaptic scaffold, gephyrin, and may converge with parallel miRNA pathways to coordinate gene upregulation to maintain inhibitory synaptic plasticity.

Impact of the COVID-19 Pandemic on the Global Delivery of Mental Health Services and Telemental Health: Systematic Review.

BACKGROUND: The COVID-19 pandemic required mental health services around the world to adapt quickly to the new restrictions and regulations put in place to reduce the risk of transmission. As face-to-face contact became difficult, virtual methods were implemented to continue to safely provide mental health care. However, it is unclear to what extent service provision transitioned to telemental health worldwide. OBJECTIVE: We aimed to systematically review the global research literature on how mental health service provision adapted during the first year of the pandemic. METHODS: We searched systematically for quantitative papers focusing on the impact of the COVID-19 pandemic on mental health services published until April 13, 2021, in the PubMed, Embase, medRxiv, and bioXriv electronic bibliographic databases, using the COVID-19 Open Access Project online platform. The screening process and data extraction were independently completed by at least two authors, and any disagreement was resolved by discussion with a senior member of the team. The findings were summarized narratively in the context of each country's COVID-19 Stringency Index, which reflects the stringency of a government's response to COVID-19 restrictions at a specific time. RESULTS: Of the identified 24,339 records, 101 papers were included after the screening process. Reports on general services (n=72) showed that several countries' face-to-face services reduced their activities at the start of the pandemic, with reductions in the total number of delivered visits and with some services forced to close. In contrast, telemental health use rapidly increased in many countries across the world at the beginning of the pandemic (n=55), with almost complete virtualization of general and specialistic care services by the end of the first year. Considering the reported COVID-19 Stringency Index values, the increased use of virtual means seems to correspond to periods when the Stringency Index values were at their highest in several countries. However, due to specific care requirements, telemental health could not be used in certain subgroups of patients, such as those on clozapine or depot treatments and those who continued to need face-to-face visits. CONCLUSIONS: During the pandemic, mental health services had to adapt quickly in the short term, implementing or increasing the use of telemental health services across the globe. Limited access to digital means, poor digital skills, and patients' preferences and individual needs may have contributed to differences in implementing and accessing telemental health services during the pandemic. In the long term, a blended approach, combining in-person and virtual modalities, that takes into consideration the needs, preferences, and digital skills of patients may better support the future development of mental health services. It will be required to improve confidence with digital device use, training, and experience in all modalities for both clinicians and service users.

Vitruvian plot: a visualisation tool for multiple outcomes in network meta-analysis.

OBJECTIVE: A network meta-analysis (NMA) usually assesses multiple outcomes across several treatment comparisons. The Vitruvian plot aims to facilitate communication of multiple outcomes from NMAs to patients and clinicians. METHODS: We developed this tool following the recommendations on the communication of benefit-risk information from the available literature. We collected and implemented feedback from researchers, statisticians, methodologists, clinicians and people with lived experience of physical and mental health issues. RESULTS: We present the Vitruvian plot, which graphically presents absolute estimates and relative performance of competing interventions against a common comparator for several outcomes of interest. We use two alternative colour schemes to highlight either the strength of statistical evidence or the confidence in the evidence. Confidence in the evidence is evaluated across six domains (within-study bias, reporting bias, indirectness, imprecision, heterogeneity and incoherence) using the Confidence in Network Meta-Analysis (CINeMA) system. CONCLUSIONS: The Vitruvian plot allows reporting of multiple outcomes from NMAs, with colourings appropriate to inform credibility of the presented evidence.

Complementary Use of Super-Resolution Imaging Modalities to Study the Nanoscale Architecture of Inhibitory Synapses.

The nanoscale architecture of synapses has been investigated using multiple super-resolution methods, revealing a common modular structure for scaffolds, neurotransmitter receptors, and presynaptic proteins. This fundamental organization of proteins into subsynaptic domains (SSDs) is thought to be important for synaptic function and plasticity and common to many types of synapses. Using 3D super-resolution Structured Illumination Microscopy (3D-SIM), we recently showed that GABAergic inhibitory synapses exhibit this nanoscale organizational principle and are composed of SSDs of GABA A receptors (GABA A Rs), the inhibitory scaffold gephyrin, and the presynaptic active zone protein, RIM. Here, we have investigated the use of 3D-SIM and dSTORM to analyze the nanoscale architecture of the inhibitory synaptic adhesion molecule, neuroligin-2 (NL2). NL2 is a crucial mediator of inhibitory synapse formation and organization, associating with both GABA A Rs and gephyrin. However, the nanoscale sub-synaptic distribution NL2 remains unknown. We found that 3D-SIM and dSTORM provide complementary information regarding the distribution of NL2 at the inhibitory synapse, with NL2 forming nanoscale structures that have many similarities to gephyrin nanoscale architecture.

COVID-19 and substance use disorders: a review of international guidelines for frontline healthcare workers of addiction services.

BACKGROUND: People with substance use disorders may be at a greater risk of contracting COVID-19 infection and developing medical complications. Several institutional and governmental health agencies across the world developed ad hoc guidance for substance use disorder services and care of individuals misusing substances. We aimed to synthesise the best available recommendations on management and care of people with or at risk of substance use disorders during the COVID-19 pandemic from existing guidelines published in UK, USA, Australia, Canada, New Zealand, and Singapore. METHODS: We systematically searched existing guidelines and websites from 28 international institutions and governmental bodies in the context of the COVID-19 pandemic (May 4th 2021). We summarized the extracted data as answers to specific clinical questions. RESULTS: We organised the available recommendations from 19 sources in three sections. First, we focused on general advice and recommendations for people who misuse alcohol or drugs during the COVID-19 pandemic, the design of contingency plans, safeguarding issues for children and families of service users and advice to the public, patients, and carers. Then, we summarised specific guidelines for people who use illicit drugs and related services, such as opioid substitution treatment and needle and syringe programmes. Finally, we provided a synthesis on specific recommendations for services supporting people who misuse alcohol and key topics in the field, such as management of alcohol detoxification and safe transition between supervised and unsupervised consumption. CONCLUSIONS: Available guidance reflected different approaches, ranging from being extremely cautious in providing recommendations other than generic statements to proposing adaptation of previously available guidelines to confront the challenges of the COVID-19 pandemic. After the early phase, guidance focused on reduction of infection transmission and service delivery. Guidance did not provide advice on infection prevention via vaccination programmes and service access strategies tailored to individuals with substance use disorders.

Teaching Telepsychiatry Skills: Building on the Lessons of the COVID-19 Pandemic to Enhance Mental Health Care in the Future.

COVID-19 has accelerated the use of telehealth and technology in mental health care, creating new avenues to increase both access to and quality of care. As video visits and synchronous telehealth become more routine, the field is now on the verge of embracing asynchronous telehealth, with the potential to radically transform mental health. However, sustaining the use of basic synchronous telehealth, let alone embracing asynchronous telehealth, requires new and immediate effort. Programs to increase digital literacy and competencies among both clinicians and patients are now critical to ensure all parties have the knowledge, confidence, and ability to equitably benefit from emerging innovations. This editorial outlines the immediate potential as well as concrete steps toward realizing the potential of a new, more personalized, scalable mental health system.