Deep Profiling of Mouse Splenic Architecture with CODEX Multiplexed Imaging.

A highly multiplexed cytometric imaging approach, termed co-detection by indexing (CODEX), is used here to create multiplexed datasets of normal and lupus (MRL/lpr) murine spleens. CODEX iteratively visualizes antibody binding events using DNA barcodes, fluorescent dNTP analogs, and an in situ polymerization-based indexing procedure. An algorithmic pipeline for single-cell antigen quantification in tightly packed tissues was developed and used to overlay well-known morphological features with de novo characterization of lymphoid tissue architecture at a single-cell and cellular neighborhood levels. We observed an unexpected, profound impact of the cellular neighborhood on the expression of protein receptors on immune cells. By comparing normal murine spleen to spleens from animals with systemic autoimmune disease (MRL/lpr), extensive and previously uncharacterized splenic cell-interaction dynamics in the healthy versus diseased state was observed. The fidelity of multiplexed spatial cytometry demonstrated here allows for quantitative systemic characterization of tissue architecture in normal and clinically aberrant samples.

Combined protein and nucleic acid imaging reveals virus-dependent B cell and macrophage immunosuppression of tissue microenvironments.

Understanding the mechanisms of HIV tissue persistence necessitates the ability to visualize tissue microenvironments where infected cells reside; however, technological barriers limit our ability to dissect the cellular components of these HIV reservoirs. Here, we developed protein and nucleic acid in situ imaging (PANINI) to simultaneously quantify DNA, RNA, and protein levels within these tissue compartments. By coupling PANINI with multiplexed ion beam imaging (MIBI), we measured over 30 parameters simultaneously across archival lymphoid tissues from healthy or simian immunodeficiency virus (SIV)-infected nonhuman primates. PANINI enabled the spatial dissection of cellular phenotypes, functional markers, and viral events resulting from infection. SIV infection induced IL-10 expression in lymphoid B cells, which correlated with local macrophage M2 polarization. This highlights a potential viral mechanism for conditioning an immunosuppressive tissue environment for virion production. The spatial multimodal framework here can be extended to decipher tissue responses in other infectious diseases and tumor biology.

Robust single-cell matching and multimodal analysis using shared and distinct features.

The ability to align individual cellular information from multiple experimental sources is fundamental for a systems-level understanding of biological processes. However, currently available tools are mainly designed for single-cell transcriptomics matching and integration, and generally rely on a large number of shared features across datasets for cell matching. This approach underperforms when applied to single-cell proteomic datasets due to the limited number of parameters simultaneously accessed and lack of shared markers across these experiments. Here, we introduce a cell-matching algorithm, matching with partial overlap (MARIO) that accounts for both shared and distinct features, while consisting of vital filtering steps to avoid suboptimal matching. MARIO accurately matches and integrates data from different single-cell proteomic and multimodal methods, including spatial techniques and has cross-species capabilities. MARIO robustly matched tissue macrophages identified from COVID-19 lung autopsies via codetection by indexing imaging to macrophages recovered from COVID-19 bronchoalveolar lavage fluid by cellular indexing of transcriptomes and epitopes by sequencing, revealing unique immune responses within the lung microenvironment of patients with COVID.

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 Update on Clinical Guidelines for Management of Major Depressive Disorder in Adults: Réseau canadien pour les traitements de l'humeur et de l'anxiété (CANMAT) 2023 : Mise à jour des lignes directrices cliniques pour la prise en charge du trouble dépressif majeur chez les adultes.

BACKGROUND: The Canadian Network for Mood and Anxiety Treatments (CANMAT) last published clinical guidelines for the management of major depressive disorder (MDD) in 2016. Owing to advances in the field, an update was needed to incorporate new evidence and provide new and revised recommendations for the assessment and management of MDD in adults. METHODS: CANMAT convened a guidelines editorial group comprised of academic clinicians and patient partners. A systematic literature review was conducted, focusing on systematic reviews and meta-analyses published since the 2016 guidelines. Recommendations were organized by lines of treatment, which were informed by CANMAT-defined levels of evidence and supplemented by clinical support (consisting of expert consensus on safety, tolerability, and feasibility). Drafts were revised based on review by patient partners, expert peer review, and a defined expert consensus process. RESULTS: The updated guidelines comprise eight primary topics, in a question-and-answer format, that map a patient care journey from assessment to selection of evidence-based treatments, prevention of recurrence, and strategies for inadequate response. The guidelines adopt a personalized care approach that emphasizes shared decision-making that reflects the values, preferences, and treatment history of the patient with MDD. Tables provide new and updated recommendations for psychological, pharmacological, lifestyle, complementary and alternative medicine, digital health, and neuromodulation treatments. Caveats and limitations of the evidence are highlighted. CONCLUSIONS: The CANMAT 2023 updated guidelines provide evidence-informed recommendations for the management of MDD, in a clinician-friendly format. These updated guidelines emphasize a collaborative, personalized, and systematic management approach that will help optimize outcomes for adults with MDD.

Update on the use and management of lithium in neuropsychiatry / Actualización en el uso y el manejo del litio en neuropsiquiatría.

Lithium is an alkaline metal, used for more than 60 years in psychiatry, and currently considered the gold standard in the treatment of bipolar disorder (BD). According to recent evidence, this active ingredient is useful for the treatment of a wide spectrum of clinical varieties of affective disorders. In addition, it is estimated that lithium reduces the risk of suicide and suicidal behavior in people with mood disorders. On the other hand, some novel studies have shown that the cation has a potential efficacy for the treatment of other neuropsychiatric processes, such as the likelihood of reducing the risk of dementia and slowing down the development of neurodegenerative diseases. Despite the enormous evidence in favor of the use of lithium, it is known that, in Argentina, medications containing it are prescribed less than expected. In view of all this, the Asociación Argentina de Psiquiatría Biológica (Argentine Association of Biological Psychiatry) (AAPB or AABP) convened a group of experts to review the available scientific literature and prepare an updated document on the management and use of lithium in neuropsychiatry. In addition to the use of the ion in daily clinical practice, the scope of this review includes other contents that have been considered of interest for the psychiatrist, such as certain pharmacological and pharmacogenetic aspects, possible clinical predictors of response to treatment with lithium, management of ion during perinatal period, management of lithium in child and adolescent population, management of adverse effects linked to cation and interactions with drugs and other substances.

El litio es un metal alcalino, usado hace más de 60 años en psiquiatría, y actualmente es considerado el estándar de oro en el tratamiento del trastorno bipolar (TB). De acuerdo con la evidencia reciente, este principio activo es útil para el tratamiento de un amplio espectro de variedades clínicas de los trastornos afectivos. Además, se estima que desde hace tiempo el litio reduce el riesgo de suicidio y de comportamiento suicida en personas con trastornos del estado de ánimo. Por otro lado, algunos estudios novedosos han demostrado que el catión posee una potencial eficacia para el tratamiento de otros procesos neuropsiquiátricos, tales como la probabilidad de disminuir el riesgo de demencia y la de ralentizar el desarrollo de enfermedades neurodegenerativas. A pesar de la enorme evidencia a favor de la utilización del litio, se sabe que, en la Argentina, las especialidades medicinales que lo contienen se prescriben menos de lo esperado. En virtud de todo lo mencionado, la Asociación Argentina de Psiquiatría Biológica (AAPB) convocó a un grupo de expertos para revisar la literatura científica disponible y elaborar un documento actualizado sobre el manejo y el uso del litio en neuropsiquiatría. Además de la utilización del ion en la práctica clínica diaria, el alcance de esta revisión incluye otros contenidos que se han considerado de interés para el médico psiquiatra, tales como ciertos aspectos farmacológicos y farmacogenéticos, posibles predictores clínicos de la respuesta al tratamiento con litio, el manejo del ion durante el período perinatal, el manejo de litio en la población infantojuvenil, el manejo de los efectos adversos vinculados con el catión y las interacciones con medicamentos y otras sustancias.

Third Argentine Consensus statement on management Bipolar Disorders. Section 2 B / Tercer Consenso Argentino sobre el manejo de los Trastornos Bipolares. Segunda Parte B.

This document constitutes the second section B of the Third Argentine Consensus on the Management of Bipolar Disorders, focused on synthesizing the most updated evidence on therapeutic approaches for adult patients. The scope of this section is to provide therapeutic recommendations for managing bipolar disorders in adults, (i) acute mania (ii) bipolar depression (iii) mixed stated (iv) suicidality and (vi) psychological interventions. In addition, the current manuscript outlines the assessment and management of side effects of pharmacotherapeutic treatments.

Este documento constituye la segunda parte B del Tercer Consenso Argentino sobre el Manejo de los Trastornos Bipolares llevada a cabo por la Asociación Argentina de Psiquiatría Biológica (AAPB). Siguiendo con el direccionamiento iniciado en el parte 2A sobre el tratamiento integral de los trastornos bipolares, esta sección se ha enfocado en sintetizar la evidencia más actualizada sobre abordajes terapéuticos para pacientes adultos. El alcance de esta sección es proporcionar recomendaciones terapéuticas para el manejo de los trastornos bipolares en adultos, (i) manía aguda, (ii) depresión bipolar, (iii) estado mixto, (iv) el suicidio en el trastorno bipolar, (v) intervenciones psicológicas. Además, el presente manuscrito aborda la evaluación y el manejo de los efectos secundarios de los tratamientos farmacoterapéuticos.

Third Argentine Consensus statement on management Bipolar Disorders. Section 2 A: Comprehensive treatment of the bipolar disorders in adults / Tercer Consenso Argentino sobre el manejo de los Trastornos Bipolares. Segunda Parte A: Tratamiento integral de los trastornos bipolares en el adulto.

This document constitutes the second section A of the Third Argentine Consensus on the Management of Bipolar Disorders, focused on synthesizing the most updated evidence on therapeutic approaches for adult patients. The aim of this section (2A) is to provide therapeutic recommendations for managing bipolar disorders in adults. In addition, the scope of this current manuscript outlines recommendations on the use of treatment guidelines, levels of evidence available to support these recommendations, general considerations for the treatment of bipolar disorders, the so-called pseudoresistance and adherence to treatment, general considerations on psychological therapies, as well as long term treatment of bipolar disorders.

Este documento corresponde a la segunda parte del Tercer Consenso Argentino sobre el manejo de los trastornos bipolares, enfocada en sintetizar la evidencia actualizada sobre los abordajes terapéuticos de esta patología en los pacientes adultos. Siguiendo la metodología descripta en la primera parte del Consenso, el panel de expertos realizó una exhaustiva revisión de la bibliografía y, como consecuencia de un posterior debate sobre la información disponible, se generó esta sección A del segundo documento que abarca el tratamiento integral de las personas adultas que padecen este trastorno. Durante la etapa de debate y discusión de estas guías, se decidió incorporar algunos puntos que estimamos serán de gran utilidad para el equipo interdisciplinario encargado del manejo de pacientes con trastornos bipolares.  En tal sentido, en la sección A de la segunda parte de este documento, se podrán encontrar las recomendaciones generales para el uso de las guías de tratamiento, los niveles de evidencia disponibles para sustentar las recomendaciones, las consideraciones generales del tratamiento de los trastornos bipolares, el fenómeno de pseudorresistencia y adherencia al tratamiento, las consideraciones generales sobre el abordaje psicológico, así como el tratamiento a largo plazo de los trastornos bipolares.

Third Argentine Consensus statement on management Bipolar Disorders. Section3: Bipolar Disorder in the context of special situations / Tercer Consenso Argentino sobre el manejo de los Trastornos Bipolares. Tercera parte: Manejo de los Trastornos Bipolares en el contexto de situaciones especiales.

This document constitutes the third and last part of the Third Argentine Consensus on the Management of Bipolar Disorders carried out by the Argentine Association of Biological Psychiatry (AAPB). Continuing with the initial objective, this section of the Consensus on the Management of Bipolar Disorders is focused on the management of bipolar disorders in special populations. This section constitutes a comprehensive review and expert consideration of the scientific evidence on: a) the management of bipolar disorders in treatment-resistant patients; b) the management of bipolar disorder in childhood and adolescence; c) the management of bipolar disorders in women during their perinatal period and, d) the management of bipolar disorders in older adults.

Este documento constituye la tercera y última parte del Tercer Consenso Argentino sobre el Manejo de los Trastornos Bipolares llevada a cabo por la Asociación Argentina de Psiquiatría Biológica (AAPB). Siguiendo con el objetivo propuesto por el comité de expertos, en la actual versión del Consenso sobre el manejo de los trastornos bipolares, esta sección está enfocada al abordaje de los Trastornos Bipolares en situaciones especiales. Esto configura una revisión exhaustiva de la evidencia científica  sobre: a) el manejo de los trastornos bipolares en pacientes resistentes al tratamiento, b) el manejo de los trastornos bipolares en la mujer en el período perinatal, c) el manejo del trastorno bipolar en la etapa infantojuvenil y d) el manejo de los trastornos bipolares en los adultos mayores.

Highly multiplexed tissue imaging using repeated oligonucleotide exchange reaction.

Multiparameter tissue imaging enables analysis of cell-cell interactions in situ, the cellular basis for tissue structure, and novel cell types that are spatially restricted, giving clues to biological mechanisms behind tissue homeostasis and disease. Here, we streamlined and simplified the multiplexed imaging method CO-Detection by indEXing (CODEX) by validating 58 unique oligonucleotide barcodes that can be conjugated to antibodies. We showed that barcoded antibodies retained their specificity for staining cognate targets in human tissue. Antibodies were visualized one at a time by adding a fluorescently labeled oligonucleotide complementary to oligonucleotide barcode, imaging, stripping, and repeating this cycle. With this we developed a panel of 46 antibodies that was used to stain five human lymphoid tissues: three tonsils, a spleen, and a LN. To analyze the data produced, an image processing and analysis pipeline was developed that enabled single-cell analysis on the data, including unsupervised clustering, that revealed 31 cell types across all tissues. We compared cell-type compositions within and directly surrounding follicles from the different lymphoid organs and evaluated cell-cell density correlations. This sequential oligonucleotide exchange technique enables a facile imaging of tissues that leverages pre-existing imaging infrastructure to decrease the barriers to broad use of multiplexed imaging.

Comparative Efficacy and Tolerability of Antipsychotics for Juvenile Psychotic Disorders: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Psychotic disorders produce important morbidity and disability in children and adolescents. There have been few relevant treatment trials, encouraging assessment of research aimed at testing efficacy and safety of antipsychotics for juveniles. We aimed to compare the short- and long-term efficacy and safety of antipsychotics to treat psychotic disorders among children and adolescents. METHODS: Four major bibliographic databases (PubMed, MEDLINE, PsycINFO, and EMBASE) were searched for clinical trials of antipsychotics in children or adolescents, from database inception to May 2021. We searched for clinical trials comparing antipsychotics with control conditions for juvenile psychosis based on blinded review by 2 independent investigators (C.S.Y. and M.L.). We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses and applied the Cochrane risk-of-bias tool to appraise study quality. One reviewer (A.B.) performed data abstraction which was confirmed by 2 independent, blinded reviewers (C.S.Y. and M.L.). Primary outcomes were scores rating psychosis symptoms and dichotomized retention in treatment protocols versus dropouts because of adverse events. Effect sizes were pooled using frequentist random-effects network meta-analysis modeling to generate summary rate ratios (RRs) and Cohen d standardized mean differences. RESULTS: Systematic searching generated 1330 unique records. Of these, short-term (n = 15, for 6 [3-12] weeks) and long-term (n = 10, for 12 [6-60] months) treatment trials involved 2208 (39.2% females; median age, 15.3 years), and 1366 subjects (35.0% females; median age, 15.6 years), respectively. Short-term reduction of psychosis scores ranked clozapine (d = -1.35; 95% confidence interval [CI], -1.97 to -0.73]), molindone (-1.22; 95% CI, -1.68 to -0.75), olanzapine (-1.12; 95% CI, -1.44 to -0.81), and risperidone (-0.93; 95% CI, -1.22 to -0.63) as the most effective agents. In longer-term treatment, only lurasidone was effective. Clozapine (RR, 12.8) and haloperidol (RR, 5.15) led to more all-cause and adverse event-related dropouts. There were few trials/drug (1 each for aripiprazole, asenapine, lurasidone, molindone, paliperidone, and ziprasidone, short term; aripiprazole, clozapine, haloperidol, lurasidone, and molindone, long-term). Heterogeneity and inconsistency were high, especially in long-term trials, without evidence of publication bias. CONCLUSIONS: Some antipsychotics were effective and tolerated short term, but longer-term evidence was very limited. The overall paucity of trials and of adequate controls indicates that more well-designed randomized controlled trials are required for adequate assessment of antipsychotic drug treatment for juveniles. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021232937.

Risk factors for early recurrence after discontinuing lithium in bipolar disorder.

BACKGROUND: Time to a new episode of bipolar disorder (BD) is shorter after discontinuing lithium rapidly. We now address this and other factors associated with the risk of early illness after discontinuing lithium. METHODS: We compared factors for association with recurrences of BD within 12 months of discontinuing long-term lithium treatment, using bivariate and multivariable analyses, as well as survival analysis to evaluate latency to new episodes versus rate of lithium-discontinuation and prior treatment duration. RESULTS: Among 227 BD subjects who received lithium for 4.47 [CI: 3.89-5.04] years and then discontinued, rapid treatment-discontinuation, and stopping for medical reasons were strongly associated with new illness-episodes within 12 months, as were diagnosis (BD-I > BD-II), greater morbidity during lithium-treatment, and less education, but neither longer treatment nor serum lithium concentrations. Discontinuation rate was strongly associated with shorter median latency to a new episode (rapid: 3.50; gradual [≥2 weeks]: 10.6 months), even with very early recurrences excluded to avoid potential contributions of emerging illness to treatment-discontinuation. Early recurrence was not associated with treatment-duration of ≥2 or ≥5 years or less. In multivariable logistic regression, rapid discontinuation, stopping for medical reasons, and BD-I diagnosis remained significantly, independently associated with early illness after lithium-discontinuation, with no effect of treatment duration. CONCLUSIONS: Early recurrence risk was again much greater after rapid discontinuation of lithium and discontinuing for medical reasons, somewhat greater with BD-I than BD-II, and following greater morbidity during lithium-treatment, but not related to dose or duration of preceding treatment exposure.

[Evaluation of the functionality and subjective well-being of bipolar patients with the Functioning Assessment Short Test (FAST) and the World Health Organization - Five Well- Being Index (WHO-5)]. / Evaluación de la funcionalidad y el bienestar subjetivo de pacientes bipolares con el Functioning Assessment Short Test (FAST) y el World Health Organization - Five Well-Being Index (WHO-5).

INTRODUCTION: Bipolar Disorders (BD) are a mood disorders group charactered by recurrent manic or hypomanic episodes, alternating with depressive episodes. Its prevalence is 4%, and several studies have shown that they generate disability. There are effective therapeutic options for acute episodes. However, the ultimate goal is to achieve functional recovery and adequate well-being. MATERIAL AND METHODS: There was done in Buenos Aires, Argentina a cross-sectional study comparing psychosocial functioning, with the Functioning Assessment Short Test (FAST) and subjective well-being with the Five Well-Being Index (WHO-5), among a sample of stabilized BD patients undergoing treatment at the Center of Medical Education and Clinical Research (Centro de Educación Médica e Investigaciones Clínicas) and the Bipolar Foundation (Fundación Bipolares de Argentina), with a control group. RESULTS: A total of 102 BD patients and 52 controls where included. The FAST mean for patients and controls was 20.71 and 9.73 respectively (P=0.0000). The WHO-5 mean for patients was 59.11 and 69.76 for controls (P=0.0011). More than 70% of the patients presented functional alteration (FAST ≥12), and almost 35% presented inadequate subjective well-being (WHO-5 ≤52). Depressive symptoms conditioned worse scores on both scales. FAST scores were better among those who participated in mutual aid groups (P=0.026). While patients who underwent psychoeducation and those who received anticonvulsant drugs, presented better WHO-5 scores (P = 0.028 and P=0.048 respectively). CONCLUSIONS: Patients with BD showed poor Functionality and poor Well-being despite being stabilized. There is direct relationship between both conditions. Depressive symptoms generated worst scores on the scales.

Third Argentine Consensus statement on management Bipolar Disorders. Section1: introduction and general concepts / Tercer Consenso Argentino sobre el manejo de los Trastornos Bipolares. Primera Parte: introducción, método de trabajo y generalidades.

The Third Argentine Consensus on the management of bipolar disorders (TB) is an initiative of the Argentine Association of Biological Psychiatry (AAPB). As a reference document, this consensus pursues two main objectives: on the one hand, to summarize and systematize the best available evidence on the comprehensive management of this pathology; on the other, to provide a useful, up-to-date instrument for psychiatrists, multidisciplinary teams dedicated to mental health, and government agencies. During a period of approximately six months of work -that is, from May to October 2022- a committee of experts made up of 18 professionals and representatives of the three most important Psychiatry and Mental Health associations in Argentina (that is, the AAPB, the Argentine Association of Psychiatrists, AAP, and the Association of Argentine Psychiatrists, APSA) have focused on updating the information regarding TB. Finally, this document was prepared as a result of an exhaustive review of the bibliography published to date, which was strategically divided into three parts: the first deals with the generalities of TB; the second deals with the comprehensive treatment of the pathology; finally, the third analyzes TB in the context of special situations.

El Tercer Consenso Argentino sobre el manejo de los Trastornos Bipolares (TB) es una iniciativa de la Asociación Argentina de Psiquiatría Biológica (AAPB). Como documento de referencia, este consenso persigue dos objetivos principales: por un lado, resumir y sistematizar la mejor evidencia disponible sobre el manejo integral de esta patología; por el otro, proporcionar un instrumento útil y actualizado a psiquiatras, a equipos multidisciplinarios abocados a la salud mental y a organismos gubernamentales. Durante un período de aproximadamente seis meses de trabajo -desde mayo a octubre de 2022- un comité de expertos integrado por 18 profesionales y por representantes de las tres asociaciones de Psiquiatría y Salud Mental más importantes de la Argentina: la AAPB, la Asociación Argentina de Psiquiatras, (AAP) y la Asociación de Psiquiatras Argentinos (APSA), se abocaron a actualizar la información respecto de los TB. Finalmente, y como resultado de una exhaustiva revisión de la bibliográfica publicada hasta la actualidad, se confeccionó este documento que fue dividido estratégicamente en tres partes: la primera versa acerca de las generalidades del TB; la segunda aborda el  tratamiento integral de la patología; y, por último, la tercera analiza los TB en el contexto de situaciones especiales.

Mapping Manuel Sandoval Vallarta (1899-1977) Scientific Contribution.

This paper employs network theory, mining data and bibliometric analysis when mapping the scientific contribution of Nobel Prize candidate; Manuel Sandoval Vallarta, the first and most renowned Mexican physicist and important figure in Latin American science. Vallarta died in 1977, and the existing literature is about his life and contributions to science but not about how those are still valuable today. This paper is the first to highlight, with mapping tools, that his contributions are relevant to the international community of cosmic rays (as he was pioneer and leader), quantum mechanics and relativity. These tools delivered three findings: Identify how he built his own field of study, same as universal knowledge. Unveil that the backward and forward Vallarta citations follow a scale-free network distribution. Determine social factors that benefited or affected his scientific activities-such as World War II interrupting Vallarta's successful productivity at Massachusetts Institute of Technology. Furthermore, this study confirmed the interdisciplinary nature of the mapping studies of the scientist's contributions using scientometric tools. As a result, several interesting questions arose throughout our research, some of which were answered from the history and philosophy of science. However, others need to be analyzed by experts in the fields of Vallarta. Mapping research sends an invitation to interdisciplinary dialogue/research between experts in different areas of study to better understand the process of knowledge production both, individual and collective.

Ketamine for Bipolar Depression: A Systematic Review.

BACKGROUND: Ketamine appears to have a therapeutic role in certain mental disorders, most notably unipolar major depressive disorder. However, its efficacy in bipolar depression is less clear. This study aimed to assess the efficacy and tolerability of ketamine for bipolar depression. METHODS: We conducted a systematic review of experimental studies using ketamine for the treatment of bipolar depression. We searched PubMed, MEDLINE, Embase, PsycINFO, and the Cochrane Central Register for relevant studies published since each database's inception. We synthesized evidence regarding efficacy (improvement in depression rating scores) and tolerability (adverse events, dissociation, dropouts) across studies. RESULTS: We identified 6 studies, with 135 participants (53% female; 44.7 years; standard deviation, 11.7 years). All studies used 0.5 mg/kg of add-on intravenous racemic ketamine, with the number of doses ranging from 1 to 6; all participants continued a mood-stabilizing agent. The overall proportion achieving a response (defined as those having a reduction in their baseline depression severity of at least 50%) was 61% for those receiving ketamine and 5% for those receiving a placebo. The overall response rates varied from 52% to 80% across studies. Ketamine was reasonably well tolerated; however, 2 participants (1 receiving ketamine and 1 receiving placebo) developed manic symptoms. Some participants developed significant dissociative symptoms at the 40-minute mark following ketamine infusion in 2 trials. CONCLUSIONS: There is some preliminary evidence supporting use of intravenous racemic ketamine to treat adults with bipolar depression. There is a need for additional studies exploring longer-term outcomes and alterative formulations of ketamine.

Prevention of suicidal behavior in bipolar disorder.

BACKGROUND: Excess mortality is a critical hallmark of bipolar disorder (BD) due to co-occurring general medical disorders and especially from suicide. It is timely to review of the status of suicide in BD and to consider the possibility of limiting suicidal risk. METHODS: We carried out a semi-systematic review of recent research reports pertaining to suicide in BD. FINDINGS: Suicide risk in BD is greater than with most other psychiatric disorders. Suicide rates (per 100,000/year) are approximately 11 and 4 in the adult and juvenile general populations, but over 200 in adults, and 100 among juveniles diagnosed with BD. Suicide attempt rates with BD are at least 20 times higher than in the adult general population, and over 50 times higher among juveniles. Notable suicidal risk factors in BD include: previous suicidal acts, depression, mixed-agitated-dysphoric moods, rapid mood-shifts, impulsivity, and co-occurring substance abuse. Suicide-preventing therapeutics for BD remain severely underdeveloped. Evidence favoring lithium treatment is stronger than for other measures, although encouraging findings are emerging for other treatments. CONCLUSIONS: Suicide is a leading clinical challenge for those caring for BD patients. Improved understanding of risk and protective factors combined with knowledge and close follow-up of BD patients should limit suicidal risk. Ethically appropriate and scientifically sound studies of plausible medicinal, physical, and psychosocial treatments aimed at suicide prevention specifically for BD patients are urgently needed.

Consensus on nomenclature for clinical staging models in bipolar disorder: A narrative review from the International Society for Bipolar Disorders (ISBD) Staging Task Force.

OBJECTIVES: Clinical staging is widely used in medicine to map disease progression, inform prognosis, and guide treatment decisions; in psychiatry, however, staging remains a hypothetical construct. To facilitate future research in bipolar disorders (BD), a well-defined nomenclature is needed, especially since diagnosis is often imprecise with blurred boundaries, and a full understanding of pathophysiology is lacking. METHODS: Under the auspices of the International Society of Bipolar Disorders, a Task Force of international experts was convened to review, discuss, and integrate findings from the scientific literature relevant to the development of a consensus staging model and standardize a terminology that could be used to advance future research including staging of BD and related disorders. RESULTS: Consensus opinion and areas of uncertainty or difference were identified in regard to terms referring to staging as it may apply to BD, to at-risk status and subthreshold stages, and to various clinical stages of BD as it is currently diagnosed. CONCLUSION: The use of a standardized nomenclature about the clinical stages of BD will facilitate communication about research on clinical and pathological components of this heterogeneous group of disorders. The concepts presented are based on current evidence, but the template provided allows for further refinements as etiological advances come to light.

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) recommendations for the management of patients with bipolar disorder with mixed presentations.

OBJECTIVES: The 2018 Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) guidelines provided clinicians with pragmatic treatment recommendations for bipolar disorder (BD). While these guidelines included commentary on how mixed features may direct treatment selection, specific recommendations were not provided-a critical gap which the current update aims to address. METHOD: Overview of research regarding mixed presentations in BD, with treatment recommendations developed using a modified CANMAT/ISBD rating methodology. Limitations are discussed, including the dearth of high-quality data and reliance on expert opinion. RESULTS: No agents met threshold for first-line treatment of DSM-5 manic or depressive episodes with mixed features. For mania + mixed features second-line treatment options include asenapine, cariprazine, divalproex, and aripiprazole. In depression + mixed features, cariprazine and lurasidone are recommended as second-line options. For DSM-IV defined mixed episodes, with a longer history of research, asenapine and aripiprazole are first-line, and olanzapine (monotherapy or combination), carbamazepine, and divalproex are second-line. Research on maintenance treatments following a DSM-5 mixed presentation is extremely limited, with third-line recommendations based on expert opinion. For maintenance treatment following a DSM-IV mixed episode, quetiapine (monotherapy or combination) is first-line, and lithium and olanzapine identified as second-line options. CONCLUSION: The CANMAT and ISBD groups hope these guidelines provide valuable support for clinicians providing care to patients experiencing mixed presentations, as well as further influence investment in research to improve diagnosis and treatment of this common and complex clinical state.

Comparative Efficacy and Tolerability of Adjunctive Pharmacotherapies for Acute Bipolar Depression: A Systematic Review and Network Meta-analysis.

OBJECTIVE: We investigated the comparative efficacy and tolerability of augmentation strategies for bipolar depression. DATA SOURCES: We conducted a systematic review and network meta-analysis of 8 electronic databases for double-blind, randomized controlled trials of adjunctive pharmacotherapies for acute bipolar depression. DATA EXTRACTION AND SYNTHESIS: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and applied the Cochrane risk of bias tool for study quality appraisal. Two reviewers independently abstracted data. We resolved all discrepancies by consensus. MAIN OUTCOMES AND MEASURES: Primary outcomes were response and completion of treatment. We estimated summary rate ratios (RRs) and standardized mean differences (SMDs) relative to placebo controls using frequentist random-effects network meta-analysis. RESULTS: We identified 69 trials meeting eligibility criteria (8,007 participants, 42.8 years, 58.0% female). Adjunctive racemic intravenous ketamine, coenzyme Q10, pramipexole, fluoxetine, and lamotrigine were more effective than placebo. Summary RRs for response ranged between 1.51 (95% confidence interval [CI], 1.11 to 2.06) for fluoxetine and 12.49 (95% CI, 3.06 to 50.93) for racemic intravenous ketamine. For completion of treatment, risperidone appeared less tolerable than placebo (RR = 0.59; 95% CI, 0.38 to 0.94), while fluoxetine seemed more tolerable than placebo (RR = 1.13; 95% CI, 1.02 to 1.24). None of the investigated agents were associated with increased treatment-emergent mood switches. CONCLUSIONS AND RELEVANCE: The evidence for augmentation strategies in bipolar depression is limited to a handful of agents. Fluoxetine appeared to have the most consistent evidence base for both efficacy and tolerability. There remains a need for additional research exploring novel treatment strategies for bipolar depression, particularly head-to-head studies.

Pharmacological treatment of adult bipolar disorder.

We summarize evidence supporting contemporary pharmacological treatment of phases of BD, including: mania, depression, and long-term recurrences, emphasizing findings from randomized, controlled trials (RCTs). Effective treatment of acute or dysphoric mania is provided by modern antipsychotics, some anticonvulsants (divalproex and carbamazepine), and lithium salts. Treatment of BD-depression remains unsatisfactory but includes some modern antipsychotics (particularly lurasidone, olanzapine + fluoxetine, and quetiapine) and the anticonvulsant lamotrigine; value and safety of antidepressants remain controversial. Long-term prophylactic treatment relies on lithium, off-label use of valproate, and growing use of modern antipsychotics. Lithium has unique evidence of antisuicide effects. Methods of evaluating treatments for BD rely heavily on meta-analysis, which is convenient but with important limitations. Underdeveloped treatment for BD-depression may reflect an assumption that effects of antidepressants are similar in BD as in unipolar major depressive disorder. Effective prophylaxis of BD is limited by the efficacy of available treatments and incomplete adherence owing to adverse effects, costs, and lack of ongoing symptoms. Long-term treatment of BD also is limited by access to, and support of expert, comprehensive clinical programs. Pursuit of improved, rationally designed pharmacological treatments for BD, as for most psychiatric disorders, is fundamentally limited by lack of coherent pathophysiology or etiology.