Repeated subcutaneous esketamine on treatment-resistant depression: An open-label dose titration study.

BACKGROUND: Ketamine has gained prominence as one of the most effective therapeutic options in unipolar treatment-resistant depression (TRD). However, most studies related to the antidepressant action of ketamine used intravenous (IV) or intranasal (IN) administration. The subcutaneous (SC) route of administration is a promising alternative, as it results in plasma levels comparable to IV, causes fewer side effects, and is easier and cheaper to administer than both IV and/or IN routes. METHODS: In this context, we conducted an open-label clinical trial for investigating the efficacy and safety of 8 weekly sessions of SC esketamine in TRD patients (n = 30). RESULTS: At the end of the treatment, a partial response rate of 26.09 %, a response rate of 52.17 % and remission rate of 34.78 % were observed, assessed by Montgomery-Åsberg Depression Rating Scale. Moreover, the self-reported depressive symptoms, as measured by the Beck Depression Inventory II (BDI-II), significantly decreased from the baseline to the final session, and the improvements were sustained throughout the week. Follow-up evaluations (BDI-II) up to the sixth month consistently showed scores lower than the baseline. LIMITATIONS: The small sample size and the drop-out during the follow-up phase may limit the generalizability of the findings. Additionally, the absence of a control group necessitates cautious interpretation of causality. CONCLUSIONS: This groundbreaking study, which addresses SC esketamine treatment for TRD, reported promising response and remission rates, as well as sustained antidepressant effects. It highlights the need for further research to improve and expand our knowledge of this innovative, more accessible, and cost-effective therapeutic approach.

Validação da escala de medo da COVID-19 em adultos com depressão resistente ao tratamento: um estudo de enfermagem / The fear of COVID-19 scale validation in adults with treatment-resistant depression: a nursing study

Cerca de um terço das pessoas com transtornos depressivos não modifica seu estado psíquico após o uso de dois ou mais medicamentos, sendo classificadas com depressão resistente ao tratamento. Nessas pessoas, medos intensos podem agravar a depressão, especialmente em cenários ameaçadores como uma pandemia. Portanto, é crucial validar instrumentos psicométricos que facilitem a detecção de reações às pandemias, como a COVID-19, nessa população. O objetivo principal deste estudo é validar a Escala de Medo da COVID-19 em adultos com depressão resistente ao tratamento. Trata-se de um estudo transversal e analítico, realizado em uma instituição psiquiátrica pública no Rio de Janeiro, envolvendo usuários diagnosticados com depressão resistente ao tratamento que atenderam aos critérios de elegibilidade para participar da pesquisa. Foi realizado um cálculo amostral com parâmetros de precisão de 5% e um nível de confiança de 95%, resultando em uma amostra ideal de, no mínimo, 103 indivíduos. O estudo teve uma taxa de adesão de 79,5%, resultando em 140 participantes. A coleta de dados ocorreu de agosto de 2021 a janeiro de 2023, de forma remota, utilizando a Escala de Medo da COVID-19, o Inventário de Depressão de Beck e um questionário sociodemográfico, via formulário on-line. A análise descritiva dos dados foi feita no SPSS®, enquanto a Análise Fatorial Confirmatória foi realizada no software Jeffreys's Amazing Statistics Program (JASP), utilizando o método robusto DWLS, com a colaboração de um psicometrista. Os resultados da validação indicaram que a Escala de Medo da COVID-19 é uma ferramenta confiável e válida para medir o medo da COVID-19 em adultos com depressão resistente ao tratamento, ampliando seu escopo de utilização. A análise estatística revelou que os itens da escala apresentaram boas cargas fatoriais, demonstrando excelente aderência à variável latente. A unidimensionalidade do instrumento foi confirmada, eliminando a possibilidade de dupla saturação. Os resultados mostraram associações significativas entre a depressão severa e o medo intenso da COVID-19 em algumas variáveis sociodemográficas, indicando que certos grupos de usuários com depressão resistente foram mais vulneráveis ao medo da COVID-19 e ao agravamento da depressão durante a pandemia. Além disso, os participantes com medo intenso da COVID-19 apresentaram níveis mais elevados de sintomas depressivos, sugerindo uma interação entre o medo da COVID-19 e a gravidade da depressão. O medo intenso refletiu mentalmente e fisicamente em sintomas de ansiedade e ataques de pânico. Os cuidados de enfermagem pós-pandemia, à luz da Teoria da Maré, podem criar um sistema de suporte que identifica e lida com esses riscos, e pode apoiar e empoderar a pessoa no enfrentamento da depressão de forma proativa. Assim, os resultados desta tese permitem aos enfermeiros fazer a prospecção de ações em saúde mental para estabelecer relações mais significativas e colaborativas com os usuários, facilitando a construção de uma rede de apoio que trabalhe ativamente para reduzir a agravamento da depressão no período pós pandemia.

About one-third of people with depressive disorders do not change their psychological state after using two or more medications, being classified as having treatment-resistant depression. In these individuals, intense fears can exacerbate depression, especially in threatening scenarios such as a pandemic. Therefore, it is crucial to validate psychometric instruments that facilitate the detection of reactions to pandemics, such as COVID-19, in this population. The main objective of this study is to validate the COVID-19 Fear Scale in adults with treatment-resistant depression. This is a cross-sectional and analytical study conducted in a public psychiatric institution in Rio de Janeiro, involving users diagnosed with treatment-resistant depression who met the eligibility criteria to participate in the research. A sample calculation was performed with 5% precision parameters and a 95% confidence level, resulting in an ideal sample of at least 103 individuals. The study had an adherence rate of 79.5%, resulting in 140 participants. Data collection took place from August 2021 to January 2023, remotely, using the COVID-19 Fear Scale, the Beck Depression Inventory, and a sociodemographic questionnaire via an online form. Descriptive data analysis was done in SPSS®, while Confirmatory Factor Analysis was performed in Jeffreys's Amazing Statistics Program (JASP) software, using the robust DWLS method, with the collaboration of a psychometrician. The validation results indicated that the COVID-19 Fear Scale is a reliable and valid tool for measuring fear of COVID-19 in adults with treatment-resistant depression, expanding its scope of use. The statistical analysis revealed that the scale items presented good factor loadings, demonstrating excellent adherence to the latent variable. The unidimensionality of the instrument was confirmed, eliminating the possibility of double saturation. The results showed significant associations between severe depression and intense fear of COVID-19 in some sociodemographic variables, indicating that certain groups of patients with treatment-resistant depression were more vulnerable to fear of COVID-19 and worsening depression during the pandemic. Additionally, participants with intense fear of COVID-19 showed higher levels of depressive symptoms, suggesting an interaction between fear of COVID-19 and the severity of depression. Intense fear manifested mentally and physically in symptoms of anxiety and panic attacks. Post-pandemic nursing care, in light of the Tidal Model, can create a support system that identifies and addresses these risks, and can support and empower individuals to proactively cope with depression. Thus, the results of this thesis allow nurses to prospect mental health actions to establish more meaningful and collaborative relationships with patients, facilitating the construction of a support network that actively works to reduce the worsening of depression in the post-pandemic period.

Online mindfulness-based cognitive therapy for treatment-resistant depression: a parallel-arm randomized controlled feasibility trial.

Introduction: Treatment-resistant depression (TRD) presents a significant challenge, affecting approximately 30% of individuals diagnosed with major depressive disorder and leading to poor treatment responses. Innovations in digital mental health, especially online mindfulness-based cognitive therapy (eMBCT), offer promising avenues for enhancing access to effective mental health care for individuals with TRD in a clinical setting. Objective: The aim of this study was to examine the feasibility of eMBCT in an individual clinical context to decrease depressive symptoms for TRD. Methods: Conducted at the Institute of Psychiatry of the Federal University of Rio de Janeiro, Brazil, this parallel-arm, randomized controlled feasibility trial involved outpatients diagnosed with TRD, aged 18 and above. Of the 39 outpatients invited, 28 were randomized into two groups: an intervention group receiving the eMBCT program (n = 15) and a control group (n = 13). The intervention, consisting of an 8-week course, was delivered via live video sessions. Following the assessment period, participants in the control group were offered the eMBCT intervention. Assessments using standardized questionnaires were conducted at the start and end of the study. Results: Within the eMBCT group, improvements were observed in depression symptoms (Z = -3.423; p = 0.001; effect size r = 0.78), anxiety symptoms (Z = -3.361; p = 0.001; effect size r = 0.77), with no significant changes in the control group. Comparatively, the eMBCT group showed significant reductions in depression symptoms and improvements in clinical global impressions over the control group (BDI2: U = 30.5; p = 0.015; effect size r = 0.47, CGI1: U = 21.0; p = 0.004; effect size r = 0.56). Conclusion: eMBCT in an individual format combined with medication, appears to be a feasible treatment for TRD, decreasing symptoms of depression. In a future trial the control group may have a manualized intervention. Clinical trial registration: The Brazilian Clinical Trials Registry: (https://ensaiosclinicos.gov.br/rg/RBR-6zndpbv) and RBR-6zndpbv.

Technical Report: Efficacy and Safety of Low-Intensity Transcranial Magnetic Stimulation in the Remission of Depressive Symptoms in Patients With Treatment-Resistant Depression in Mexico.

Transcranial magnetic stimulation (TMS) is a non-invasive neuromodulation technique that induces action potentials in the stimulated cortical area and has been approved by the Food and Drug Administration (FDA) for the treatment of major depressive disorder (MDD). The prevalence of MDD in Mexico almost tripled after the COVID-19 pandemic. In this study, we evaluated the safety and therapeutic effects of low-intensity TMS (Li-TMS) - characterized by inducing electric currents below the action potential threshold on the cerebral cortex - in 41 subjects diagnosed with treatment-resistant depression (TRD). A Li-TMS device dispensed repetitive magnetic pulses at 30 mT for 60 minutes during 20 sessions (once daily from Monday to Saturday) with the theta burst pattern. Our results suggest that Li-TMS is a safe therapy with antidepressant effects, demonstrated by the decrease in Beck Depression Inventory (BDI) scores and lessening of depressive symptoms.

Rapid and long-lasting effects of subcutaneous esketamine on suicidality: An open-label study in patients with treatment-resistant depression.

Therapeutics for suicide management is limited, taking weeks to work. This open-label clinical trial with 18 treatment-resistant depressive patients tested subcutaneous esketamine (8 weekly sessions) for suicidality. We noted a rapid and enduring effect of subcutaneous esketamine, lasting from one week to six months post-treatment, assessed by the Beck Inventory for Suicidality (BSI). There was an immediate drop in suicidality, 24 h following the initial dose, which persisted for seven days throughout the eight-week dosing period. Additionally, this study is the first to examine a six-month follow-up after multiple administrations of subcutaneous esketamine, finding consistently lower levels of suicidality throughout this duration. Conversely, suicidality also was measured along the 8-weeks of treatment by a psychiatrist using the Montgomery-Asberg Depression Rating Scale (MADRS), which showed significant reduction only after two treatment sessions expanding until the last session. Moreover, notably, 61% of patients achieved remission on suicidality (MADRS). These results suggest that weekly subcutaneous esketamine injections offer a cost-effective approach that induces a rapid and sustained response to anti-suicide treatment. This sets the stage for further, more controlled studies to corroborate our initial observations regarding the effects of SC esketamine on suicidality. Registered trial at: https://ensaiosclinicos.gov.br/rg/RBR-1072m6nv.

A real-world retrospective cohort study comparing two bilateral stimulation protocols of add-on rTMS in patients with treatment resistant depression and severe anxiety.

BACKGROUND: Transcranial magnetic stimulation (TMS) has been shown to improve response and remission in patients with treatment resistant depression. The objective of this study was to compare the efficacy of two bilateral rTMS protocols with different protocols in patients with treatment resistant depression and comorbid severe anxiety. METHODS: A retrospective cohort study involving 67 patients who underwent two different bilateral TMS protocols and who met the specified eligibility criteria was conducted. Group 1 received stimulation with 85% RMT intermittent theta burst (iTBS) in the left DLPFC + 120% RMT (1 Hz) in the right DLPFC. Group 2 received stimulation with 100% RMT (iTBS) in the left DLPFC + 110% RMT (1 Hz) in the left DLPFC. RESULTS: After the magnetic stimulation treatment, 55% (n=22) achieved response to depression symptoms in group 1 and 62% (n=18) in group 2. Remission of depression symptoms was achieved in 13% in group 1 (n=5) and 24% in group 2 (n=7). There were no significant differences between the two protocols after TMS CONCLUSIONS: Different bilateral protocol parameters in individuals undergoing TMS may have an impact on symptom response and remission. Further studies with larger sample sizes are needed.

Corrigendum: Deep brain stimulation neuromodulation for the treatment of mood disorders: obsessive compulsive disorder and treatment resistant depression.

[This corrects the article DOI: 10.3389/fpsyt.2021.764776.].

Brain-Derived Neurotrophic Factor (BDNF) as a Predictor of Treatment Response in Major Depressive Disorder (MDD): A Systematic Review.

Brain-derived neurotrophic factor (BDNF) has been studied as a biomarker of major depressive disorder (MDD). Besides diagnostic biomarkers, clinically useful biomarkers can inform response to treatment. We aimed to review all studies that sought to relate BDNF baseline levels, or BDNF polymorphisms, with response to treatment in MDD. In order to achieve this, we performed a systematic review of studies that explored the relation of BDNF with both pharmacological and non-pharmacological treatment. Finally, we reviewed the evidence that relates peripheral levels of BDNF and BDNF polymorphisms with the development and management of treatment-resistant depression.

Brain stimulation for treatment-resistant depression.

Depression is one of the main public health problems in the world, having a high prevalence and being considered the main cause of disability. An important portion of patients does not respond to treatment with the initial trial of conventional antidepressants in the current depressive episode of moderate to severe intensity, which characterizes treatment-resistant depression. In this context, non-invasive neuromodulation procedures use an electric current or magnetic field to modulate the central nervous system, and they represent a new option for patients with treatment-resistant depression.

The Role of the Adrenal-Gut-Brain Axis on Comorbid Depressive Disorder Development in Diabetes.

Diabetic patients are more affected by depression than non-diabetics, and this is related to greater treatment resistance and associated with poorer outcomes. This increase in the prevalence of depression in diabetics is also related to hyperglycemia and hypercortisolism. In diabetics, the hyperactivity of the HPA axis occurs in parallel to gut dysbiosis, weakness of the intestinal permeability barrier, and high bacterial-product translocation into the bloodstream. Diabetes also induces an increase in the permeability of the blood-brain barrier (BBB) and Toll-like receptor 4 (TLR4) expression in the hippocampus. Furthermore, lipopolysaccharide (LPS)-induced depression behaviors and neuroinflammation are exacerbated in diabetic mice. In this context, we propose here that hypercortisolism, in association with gut dysbiosis, leads to an exacerbation of hippocampal neuroinflammation, glutamatergic transmission, and neuronal apoptosis, leading to the development and aggravation of depression and to resistance to treatment of this mood disorder in diabetic patients.

Psychedelic Experiences: Phenomenology, Therapeutic Potentials and Explanatory Models / Experiencias psicodélicas: fenomenología, potenciales terapéuticos y modelos explicativos.

Traditional psychedelics, such as LSD, psilocybin, or DMT, are psychoactive compounds that exert their effects mainly through agonism over serotonergic receptors. In appropriate doses and contexts, they produce profound changes in the subjective experience, configuring altered states of consciousness that, upon reaching a critical point, involve the appearance of phenomena of mystical, transcendental, or ego dissolution experiences. These events are associated with diverse therapeutic effects in several mental conditions. Psychedelics are safe substances, with minimal risk of serious or long-lasting adverse effects and without addictive potential. Current evidence comes from systematic reviews and meta-analyses based on phase II clinical studies, with small groups of subjects, strict exclusion criteria, and difficulties in applying the double-blind methodology. Worldwide there is a growing number of clinical trials, which seek to promote the approval of psychedelic-assisted therapies as therapeutic tools in the coming years. In this bibliographic review, we will address the phenomenological characteristics of the psychedelic experience, its potential therapeutic uses, and the mechanisms that underlie them.

Los psicodélicos tradicionales, como el LSD, la psilocibina, o el DMT, son compuestos psicoactivos que ejercen sus efectos, principalmente, a través del agonismo sobre receptores serotoninérgicos. En dosis y contextos adecuados, se caracterizan por producir cambios profundos en la experiencia subjetiva, configurando estados alterados de consciencia que al alcanzar un punto crítico implican la aparición de fenómenos que se agrupan dentro de la categoría de experiencia mística, trascendental o de disolución yoica. Estos eventos se asocian a diversos efectos terapéuticos en una variedad de padecimientos mentales. Los psicodélicos son drogas seguras, con mínimo riesgo de efectos adversos graves o duraderos y sin potencial adictivo. Por el momento, contamos con revisiones sistemáticas y metaanálisis basados en estudios clínicos de fase II, con grupos pequeños de personas, criterios de exclusión estrictos y marcada dificultad para aplicar metodología de doble ciego. Actualmente, existen en desarrollo un creciente número de ensayos clínicos alrededor del mundo, que buscan propiciar la aprobación de las terapias asistidas por psicodélicos como herramientas terapéuticas en los próximos años. En esta revisión bibliográfica abordaremos las características fenomenológicas de la experiencia psicodélica, sus potenciales usos terapéuticos y los mecanismos que los subyacen.

Therapeutic Protocols Using Ketamine and Esketamine for Depressive Disorders: A Systematic Review.

Depression is one of the most prevalent mental health disorders globally, causing severe emotional suffering, reducing life expectancy and increasing the risk of suicide. Recently, the use of dissociative psychedelic substances such as ketamine and esketamine for depressive disorders has expanded treatment options. We sought to analyze, through a systematic review, the existing protocols for the treatment of depression with ketamine and esketamine. The search adopted PRISMA criteria and was performed using PubMed and Web of Science databases. Procedures in each study were compared, focusing on the sample recruited, therapeutic approaches, including the clinical team and professionals engaged in treatment, medical procedures, description of the setting (including music) and factors such as specific medication (ketamine or esketamine), route of administration and dosage employed. Results indicated the predominance of a medical approach, with a limited number of studies on ketamine assisted psychotherapy (KAP) and other modalities of psychedelic assisted therapy. Additionally, there is limited information on psychosocial elements such as preparation, psychological support during session and integration of experience. Altogether these findings suggest that treatment of depression with ketamine or esketamine diverges in relation to the practices employed with psychedelic substances. This is discussed considering future research directions in the field.

Magnetic Waves vs. Electric Shocks: A Non-Inferiority Study of Magnetic Seizure Therapy and Electroconvulsive Therapy in Treatment-Resistant Depression.

Treatment-resistant depression (TRD), characterized by the failure to achieve symptomatic remission despite multiple pharmacotherapeutic treatments, poses a significant challenge for clinicians. Electroconvulsive therapy (ECT) is an effective but limited option due to its cognitive side effects. In this context, magnetic seizure therapy (MST) has emerged as a promising alternative, offering comparable antidepressant efficacy with better cognitive outcomes. However, the clinical outcomes and cognitive effects of MST require further investigation. This double-blinded, randomized, non-inferiority study aims to compare the efficacy, tolerability, cognitive adverse effects, and neurophysiological biomarkers of MST with bilateral ECT (BT ECT) in patients with TRD. This study will employ multimodal nuclear magnetic resonance imaging (MRI) and serum neurotrophic markers to gain insight into the neurobiological basis of seizure therapy. Additionally, neurophysiological biomarkers will be evaluated as secondary outcomes to predict the antidepressant and cognitive effects of both techniques. The study design, recruitment methods, ethical considerations, eligibility criteria, interventions, and blinding procedures are described. The expected outcomes will advance the field by offering a potential alternative to ECT with improved cognitive outcomes and a better understanding of the underlying pathophysiology of depression and antidepressant therapies.

Gravidade da depressão, resposta ao tratamento e PRO (incapacidade e QoL) em pacientes com DRT em um ano de acompanhamento com tratamento padrão: análise do subgrupo brasileiro do estudo observacional multinacional TRAL / Depression severity, treatment response and PRO (disability and QoL) in TRD patients over a 1-year follow-up with standard of care: Analysis of the Brazilian subset of the multicenter, observational TRAL study

Objetivo: A depressão resistente ao tratamento (DRT) é uma preocupação primária no Brasil devido à sua natureza onerosa e complexa, enquanto o diagnóstico e o tratamento geralmente são desafiadores. O presente manuscrito apresenta os resultados clínicos de um ano de acompanhamento em pacientes com DRT em tratamento padrão (SOC) no subgrupo brasileiro do estudo de Depressão Resistente ao Tratamento na América Latina (TRAL). Métodos: Essa fase longitudinal do estudo TRAL tinha como meta caracterizar alterações nos resultados clínicos e outras variáveis de interesse (p. ex., qualidade de vida, incapacidade) em um ano de acompanhamento em pacientes com DRT em 10 centros no Brasil. Os pacientes incluídos tinham diagnóstico clínico de DRT com base nos critérios DSM-5 e confirmado por MINI. A Escala de Depressão de Montgomery-Asberg (MADRS) era usada para avaliar a gravidade da doença e os resultados clínicos. Outras escalas de depressão e instrumentos classificados pelo paciente eram usadas para medir resultados correlacionados. Resultados: Cento e cinquenta e oito pacientes com DRT, na maioria mulheres (84,4%) com idade média de 48,55 anos, foram incluídos na análise. Apenas 31,4% dos pacientes apresentaram uma resposta clinicamente significativa, 10,3% tiveram recidiva e 26,7% alcançaram remissão, conforme medido pela MADRS no final do estudo (EOS). Aproximadamente 55% dos pacientes apresentavam depressão grave/moderadamente grave no EOS. Problemas de mobilidade, cuidados pessoais, problemas nas atividades usuais e dor e desconforto foram relatados pela maioria dos pacientes no EOS, assim como comprometimento marcado/extremo das atividades no trabalho/escola e da vida social/das atividades de lazer no EOS. Conclusões: Os resultados clínicos alcançados atualmente ainda são notavelmente insatisfatórios para DRT. Portanto, o envolvimento de todas as partes interessadas é essencial para implementar protocolos de tratamento mais eficazes no Brasil.

Objective: Treatment-resistant depression (TRD) is a primary concern in Brazil due to its burdensome and complex nature, while diagnosis and treatment is often challenging. The current manuscript presents the clinical outcomes in a one-year follow-up of TRD patients under Standard-of-care (SOC) in the Brazilian subset of the Treatment-Resistant Depression in America Latina (TRAL) study. Methods: This longitudinal phase of TRAL aimed to characterize changes in the clinical outcomes and other variables of interest (e.g. quality of life, disability) in a one-year follow-up of TRD patients in 10 centers in Brazil. Included patients were clinically diagnosed with TRD based on DSM-5 criteria and confirmed by MINI. Montgomery-Asberg Depression Rating Scale (MADRS) was used to assess disease severity and clinical outcomes. Other depression scales and patient rated instruments were used to measure correlated outcomes. Results: One hundred fifty-eight TRD patients, mostly female (84.4%), averaging 48.55 years, were included in the analysis. Only 31.4% of the patients showed a clinically significant response, 10.3% had a relapse and 26.7% achieved remission, as measured through MADRS at end-of-study (EOS). Almost 55% of the patients showed moderately severe/severe depression at EOS. Mobility issues, self-care, problems with usual activities and pain and discomfort were reported by the majority of the patients at EOS, as well as marked/extreme disruption of school/work and social life/leisure activities at EOS. Conclusions: Currently achieved clinical outcomes are still remarkably unsatisfactory for TRD. Therefore, the involvement of all relevant stakeholders is essential to implement more effective treatment protocols in Brazil.

Arketamine as adjunctive therapy for treatment-resistant depression: A placebo-controlled pilot study.

BACKGROUND: Racemic ketamine is a mixture of (R)-ketamine (arketamine) and (S)-ketamine (esketamine), with the latter regarded as the main isomer for antidepressant effects. However, preclinical data and one open-label human trial suggest arketamine might exert a more potent and longer-lasting antidepressant effect with fewer side effects. We aimed to explore the feasibility of a randomized controlled trial of arketamine for treatment-resistant depression (TRD) and to assess its efficacy and safety compared to placebo. METHODS: This is a, randomized, double-blind, crossover, pilot trial (n = 10). All participants received saline and arketamine (0.5 mg/kg) with a one-week interval. Treatment effects were analyzed with a linear mixed effects (LME) model. RESULTS: Our analysis suggested the presence of a carryover effect, so the main efficacy analysis was limited to the first week, which demonstrated a main effect of time (p = 0.038) but not for treatment (p = 0.40) or their interaction (p = 0.95). This indicates that depression improved over time, but without significant difference between arketamine and placebo. Analyzing the two weeks together, findings were the same. Dissociation and other adverse events were minimal. LIMITATIONS: This was a pilot study with a small sample and underpowered. CONCLUSIONS: Arketamine was not superior to placebo for TRD but demonstrated to be extremely safe. Our findings reinforce the importance of continuing studies with this drug, with better powered clinical trials, perhaps considering a parallel design with higher or flexible doses and repeated administrations.

The effects of ketamine and classic hallucinogens on neurotrophic and inflammatory markers in unipolar treatment-resistant depression: a systematic review of clinical trials.

Although results are still preliminary, ketamine and classical hallucinogens have shown promise in recent years as novel, fast-acting antidepressants, especially for the treatment of unipolar treatment-resistant depression (TRD). Depression also seems to be related to abnormal levels of peripheral inflammatory and neurotrophic biomarkers, which may one day help to diagnose of this disorder. In this context, this systematic review of clinical trials evaluated the current evidence that relates the antidepressant effects of ketamine and classical hallucinogens on TRD with changes in inflammatory and neurotrophic biomarkers. Twelve studies were found (n = 587), 2 with oral ayahuasca (1 mL/kg) and 10 with ketamine (mostly intravenous 0.5 mg/kg) administration. Results for all biomarkers assessed were contradictory and thus inconclusive. Randomized controlled trials with bigger samples and higher statistical power are warranted to clarify if peripheral biomarkers can confidently be used to indicate and measure ketamine's and classical hallucinogens' antidepressant effect. The PROSPERO ID for this study is CRD42021249089.

Depression and suicidality severity among TRD patients after 1-year under standard of care: Findings from the TRAL study, a multicenter, multinational, observational study in Latin America.

INTRODUCTION: Treatment resistant depression (TRD) is one of the most pressing issues in mental healthcare in LatAm. However, clinical data and outcomes of standard of care (SOC) are scarce. The present study reported on the Treatment-Resistant Depression in America Latina (TRAL) project 1-year follow-up of patients under SOC assessing clinical presentation and outcomes. MATERIALS AND METHODS: 420 patients with clinical diagnoses of TRD from Argentina, Brazil, Colombia and Mexico were included in a 1-year follow-up to assess clinical outcomes of depression (MADRS) and suicidality (C-SSRS), as well as evolution of clinical symptoms of depression. Patients were assessed every 3 months and longitudinal comparison was performed based on change from baseline to each visit and end of study (12 months). Socio demographic characterization was also performed. RESULTS: Most patients were female (80.9%), married (42.5%) or single (34.4%), with at least 10 years of formal education (71%). MDD diagnosis was set at 37.29 (SD=14.00) years, and MDD duration was 11.11 years (SD=10.34). After 1-year of SOC, 79.1% of the patients were still symptomatic, and 40% of the patients displayed moderate/severe depression. Only 44.1% of the patients achieved a response (≥50% improvement in MADRS), and 60% of the sample failed to achieve remission. Suicidal ideation was reported by more than half of the patients at the end of study. CONCLUSIONS: Depression and suicidality symptoms after a 1-year of SOC is of great concern. Better therapeutic options are needed to tackle this debilitating and burdensome disease.

Latin American consensus recommendations for the management and treatment of patients with treatment-resistant depression (TRD).

Despite the abundance of literature on treatment-resistant depression (TRD), there is no universally accepted definition of TRD, and available treatment pathways for the management of TRD vary across the Latin American region, highlighting the need for a uniform definition and treatment principles to optimize the management of TRD in Latin America. METHODS: Following a thematic literature review and pre-meeting survey, a Latin America expert panel comprising 14 psychiatrists with clinical experience in managing patients with TRD convened and utilized the RAND/UCLA appropriateness method to develop consensus-based recommendations on the appropriate definition of TRD and principles for its management. RESULTS: The expert panel agreed that 'treatment-resistant depression' (TRD) is defined as 'failure of two drug treatments of adequate doses, for 4-8 weeks duration with adequate adherence, during a major depressive episode'. A stepwise treatment approach should be employed for the management of TRD - treatment strategies can include maximizing dose, switching to a different class, and augmenting or combining treatments. Nonpharmacological treatments, such as electroconvulsive therapy, are also appropriate options for patients with TRD. CONCLUSION: These consensus recommendations on the operational definition of TRD and approved treatments for its management can be adapted to local contexts in the Latin American countries but should not replace clinical judgement. Individual circumstances and benefit-risk balance should be carefully considered while determining the most appropriate treatment option for patients with TRD.

Diretrizes clínicas para tratamento da depressão: análise de fatores associados à qualidade e comparação de recomendações para pacientes não respondedores e com depressão resistente / Clinical guidelines for the treatment of depression: analysis of factors associated with quality and comparison of recommendations for nonresponding patients and for patients with resistant depression

Diretrizes clínicas (DCs) de alta qualidade são importantes para a assistência efetiva de pacientes com doenças crônicas, incluindo a depressão. A depressão é um dos principais problemas de saúde mundial, sendo um dos transtornos psiquiátricos mais comumente encontrados na prática médica, afetando cerca de 300 milhões de pessoas. Além de sua natureza debilitante e onerosa, muitas vezes pode levar a desfechos graves, tal como o suicídio, principalmente em pacientes que não respondem aos tratamentos. Assim, o objetivo geral desta tese foi identificar fatores das DCs associados à qualidade metodológica desses documentos e de suas recomendações, e comparar as recomendações para duas situações de falhas da farmacoterapia: pacientes não respondedores e pacientes com depressão resistente ao tratamento (DRT). Operacionalmente, foram feitas revisões sistemáticas da literatura em bases científicas e específicas de DCs, e incluídas DCs publicadas nos últimos onze anos que contivessem recomendações para o tratamento farmacológico de adultos com depressão. Para avaliação geral das DCs, foi aplicado o instrumento AGREE II, e para avaliação específica das recomendações, o instrumento AGREE-REX. As DCs foram consideradas de alta qualidade quando pontuaram com escores maiores ou iguais a 60% (no estudo descrito no capítulo 2) e maiores ou iguais a 80% (no estudo descrito no capítulo 3) no domínio 3 (Rigor de desenvolvimento) do AGREE II. As DCs com recomendações de alta qualidade foram as que pontuaram com mais de 60% no domínio 1 (Aplicabilidade Clínica) do AGREE-REX. Das 63 DCs selecionadas, 17 (27%) apresentaram alta qualidade, e 7 (11%) apresentaram recomendações de alta qualidade. Os fatores associados à maior qualidade foram gerenciamento de conflitos de interesses, equipe multiprofissional e tipo de instituição. A inclusão de representante do paciente na equipe também foi associada a recomendações de maior qualidade. Verificou-se que a maioria das DCs concorda com a necessidade de: reavaliar o diagnóstico, a presença de comorbidades, a adesão ao tratamento, ajustar a dosagem do antidepressivo e adicionar psicoterapia como os primeiros passos para aqueles que não respondem ao tratamento antidepressivo de primeira linha. Em relação às recomendações, há falhas importantes, incluindo a não apresentação de definição padronizada de resposta adequada/inadequada/parcial, e o não estabelecimento de tempo de tratamento necessário para declarar DRT. Todas as DCs incluíram a possibilidade de substituição do antidepressivo, potencialização com outros medicamentos e combinação de antidepressivos. Todavia, três DCs não recomendaram uma sequência entre eles. Por fim, verificou-se que das 17 DCs de alta qualidade e das 7 DCs com recomendações de alta qualidade, apenas duas incluíram definição e recomendações para DRT. Não existe consenso entre as DCs de alta qualidade quanto à definição e uso do termo DRT. Não foi possível extrair uma estratégia terapêutica convergente para DRT em adultos. Os resultados obtidos reforçam a necessidade de maior foco no aprimoramento da qualidade das DCs e de suas recomendações, especialmente nos subgrupos relativos à resposta inadequada ao tratamento e a DRT, nas quais as definições não são claras

High-quality clinical practice guidelines (CPGs) are important for treating patients with chronic diseases such as depression. Depression is a major health concern worldwide, affecting approximately 300 million people. It is one of the most prevalent psychiatric disorders in medical practice. It is not only debilitating and costly but can also lead to tragic consequences such as suicide, particularly in patients who do not respond to treatment. The objective of this thesis was to identify CPGs factors associated with the methodological quality of these documents and their recommendations. Furthermore, this thesis aimed to compare the recommendations in two pharmacotherapy failure situations: inadequate response to treatment and treatment-resistant depression (TRD). Systematic literature reviews were conducted on scientific and CPG-specific databases. Reviews were also conducted on CPGs published in the last eleven years that included recommendations for pharmacological treatment of adults with depression. The AGREE II instrument was used for the CPGs general assessment, while the AGREE-REX instrument was used specifically to assess their recommendations. CPGs were considered high quality if they achieved a score of at least 60% in the study mentioned in Chapter 2 and a score of at least 80% in the study mentioned in Chapter 3 in the AGREE II, rigour of development domain. The CPGs with high-quality recommendations were those that scored greater than 60% in Domain 1 (Clinical Applicability) of the AGREE-REX. Of the 63 selected CPGs, 17 (27%) were high quality, and 7 (11.1%) had recommendations of high quality. Factors associated with higher quality were conflict of interest management, multi-professional team, and type of institution. Inclusion of a patients representative on the team was associated with higher quality recommendations. Most CPGs agreed with the need to reassess diagnoses, comorbidities, and treatment adherence. They also agreed on adjusting antidepressant dosage and providing psychotherapy as a first step for patients who do not respond to first-line antidepressant treatment. There are significant shortcomings in the recommendations. In particular, the lack of a standardized definition of adequate, inadequate, or partial response to treatment and the lack of clarity surrounding the duration of treatment required to establish TRD. All CPGs included the possibility of antidepressant substitution, potentiation with other drugs, and a combination of antidepressants. However, three CPGs did not recommend a preferred sequence for these interventions. Finally, of the 17 high-quality CPGs and the 7 CPGs with high-quality recommendations, only two included definition and recommendations for TRD. There is no consensus among the high-quality CPGs regarding the definition and use of the term TRD. Ultimately, finding a convergent therapeutic strategy for TRD in adults was not possible. These results highlighted the need to focus more on improving the quality of CPGs and their recommendations, especially in the subgroups related to inadequate response to treatment and TRD, where definitions are unclear

Intramuscular ketamine vs. escitalopram and aripiprazole in acute and maintenance treatment of patients with treatment-resistant depression: A randomized double-blind clinical trial.

Objective: Ketamine, an N-methyl D-aspartate (NMDA) receptor antagonist, can promote rapid action in the management of individuals with treatment-resistant depression (TRD) at sub-anesthetic doses. However, few studies have investigated the long-term use of ketamine administered intravenously (IV) and intranasally (IN). We report the design and rationale of a therapeutic trial for assessing the efficacy, safety, and tolerability of repeated-dose intramuscular (IM) ketamine vs. active treatment (escitalopram and aripiprazole) in TRD patients. Methods: A comparative, parallel-group, randomized double-blind trial assessing the efficacy, safety, and tolerability of acute (4 weeks) and maintenance (24 weeks) use of IM ketamine (0.75 mg/kg) vs. active control (escitalopram 15 mg and aripiprazole 5 mg) in individuals with moderate-severe intensity TRD (no psychotic symptoms) with or without suicide risk will be conducted. Patients with TRD (18-40 years) will be randomized and blinded to receive ketamine IM or active treatment at a 1:1 ratio for 4 weeks (active treatment) and 24 weeks (maintenance treatment). Subjects will be assessed using clinical scales, monitored for vital signs (VS) after application of injectable medication, and undergo neuropsychological tests. The primary outcome will be changed on the Montgomery-Åsberg Depression Rating Scale (MADRS) during the course of the trial. The study is in running. Results: This study can potentially yield evidence on the use of IM ketamine in the treatment of depressive disorders as an ultra-rapid low-cost therapy associated with less patient discomfort and reduced use of medical resources, and can elucidate long-term effects on different outcomes, such as neuropsychological aspects. Conclusions: The trial can help promote the introduction of a novel accessible approach for the treatment of complex disease (TRD) and also allow refinement of its long-term use. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT04234776, identifier: NCT04234776.