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.

Progress of non-pharmacological treatments for treatment-resistant depression / 实用医学杂志

Depression,with its characteristics of high prevalence,younger onset age,and high suicide rate,has repeatedly become the focus of societal discussion.It severely impairs the quality of life of patients and affects the development of the economy.Currently,treatments for depression are limited and vary in effectiveness.An increasing number of patients are classified as having treatment-resistant depression.In order to improve the cure rate further,numerous non-pharmacological treatments have been explored,among which physical therapies have garnered significant attention.This article provides a brief overview and discussion of recent physical treatments for treatment-resistant depression,offering new prospects for the field and inspiring readers with fresh ideas.

Treatment resistance in schizophrenia: a meta-analysis of prevalence and correlates

Objectives: To determine the prevalence and correlates of treatment-resistant schizophrenia (TRS) through a systematic review and meta-analysis. Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria, an electronic search was performed in PubMed and Embase through May 17, 2022. All study designs that assessed a minimum of 20 schizophrenia-spectrum patients and provided data on TRS prevalence or allowed its calculation were included. Estimates were produced using a random-effects model meta-analysis. Results: The TRS prevalence across 50 studies (n = 29,390) was 36.7% (95%CI 33.1-40.5, p < 0.0001). The prevalence ranged from 22% (95%CI 18.4-25.8) in first-episode to 39.5% (95%CI 32.2-47.0) in multiple-episode samples (Q = 18.27, p < 0.0001). Primary treatment resistance, defined as no response from the first episode, was 23.6% (95%CI 20.5-26.8) vs. 9.3% (95%CI 6.8-12.2) for later-onset/secondary (≥ 6 months after initial treatment response). Longer illness duration and recruitment from long-term hospitals or clozapine clinics were associated with higher prevalence estimates. In meta-regression analyses, older age and poor functioning predicted greater TRS. When including only studies with lower bias risk, the TRS prevalence was 28.4%. Conclusion: Different study designs and recruitment strategies accounted for most of the observed heterogeneity in TRS prevalence rates. The results point to early-onset and later-onset TRS as two separate disease pathways requiring clinical attention. Registration number: PROSPERO CRD42018092033.

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.

Tiaoqi Jieyu acupuncture for treatment-resistant depression: a randomized controlled trial / 中国针灸

OBJECTIVE@#To observe the effect of Tiaoqi Jieyu (regulating qi and relieving depression) acupuncture on the clinical symptoms of treatment-resistant depression (TRD), and to explore the relationship between the acupuncture pain sensitivity and symptom's improvement.@*METHODS@#A total of 78 patients with TRD were randomly divided into an observation group (39 cases, 3 cases dropped off) and a control group (39 cases, 4 cases dropped off). The patients in the control group were treated with medications according to the treatment plan of psychiatrists (at least one medication was 5-hydroxytryptamine reuptake inhibitor). On the basis of the control group, the patients in the observation group were treated with Tiaoqi Jieyu acupuncture, and Baihui (GV 20), Yintang (GV 24+), Yanglingquan (GB 34), Taichong (LR 3), Hegu (LI 4), Neiguan (PC 6), Yinlingquan (SP 9) and Zusanli (ST 36), etc. were selected. The acupuncture was given three times a week. Both groups were treated for 8 weeks. After 8-week treatment, the response rate of Hamilton depression scale-24 (HAMD-24) score after was evaluated in the two groups. The scores of HAMD-24 and Hamilton anxiety scale (HAMA) were compared between the two groups before treatment, after 4, 8-week treatment and 12 weeks after treatment (follow-up). After the first treatment and 8-week treatment, the visual analogue scale (VAS) score in the observation group was evaluated, and the correlation between VAS score after the first treatment and HAMD-24 score before treatment, between VAS score after the first treatment and the course of disease in the observation group was analyzed, and the correlation between difference of VAS after 8-week treatment and after the first treatment and difference of HAMD-24 score before treatment and after 8-week treatment was analyzed.@*RESULTS@#After 8-week treatment, the response rate of HAMD-24 score in the observation group was 52.8% (19/36), higher than 17.1% (6/35) in the control group (P<0.001). Compared before treatment, the scores of HAMD-24 and HAMA in the two groups were decreased after 4-week treatment, 8-week treatment and in follow-up (P<0.05), and those in the observation group were superior to the control group (P<0.05). After 8-week treatment, the acupuncture pain VAS score in the observation group was (5.28±2.13) points, which was higher than (3.33±1.62) points after the first treatment (P<0.001). There was a negative correlation between VAS score after the first treatment and HAMD-24 score before treatment in the observation group (r =-0.486, P=0.003); there was no correlation between acupuncture pain VAS score after the first treatment and the course of disease in the observation group (P>0.05). After 8-week treatment, there was a positive correlation between the difference of VAS score and the difference of HAMD-24 score in the observation group (r =0.514, P=0.001).@*CONCLUSION@#Tiaoqi Jieyu acupuncture could improve the depression and anxiety in patients with TRD, and the symptom's improvement is related to the recovery of acupuncture pain sensitivity.

Clinical effectiveness and its mechanisms of deep brain stimulation in treatment-resistant depressive disor-ders / 中国神经精神疾病杂志

Deep brain electrical stimulation is one of the emerging therapeutic approaches for treatment-resistant depressive disorders.This article outlines a variety of potential targets for deep brain electrical stimulation in the treatment of treatment-resistant depressive disorders and summarizes the results of relevant clinical studies.These targets include the subgenual cingulate gyrus,nucleus accumbens,ventral capsule and ventral striatum area,medial forebrain bundle,and lateral habenula,among other regions.Based on these studies,the article integrates relevant basic research and further discusses the possible mechanisms through which deep brain stimulation may exert therapeutic effects,including synaptic plasticity,neurophysiology,neural circuits,and neurotransmitters.The article also assesses and prospects the further application potential of deep brain electrical stimulation.The authors believe that the multi-target stimulation combining existing clinical research results and neurobiological mechanisms could be a crucial development direction to enhance the treatment of treatment-resistant depressive disorders using deep brain electrical stimulation.

Association of cognitive function,plasma C-reactive protein level in patients with treatment-resistant obsessive-compulsive disorder / 中国心理卫生杂志

Objective:To evaluate the association of cognitive function,clinical symptoms,and plasma C-reac-tive protein(CRP)level in patients with treatment-resistant obsessive-compulsive disorder(trOCD).Methods:Fif-ty-five patients with trOCD,45 patients with non-trOCD,and 65 normal controls were enrolled.The Yale-Brown Obsessive-Compulsive Scale(YBOCS),Hamilton depression scale,Hamilton anxiety scale,MATRICS Consensus Cognitive Battery(MCCB)were used to evaluate the OCD,depressive or anxious clinical symptoms,as well as cognitive function,in above-mentioned subjects.The plasma CRP level were examined by using the latex-enhanced immunoturbidimetry methods in three groups.Results:Compared with the other two groups,the MCCB cognition scores,especially information processing speed,working memory,inferential knowledge and problem-solving skills were higher in the trOCD group,respectively(Ps＜0.05).The plasma CRP level and percentage of cases with high CRP level(≥3 mg/L)in the trCOD group were higher than those in other two groups(P＜0.05).However,difference of MCCB and its factorial scores revealed no statistical significances in non-trOCD group(Ps＞0.05).Logistic regression analysis showed that potential risk factors of treatment-resistant OCD including,more obsessive-compulsive symptoms(OR=2.01),higher severity of OCD(OR=2.29),lower MCCB total scores(OR=4.01),higher plasma CRP level(OR=4.24),and longer disease course of OCD(OR=3.23)(P＜0.05).Conclusion:Impaired cognitive function,high plasma C-reactive protein level,may be associated with more obsessive-compul-sive symptoms,higher severity of OCD,as well as long disease course of OCD.

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

Clozapine prescription trends in Brazil in the last decade

Objective: Clozapine is a second-generation antipsychotic indicated for treatment-resistant schizophrenia. Studies in several countries have shown a low rate of clozapine use despite the fact that approximately 30% of schizophrenia cases are treatment-resistant. In Brazil, few studies have addressed the frequency and variety of antipsychotic use in individuals diagnosed with schizophrenia (ICD F20). The objective of this study was to measure the rates of clozapine use in this population in the last decade using Brazilian Ministry of Health data. Methods: Prescriptions made between 2010 and 2020 in all 26 states and the Federal District registered at the Outpatient Information System Database from the Brazilian Health System (SIASUS) were evaluated. Results: A total of 25,143,524 prescriptions were recorded in this period, with clozapine representing 8.86% of all antipsychotics. The most frequently prescribed antipsychotic for patients with schizophrenia was olanzapine (35.8%), followed by quetiapine (27.5%). From 2010 to 2020, the rate of clozapine prescriptions in Brazil increased from 7.2% to 10.9%. Conclusions: Despite a slight increase in prescriptions in the last decade, clozapine is still underutilized in Brazil.

Esquizofrenia resistente al tratamiento. I, concepto e impacto clínico / Treatment resistant schizophrenia. I, concept and clinical impact

La esquizofrenia es una psicosis crónica que se caracteriza por tres dominios sintomáticos: síntomas positivos, síntomas negativos y síntomas cognitivos. Se estima que afecta al 1 % de la población. El desarrollo de la psicofarmacología y del tratamiento de la esquizofrenia ha permitido distinguir genios evolutivos según la respuesta terapéutica. En este sentido es que se delinea el concepto de esquizofrenia resistente al tratamiento (ERT). Se estima ERT en un 30 % aproximadamente de los sujetos que padecen esquizofrenia. La identificación temprana y adecuada de este subgrupo de individuos se relaciona con una mejor respuesta. Este artículo es una narrativa sobre el concepto de ERT y su impacto clínico.

Schizophrenia is a chronic psychosis characterized by three symptom domains: positive symptoms, negative symptoms and cognitive symptoms. Its prevalence is about 1 % of the general population. The development of psychopharmacology and schizophrenia treatment have made possible the distinction between different clinical courses and outcomes according to treatment response. This is the basis for the concept of treatment resistant schizophrenia (TRS), which can be present in 30 % of schizophrenic patients. Early and adequate identification of this subgroup is related to better outcomes. Authors analyze the previously mentioned concept and its clinical impact.

Uso da cetamina na depressão resistente ao tratamento: uma revisão sistemática / Use of ketamine in treatment-resistant depression: a systematic review

RESUMO Objetivo A cetamina apresenta-se como uma alternativa promissora contra a depressão resistente ao tratamento (DRT), no entanto o conhecimento de sua aplicação como antidepressivo ainda é restrito. Diante disso, objetivou-se investigar sua eficácia em pacientes com DRT. Métodos A busca da literatura foi efetuada na base de dados MedLine. Os critérios de inclusão foram: estudos clínicos controlados e randomizados dos últimos cinco anos e em inglês. Excluímos os artigos que não responderam à pergunta PICO e aqueles com tamanho de amostra e metodologia de estudo destoantes, quando comparados aos ensaios que basearam esta revisão. Resultados Considerando uma amostra final de seis artigos, observou-se uma melhor resposta à cetamina (principalmente em ganho de humor), quando comparada ao tratamento convencional contra a DRT. Já com sua primeira infusão, na dose de 0,5 mg/kg, foi possível perceber seus efeitos antidepressivos. A manutenção desses efeitos parece ser obtida com a administração de 0,5 mg/kg do medicamento, três vezes por semana. Por outro lado, a redução de tal dosagem pode diminuir ou anular os efeitos. Conclusões O uso da cetamina apresentou resultados efetivos na melhora do quadro de DRT, com efeitos adversos de pequena gravidade e de fácil controle. Entretanto, outros estudos, com amostras maiores e métodos diferentes, são necessários, para uma conclusão de maior consistência.

ABSTRACT Objective Ketamine presents itself as a promising alternative against treatment-resistant depression (TRD), however, the knowledge of its application as an antidepressant is still restricted. Therefore, the objective was to investigate its effectiveness in patients with TRD. Methods The literature search was carried out in the MedLine database. Inclusion criteria were: controlled and randomized clinical studies from the last five years and in English. We excluded articles that did not answer the PICO question and those with different sample size and study methodology, when compared to the tests that based this review. Results Considering a final sample of six articles, a better response to ketamine was observed (mainly in mood gain), when compared to conventional treatment against TRD. With its first infusion, at a dose of 0.5 mg/kg, it was possible to notice its antidepressant effects. The maintenance of these effects seems to be achieved with the administration of 0.5 mg/kg of the drug, three times a week. On the other hand, the reduction of such a dosage can diminish or cancel the effects. Conclusions The use of ketamine showed effective results improving the condition of TRD, with adverse effects of small severity and easy control. However, further studies, with larger samples and different methods, are needed, for a more consistent conclusion.

Effect of Mentone® on depression- and anxiety-like profiles and regional brain neurochemistry in the adolescent Wistar Kyoto rat, a putative model of endogenous depression

Objectives: Antidepressants, when prescribed to treat adolescent depression tend to induce adverse effects, including suicidal tendencies. This is because the adolescent brain circuitry is still maturing and is therefore extremely vulnerable. As such, the search is on for compounds for use in complementary/alternative medicine. Polyherbal formulations are widely used as therapeutic alternatives for the treatment of depression. Such formulations and plant extracts are being studied in adult rodent models using standard pharmacological parameters, but not much emphasis has been given to testing the same in adolescents and endogenous animal models of depression. Therefore, the present study was focused on testing out the effect of the polyherbal formulation Mentone® on depression- and anxiety-like profiles and brain neurochemistry in the adolescent Wistar Kyoto rat (WKY), a putative model of endogenous and treatment-resistant depression (TRD). Materials and Methods: Mentone®, a polyherbal formulation comprising of four different plant species: Centella asiatica (Brahmi), Evolvulus alsinoides (Shankapushpi), Tinospora cordifolia (Guduchi), and Glycyrrhiza glabra (Yashtimadhu) was tested at two (18 and 36 mg/kg body weight) doses from the post-natal day (pnd) 25 to pnd 42 using standard neurobehavioral paradigms. Vehicular controls were intubated with saline and positive controls with 10 mg/kg body weight of conventional antidepressant, Fluoxetine. From pnd 35 onwards, animals were tested on a battery of tests, including sucrose preference, novel open field, elevated plus maze, and forced swim or Porsolt’s learned helplessness test. On pnd 42, animals were sacrificed and brain regional tissues such as the Prefrontal cortex (PFC), Striatum (Str), Nucleus Accumbens (NAc), and Hippocampus were microdissected out and subjected to reverse phase HPLC for the separation and quantification of monoamines: Norepinephrine (NE), dopamine (DA), serotonin (5-HT) and their metabolites, 3,4-Dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) in reference to external standards. Results: Mentone® reversed anhedonia by increasing sucrose consumption in Mentone®-treated as compared to Fluoxetine-treated groups. However, there was no effect on anxiety-related parameters in the novel open field or elevated plus-maze. Mentone® exhibited significant anti-depressant-like effects as indicated by its ability to reduce swim stress-induced immobility in Porsolt’s behavioural despair test with a concomitant increase in climbing or struggling behaviour, signifying reversal of depressive-like symptomatology. HPLC-based separation and quantification of brain regional levels of monoamines and their metabolites revealed increased DA levels in NAc and Str in treated groups with decreased levels of metabolite DOPAC in Mentone®-treated groups indicating increased DA tone. Significantly reduced 5-HT metabolite 5-HIAA levels in both PFC and Str is indicative of increased 5-HT tone in both Mentone®- and Fluoxetine-treated groups. NE was variably affected. Conclusion: While no anxiolytic effects and differential neurochemical effects were observed in brain regional areas in relation to Mentone® and Fluoxetine treatment, anhedonia and forced swim test, which are gold-standard tests for assessing depressive-like profiles indicated an effect of Mentone® that was on par with Fluoxetine. Thus, studies on such Ayurvedic formulations would enable a teasing out or differentiation between anxiolytic-like and depressive-like symptomatology and could constitute a source that holds promise in the development of complementary/alternative therapies for the treatment of depression in general and TRD in particular.

A narrative review on invasive brain stimulation for treatment-resistant depression

While most patients with depression respond to pharmacotherapy and psychotherapy, about one-third will present treatment resistance to these interventions. For patients with treatment-resistant depression (TRD), invasive neurostimulation therapies such as vagus nerve stimulation, deep brain stimulation, and epidural cortical stimulation may be considered. We performed a narrative review of the published literature to identify papers discussing clinical studies with invasive neurostimulation therapies for TRD. After a database search and title and abstract screening, relevant English-language articles were analyzed. Vagus nerve stimulation, approved by the U.S. Food and Drug Administration as a TRD treatment, may take several months to show therapeutic benefits, and the average response rate varies from 15.2-83%. Deep brain stimulation studies have shown encouraging results, including rapid response rates (> 30%), despite conflicting findings from randomized controlled trials. Several brain regions, such as the subcallosal-cingulate gyrus, nucleus accumbens, ventral capsule/ventral striatum, anterior limb of the internal capsule, medial-forebrain bundle, lateral habenula, inferior-thalamic peduncle, and the bed-nucleus of the stria terminalis have been identified as key targets for TRD management. Epidural cortical stimulation, an invasive intervention with few reported cases, showed positive results (40-60% response), although more extensive trials are needed to confirm its potential in patients with TRD.

Treatment-resistant bipolar depression: concepts and challenges for novel interventions

Treatment-resistant bipolar depression (TRBD) has been reported in about one-quarter of patients with bipolar disorders, and few interventions have shown clear and established effectiveness. We conducted a narrative review of the published medical literature to identify papers discussing treatment-resistant depression concepts and novel interventions for bipolar depression that focus on TRBD. We searched for potentially relevant English-language articles published in the last decade. Selected articles (based on the title and abstract) were retrieved for a more detailed evaluation. A number of promising new interventions, both pharmacological and non-pharmacological, are being investigated for TRBD treatment, including ketamine, lurasidone, D-cycloserine, pioglitazone, N-acetylcysteine, angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor blockers, cyclooxygenase 2 inhibitors, magnetic seizure therapy, intermittent theta-burst stimulation, deep transcranial magnetic stimulation, vagus nerve stimulation therapy, and deep brain stimulation. Although there is no consensus about the concept of TRBD, better clarification of the neurobiology associated with treatment non-response could help identify novel strategies. More research is warranted, mainly focusing on personalizing current treatments to optimize response and remission rates.

Application of psychotherapy in treatment-resistant depression / 中华行为医学与脑科学杂志

Treatment-resistant depression (TRD) is characterized by a high suicide rate and a high recurrence rate. The effect of the medicine on TRD is not ideal with obvious side effects. Psychotherapy is an important method recommended in many guidelines for the treatment of depression. However, previous studies and clinical applications have paid little attention to the application of psychotherapy in TRD. Therefore, based on recent studies, this paper reviews the effects of psychotherapy on the depressive symptoms, suicide risk, and recurrence risk in TRD. Further, the possible therapeutic mechanisms are discussed, including the improvement of interpersonal function by dealing with early trauma in TRD, therefore alleviating symptoms; intervening in the dysfunctional cognitive pattern of TRD to help them cope with negative life events, therefore reducing stress and depression. Combined with the limitations of existing studies, the following directions can be considered in the future: improving the research quality, measuring behavioral and physiological indicators to further clarify the therapeutic mechanism, identifying ways in which psychotherapy can be combined with other treatments, exploring the group and online therapy to increase accessibility of psychotherapy for TRD.

Treatment-resistant depression and its diagnosis and treatment / 四川精神卫生

The aim of this study is to explore the diagnostic strategies and options for treatment-resistant depression （TRD）. Despite the well-established efficacy of antidepressants， 20%~30% of depressive patients in the clinic fail to respond or respond poorly to normative treatment with antidepressants. Patients with TRD are forced to bear a heavy burden of medical costs and disease. Therefore， this article discusses the TRD in terms of the definition， prevalence， disease burden， etiological mechanism， risk factors， assessment grading， highlighting different treatment strategies and options to inform clinical practice and scientific research on TRD.

Comparison of cognitive function in patients with treatment-resistant depression and drug-naive first-episode major depressive disorder / 四川精神卫生

ObjectiveTo explore the differences of cognitive function in patients with treatment-resistant depression and drug-naive first-episode major depressive disorder， and to examine the relationship between severity of clinical symptoms and cognitive function， so as to provide references for prognosis improvement. MethodsFrom November 2016 to December 2019， 119 patients with drug-naive first-episode major depressive disorder and 82 patients with treatment-resistant depression in a hospital in Guangzhou were enrolled， meantime， another 71 healthy individuals recruited from the community were set as healthy control group. Clinical symptoms were assessed using Hamilton Depression Scale-17 item （HAMD-17） and Hamilton Anxiety Scale （HAMA）. Cognitive domains， including speed of processing， working memory， verbal learning and memory， and visual learning and memory were measured with the MATRICS Consensus Cognitive Battery （MCCB）. Multiple covariance analysis was used to compare the differences in cognitive function among three groups. Thereafter， partial correlation analysis was performed within patient groups to explore the relationship of HAMD-17/HAMA score with the four dimensions of MCCB. ResultsThe speed of processing， visual learning and memory scores of treatment-resistant depression group and drug-naive first-episode depression group were lower than those of healthy control group， and the working memory score of the treatment-resistant depression group was lower than that of the healthy control group， with statistical significance （P<0.05 or 0.01）. The speed of processing， visual learning and memory scores of treatment-resistant depression group were significantly lower than those of drug-naive first-episode depression group （P<0.05 or 0.01）. Partial correlation analysis within patient groups found that HAMD-17/HAMA total score had no correlation with the four dimensions of MCCB （P>0.05）. ConclusionCompared with drug-naive first-episode major depressive disorder patients and healthy controls， the impairments of speed of processing， visual learning and memory are more severe in patients with treatment-resistant depression. Moreover， the cognitive function impairment in patients with drug-naive first-episode major depressive disorder and treatment-resistant depression has no correlation with the severity of depressive and anxious symptoms.

Research progress in the treatment of treatment-resistant depression by deep brain stimulation / 四川精神卫生

In recent years， plenty of studies have demonstrated that deep brain stimulation （DBS） has potential efficacy for treatment-resistant depression. This paper reviews the worldwide research progress of DBS in the treatment of treatment-resistant depression， in which the DBS treatment mechanism， targets and outcomes are discussed， the limitations of current DBS treatment are summarized， and the development direction of DBS is also forecasted， therefore providing a factual basis for relevant experiments in China.

Clozapine use decreases the number of hospitalizations per year in patients with treatment-resistant schizophrenia

For years, the management of schizophrenia has represented a challenge for clinicians, with antipsychotic treatments usually resulting in relapses and new hospitalizations. Clozapine has been shown to be an effective medication for treatment-resistant schizophrenia (TRS), but is currently underused due to its potential side effects. Nevertheless, research has suggested that clozapine reduces future hospitalizations in patients with TRS. This study aims to verify the rates of hospitalizations in patients with TRS under long-term use of clozapine. We retrospectively analyzed clinical data from 52 individuals with TRS before and after the use of clozapine. The mean duration of treatment with and without clozapine was 6.6 (± 3.9) and 8.5 years (± 6.6), respectively. Patients had a median of 0.5 (0.74) hospitalizations per year before the use of clozapine and 0 (0.74) hospitalizations after it (p = 0.001). Therefore, the use of clozapine resulted in an expected reduction in the number of hospitalizations per year in individuals with TRS. (AU)

Epidemiologia e ônus da depressão resistente ao tratamento no Brasil: análise do subgrupo brasileiro do estudo de observação multicêntrico TRAL / Epidemiology and burden of treatment-resistant depression in Brazil: analysis of the Brazilian subset of multicenter observational TRAL study

Objetivos: A epidemiologia da depressão resistente ao tratamento (DRT) varia mundialmente, mas é incerta na América Latina. Este artigo relata a epidemiologia e o ônus da DRT em pacientes com transtorno depressivo maior (TDM) no Brasil, no estudo observacional multinacional, multicêntrico, de DRT na América Latina (TRAL). Métodos: Trezentos e noventa e seis pacientes adultos com TDM (tratados ou não) no Brasil, com diagnóstico de TDM usando o Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) e confirmado por MINI Entrevista Neuropsiquiátrica Internacional v7.0.2, foram incluídos em 10 centros. Os pacientes forneceram consentimento e concluíram as avaliações. Os critérios de exclusão incluíram pacientes com psicose, esquizofrenia, transtorno bipolar, transtorno esquizoafetivo, demência, transtorno de uso de substância ou participação atual em outro estudo. A MADRS foi usada para gravidade da doença. Escalas de depressão e instrumentos classificados pelos pacientes foram usados para medir os resultados. Resultados: A prevalência de DRT em pacientes com TDM na América Latina corresponde a 29,1% (IC 95% [26,8%; 31,4%]), embora no Brasil corresponda a 40,4% (IC 95%: 35,6%-45,2%), a mais alta no estudo TRAL. Os pacientes com DRT são mais velhos e apresentam maior proporção de divórcios e menor nível educacional, com pontuação mais alta na Escala de Classificação da Depressão de Montgomery-Asberg (MADRS), comparados a pacientes sem DRT. Os custos de saúde foram maiores em pacientes com DRT, com menor qualidade de vida e maiores custos de saúde e comprometimento laboral. Conclusões: Estes achados confirmam que a DRT apresenta alta prevalência no Brasil, consistentemente com estudos anteriores sobre transtornos depressivos. Globalmente, os pacientes com DRT apresentam maior ônus da doença, sugerindo a necessidade de melhorar os cuidados para pacientes com DRT no Brasil

Objectives: Treatment-resistant depression (TRD) epidemiology varies worldwide, but uncertain in Latin America (LatAm). This paper reports on the epidemiology and burden of TRD in major depressive disorder (MDD) patients in Brazil from the TRD in America Latina (TRAL) multicenter, multinational, observational study. Methods: 396 adult patients (treated or untreated) with MDD diagnosis in Brazil using Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) and confirmed by MINI International Neuropsychiatric Interview v7.0.2 were consecutively enrolled from 10 clinical sites in Brazil. Patients provided consent and complete assessments. Exclusion criteria included patients with psychosis, schizophrenia, bipolar disorder, schizoaffective disorder, dementia, with substance use disorder or currently participating in another clinical trial. Montgomery-Asberg Depression Rating Scale (MADRS) was used for disease severity. Depression scales and patient rated instruments were used to measure outcomes. Results: The prevalence of TRD in MDD patients in LatAm is 29.1% (95%CI [26.8%; 31.4%]), though the values for Brazil are 40.4% (95%CI: 35.6%-45.2%), the highest in the TRAL study. TRD patients are older, have higher proportion of divorce and lower education, with higher MADRS score compared to non-TRD patients. Healthcare costs were higher in TRD patients, with lower quality of life (QoL) and higher work impairment and healthcare costs. Conclusions: Present findings confirms that TRD is highly prevalent in Brazil, which is consistent with previous studies concerning depressive disorders. Globally, TRD patients experience higher burden of the disease. These findings suggest the need to improve care among TRD patients in Brazil