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.

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

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.

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.

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.

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.

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

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.

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.

Estimulación cerebral profunda en el núcleo accumbens en pacientes con depresión resistente al tratamiento: reporte de casos / Nucleus accumbens deep brain stimulation in patients with treatment-resistant depression: report of four cases

INTRODUCCIÓN: La estimulación cerebral profunda (DBS) se ha propuesto como una alternativa terapéutica para el manejo de la depresión resistente al tratamiento (DRT). Sin embargo, existen múltiples blancos para neuroestimulación y se desconoce el punto neuroanatómico óptimo en esta patología. Como parte del circuito de recompensa, el núcleo accumbens (NAc) ha sido estudiado en modelos de depresión y anhedonia. El objetivo de este artículo fue describir la experiencia clínica de la implantación de electrodos bilaterales de DBS en el NAc. REPORTE DE CASOS: Se describe la experiencia en cuatro mujeres entre los 17 a 41 años con DRT. Los casos presentaban antecedente de múltiples hospitalizaciones e intentos de suicidio serios, a pesar de haber sido tratadas previamente con terapia farmacológica, psicoterapia y TECAR (Terapia electroconvulsiva con anestesia y relajación). A los 6 meses del inicio del DBS, se observó una mejoría de los síntomas depresivos en la escala de Hamilton y un incremento en la escala de funcionalidad global. La anhedonia y la abulia persistieron luego de la cirugía, aunque con menor intensidad. CONCLUSIÓN: La DBS del NAc puede ser una estrategia efectiva en el tratamiento de pacientes con DRT, impactando en la funcionalidad y en la disminución del riesgo suicida.

INTRODUCTION: Deep brain stimulation (DBS) has been proposed as a therapeutic alternative for Treatment-resistant depression (TRD) patients. However, there are multiple targets for neurostimulation and the optimal neuroanatomical landmark for this pathology is unknown. Nucleus accumbens (NAc) is a crucial part of the reward circuit and has been studied extensively in models of depression and anhedonia. The objective of this study was to describe our clinical experience with DBS of the NAc patients with TRD. CASE SERIES: It described the experience in four females between 17 and 41 years of age. All cases presented with a history of multiple hospitalizations and serious suicide attempts, despite having been treated with optimal pharmacological regimes, psychotherapy and ECT (Electroconvulsive therapy). Six months after the initiation of DBS, an improvement in the Hamilton Depression Scale and in the Global Assessment of Functioning Scale was observed. Anhedonia and abulia persisted after the surgery, although less severe. CONCLUSION: DBS of NAc seems to offer favorable surgical outcomes in patients with TRD, impacting functionality and suicidal risk.

Research progress in combination applications of antidepressant drugs / 中国中药杂志

Depression is a common affective disorder. The application of antidepressants can significantly alleviate the symptoms of depression, which is the most important way to treat depression in clinical practice. Due to the complex etiology, wide variety, as well as diversity and severity of serious concomitant symptoms, rational addition of other drugs into antidepressants can significantly improve the cure rates of depression, reduce adverse reactions, and improve patient compliances. Therefore, the combined applications of differential drugs have been commonly used in clinic. In this paper, more than 600 literatures about depression from 2010 to 2019 were collected based on the key words of antidepressant, depression, combined medication, synergism and increase efficiency. Based on this, by summarizing and classifying the existing combinations of antidepressant drugs, this paper systematically expounds the current combined applications of antidepressant drugs in three categories, i.e. western medicines combined with western medicines, western medicines combined with traditional Chinese medicines, and traditional Chinese medicines combined with traditional Chinese medicines, in the expectation of providing the direction and basis for the selection of rational combinations of antidepressant drugs in clinic.

Deep Brain Stimulation for the Treatment of Resistant Depression: Systematic Review of the Literature

Depression is the leading cause of disability worldwide, and it is related to high suicide rates. Furthermore, a great number of patients do not respond to any of the available treatments. Deep brain stimulation (DBS), a versatile technology with expanding indications, is considered a potential treatment for resistant depression. However, in over 10 years of clinical research, its efficacy has not been completely proven. Although new trials using DBS for treatment-resistant depression keep emerging, two of the three Level I evidence-based studies recently conducted have not provided conclusive data. Methodological limitations andmajor biases have compromised the obtention of clearer results. In this systematic review of the literature, we intend to critically assess the clinical trials performed in this field.

Neurofeedback Treatment on Depressive Symptoms and Functional Recovery in Treatment-Resistant Patients with Major Depressive Disorder: an Open-Label Pilot Study

BACKGROUND: We evaluated the effects of neurofeedback as an augmentation treatment on depressive symptoms and functional recovery in patients with treatment-resistant depression (TRD). METHODS: We included 24 adult patients with TRD and 12 healthy adults. 24 TRD patients were assigned to the neurofeedback augmentation group (n = 12) and the medication-only (treatment as usual [TAU]) group (n = 12). The neurofeedback augmentation group underwent combined therapy comprising medication and 12–24 sessions of neurofeedback training for 12 weeks. To assess the serum levels of brain-derived neurotrophic factor (BDNF) in both groups, pre- and post-treatment blood samples were obtained. Patients were evaluated using the Hamilton Depression Rating Scale (HAM-D), Beck Depression Inventory (BDI), Clinical Global Impression-Severity (CGI-S), 5-level version of European Quality of Life Questionnaire 5-Dimensional Classification (EQ-5D-5L), and Sheehan Disability Scale (SDS) at baseline, and at the 1-, 4-, and 12-week. RESULTS: From baseline to week 12, neurofeedback training reduced mean scores on HAM-D, BDI-II, CGI-S, and SDS, and increased mean EQ-5D-5L tariff score. In the neurofeedback augmentation group, the response and remission rates were 58.3% and 50.0%, respectively, at week 12. Changes in HAM-D, EQ-5D-5L tariff score, and SDS were significantly larger in the neurofeedback group than in the medication-only (TAU) group. No significant difference in BDNF level was found pre- vs. post-treatment in any of the groups. CONCLUSION: Despite the small sample size, these results suggest that neurofeedback treatment may be effective as an augmentation treatment, not only for depressive symptoms, but also for functional recovery, in patients with TRD. TRIAL REGISTRATION: Clinical Research Information Service Identifier: KCT0004183 ClinicalTrials.gov Identifier: NCT04078438

Comparison of the Bupropion versus Aripiprazole Adjunctive Therapy for the Treatment of Female Depression : Post-Hoc Analyses from a Randomized Prospective Open-Label Multi-Center Study / 우울ㆍ조울병

OBJECTIVES: The purpose of this study was to examine effects of adjunctive aripiprazole versus bupropion, on depressive symptoms of female depression.METHODS: Sixty six female patients with major depressive disorders were enrolled from a six-week, randomized prospective open-label multi-center study. Participants were randomized to receive aripiprazole (2.5–10 mg/day) or bupropion (150–300 mg/day). Montgomery Asberg Depression Rating Scale, 17-item Hamilton Depression Rating scale (HAM-D17), Iowa Fatigue Scale, Drug-Induced Extrapyramidal Symptoms Scale, Psychotropic-Related Sexual Dysfunction Questionnaire scores, and Clinical Global Impression-Severity (CGI-S) were obtained at baseline and after one, two, four, and six weeks. Changes on individual items of HAM-D17 were assessed as well as on composite scales (anxiety, insomnia and drive), and on four core subscales that capture core depression symptoms.RESULTS: Overall, both treatments improved depressive symptoms, without causing serious adverse events. There were significant differences in the HAM-D17 total score (p=0.046) and CGI-S (p=0.004), between aripiprazole and bupropion augmentation, favoring aripiprazole over bupropion. Aripiprazole revealed significantly greater effect size in depressed mood (p=0.006), retardation (p=0.005), anxiety psychic (p=0.032), and general somatic symptom (p=0.01).CONCLUSION: While both treatments were effective, results of this study suggested that aripiprazole may be preferable, in treating general and core symptoms of female depression.

Current progress in neuroimaging research on treatment resistant depression / 生物医学工程学杂志

Depression is a common psychiatric disorder, and approximately 30% patients with depression do not respond effectively to standard antidepressant medication; this condition is termed treatment resistant depression (TRD) and its neurobiological mechanism remains unclear. Neuroimaging techniques can non-invasively explore changes in brain structure, function and metabolism. These techniques have been applied in neurobiological research of TRD and revealed critical abnormalities in brain structure, function and metabolism in fronto-limbic system. In this paper, we reviewed the latest progress in neuroimaging researches on TRD, providing new insight and imaging evidence for further neurobiological studies of TRD.

Belief about medicines in patients with treatment-resistant depression and its influencing factors / 中华行为医学与脑科学杂志

Objective To explore the belief about medicines in patients with treatment-resistant de-pression ( TRD) and its influencing factors. Methods 106 patients with TRD were recruited to complete the survey of demographic characteristics,Hamilton Depression Scale-17 ( HAMD-17) and belief about Med-icine Questionnaire-Specific ( BMQ-S) . Results ①The score of BMQ-s was higher in TRD patients with medical insurance than that of patients with self-funded(rural social insurance(1.11±0.96),medical insur-ance(0.84±1.33),self expense(0.13±1.72),F=2.81,P<0.01).The score of BMQ-s was higher in TRD pa-tients with serious depression than that of patients with mild to moderate depression((1.07±1.19),(0.34± 1.41),t=2.77,P<0.01).The score of BMQ-s was higher in TRD patients with fewer episodes of depression than that of patients with more episodes of depression (0 time(1.10±0.99),once and twice(0.95±1.31),3 times and above(0.31±1.56),F=3.42,P<0.05).The score of BMQ-s was higher in TRD patients without stigma than those with stigma((1.03±1.21),(0.34±1.43),t=2.58,P<0.01).The score of BMQ-s was high-er in TRD patients with more knowledge about the antidepressant than that of patients with less knowledge (most of understanding(1.21±1.09),part of understanding(0.54±1.32),hardly understanding(0.33± 1.63) ,F=3.69,P<0.01) . The score of BMQ-s was higher in TRD patients without side effects of antidepres-sant than those with side effects ((1.04±1.24),(0.19±1.35),t=2.96,P<0.01). ②Stepwise multivariate linear regression analysis showed that payment methods,knowledge about the antidepressant,stigma about the antidepressant and episodes of depression were the influencing factors of BMQ-S in patients with TRD( all P<0.01) . Conclusion Different demographic characteristics and clinical features have different beliefs about antidepressant medication in patients with TRD.The payment methods,knowledge about the antidepressant, stigma about the antidepressant and episodes of depression are the influencing factors of BMQ in patients with TRD.

A control study of cognitive function in patients with treatment-resistant depression and first-episode depression / 天津医药

Objective To compare the cognitive functions between patients with treatment-resistant depression and first-episode depression. Methods A total of 80 major depressive disorder patients admitted in our hospital from March 2015 to December 2016 were included in this study. The patients were divided into treatment-resistant depression group (n=40) and first-episode depression group (n=40). Another 40 healthy individuals were used as the control group. The basic data of patients were collected, and Hamilton depression scale (HAMD)-17 was used to assess the severity of the disease. The performing functions were assessed by trail marking test and stroop color-word test. The attention functions were assessed by digital span test. Memory functions were assessed by Hopkins verbal learning test revise (HVLT-R). After treatment for 6 months, cognitive functions were assessed again in first-episode depression group. Results Compared with control group, the scores of trail marking test (TMT) increased, while the scores of digital span test, stroop color-word test, stroop color-colorword test, HVLT-R reduced in treatment-resistant depression group and first-episode depression group ( P<0.05). The scores of TMT, HAMD-17 were lower in first-episode depression group than those of treatment-resistant depression group (P < 0.05). There were no significant differences in other indexes between groups. After six months treatment, the trail marking test score and HAMD-17 reduced, but digital span test, stroop color-word test increased in first-episode depression group (P<0.05). Conclusion The cognitive function damages severely in patients with treatment-resistant depression and first-episode depression, but there is no obvious difference in severity between two groups of patients.

Novel Pharmacological Treatment for Depression

Development of various antidepressants such as monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and noradrenergic and specific serotonergic antidepressant has led to a tremendous progression of pharmaceutical treatment for depression, but still there are some limitations of current antidepressants, such as treatment-resistant depression and delayed onset of antidepressants. The pathogenesis of depression is unclear because depression is a heterogeneous disease state, and the mechanisms of antidepressants remain uncertain as well. Nevertheless, in an attempt to develop novel antidepressants, some trials have been conducted based on the potential biological mechanism discovered in the numerous research results. This review will provide information about the potential novel antidepressants and the current states of clinical studies using them. In particular, some potential novel antidepressants anti-inflammatory agents, antioxidants, anticholinergics, modulators of Hypothalamic Pituitary Adrenal Axis, glutamate, and opioid systems, as well as some neuropeptides such as susbstance P, neuropeptide Y, and galanin will be discussed.

Treatment-Resistant Depression Entering Remission Following a Seizure during the Course of Repetitive Transcranial Magnetic Stimulation

Major depressive disorder is often resistant to antidepressant treatment. Repetitive transcranial magnetic stimulation (rTMS) has been used in treatment-resistant depression (TRD). Known adverse events of rTMS include transient headache, local pain, syncope, seizure induction, and hypomania induction. This report outlines a patient with TRD who unexpectedly improved following a seizure during the course of rTMS, which has never been reported.