Acteoside Attenuates Recognition Memory Impairment in CUMS Rats via Regulating Synaptic Plasticity and mTOR Signaling Pathway / El Acteoside Atenúa el Deterioro de la Memoria de Reconocimiento en Ratas ELCI Mediante la Regulación de la Plasticidad Sináptica y la Vía de Señalización mTOR

SUMMARY: We evaluated the role and mechanism of acteoside in the regulation of memory impairment induced by chronic unpredictable mild stress (CUMS). CUMS was used to induce depression in rats and the successful establishment of CUMS model were verified by forced swimming test and sucrose preference test. The Y-maze test and novel object recognition test assessed memory functions. The structural changes in the cortex and hippocampus were observed by hematoxylin and eosin (HE) staining. Immunofluorescence staining and western blotting determined the protein levels. Y-maze test and novel object recognition test showed that there was memory performance impairment in rats of CUMS group, which was improved by the acteoside treatment. HE staining showed that CUMS exposure damaged the structure in the cortex and hippocampus, while the acteoside treatment alleviated the structural changes. Compared with the control group, the levels of BNDF and CREB in the cortex and hippocampus of the CUMS group were significantly decreased. Acteoside significantly reversed the expressions of these proteins in CUMS rats. Meanwhile, compared with the control group, the levels of p-mTOR and p- P70S6K in the cortex and hippocampus of the CUMS group were significantly increased, and these changes were significantly reversed by acteoside. Nevertheless, the effect of acteoside on mTOR signaling was markedly blocked by rapamycin, a specific inhibitor of mTOR signaling. Acteoside can attenuate memory impairment and ameliorate neuronal damage and synaptic plasticity in depression rats probably via inhibiting the mTOR signaling pathway. Acteoside may serve as a novel reagent for the prevention of depression.

Evaluamos el papel y el mecanismo del acteoside en la regulación del deterioro de la memoria inducido por estrés leve crónico impredecible (ELCI). Se utilizó ELCI para inducir depresión en ratas y el establecimiento exitoso del modelo ELCI se verificó mediante una prueba de natación forzada y una prueba de preferencia de sacarosa. La prueba del laberinto en Y y la prueba de reconocimiento de objetos novedosos evaluaron las funciones de la memoria. Los cambios estructurales en la corteza y el hipocampo se observaron mediante tinción con hematoxilina y eosina (HE). La tinción por inmunofluorescencia y la transferencia Western determinaron los niveles de proteína. La prueba del laberinto en Y y la prueba de reconocimiento de objetos novedosos mostraron que había un deterioro del rendimiento de la memoria en ratas del grupo ELCI, que mejoró con el tratamiento con acteósidos. La tinción con HE mostró que la exposición a ELCI dañó la estructura de la corteza y el hipocampo, mientras que el tratamiento con actósidos alivió los cambios estructurales. En comparación con el grupo de control, los niveles de BNDF y CREB en la corteza y el hipocampo del grupo ELCI disminuyeron significativamente. Acteoside revirtió significativamente las expresiones de estas proteínas en ratas ELCI. Mientras tanto, en comparación con el grupo control, los niveles de p-mTOR y p-P70S6K en la corteza y el hipocampo del grupo ELCI aumentaron significativamente, y estos cambios fueron revertidos significativamente ELCI por el acteoside. Sin embargo, el efecto del acteoside sobre la señalización de mTOR fue notablemente bloqueado por la rapamicina, un inhibidor específico de la señalización de mTOR. El acteoside puede atenuar el deterioro de la memoria y mejorar el daño neuronal y la plasticidad sináptica en ratas con depresión, probablemente mediante la inhibición de la vía de señalización mTOR. Acteoside puede servir como un reactivo novedoso para la prevención de la depresión.

Neuropharmacological and anxiolytic effects of extracts of Passiflora tripartita var. mollissima on mice / Efecto neurofarmacológico y ansiolítico de extractos de Passiflora tripartita var. mollissima en ratones

Anxiety and depression cause alterations in the physiology of an organism. Extracts from the leaves of several Passiflora species are traditionally use d Peru and in many countries as anxiolytic and in treatment for inflammatory problems. T his study aimed to determine the neuropharmacological effect of the ethanolic extract of Passiflora tripartita var. mollissima (Kunth) Holm - Niels. & P. Jørg. and its an xiolytic effect on mouse ( Mus musculus var. albinus ). A nxiety was evaluated with the marble burying test and the depressant effect with the Irwin test (locomotor activity, base of support, wobbly gait, immobility, escape, ease of handling, muscular strengt h, tight rope, inclined plane, catatonia, nociceptive reflex and death). Doses of 100 mg/Kg/body weight and 200 mg/kg/body weight by intraperitoneal route (i.p.) significantly decreased anxiety levels (p<0.05) in mice, and had a non - significant depressant effect in 11 of the 12 tests, showing a similar direction of correlation between diazepam and Passiflora extract effect. A greater anxiolytic and anti - depressant effects in mice was observed with the extract dose of 200 mg/kg/body weight with neuropharmaco logical manifestations found where no death was observed at any dose used.

L a ansiedad y la depresión provocan alteraciones fisiológicas. Las especies de Pa ssiflora se utilizan tradicionalmente en Perú como ansiolíticos y para tratar problemas inflamatorios. D eterminar el efecto neurofarmacológico del extracto etanólico de Passiflora tripartita var. mollissima (Kunth) Holm - Niels. & P. Jørg. y su efecto ansiol ítico en ratones. S e evaluó la ansiedad con el test de enterramiento de canicas y el efecto depresor con el test de Irwin . Las dosis de 100 mg/kg/peso corporal y 200 mg/kg/peso corporal por vía intraperitoneal (i.p.) disminuyeron significativamente la ansi edad ( p <0,05) con efecto depresor no significativo en 11 de las 12 pruebas, mostrando una correlación similar entre el diazepam aplicado a dosis de 1 mg/Kg/p.c. (i.p) y el efecto de Passiflora . S e observó un mayor efecto ansiolítico y antidepresivo en rato nes con 200 mg/kg/peso corporal encontrándose manifestaciones neurofarmacológicas pero no se observó muerte a ninguna de las dosis empleadas.

Análisis del conocimiento sobre los inhibidores selectivos de la recaptura de serotonina (ISRS) en el manejo de la depresión por médicos residentes y concurrentes de clínica médica de 5 hospitales de CABA / Review of the Knowledge on Selective Serotonin Reuptake Inhibitors (SSRIs) for Depression Management by Resident and Intern Physicians of the Medical Clinic of 5 Hospitals in CABA

Introducción: la depresión es un trastorno cada vez más prevalente alrededor del mundo. Los médicos generales son los profesionales de la salud más consultados por pacientes deprimidos. Más del 70% de los pacientes con depresión son vistos por médicos generales y no por especialistas en Psiquiatría. Según estudios realizados en Buenos Aires, más del 25% de los pacientes internados en Servicios de Clínica Médica en hospitales generales presenta depresión. Estos pacientes suelen ser atendidos y seguidos por médicos en formación, sean residentes o concurrentes de Clínica Médica. El objetivo del trabajo fue analizar el conocimiento sobre los inhibidores selectivos de la recaptura de serotonina (ISRS) que tienen los médicos residentes y concurrentes de Clínica Médica de 5 hospitales de la Ciudad Autónoma de Buenos Aires (CABA) y describir el tratamiento de un paciente depresivo por ellos. Material y métodos: se realizó un estudio descriptivo de corte transversal con un muestreo de tipo no probabilístico. Se utilizó como instrumento de medición un cuestionario semiestructurado organizado en dos secciones, una de datos demográficos que permiten caracterizar la muestra. La otra, de 15 ítems, explora los conocimientos sobre los ISRS y el tratamiento de la depresión. Dicho cuestionario fue revisado por 4 expertos. El instrumento es anónimo. Se aplicó a 59 médicos en formación en Clínica Médica, residentes y concurrentes, de 5 hospitales de la CABA, que participaron de forma voluntaria, durante el período agosto-septiembre de 2022. Resultados: la mayoría de los médicos en formación en Clínica Médica no tratan cuadros depresivos y, ante un paciente deprimido, solicitan la evaluación por un especialista en Salud Mental. Solo un 6,8% lo medica con un antidepresivo. Más del 75% de la muestra refiere recordar los conocimientos que tiene sobre de los ISRS de la cursada de Farmacología y un 13,6 de la cursada de Psiquiatría en la Facultad de Medicina. Conclusión: se observa un conocimiento deficitario sobre los ISRS en médicos residentes y concurrentes de Clínica Médica. Se considera necesario reforzar la formación sobre depresión y manejo de antidepresivos durante la residencia/concurrencia de Clínica Médica. (AU)

Introduction: depression is an increasingly common disorder around the world. General practitioners are the most frequently consulted health professionals by depressed patients. More than 70% of all depressed patients receive treatment by general practitioners and not by psychiatric specialists. According to studies conducted in Buenos Aires, more than 25% of all patients admitted to the Clinical Services in public hospitals present depression. These patients are usually under the care and follow-up of clinical trainee physicians, residents, or interns.This study aimed to analyze the knowledge about selective serotonin reuptake inhibitors (SSRIs) of clinical trainee residents and interns in five hospitals in the Ciudad Autónoma de Buenos Aires (CABA) and to describe their treatment of a depressive patient. Material and methods: we conducted a descriptive cross-sectional study with a non-probabilistic sampling. We used a semi-structured questionnaire arranged into two sections as a measuring tool. One, with demographic data to describe the sample. The other, with 15 items, explores respondents' knowledge of SSRIs and the treatment of depression. Four experts reviewed the questionnaire, which was anonymous. We applied it to 59 clinical medical trainees, residents, and interns from five CABA hospitals who volunteered to participate during August-September 2022. Results: most clinical trainees do not treat depressive conditions and, when confronted with a depressed patient, request an assessment by a Mental Health specialist. Only 6.8% medicate the patient with an antidepressant. More than 75% of the sample reported remembering their knowledge of SSRIs from the Pharmacology course and 13.6% from the Psychiatry course at the School of Medicine. Conclusion: there is a deficient knowledge about SSRIs in trainee residents and interns of Clínica Médica. We believe it is necessary to reinforce training on depression and management of antidepressants during residency/internship practice in Clínica Médica. (AU)

Anti-depression targets and mechanism study of Kaixin San / 中国中药杂志

This study identified the anti-depression targets of Kaixin San(KXS) in the brain tissue with "target fishing" strategy, and explored the target-associated pharmacological signaling pathways to reveal the anti-depression molecular mechanism of KXS. The Balb/c mouse model of depression was established by chronic unpredictable mild stress(CUMS) and the anti-depression effect of KXS was evaluated by forced swimming test and sucrose preference test. KXS active components were bonded to the benzophenone-modified magnetic nanoparticles by photocrosslinking reaction for capturing target proteins from cortex, thalamus and hippocampus of depressive mice. The target proteins were identified by liquid chromatography-mass spectrometry/mass spectrometry(LC-MS/MS). The enrichment analysis on signaling pathways was performed by Cytoscape. The potential biological functions of targets were verified by immunohistochemistry and Western blot assay. The results showed that KXS significantly improved the behavioral indexes. There were 64, 91, and 44 potential targets of KXS identified in cortex, thalamus, and hippocampus, respectively, according to the target identification experiment. The functions of these targets were mainly associated with vasopressin-regulated water reabsorption, salmonella infection, thyroid hormone synthesis, and other signaling pathways. Besides, the results of immunohistochemistry and Western blot showed that KXS up-regulated the expressions of argipressine(AVP) in the cortex, heat shock protein 60(HSP60), cytochrome C oxidase 4(COX4), and thyrotropin-releasing hormone(TRH) in the thalamus, and down-regulated the expressions of tumor necrosis factor-α(TNF-α) and nuclear factor kappa B(NF-κB) p65 in the thalamus. Therefore, KXS may exert anti-depression effect through regulating vasopressin signaling pathway in the cortex and inflammation, energy metabolism, and thyroid hormone signaling pathways in the thalamus, and the effect of KXS on hippocampus is not significant.

Ginkgo biloba extract protects against depression-like behavior in mice through regulating gut microbial bile acid metabolism / 中国天然药物

Depression is a mental disorder with high morbidity, disability and relapse rates. Ginkgo biloba extract (GBE), a traditional Chinese medicine, has a long history of clinical application in the treatment of cerebral and mental disorders, but the key mechanism remains incompletely understood. Here we showed that GEB exerted anti-depressant effect in mice through regulating gut microbial metabolism. GBE protected against unpredictable mild stress (UMS)-induced despair, anxiety-like and social avoidance behavior in mice without sufficient brain distribution. Fecal microbiome transplantation transmitted, while antibiotic cocktail abrogated the protective effect of GBE. Spatiotemporal bacterial profiling and metabolomics assay revealed a potential involvement of Parasutterella excrementihominis and the bile acid metabolite ursodeoxycholic acid (UDCA) in the effect of GBE. UDCA administration induced depression-like behavior in mice. Together, these findings suggest that GBE acts on gut microbiome-modulated bile acid metabolism to alleviate stress-induced depression.

Mechanism of stress-induced microglial activation in depression and traditional Chinese medicine regulation / 中国中药杂志

Depression exists with high prevalence and heavy disease burden. Stress events play a key role in the occurrence of depression, but the pathological mechanism has not been fully clarified by reason of the complexity and heterogeneity. In recent years, neuroinflammation as a pathological mechanism of depression has received extensive attention. The activated microglia is regarded as the marker of neuroinflammation, which is an important link of stress-induced depression. Stress might induce microglia activation through pattern recognition receptors(PRR), intestinal flora, hypothalamic-pituitary-adrenal(HPA) axis, and other pathways. Cross-talk between impaired microglia function and neurobiological factors such as inflammatory cytokines, serotonin metabolism, and neuroplasticity may lead to depression. At present, a large number of studies have proved that traditional Chinese medicine(TCM) plays an anti-depressive role by inhibiting microglia activation, which may be potential treatment strategies for depressive disorder. This paper reviewed the research progress of stress-induced microglia activation in depression and summarized the mechanism of TCM against depression with regard to microglia, hoping to provide experimental evidence and consideration for TCM against depression through microglia.

Neuroprotective effect and mechanism of Zuogui Jiangtang Jieyu Formula on diabetes mellitus complicated with depression model rats based on CX3CL1-CX3CR1 axis / 中国中药杂志

Based on the CX3C chemokine ligand 1(CX3CL1)-CX3C chemokine receptor 1(CX3CR1) axis, this study explored the potential mechanism by which Zuogui Jiangtang Jieyu Formula(ZGJTJY) improved neuroinflammation and enhanced neuroprotective effect in a rat model of diabetes mellitus complicated with depression(DD). The DD rat model was established by feeding a high-fat diet combined with streptozotocin(STZ) intraperitoneal injection for four weeks and chronic unpredictable mild stress(CUMS) combined with isolated cage rearing for five weeks. The rats were divided into a control group, a model group, a positive control group, an inhibitor group, and a ZGJTJY group. The open field test and forced swimming test were used to assess the depression-like behaviors of the rats. Enzyme-linked immunosorbent assay(ELISA) was performed to measure the expression levels of the pro-inflammatory cytokines interleukin-1β(IL-1β) and tumor necrosis factor-α(TNF-α) in plasma. Immunofluorescence staining was used to detect the expression of ionized calcium-binding adapter molecule 1(Iba1), postsynaptic density protein-95(PSD95), and synapsin-1(SYN1) in the hippocampus. Hematoxylin-eosin(HE) staining, Nissl staining, and TdT-mediated dUTP nick end labeling(TUNEL) fluorescence staining were performed to assess hippocampal neuronal damage. Western blot was used to measure the expression levels of CX3CL1, CX3CR1, A2A adenosine receptor(A2AR), glutamate receptor 2A(NR2A), glutamate receptor 2B(NR2B), and brain-derived neurotrophic factor(BDNF) in the hippocampus. Compared with the model group, the ZGJTJY group showed improved depression-like behaviors in DD rats, enhanced neuroprotective effect, increased expression of PSD95, SYN1, and BDNF(P<0.01), and decreased expression of Iba1, IL-1β, and TNF-α(P<0.01), as well as the expression of CX3CL1, CX3CR1, A2AR, NR2A, and NR2B(P<0.01). These results suggest that ZGJTJY may exert its neuroprotective effect by inhibiting the CX3CL1-CX3CR1 axis and activation of hippocampal microglia, thereby improving neuroinflammation and abnormal activation of N-methyl-D-aspartate receptor(NMDAR) subunits, and ultimately enhancing the expression of synaptic-related proteins PSD95, SYN1, and BDNF in the hippocampus.

Mechanism of Jiaotai Pills in treatment of depression based on quantitative proteomics / 中国中药杂志

This study aimed to investigate the effect of Jiaotai Pills on protein expression in the hippocampus of the rat model of chronic unpredictable mild stress(CUMS)-induced depression by quantitative proteomics and explore the anti-depression mechanism of Jiaotai Pills. The SD rats were randomized into control, model, Jiaotai Pills, and fluoxetine groups(n=8). Other groups except the control group were subjected to CUMS modeling for 4 weeks. After 4 weeks of continuous administration, the changes of behavior and pathological morphology of the hippocampal tissue were observed. Proteins were extracted from the hippocampal tissue, and bioinformatics analysis was performed for the differentially expressed proteins(DEPs) identified by quantitative proteomics. Western blot was employed to verify the key DEPs. The results showed that Jiaotai Pills significantly alleviated the depression behaviors and hippocampal histopathological changes in the rat model of CUMS-induced depression. A total of 5 412 proteins were identified in the hippocampus of rats, including 65 DEPs between the control group and the model group and 35 DEPs between the Jiaotai Pills group and the model group. There were 16 DEPs with the same trend in the Jiaotai Pills group and the control group, which were mainly involved in sphingolipid, AMPK, and dopaminergic synapse signaling pathways. The Western blot results of Ppp2r2b, Cers1, and Ndufv3 in the hippocampus were consistent with the results of proteomics. In conclusion, Jiaotai Pills may play an anti-depression role by modulating the levels of Ppp2r2b, Cers1, Ndufv3 and other proteins and regulating sphingolipid, AMPK, and dopaminergic synapse signaling pathways.

Plasma components of Danzhi Xiaoyao Formula and its mechanism of action in treating perimenopausal depression based on UPLC-Q-TOF-MS~E integrated with network pharmacology / 中国中药杂志

In this study, ultra-performance liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry(UPLC-Q-TOF-MS~E) was used to analyze the plasma components of Danzhi Xiaoyao Formula after oral administration. Forty-nine plasma components were found in the serum of rats by comparing the compound extract, drug-containing serum, and blank serum. Components, such as 6-hydroxycoumarin, poricoic acid F, deoxoglabrolide, 30-norhederagenin, kanzonol R, 3',6'-di-O-galloylpaeoniflorin, 16α-hydroxytrametenolic acid, 16-deoxyporicoic acid B, 3-O-acetyl-16α-hydroxytrametenolic acid, and 16α,25-dihydroxydehydroeburiconic acid, were first found in rat serum. Behavioral tests, including the tail suspension test, novel object recognition test, and novelty-suppressed feeding test, were conducted for behavioral analysis. It was confirmed that this formula had therapeutic effects on perimenopausal depression. Furthermore, in combination with the network pharmacology method, 53 core targets including MAPK1, HRAS, AKT1, EGFR, and ESR1 were screened, and these targets participated in 165 signaling pathways, including PI3K-AKT, AMPK, VEGFA, MAPK, and HIF-1. In summary, the potential effects of Danzhi Xiaoyao Formula in treating perimenopausal depression are associated with mechanisms in accelerating inflammation repair, improving neuroplasticity, affecting neurotransmitters, regulating estrogen levels, and promoting new blood vessel formation.

Manifestaciones psicopatológicas en una adolescente debido al impacto de la COVID-19 / Psycho-Pathological Manifestations In An Adolescent Due to The Impact of COVID-19

Introducción: La adolescencia es una de las etapas más trascendentales de la vida; en ella el cerebro experimenta una serie de cambios y conexiones que suponen un antes y un después para la persona. Cada adolescente vive esta experiencia de una manera diferente. Muchos estudios muestran las devastadoras consecuencias que ha dejado el confinamiento generado por la pandemia de COVID-19 en este segmento poblacional y la importancia de aplicar un tratamiento adecuado. Objetivo: Identificar las manifestaciones psicopatológicas frente al impacto de la COVID-19. Presentación del caso: Adolescente femenina, de 13 años, de procedencia urbana, con antecedentes de salud mental previa, que convive con ambos padres y una hermana menor, en un ambiente familiar armónico. Acudió al cuerpo de guardia en compañía de su madre, por presentar manifestaciones depresivas y ansiosas dadas por miedo a contagiarse, a la muerte, a estar sola, a la oscuridad, a perder a sus familiares, deambulaba de un lado a otro sin ningún propósito y se negaba a ingerir alimentos. Todo comenzó al inicio de la pandemia por la COVID-19. Se decidió su ingreso en la sala de psiquiatría del Hospital Pediátrico Docente Sur Dr. Antonio María Béguez César Santiago de Cuba en abril de 2020. Conclusiones: La intervención psicoterapéutica y el tratamiento psicofarmacológico, resultaron efectivos para disminuir la ansiedad, el miedo a la muerte, la fobia y los elementos obsesivos, la depresión y el insomnio, generados por el confinamiento debido a la pandemia por COVID-19 (AU)

Introduction: Adolescence is one of the most transcendental stages of life. In it the brain undergoes a series of changes and connections that represent a before and after for the person. Every teenager lives this experience in a different way. Many studies show the devastating consequences left by the confinement generated by the COVID-19 pandemic in this population segment, and the importance of applying adequate treatment. Objective: To identify the psycho-pathological manifestations against the impact of COVID-19. Case presentation: Female adolescent, 13 years old, of urban origin, with a previous mental health history, who lives with both parents and a younger sister, in a harmonious family environment. She went to the emergency service in the company of her mother, after presenting depressive and anxious manifestations given by fears of being infected, of death, of being alone, of darkness, of losing her relatives; she wandered back and forth without any purpose and refused to eat food. It all started at the beginning of the COVID-19 pandemic. It was decided to admit her to the psychiatric service of Dr. Antonio María Béguez César South Teaching Pediatric Hospital, in Santiago de Cuba province in April 2020. Conclusions: Psychotherapeutic intervention and psycho-pharmacological treatment were effective in reducing anxiety, fear of death, phobia and obsessive elements, and depression and insomnia generated by the confinement due to the COVID-19 pandemic(AU)

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

Manejo farmacológico del episodio depresivo bipolar en adolescentes: actualización bibliográfica / Pharmacological management of bipolar depressive episode in adolescents: bibliographic update

El manejo farmacológico del episodio depresivo en contexto del trastorno bipolar constituye un desafío para el clínico tanto en psiquiatría adultos como infantoadolescente. El presente trabajo tiene por objetivo actualizar y sintetizar la evidencia disponible respecto al manejo farmacológico para la depresión bipolar en población pediátrica. Metodología: Se realizó una búsqueda de las publicaciones de los últimos 5 años en bases de datos. Resultados: La evidencia muestra como primera línea el uso de antipsicóticos de segunda generación por sobre los estabilizadores del ánimo en este grupo etario; demostrando lurasidona y lanzapina/fluoxetina eficacia similares. Lurasidona es una opción con mejor perfil de seguridad por asociarse a menos efectos adversos y mejor adherencia. El uso de antidepresivos debe considerarse dentro de los pasos iniciales del manejo, asociado a un antipsicótico de segunda generación. Conclusiones: Se destaca la importancia de la sospecha, evaluación y diagnóstico adecuado para guiar la decisión de manejo integral. A pesar de los riesgos y consideraciones existentes, es importante considerar el uso en primera línea de antipsicóticos de segunda generación y de antidepresivos en el manejo de un cuadro depresivo en contexto de la enfermedad bipolar. La escasez de estudios en el tratamiento farmacológico de la depresión bipolar en general y especialmente en población pediátrica limita la generalización y extrapolación de los resultados a la realidad local.

The pharmacological management of the depressive episode in the context of bipolar disorder constitutes a challenge for the clinician both in adult and child-adolescent population. The objective of this paper is to update and synthesize the available evidence regarding the pharmacological management of bipolar depression in the pediatric population. Methodology: A search of the publications of the last 5 years in databases was carried out. Results: The evidence shows the use of second generation antipsychotics over mood stabilizers as the first line in this age group; demonstrating similar efficacy. Results: The evidence shows the use of second generation antipsychotics over mood stabilizers as the first line in this age group; demonstrating similar efficacy lurasidone and lanzapine/fluoxetine. Lurasidone is an option with a better safety profile as it is associated with fewer adverse effects and better adherence. The use of antidepressants should be considered within the initial steps of management, associated with a second generation antipsychotic. Conclusions: The importance of suspicion, evaluation and adequate diagnosis to guide the decision of comprehensive management is highlighted. Despite the existing risks and considerations, it is important to consider the first-line use of second-generation antipsychotics and antidepressants in the management of a depressive episode in the context of bipolar illness. The scarcity of studies on the pharmacological treatment of bipolar depression in general and especially in the pediatric population limits the generalization and extrapolation of the results to the local reality.

Plantas com ação no sistema nervoso central que constam na relação nacional de plantas medicinais de interesse ao sus (RENISUS) / Plants acting on the central nervous system: review plantas com ação no sistema nervoso central que constam na relação nacional de plantas medicinais de interesse ao sus (RENISUS) / Plantas con acción sobre el sistema nervioso central incluidas en la lista nacional de plantas medicinales de interés para sus (RENISUS)

A depressão é uma doença grave que atinge a população em geral, estudos epidemiológicos estimam que a prevalência da depressão ao longo da vida no Brasil está em torno de 15,5%. Os fatores que desencadeiam o aparecimento da depressão incluem fatores sociais, psicológicos, biológicos e também fatores externos específicos como eventos estressantes, solidão, consumo de álcool e drogas, doenças crônicas e dar á luz (depressão pós-parto). O objetivo da presente pesquisa consistiu em realizar uma revisão bibliográfica sobre as principais plantas medicinais com ação antidepressiva. A ansiedade vem se tornando um dos principais problemas da atualidade, sendo intensificada pela pandemia causada pelo coronavírus, onde constatou-se que durante o pico da pandemia onde os casos confirmados de COVID-19 no Brasil ascenderam de 45.757 para 330.890, e as mortes, de 2.906 para 21.048, o sentimento de tristeza/depressão atingiu 40% dos adultos brasileiros. Os sintomas de depressão podem ser amenizados quando a disponibilidade sináptica de monoaminas são aumentadas, e esse aumento pode ocorrer através da diminuição da metabolização desses neurotransmissores. Neste sentido, busca-se através da farmacoterapia a utilização de antidepressivos que disponibilizem as monoaminas na fenda sináptica. A escolha do fármaco é feita com base nos sintomas da depressão e na boa resposta a uma determinada classe de antidepressivos. Em fevereiro de 2009 o Ministério da saúde lançou a Relação Nacional de Plantas Medicinais de Interesse ao SUS (RENISUS), contendo 71 espécies vegetais que são distribuídas de forma in natura nas unidades básicas de saúde (UBS). Destas, somente três espécies apresentam efeito antidepressivo e ansiolítico comprovados na literatura sendo Matricharia chamomilla, Erytrinum mulungu e a Passiflora incarnata que também fazem parte da RENISUS. Além destas, outras espécies como a Melissa officinalis, Lippia alba, Valeriana officinalis e Piper methysticum são utilizadas pela população para tratar ansiedade, insônia e depressão, sugerindo desta forma que estas espécies sejam incluídas na RENISUS.

Depression is a serious disease that affects the general population, epidemiological studies estimate that the prevalence of depression throughout life in Brazil is around 15.5%. The factors that trigger the onset of depression include social, psychological, biological and also specific external factors such as stressful events, loneliness, alcohol and drug consumption, chronic diseases and giving birth (postpartum depression). The objective of the present research was to carry out a literature review on the main medicinal plants with antidepressant action. Anxiety has become one of the main problems of today, being intensified by the pandemic caused by the coronavirus, where it was found that during the peak of the pandemic where confirmed cases of COVID-19 in Brazil rose from 45,757 to 330,890, and deaths, from 2,906 to 21,048, the feeling of sadness/depression reached 40% of Brazilian adults. Symptoms of depression can be alleviated when synaptic availability of monoamines is increased, and this increase can occur through decreased metabolization of these neurotransmitters. In this sense, the use of antidepressants that make monoamines available in the synaptic cleft is sought through pharmacotherapy. The choice of drug is based on symptoms of depression and good response to a particular class of antidepressants. In February 2009, the Ministry of Health launched the National List of Medicinal Plants of Interest to the SUS (RENISUS), containing 71 plant species that are distributed in natura form in basic health units (UBS). Of these, only three species have antidepressant and anxiolytic effects proven in the literature, being Matricharia chamomilla, Erytrinum mulungu and Passiflora incarnata, which are also part of RENISUS. In addition to these, other species such as Melissa officinalis, Lippia alba, Valeriana officinalis and Piper methysticum are used by the population to treat anxiety, insomnia and depression, thus suggesting that these species are included in RENISUS.

Los estudios epidemiológicos estiman que la prevalencia de la depresión a lo largo de la vida en Brasil es de alrededor del 15,5%. Los factores que desencadenan la aparición de la depresión son sociales, psicológicos, biológicos y también factores externos específicos, como los acontecimientos estresantes, la soledad, el consumo de alcohol y drogas, las enfermedades crónicas y el parto (depresión posparto). El objetivo de esta investigación fue realizar una revisión bibliográfica sobre las principales plantas medicinales con acción antidepresiva. La ansiedad se ha convertido en uno de los principales problemas de la actualidad, intensificándose por la pandemia causada por el coronavirus, donde se encontró que durante el pico de la pandemia donde los casos confirmados de COVID-19 en Brasil aumentaron de 45.757 a 330.890, y las muertes, de 2.906 a 21.048, el sentimiento de tristeza/depresión alcanzó el 40% de los adultos brasileños. Los síntomas de la depresión pueden aliviarse cuando se aumenta la disponibilidad sináptica de las monoaminas, y este aumento puede producirse mediante una disminución de la metabolización de estos neurotransmisores. En este sentido, se busca a través de la farmacoterapia el uso de antidepresivos que hagan disponibles las monoaminas en la hendidura sináptica. La elección del fármaco se hace en función de los síntomas de la depresión y de la buena respuesta a una clase concreta de antidepresivos. En febrero de 2009, el Ministerio de Salud lanzó la Lista Nacional de Plantas Medicinales de Interés para el SUS (RENISUS), que contiene 71 especies de plantas que se distribuyen in natura en unidades básicas de salud (UBS). De ellas, sólo tres especies tienen efectos antidepresivos y ansiolíticos probados en la literatura: Matricharia chamomilla, Erytrinum mulungu y Passiflora incarnata, que también forman parte del RENISUS. Además de éstas, otras especies como Melissa officinalis, Lippia alba, Valeriana officinalis y Piper methysticum son utilizadas por la población para tratar la ansiedad, el insomnio y la depresión, lo que sugiere que estas especies se incluyan en el RENISUS.

A Network Pharmacology-Based Study on Antidepressant Effect of Salicornia europaea L. Extract with Experimental Support in Chronic Unpredictable Mild Stress Model Mice / 中国结合医学杂志

OBJECTIVE@#To investigate the pharmacodynamic material basis, mechanism of actions and targeted diseases of Salicornia europaea L. (SE) based on the network pharmacology method, and to verify the antidepressant-like effect of the SE extract by pharmacological experiments.@*METHODS@#Retrieval tools including Chinese medicine (CM), PubMed, PharmMapper, MAS 3.0 and Cytoscape were used to search the components of SE, predict its targets and related therapeutic diseases, and construct the "Component-Target-Pathway" network of SE for central nervous system (CNS) diseases. Further, protein-protein interaction (PPI) network, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) function annotation of depression-related targets were analyzed to predict the antidepressant mechanism of SE. Chronic unpredictable mild stress (CUMS) model was used to construct a mouse model with depression-like symptoms. And the animals were randomly divided into 6 groups (n=10) including the normal group (nonstressed mice administered with distilled water), the CUMS group (CUMS mice administered with distilled water), the venlafaxine group (CUMS mice administered with venlafaxine 9.38 mg/kg), SE high-, medium-, and low-dose groups (CUMS mice administered with SE 1.8, 1.35 and 0.9 g/kg, respectively). Then some relevant indicators were determined for experimental verification by the forced swim test (FST), the tail suspension test (TST) and open-field test (OFT). Dopamine (DA) concentration in hippocampus and cerebral cortex, IL-2 and corticosterone (CORT) levels in blood, and nuclear factor E2 related factor 2 (Nrf2), kelch-like epichlorohydrin related protein 1 (Keap1), NAD(P) H dehydrogenase [quinone] 1 (NQO1) and heme oxygenase-1 (HO-1) levels in mice were measured by enzyme linked immunosorbent assay (ELISA) and Western blot respectively to explore the possible mechanisms.@*RESULTS@#The "target-disease" network diagram predicted by network pharmacology, showed that the potential target of SE involves a variety of CNS diseases, among which depression accounts for the majority. The experimental results showed that SE (1.8, 1.35 g/kg) significantly decreased the immobility period, compared with the CUMS group in FST and TST in mice after 3-week treatment, while SE exhibited no significant effect on exploratory behavior in OFT in mice. Compared with CUMS group, the SE group (0.9 g/kg) showed significant differences (P<0.05) in DA levels in the hippocampus and cerebral cortex. In addition, compared with CUMS control group, SE (1.8 g/kg) group showed a significant effect on decreasing the activities of CORT (P<0.05), and serum IL-2 level with no statistical significance. Finally, Western blot results showed that compared with the model group, Nrf2, Keap1, NQO1 and HO-1 protein expressions in SE group (1.8 g/kg) were up-regulated (all P<0.01).@*CONCLUSION@#The SE extract may have an antidepressant effect, which appeared to regulate Nrf2-ARE pathway and increased levels of DA and CORT in the hippocampus and cortex.

Yixin Ningshen Tablet Alleviates Comorbidity of Myocardial Infarction and Depression by Enhancing Myocardial Energy Metabolism and Increasing Availability of Monoamine Neurotransmitter / 中国结合医学杂志

OBJECTIVE@#To investigate the therapeutic effect of Yixin Ningshen Tablet (YXNS) on comorbidity of myocardial infarction (MI) and depression in rats and explore the underlying mechanism.@*METHODS@#The Sprague-Dawley rats were randomly divided into 5 groups with 7 rats in each group according to their weights, including control, model, fluoxetine (FLXT, 10 mg/kg), low-dose YXNS (LYXNS, 100 mg/kg), and high-dose YXNS (HYXNS, 300 mg/kg) groups. All rats were pretreated with corresponding drugs for 12 weeks. The rat model of MI and depression was constructed by ligation of left anterior descending coronary artery and chronic mild stress stimulation. The echocardiography, sucrose preference test, open field test, and forced swim test were performed. Myocardial infarction (MI) area and myocardial apoptosis was also detected. Serum levels of interleukin (IL)-6, IL-1β, tumor necrosis factor-α (TNF-α), 5-hydroxytryptamine (5-HT), adrenocorticotrophic hormone (ACTH), corticosterone (CORT), and norepinephrine (NE) were determined by enzyme linked immunosorbent assay. The proteins of adenosine 5'-monophosphate -activated protein kinase (AMPK), p-AMPK, peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), and nuclear respiratory factor 1 (NRF1) in heart were detected by Western blot analysis. The expression levels of TNF-α, IL-6, indoleamine 2,3-dioxygenase (IDO1), kynurenine 3-monooxygenase (KMO), and kynureninase (KYNU) in hippocampus were detected by real-time quantitative polymerase chain reaction.@*RESULTS@#Compared with the model group, the cardiac function of rats treated with YXNS improved significantly (P<0.01). Meanwhile, YXNS effectively reduced MI size and cardiomyocytes apoptosis of rats (P<0.01 or P<0.05), promoted AMPK phosphorylation, and increased PGC-1α protein expression (P<0.01 or P<0.05). HYXNS significantly increased locomotor activity of rats, decreased the levels of TNF-α, IL-6 and IL-1β, and increased the serum levels of 5-HT, NE, ACTH, and CORT (all P<0.05). Moreover, HYXNS decreased the mRNA expressions of IDO1, KMO and KYNU (P<0.05).@*CONCLUSIONS@#YXNS can relieve MI by enhancing myocardial energy metabolism. Meanwhile, YXNS can alleviate depression by resisting inflammation and increasing availability of monoamine neurotransmitters. It may be used as a potential drug to treat comorbidity of MI and depression.

Effect of high-intensity interval exercise on depression-related behavior in mice / 生理学报

This paper was aimed to clarify the effect of high-intensity interval training (HIIT) on depression. Animal running platforms were used to establish HIIT exercise models, depression models were prepared by chronic unpredictable mild stress (CUMS), and depression-related behaviors were detected by behavioral experiments. The results showed that HIIT exercise improved depression-related behavior in CUMS model mice. Western blot and ELISA results showed that in the hippocampus, medial prefrontal cortex (mPFC) and amygdala of the CUMS model mice, glucocorticoid receptor (GR) protein expression was down-regulated, and the content of tumor necrosis factor α (TNF-α) was increased, compared with those in the control group, whereas HIIT exercise could effectively reverse these changes in CUMS model mice. These results suggest that HIIT exercise can exert antidepressant effect, which brings new ideas and means for the clinical treatment of depressive diseases.

Can acupuncture enhance therapeutic effectiveness of antidepressants and reduce adverse drug reactions in patients with depression? A systematic review and meta-analysis / 中西医结合学报

BACKGROUND@#Some depressed patients receive acupuncture as an adjunct to their conventional medications.@*OBJECTIVE@#This review aims to provide evidence on whether acupuncture can enhance the therapeutic effectiveness of antidepressants for treating depression, and explore whether acupuncture can reduce the adverse reactions associated with antidepressants.@*SEARCH STRATEGY@#English and Chinese databases were searched for randomized controlled trials (RCTs) published until December 1, 2021.@*INCLUSION CRITERIA@#RCTs with a modified Jadad scale score ≥ 4 were included if they compared a group of participants with depression that received acupuncture combined with antidepressants with a control group that received antidepressants alone.@*DATA EXTRACTION AND ANALYSIS@#Meta-analysis was performed, and statistical heterogeneity was assessed based on Cochran's Q statistic and its related P-value. Primary outcomes were the reduction in the severity of depression and adverse reactions associated with antidepressants, while secondary outcomes included remission rate, treatment response, social functioning, and change in antidepressant dose. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework was used to evaluate the overall quality of evidence in the included studies.@*RESULTS@#This review included 16 studies (with a total of 1958 participants). Most studies were at high risk of performance bias and at low or unclear risk of selection bias, detection bias, attrition bias, reporting bias, and other bias. Analysis of the 16 RCTs showed that, compared with antidepressants alone, acupuncture along with antidepressants reduced the Hamilton Depression Rating Scale-17 (HAMD-17) scores (standard mean difference [SMD] -0.44, 95% confidence interval [CI] -0.55 to -0.33, P < 0.01; I2 = 14%), Self-rating Depression Scale (SDS) scores (SMD -0.53, 95% CI -0.84 to -0.23, P < 0.01; I2 = 79%), and the Side Effect Rating Scale (SERS) scores (SMD -1.11, 95% CI -1.56 to -0.66, P < 0.01; I2 = 89%). Compared with antidepressants alone, acupuncture along with antidepressants improved World Health Organization Quality of Life-BREF scores (SMD 0.31, 95% CI 0.18 to 0.44, P < 0.01; I2 = 15%), decreased the number of participants who increased their antidepressant dosages (relative risk [RR] 0.32, 95% CI 0.22 to 0.48, P < 0.01; I2 = 0%), and resulted in significantly higher remission rates (RR 1.52, 95% CI 1.26 to 1.83, P < 0.01; I2 = 0%) and treatment responses (RR 1.35, 95% CI 1.24 to 1.47, P < 0.01; I2 = 19%) in terms of HAMD-17 scores. The HAMD-17, SDS and SERS scores were assessed as low quality by GRADE and the other indices as being of moderate quality.@*CONCLUSION@#Acupuncture as an adjunct to antidepressants may enhance the therapeutic effectiveness and reduce the adverse drug reactions in patients receiving antidepressants. These findings must be interpreted with caution, as the evidence was of low or moderate quality and there was a lack of comparative data with a placebo control.@*SYSTEMATIC REVIEW REGISTRATION@#INPLASY202150008.

Xiaoyao San, a Chinese herbal formula, ameliorates depression-like behavior in mice through the AdipoR1/AMPK/ACC pathway in hypothalamus / 中西医结合学报

OBJECTIVE@#Depression and metabolic disorders have overlapping psychosocial and pathophysiological causes. Current research is focused on the possible role of adiponectin in regulating common biological mechanisms. Xiaoyao San (XYS), a classic Chinese medicine compound, has been widely used in the treatment of depression and can alleviate metabolic disorders such as lipid or glucose metabolism disorders. However, the ability of XYS to ameliorate depression-like behavior as well as metabolic dysfunction in mice and the underlying mechanisms are unclear.@*METHODS@#An in vivo animal model of depression was established by chronic social defeat stress (CSDS). XYS and fluoxetine were administered by gavage to the drug intervention group. Depression-like behaviors were analyzed by the social interaction test, open field test, forced swim test, and elevated plus maze test. Glucose levels were measured using the oral glucose tolerance test. The involvement of certain molecules was validated by immunofluorescence, histopathology, and Western blotting. In vitro, hypothalamic primary neurons were exposed to high glucose to induce neuronal damage, and the neuroprotective effect of XYS was evaluated by cell counting kit-8 assay. Immunofluorescence and Western blotting were used to evaluate the influences of XYS on adiponectin receptor 1 (AdipoR1), adenosine 5'-monophosphate-activated protein kinase (AMPK), acetyl-coenzyme A carboxylase (ACC) and other related proteins.@*RESULTS@#XYS ameliorated CSDS-induced depression-like behaviors and glucose tolerance impairment in mice and increased the level of serum adiponectin. XYS also restored Nissl bodies in hypothalamic neurons in mice that exhibited depression-like behaviors and decreased the degree of neuronal morphological damage. In vivo and in vitro studies indicated that XYS increased the expression of AdipoR1 in hypothalamic neurons.@*CONCLUSION@#Adiponectin may be a key regulator linking depression and metabolic disorders; regulation of the hypothalamic AdipoR1/AMPK/ACC pathway plays an important role in treatment of depression by XYS.

El rol de los suplementos vitamínicos en pacientes con depresión / The role of vitamin supplements in patients with depression

La depresión es un trastorno del estado de ánimo que se caracteriza por la existencia de un sentimiento de tristeza lo suficientemente intenso como para interferir en el desarrollo de las actividades habituales. A partir de un caso clínico real, en el que una paciente con depresión solicita a su médico de cabecera sumar un suplemento de vitaminas a su plan terapéutico, revisamos la evidencia disponible sobre el uso de estos micronutrientes para el tratamiento de la depresión, y encontramos que no existen pruebas robustas que avalen la suplementación vitamínica en pacientes con este problema de salud. (AU)

Depression is a mood disorder characterised by the existence of a feeling of sadness intense enough to interfere with the performance of normal activities. Based on a real clinical case, in which a patient with depression asked her family doctor to add a vitamin supplement to her therapeutic plan, we reviewed the available evidence on the use of these micronutrients for the treatment of depression and found that there is no robust evidence to support vitamin supplementation in patients with this health problem. (AU)