Gut microbiota, innate immune pathways, and inflammatory control mechanisms in patients with major depressive disorder

Although alterations in the gut microbiota have been linked to the pathophysiology of major depressive disorder (MDD), including through effects on the immune response, our understanding is deficient about the straight connection patterns among microbiota and MDD in patients. Male and female MDD patients were recruited: 46 patients with a current active MDD (a-MDD) and 22 in remission or with only mild symptoms (r-MDD). Forty-five healthy controls (HC) were also recruited. Psychopathological states were assessed, and fecal and blood samples were collected. Results indicated that the inducible nitric oxide synthase expression was higher in MDD patients compared with HC and the oxidative stress levels were greater in the a-MDD group. Furthermore, the lipopolysaccharide (an indirect marker of bacterial translocation) was higher in a-MDD patients compared with the other groups. Fecal samples did not cluster according to the presence or the absence of MDD. There were bacterial genera whose relative abundance was altered in MDD: Bilophila (2-fold) and Alistipes (1.5-fold) were higher, while Anaerostipes (1.5-fold) and Dialister (15-fold) were lower in MDD patients compared with HC. Patients with a-MDD presented higher relative abundance of Alistipes and Anaerostipes (1.5-fold) and a complete depletion of Dialister compared with HC. Patients with r-MDD presented higher abundance of Bilophila (2.5-fold) compared with HC. Thus, the abundance of bacterial genera and some immune pathways, both with potential implications in the pathophysiology of depression, appear to be altered in MDD, with the most noticeable changes occurring in patients with the worse clinical condition, the a-MDD group. © 2021, The Author(s)

COVID Isolation Eating Scale (CIES): Analysis of the impact of confinement in eating disorders and obesity-A collaborative international study

Confinement during the COVID-19 pandemic is expected to have a serious and complex impact on the mental health of patients with an eating disorder (ED) and of patients with obesity. The present manuscript has the following aims: (1) to analyse the psychometric properties of the COVID Isolation Eating Scale (CIES), (2) to explore changes that occurred due to confinement in eating symptomatology; and (3) to explore the general acceptation of the use of telemedicine during confinement. The sample comprised 121 participants (87 ED patients and 34 patients with obesity) recruited from six different centres. Confirmatory Factor Analyses (CFA) tested the rational-theoretical structure of the CIES. Adequate goodness-of-fit was obtained for the confirmatory factor analysis, and Cronbach alpha values ranged from good to excellent. Regarding the effects of confinement, positive and negative impacts of the confinement depends of the eating disorder subtype. Patients with anorexia nervosa (AN) and with obesity endorsed a positive response to treatment during confinement, no significant changes were found in bulimia nervosa (BN) patients, whereas Other Specified Feeding or Eating Disorder (OSFED) patients endorsed an increase in eating symptomatology and in psychopathology. Furthermore, AN patients expressed the greatest dissatisfaction and accommodation difficulty with remote therapy when compared with the previously provided face-to-face therapy. The present study provides empirical evidence on the psychometric robustness of the CIES tool and shows that a negative confinement impact was associated with ED subtype, whereas OSFED patients showed the highest impairment in eating symptomatology and in psychopathology.This manuscript and research was supported by grants from the Ministeriode Economía y Competitividad (PSI2015-68701-R), Instituto de Salud Carlos III (ISCIII) (FIS PI14/00290/ INT19/00046nd PI17/01167) and co-funded by FEDER funds/European Regional Development Fund (ERDF), a way to build Europe. CIBERobn, CIBERsam and CIBERDEM are all initiatives of ISCIII. GMB is supported by a postdoctoral grant from FUNCIVA. This initiative is supported by Generalitat de Catalunya. LM is supported by a postdoctoral grant of the mexican institution Consejo Nacional de Ciencia y Tecnología (CONACYT). PPM was supported, in part, by a Portuguese Foundation for Science and Technology grant (POCI-01-0145-FEDER-028145). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript

Impact of COVID-19 Lockdown in Eating Disorders: A Multicentre Collaborative International Study

Background. The COVID-19 lockdown has had a significant impact on mental health. Patients with eating disorders (ED) have been particularly vulnerable. Aims. (1) To explore changes in eating-related symptoms and general psychopathology during lockdown in patients with an ED from various European and Asian countries; and (2) to assess differences related to diagnostic ED subtypes, age, and geography. Methods. The sample comprised 829 participants, diagnosed with an ED according to DSM-5 criteria from specialized ED units in Europe and Asia. Participants were assessed using the COVID-19 Isolation Scale (CIES). Results. Patients with binge eating disorder (BED) experienced the highest impact on weight and ED symptoms in comparison with other ED subtypes during lockdown, whereas individuals with other specified feeding and eating disorders (OFSED) had greater deterioration in general psychological functioning than subjects with other ED subtypes. Finally, Asian and younger individuals appeared to be more resilient. Conclusions. The psychopathological changes in ED patients during the COVID-19 lockdown varied by cultural context and individual variation in age and ED diagnosis. Clinical services may need to target preventive measures and adapt therapeutic approaches for the most vulnerable patients

Alteraciones cerebrales en la depresión mayor como factores predictores del curso de la enfermedad: hallazgos transversales y longitudinales en la sustancia blanca de pacientes con un primer episodio depresivo

El trastorno depresivo mayor (TDM) presenta un curso muy heterogéneo y que conlleva un importante sufrimiento y pérdida de funcionalidad a aquellos que lo sufren. El objetivo principal de esta tesis es la identificación de estructuras cerebrales que puedan estar alteradas en primeros episodios depresivos (PED) para su caracterización como marcadores del trastorno y de aquellas estructuras que predecirán y/o mostrarán alteraciones con la aparición de recurrencias. Para ello se ha estudiado la habénula mediante técnicas de neuroimagen estructural, desde un enfoque transversal con el objetivo de encontrar diferencias entre los pacientes en diferentes estadios de la depresión y los controles sanos. Posteriormente se ha realizado un estudio longitudinal mediante morfometría basada en vóxel (VBM) de los pacientes PED para identificar qué estructuras se alteran de forma temprana en la depresión y si se relacionan con la aparición de recurrencias. El primer artículo cuenta con una muestra de 95 pacientes en diferentes estadios de la depresión i.e., PED, pacientes recurrentes en estado de remisión y pacientes con depresión crónica refractaria. Los resultados muestran que la sustancia blanca (SB) de la habénula es significativamente mayor en mujeres con un primer episodio depresivo en comparación con las que sufren depresión crónica y las pacientes control. Entre las mujeres se observa que mayores volúmenes de SB habenular correlacionan con una mayor edad de debut y una menor duración de la enfermedad, aunque este resultado no pudo confirmarse en el análisis por grupos. El segundo artículo cuenta con una muestra de 33 PED y 33 controles sanos a los que se ha seguido durante dos años. Los PED presentan a nivel basal menores volúmenes de SB en el giro frontal superior derecho y la corona radiada anterior que los controles sanos, aunque estas diferencias se desvanecen a lo largo del seguimiento. Los PED que presentan recurrencias (n=15), tienen volúmenes mayores de SB en áreas que corresponderían a la corona radiada posterior izquierda y la radiación talámica posterior derecha al finalizar el seguimiento en comparación con los PED que no presentan recurrencias. No se han encontrado diferencias en sustancia gris en ningún momento del seguimiento. En conclusión, el primer estudio sugiere que la SB de la habénula se ve alterada en los primeros estadios de la depresión mayor y avoca por una más temprana implicación de la sustancia blanca, frente a la sustancia gris. La SB habenular podría traducir esos cambios neuroplásticos que se dan durante la remisión temprana. El segundo estudio apoya la presencia de alteraciones en la SB cerebral de las regiones prefrontales en las primeras fases de la depresión. La desaparición de dichas alteraciones sugiere que son un marcador de estado y que, por tanto, pueden remitir tras una intervención temprana. Los incrementos de SB de regiones más posteriores en pacientes PED recurrentes podrían traducir un efecto compensatorio propio del cerebro y más específico de la sustancia blanca para hacer frente a la enfermedad en las fases más tempranas.Major depressive disorder (MDD) is characterized by a very heterogeneous course and by a significant suffering and loss of functionality for people who develop it. The main objective of this thesis is to identify those brain structures that could be altered in first depressive episodes (FED) for their characterization as markers of the disorder and those structures that will predict or will show alterations while recurrences appear. To do this, the habenula was studied from a structural transversal neuroimaging approach to find potential differences between patients at different stages of depression and healthy controls. Subsequently, a longitudinal study of FED patients using voxel-based morphometry (VBM) has been carried out to identify which structures could be are altered in early stages of MDD and to identify if they are related to the appearance of recurrences. The first article included 95 patients in different stages of depression i.e., FED, remitted-recurrent and chronic refractory depression patients and healthy controls (HC). The results showed that habenula white matter volume (WMV) was significantly higher in women-FED compared to those who suffered from chronic depression and with healthy control patients. Among the women, it is observed that greater habenular WMV correlate with elderly onset and shorter duration of the disease, although this result could not be confirmed in the analysis by groups. The second article has a sample of 33 FED and 33 HC that have been followed for two years. FED patients present lower WMV in the superior right frontal gyrus and in the anterior corona radiata than the healthy controls at baseline, although these differences seem to vanish during the follow-up. Longitudinal analysis showed that FED patients who suffered recurrences (n = 15) have enlarged WMV in left posterior corona radiata and right posterior thalamic radiation at the end of the follow-up. By contrasts, no differences in gray matter volume were observed between groups either at baseline nor at follow-up. In conclusion, the first study suggests that habenula’s WMV is altered in the first stages of major depression and stands up for a putative preferential contribution of white matter over grey matter changes within this structure associated with early stages of MDD, particularly in women. Habenular WMV could translate those neuroplastic changes that occur during early remission. The second study supports the presence of prefrontal WM alterations in the early stages of depression. The disappearance of these alterations suggests that they are a state marker therefore, they may remit after an early intervention. WMV increases in posterior regions in recurrent FED patients could translate a compensatory effect of the brain, more specific for the white matter, to cope with the disease in the earliest phases

Alteraciones cerebrales en la depresión mayor como factores predictores del curso de la enfermedad: hallazgos transversales y longitudinales en la sustancia blanca de pacientes con un primer episodio depresivo

El trastorno depresivo mayor (TDM) presenta un curso muy heterogéneo y que conlleva un importante sufrimiento y pérdida de funcionalidad a aquellos que lo sufren. El objetivo principal de esta tesis es la identificación de estructuras cerebrales que puedan estar alteradas en primeros episodios depresivos (PED) para su caracterización como marcadores del trastorno y de aquellas estructuras que predecirán y/o mostrarán alteraciones con la aparición de recurrencias. Para ello se ha estudiado la habénula mediante técnicas de neuroimagen estructural, desde un enfoque transversal con el objetivo de encontrar diferencias entre los pacientes en diferentes estadios de la depresión y los controles sanos. Posteriormente se ha realizado un estudio longitudinal mediante morfometría basada en vóxel (VBM) de los pacientes PED para identificar qué estructuras se alteran de forma temprana en la depresión y si se relacionan con la aparición de recurrencias. El primer artículo cuenta con una muestra de 95 pacientes en diferentes estadios de la depresión i.e., PED, pacientes recurrentes en estado de remisión y pacientes con depresión crónica refractaria. Los resultados muestran que la sustancia blanca (SB) de la habénula es significativamente mayor en mujeres con un primer episodio depresivo en comparación con las que sufren depresión crónica y las pacientes control. Entre las mujeres se observa que mayores volúmenes de SB habenular correlacionan con una mayor edad de debut y una menor duración de la enfermedad, aunque este resultado no pudo confirmarse en el análisis por grupos. El segundo artículo cuenta con una muestra de 33 PED y 33 controles sanos a los que se ha seguido durante dos años. Los PED presentan a nivel basal menores volúmenes de SB en el giro frontal superior derecho y la corona radiada anterior que los controles sanos, aunque estas diferencias se desvanecen a lo largo del seguimiento. Los PED que presentan recurrencias (n=15), tienen volúmenes mayores de SB en áreas que corresponderían a la corona radiada posterior izquierda y la radiación talámica posterior derecha al finalizar el seguimiento en comparación con los PED que no presentan recurrencias. No se han encontrado diferencias en sustancia gris en ningún momento del seguimiento. En conclusión, el primer estudio sugiere que la SB de la habénula se ve alterada en los primeros estadios de la depresión mayor y avoca por una más temprana implicación de la sustancia blanca, frente a la sustancia gris. La SB habenular podría traducir esos cambios neuroplásticos que se dan durante la remisión temprana. El segundo estudio apoya la presencia de alteraciones en la SB cerebral de las regiones prefrontales en las primeras fases de la depresión. La desaparición de dichas alteraciones sugiere que son un marcador de estado y que, por tanto, pueden remitir tras una intervención temprana. Los incrementos de SB de regiones más posteriores en pacientes PED recurrentes podrían traducir un efecto compensatorio propio del cerebro y más específico de la sustancia blanca para hacer frente a la enfermedad en las fases más tempranas.Major depressive disorder (MDD) is characterized by a very heterogeneous course and by a significant suffering and loss of functionality for people who develop it. The main objective of this thesis is to identify those brain structures that could be altered in first depressive episodes (FED) for their characterization as markers of the disorder and those structures that will predict or will show alterations while recurrences appear. To do this, the habenula was studied from a structural transversal neuroimaging approach to find potential differences between patients at different stages of depression and healthy controls. Subsequently, a longitudinal study of FED patients using voxel-based morphometry (VBM) has been carried out to identify which structures could be are altered in early stages of MDD and to identify if they are related to the appearance of recurrences. The first article included 95 patients in different stages of depression i.e., FED, remitted-recurrent and chronic refractory depression patients and healthy controls (HC). The results showed that habenula white matter volume (WMV) was significantly higher in women-FED compared to those who suffered from chronic depression and with healthy control patients. Among the women, it is observed that greater habenular WMV correlate with elderly onset and shorter duration of the disease, although this result could not be confirmed in the analysis by groups. The second article has a sample of 33 FED and 33 HC that have been followed for two years. FED patients present lower WMV in the superior right frontal gyrus and in the anterior corona radiata than the healthy controls at baseline, although these differences seem to vanish during the follow-up. Longitudinal analysis showed that FED patients who suffered recurrences (n = 15) have enlarged WMV in left posterior corona radiata and right posterior thalamic radiation at the end of the follow-up. By contrasts, no differences in gray matter volume were observed between groups either at baseline nor at follow-up. In conclusion, the first study suggests that habenula’s WMV is altered in the first stages of major depression and stands up for a putative preferential contribution of white matter over grey matter changes within this structure associated with early stages of MDD, particularly in women. Habenular WMV could translate those neuroplastic changes that occur during early remission. The second study supports the presence of prefrontal WM alterations in the early stages of depression. The disappearance of these alterations suggests that they are a state marker therefore, they may remit after an early intervention. WMV increases in posterior regions in recurrent FED patients could translate a compensatory effect of the brain, more specific for the white matter, to cope with the disease in the earliest phases

Alteraciones cerebrales en la depresión mayor como factores predictores del curso de la enfermedad : hallazgos transversales y longitudinales en la sustancia blanca de pacientes con un primer episodio depresivo /

El trastorno depresivo mayor (TDM) presenta un curso muy heterogéneo y que conlleva un importante sufrimiento y pérdida de funcionalidad a aquellos que lo sufren. El objetivo principal de esta tesis es la identificación de estructuras cerebrales que puedan estar alteradas en primeros episodios depresivos (PED) para su caracterización como marcadores del trastorno y de aquellas estructuras que predecirán y/o mostrarán alteraciones con la aparición de recurrencias. Para ello se ha estudiado la habénula mediante técnicas de neuroimagen estructural, desde un enfoque transversal con el objetivo de encontrar diferencias entre los pacientes en diferentes estadios de la depresión y los controles sanos. Posteriormente se ha realizado un estudio longitudinal mediante morfometría basada en vóxel (VBM) de los pacientes PED para identificar qué estructuras se alteran de forma temprana en la depresión y si se relacionan con la aparición de recurrencias. El primer artículo cuenta con una muestra de 95 pacientes en diferentes estadios de la depresión i.e., PED, pacientes recurrentes en estado de remisión y pacientes con depresión crónica refractaria. Los resultados muestran que la sustancia blanca (SB) de la habénula es significativamente mayor en mujeres con un primer episodio depresivo en comparación con las que sufren depresión crónica y las pacientes control. Entre las mujeres se observa que mayores volúmenes de SB habenular correlacionan con una mayor edad de debut y una menor duración de la enfermedad, aunque este resultado no pudo confirmarse en el análisis por grupos. El segundo artículo cuenta con una muestra de 33 PED y 33 controles sanos a los que se ha seguido durante dos años. Los PED presentan a nivel basal menores volúmenes de SB en el giro frontal superior derecho y la corona radiada anterior que los controles sanos, aunque estas diferencias se desvanecen a lo largo del seguimiento. Los PED que presentan recurrencias (n=15), tienen volúmenes mayores de SB en áreas que corresponderían a la corona radiada posterior izquierda y la radiación talámica posterior derecha al finalizar el seguimiento en comparación con los PED que no presentan recurrencias. No se han encontrado diferencias en sustancia gris en ningún momento del seguimiento. En conclusión, el primer estudio sugiere que la SB de la habénula se ve alterada en los primeros estadios de la depresión mayor y avoca por una más temprana implicación de la sustancia blanca, frente a la sustancia gris. La SB habenular podría traducir esos cambios neuroplásticos que se dan durante la remisión temprana. El segundo estudio apoya la presencia de alteraciones en la SB cerebral de las regiones prefrontales en las primeras fases de la depresión. La desaparición de dichas alteraciones sugiere que son un marcador de estado y que, por tanto, pueden remitir tras una intervención temprana. Los incrementos de SB de regiones más posteriores en pacientes PED recurrentes podrían traducir un efecto compensatorio propio del cerebro y más específico de la sustancia blanca para hacer frente a la enfermedad en las fases más tempranas.Major depressive disorder (MDD) is characterized by a very heterogeneous course and by a significant suffering and loss of functionality for people who develop it. The main objective of this thesis is to identify those brain structures that could be altered in first depressive episodes (FED) for their characterization as markers of the disorder and those structures that will predict or will show alterations while recurrences appear. To do this, the habenula was studied from a structural transversal neuroimaging approach to find potential differences between patients at different stages of depression and healthy controls. Subsequently, a longitudinal study of FED patients using voxel-based morphometry (VBM) has been carried out to identify which structures could be are altered in early stages of MDD and to identify if they are related to the appearance of recurrences. The first article included 95 patients in different stages of depression i.e., FED, remitted-recurrent and chronic refractory depression patients and healthy controls (HC). The results showed that habenula white matter volume (WMV) was significantly higher in women-FED compared to those who suffered from chronic depression and with healthy control patients. Among the women, it is observed that greater habenular WMV correlate with elderly onset and shorter duration of the disease, although this result could not be confirmed in the analysis by groups. The second article has a sample of 33 FED and 33 HC that have been followed for two years. FED patients present lower WMV in the superior right frontal gyrus and in the anterior corona radiata than the healthy controls at baseline, although these differences seem to vanish during the follow-up. Longitudinal analysis showed that FED patients who suffered recurrences (n = 15) have enlarged WMV in left posterior corona radiata and right posterior thalamic radiation at the end of the follow-up. By contrasts, no differences in gray matter volume were observed between groups either at baseline nor at follow-up. In conclusion, the first study suggests that habenula's WMV is altered in the first stages of major depression and stands up for a putative preferential contribution of white matter over grey matter changes within this structure associated with early stages of MDD, particularly in women. Habenular WMV could translate those neuroplastic changes that occur during early remission. The second study supports the presence of prefrontal WM alterations in the early stages of depression. The disappearance of these alterations suggests that they are a state marker therefore, they may remit after an early intervention. WMV increases in posterior regions in recurrent FED patients could translate a compensatory effect of the brain, more specific for the white matter, to cope with the disease in the earliest phases

Gut microbiota, innate immune pathways, and inflammatory control mechanisms in patients with major depressive disorder

Altres ajuts: JdD-A was supported by the Catalan Intensification Programme (PERIS, SLT008/18/00092; Generalitat de Catalunya).Although alterations in the gut microbiota have been linked to the pathophysiology of major depressive disorder (MDD), including through effects on the immune response, our understanding is deficient about the straight connection patterns among microbiota and MDD in patients. Male and female MDD patients were recruited: 46 patients with a current active MDD (a-MDD) and 22 in remission or with only mild symptoms (r-MDD). Forty-five healthy controls (HC) were also recruited. Psychopathological states were assessed, and fecal and blood samples were collected. Results indicated that the inducible nitric oxide synthase expression was higher in MDD patients compared with HC and the oxidative stress levels were greater in the a-MDD group. Furthermore, the lipopolysaccharide (an indirect marker of bacterial translocation) was higher in a-MDD patients compared with the other groups. Fecal samples did not cluster according to the presence or the absence of MDD. There were bacterial genera whose relative abundance was altered in MDD: Bilophila (2-fold) and Alistipes (1.5-fold) were higher, while Anaerostipes (1.5-fold) and Dialister (15-fold) were lower in MDD patients compared with HC. Patients with a-MDD presented higher relative abundance of Alistipes and Anaerostipes (1.5-fold) and a complete depletion of Dialister compared with HC. Patients with r-MDD presented higher abundance of Bilophila (2.5-fold) compared with HC. Thus, the abundance of bacterial genera and some immune pathways, both with potential implications in the pathophysiology of depression, appear to be altered in MDD, with the most noticeable changes occurring in patients with the worse clinical condition, the a-MDD group

Gut microbiota, innate immune pathways, and inflammatory control mechanisms in patients with major depressive disorder

Although alterations in the gut microbiota have been linked to the pathophysiology of major depressive disorder (MDD), including through effects on the immune response, our understanding is deficient about the straight connection patterns among microbiota and MDD in patients. Male and female MDD patients were recruited: 46 patients with a current active MDD (a-MDD) and 22 in remission or with only mild symptoms (r-MDD). Forty-five healthy controls (HC) were also recruited. Psychopathological states were assessed, and fecal and blood samples were collected. Results indicated that the inducible nitric oxide synthase expression was higher in MDD patients compared with HC and the oxidative stress levels were greater in the a-MDD group. Furthermore, the lipopolysaccharide (an indirect marker of bacterial translocation) was higher in a-MDD patients compared with the other groups. Fecal samples did not cluster according to the presence or the absence of MDD. There were bacterial genera whose relative abundance was altered in MDD:Bilophila(2-fold) andAlistipes(1.5-fold) were higher, whileAnaerostipes(1.5-fold) andDialister(15-fold) were lower in MDD patients compared with HC. Patients with a-MDD presented higher relative abundance ofAlistipesandAnaerostipes(1.5-fold) and a complete depletion ofDialistercompared with HC. Patients with r-MDD presented higher abundance ofBilophila(2.5-fold) compared with HC. Thus, the abundance of bacterial genera and some immune pathways, both with potential implications in the pathophysiology of depression, appear to be altered in MDD, with the most noticeable changes occurring in patients with the worse clinical condition, the a-MDD group.Spanish Ministry of Science and InnovationCIBERSAMCatalan Intensification ProgrammeInstituto de Salud Carlos IIIDepto. de Farmacología y ToxicologíaDepto. de Microbiología y ParasitologíaDepto. de Medicina Legal, Psiquiatría y PatologíaFac. de MedicinaTRUEpu