Treating Treatment-resistant Depression with Esketamine Nasal Spray When All Therapeutic Options Have Been Exhausted: Clinical Experience from a Spanish Cohort of Expanded Use.

Objective: : Treatment Resistant Depression (TRD) is commonly defined as the lack of response to two or more anti-depressants with different mechanisms of action. Up to 30% of patients diagnosed with major depressive disorder might be considered to present TRD. The objective of this study was to assess the effectiveness and tolerability of esketamine in patients diagnosed with TRD, who were referred to our program after exhausting all available treatments. A secondary objective consisted in researching the relationship between response and previous use of electroconvulsive therapy. Methods: : A prospective, observational study was carried out in patients enrolled in the expanded use of esketamine in our center. They received esketamine prior to its marketing authorisation, for therapeutic purposes. Sixteen subjects were analyzed. Effectiveness was assessed with the Montgomery-Asberg depression rating scale (MADRS). Patients were followed up to 4 months after the administration. Results: : Esketamine showed a rapid, robust effect in improving depressive symptoms, with no specific correlation between outcome and any demographic or clinical traits evaluated. No differences were found between patients that previously received Electroconvulsive Therapy, and those that didn't. 10 out of 16 patients responded (＞ 50% change in baseline MADRS scores), but only five achieved remission (＜ 12 points in the global MADRS score). We provide some recommendations, based on clinical experience, to improve tolerability and adherence, and to manage adverse effects. Conclusion: : Results suggest that esketamine is a safe, effective and rapid-acting option for TRD. More studies are needed to properly assess predictors of response outcome.

Genome-wide multi-trait analysis of irritable bowel syndrome and related mental conditions identifies 38 new independent variants.

BACKGROUND: Irritable bowel syndrome (IBS) is a chronic disorder of gut-brain interaction frequently accompanied by mental conditions, including depression and anxiety. Despite showing substantial heritability and being partly determined by a genetic component, the genetic underpinnings explaining the high rates of comorbidity remain largely unclear and there are no conclusive data on the temporal relationship between them. Exploring the overlapping genetic architecture between IBS and mental conditions may help to identify novel genetic loci and biological mechanisms underlying IBS and causal relationships between them. METHODS: We quantified the genetic overlap between IBS, neuroticism, depression and anxiety, conducted a multi-trait genome-wide association study (GWAS) considering these traits and investigated causal relationships between them by using the largest GWAS to date. RESULTS: IBS showed to be a highly polygenic disorder with extensive genetic sharing with mental conditions. Multi-trait analysis of IBS and neuroticism, depression and anxiety identified 42 genome-wide significant variants for IBS, of which 38 are novel. Fine-mapping risk loci highlighted 289 genes enriched in genes upregulated during early embryonic brain development and gene-sets related with psychiatric, digestive and autoimmune disorders. IBS-associated genes were enriched for target genes of anti-inflammatory and antirheumatic drugs, anesthetics and opioid dependence pharmacological treatment. Mendelian-randomization analysis accounting for correlated pleiotropy identified bidirectional causal effects between IBS and neuroticism and depression and causal effects of the genetic liability of IBS on anxiety. CONCLUSIONS: These findings provide evidence of the polygenic architecture of IBS, identify novel genome-wide significant variants for IBS and extend previous knowledge on the genetic overlap and relationship between gastrointestinal and mental disorders.

The Conners Continuous Performance Test CPT3™: Is it a reliable marker to predict neurocognitive dysfunction in Myalgic encephalomyelitis/chronic fatigue syndrome?

Introduction: The main objective is to delimit the cognitive dysfunction associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in adult patients by applying the Continuous Performance Test (CPT3™). Additionally, provide empirical evidence on the usefulness of this computerized neuropsychological test to assess ME/CFS. Method: The final sample (n = 225; 158 Patients/67 Healthy controls) were recruited in a Central Sensitization Syndromes (CSS) specialized unit in a tertiary hospital. All participants were administered this neuropsychological test. Results: There were significant differences between ME/CFS and healthy controls in all the main measures of CPT3™. Mainly, patients had a worse indicator of inattentiveness, sustained attention, vigilance, impulsivity, slow reaction time, and more atypical T-scores, which is associated with a likelihood of having a disorder characterized by attention deficits, such as Attention Deficit Hyperactivity Disorder (ADHD). In addition, relevant correlations were obtained between the CPT3™ variables in the patient's group. The most discriminative indicators of ME/CFS patients were Variability and Hit Reaction Time, both measures of response speed. Conclusion: The CPT3™ is a helpful tool to discriminate neurocognitive impairments from attention and response speed in ME/CFS patients, and it could be used as a marker of ME/CFS severity for diagnosing or monitoring this disease.

Mucosal Plasma Cell Activation and Proximity to Nerve Fibres Are Associated with Glycocalyx Reduction in Diarrhoea-Predominant Irritable Bowel Syndrome: Jejunal Barrier Alterations Underlying Clinical Manifestations.

Irritable bowel syndrome (IBS) is a disorder of brain-gut interaction characterised by abdominal pain and changes in bowel habits. In the diarrhoea subtype (IBS-D), altered epithelial barrier and mucosal immune activation are associated with clinical manifestations. We aimed to further evaluate plasma cells and epithelial integrity to gain understanding of IBS-D pathophysiology. One mucosal jejunal biopsy and one stool sample were obtained from healthy controls and IBS-D patients. Gastrointestinal symptoms, stress, and depression scores were recorded. In the jejunal mucosa, RNAseq and gene set enrichment analyses were performed. A morphometric analysis by electron microscopy quantified plasma cell activation and proximity to enteric nerves and glycocalyx thickness. Immunoglobulins concentration was assessed in the stool. IBS-D patients showed differential expression of humoral pathways compared to controls. Activation and proximity of plasma cells to nerves and IgG concentration were also higher in IBS-D. Glycocalyx thickness was lower in IBS-D compared to controls, and this reduction correlated with plasma cell activation, proximity to nerves, and clinical symptoms. These results support humoral activity and loss of epithelial integrity as important contributors to gut dysfunction and clinical manifestations in IBS-D. Additional studies are needed to identify the triggers of these alterations to better define IBS-D pathophysiology.

Incongruent Views of Functioning between Patients and Gastroenterologists: A Mixed Methods Study.

Gastrointestinal patients, especially those diagnosed with functional digestive disorders (FGIDs), usually present a complex clinical picture that poses a challenge for their management in primary care. The main objective of the current research was to examine the relationship of the congruence of the perception of severity and quality of life between gastroenterologists and their patients with psychological distress and the helping attitude experienced by the latter attended in primary care centres. Additionally, we wanted to explore patients' and practitioners' perceptions. We performed a cross-sectional study with a total of 2261 patients (1562 analysed) that attended three primary care centres. Patients completed questionnaires that measured physical functioning, distress, and perception of helping attitude. Gastroenterologists registered the functional status of each participating patient. Patients were then invited to take part in the qualitative part of the study if they were considered to have incongruent views on their functioning with their gastroenterologist. In total, 52 patients took part in one of eight focus groups. Additionally, four individual interviews were carried out with three gastroenterologists and one consultation-liaison psychiatrist specialised in FGIDs. Both incongruence and functional diagnosis correlated with distress. However, incongruent views between patients and gastroenterologists explained more variance. Statistically significant differences in patients' helping attitude perception were detected between diagnostic but no incongruence groups. In the second stage of the study, a total of five themes were identified from the patient focus groups and the gastroenterologist interviews: illness-emotional and personal problems, disease-health system interaction, health system, intervention, and patients. The current research allowed us to confirm that incongruence in the perception of severity and quality of life between gastroenterologists and patients is related to psychological distress and that this occurs in a multifactorial context where the characteristics of the disorder interact with those of the health system.

Improvement of functional neurological disorder after administration of esketamine nasal spray: a case report.

Functional neurological disorder (FND) is a complex neuropsychiatric condition characterized by the presence of neurological symptoms and signs (either motor or sensory) that cannot be explained by any known medical or mental disease. It is frequently presented with psychiatric comorbidities, such as major depression. Its prognosis is poor, with low improvement or recovery rates at 1 year after their onset, and no particular treatment has demonstrated significant efficacy in this regard. Here, we describe the management of a patient affected by treatment-resistant depression (TRD) and FND characterized by mixed paralysis (sensory and motor) in the left arm, and who was successfully treated with esketamine nasal spray, achieving remission in both disorders. The US Food and Drug Administration and the European Medicines Agency recently approved esketamine, the S-enantiomer of ketamine, for treatment of TRD. It is a fast-acting drug that provides a rapid-onset improvement of depressive symptoms. We have presented the first case, to our knowledge, of functional neurological symptoms being successfully treated with esketamine in a patient with comorbid TRD. While the novelty of this data implies a clear need for further research, it is suggested that esketamine might be a useful tool for the treatment of FND, acting through different theorized mechanisms that are in tune with recent advances in knowledge of the etiopathology of FND.

Overexpression of corticotropin-releasing factor in intestinal mucosal eosinophils is associated with clinical severity in Diarrhea-Predominant Irritable Bowel Syndrome.

Corticotropin-releasing factor (CRF) has been identified in intestinal mucosal eosinophils and associated with psychological stress and gut dysfunction. Irritable bowel syndrome (IBS) is commonly characterized by altered intestinal motility, immune activation, and increased gut barrier permeability along with heightened susceptibility to psychosocial stress. Despite intensive research, the role of mucosal eosinophils in stress-associated gut dysfunction remains uncertain. In this study, we evaluated eosinophil activation profile and CRF content in the jejunal mucosa of diarrhea-predominant IBS (IBS-D) and healthy controls (HC) by gene/protein expression and transmission electron microscopy. We also explored the association between intestinal eosinophil CRF and chronic stress, and the potential mechanisms underlying the stress response by assessing eosinophil response to neuropeptides. We found that mucosal eosinophils displayed higher degranulation profile in IBS-D as compared to HC, with increased content of CRF in the cytoplasmic granules, which significantly correlated with IBS clinical severity, life stress background and depression. Eosinophils responded to substance P and carbachol by increasing secretory activity and CRF synthesis and release, without promoting pro-inflammatory activity, a profile similar to that found in mucosal eosinophils from IBS-D. Collectively, our results suggest that intestinal mucosal eosinophils are potential contributors to stress-mediated gut dysfunction through CRF production and release.

Psychotic disorders versus other psychiatric diagnoses in consultation-liaison psychiatry: 10 years of a single-center experience.

INTRODUCTION: The clinical management of patients with psychotic disorders (PDs) can be particularly complex if it takes place in the context of consultation-liaison psychiatry (CLP) services within a general hospital. However, there are few studies specifically investigating the acute treatment procedures for these patients in CLP settings. OBJECTIVES: To examine the characteristics of a sample of inpatients with a primary PD referred to a CLP service over a 10-year period and to compare the clinical features of this subgroup with patients with other diagnoses (ODs). MATERIALS AND METHODS: Observational and descriptive study over a 10-year period (2005-2014) assessing prospectively adult inpatients admitted to non-psychiatric units of the University Clinical Hospital of Barcelona who were consecutively referred to our CLP service. We performed a posthoc analysis to compare the clinical features between the subgroup of patients with PDs and the rest of patients who meet the criteria for ODs. RESULTS: We requested 393 consultations for patients who either already had the diagnosis of a primary PD and 9,415 for patients with ODs. Our results showed that patients with PDs were younger than the patients with ODs, had a higher prevalence of somatic illnesses related with an unhealthy lifestyle (such as infectious, endocrine, or metabolic diseases), less frequency of cancer, and a need to receive a more intensive psychiatric care. CONCLUSIONS: Inpatients with PDs referred to CLP have different clinical features compared with those who met the criteria for ODs. They are a highly complex group with specific psychiatric care needs.

Translation, adaptation, and reliability of the Stanford Integrated Psychosocial Assessment for Transplantation in the Spanish population.

BACKGROUND: Psychosocial risk factors influence the course of transplantation. Psychosocial evaluation is an important part of pre-transplantation evaluation processes, yet there are no standardized instruments in Spanish. OBJECTIVE: To translate, adapt, and test the reliability of the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) in organ and cell transplantation patients in the Spanish context. METHOD: A Spanish version was developed and adapted using WHO's guidelines. The first 30 candidates' SIPAT interviews were recorded and scored by four independent examiners to test the inter-rater reliability. The internal consistency of the SIPAT items was calculated with a sample of 150 heart, liver, and allogeneic haematopoietic stem cell transplant candidates. Evaluations were conducted by SIPAT-trained and transplantation-experienced clinical psychologists and psychiatrists. RESULTS: Stanford Integrated Psychosocial Assessment for Transplantation achieved excellent intra-class correlation reliability coefficients between investigators (ICC = 0.93 for the general score and from 0.77 to 0.94 for domain scores). Good internal consistency was found with Cronbach's alpha of 0.84 (from 0.69-0.71 for domains). DISCUSSION: This study presents the translated and adapted version of SIPAT. It has been found to have strong inter-rater reliability and good internal consistency. Further research is needed to confirm reliability (eg, test-retest) and establish its validity (eg, concurrent, predictive).

Trastornos psicóticos versus otros diagnósticos psiquiátricos en psiquiatría de enlace e interconsulta: estudio unicéntrico durante un periodo de 10 años / Psychotic disorders versus other psychiatric diagnoses in consultation-liaison psychiatry: 10 years of a single-center experience

Introducción. El manejo clínico de los pacientes con trastornos psicóticos (TPs) es particularmente complejo si se lleva a cabo en el contexto de los servicios de psiquiatría de enlace e interconsulta (PEI) de un hospital general. Sin embargo, disponemos de pocos estudios que hayan investigado de forma específica los procedimientos asistenciales de tratamiento agudo para estos pacientes en entornos PEI. Objetivos. Examinar las características de una muestra de pacientes hospitalizados que presentan un TPs primario, que son remitidos a un servicio de PEI durante un período de 10 años y comparar las características clínicas de este subgrupo con respecto a los pacientes con otros diagnósticos (OD). Material y métodos. Estudio observacional y descriptivo llevado a cabo durante un período de 10 años (2005-2014), evaluando prospectivamente pacientes adultos ingresados en unidades no psiquiátricas del Hospital Clínico Universitario de Barcelona, que fueron remitidos de forma consecutiva a nuestro servicio de PEI. Realizamos un análisis post-hocpara comparar las características clínicas entre el subgrupo de pacientes con TPs y el resto de pacientes que cumplían los criterios para OD. Resultados. Se recibieron 393 interconsultas referentes a pacientes que presentaban un diagnóstico de TPs primario y 9.415 derivaciones de pacientes con OD. Nuestros resulta-dos mostraron que los pacientes con TPs eran más jóvenes que los pacientes con OD, tenían una mayor prevalencia de enfermedades somáticas relacionadas con un estilo de poco saludable (como enfermedades infecciosas, endocrinas o metabólicas), una menor frecuencia de cáncer y una necesidad de recibir asistencia psiquiátrica de forma más intensiva. Conclusiones. Los pacientes hospitalizados con TPs que son remitidos a los servicios de PEI tienen diferentes características clínicas en comparación con aquellos que cumplen con los criterios para OD. Se trata de un grupo complejo, con necesidades específicas en cuanto a la atención psiquiátrica

Introduction. The clinical management of patients with psychotic disorders (PDs) can be particularly complex if it takes place in the context of consultation-liaison psychiatry (CLP) services within a general hospital. However, there are few studies specifically investigating the acute treatment procedures for these patients in CLP settings. Objectives. To examine the characteristics of a sample of inpatients with a primary PD referred to a CLP service over a 10-year period and to compare the clinical features of this subgroup with patients with other diagnoses (ODs).Materials and methods. Observational and descriptive study over a 10-year period (2005-2014) assessing prospectively adult inpatients admitted to non-psychiatric units of the University Clinical Hospital of Barcelona who were consecutively referred to our CLP service. We performed a post-hoc analysis to compare the clinical features between the subgroup of patients with PDs and the rest of patients who meet the criteria for ODs. Results. We requested 393 consultations for patients who either already had the diagnosis of a primary PD and 9,415 for patients with ODs. Our results showed that patients with PDs were younger than the patients with ODs, had a higher prevalence of somatic illnesses related with an unhealthy lifestyle (such as infectious, endocrine, or metabolic diseases), less frequency of cancer, and a need to receive a more intensive psychiatric care. Conclusions. Inpatients with PDs referred to CLP have different clinical features compared with those who met the criteria for ODs. They are a highly complex group with specific psychiatric care needs

Intestinal Mucosal Mast Cells: Key Modulators of Barrier Function and Homeostasis.

The gastrointestinal tract harbours the largest population of mast cells in the body; this highly specialised leukocyte cell type is able to adapt its phenotype and function to the microenvironment in which it resides. Mast cells react to external and internal stimuli thanks to the variety of receptors they express, and carry out effector and regulatory tasks by means of the mediators of different natures they produce. Mast cells are fundamental elements of the intestinal barrier as they regulate epithelial function and integrity, modulate both innate and adaptive mucosal immunity, and maintain neuro-immune interactions, which are key to functioning of the gut. Disruption of the intestinal barrier is associated with increased passage of luminal antigens into the mucosa, which further facilitates mucosal mast cell activation, inflammatory responses, and altered mast cell⁻enteric nerve interaction. Despite intensive research showing gut dysfunction to be associated with increased intestinal permeability and mucosal mast cell activation, the specific mechanisms linking mast cell activity with altered intestinal barrier in human disease remain unclear. This review describes the role played by mast cells in control of the intestinal mucosal barrier and their contribution to digestive diseases.

The role of incongruence between the perceived functioning by patients and clinicians in the detection of psychological distress among functional and motor digestive disorders.

OBJECTIVES: Previous research on gastrointestinal and other medical conditions has shown the presence of incongruence between self- and clinician-reported functioning and its relation with psychopathology. The main objective of this study was to test whether inconsistencies between clinician- and self-assessed functionality can be used to detect psychopathology among patients diagnosed of motor or functional gastrointestinal disorders. METHODS: One hundred and three patients from a gastroenterology inpatient unit were included in this study. All patients underwent clinical assessment, including intestinal manometry, Rome III criteria for functional gastrointestinal disorders, and psychological and psychiatric evaluation. Patients with suspected gastroparesis underwent a scintigraphic gastric emptying test. Definitive diagnoses were made at discharge. RESULTS: Patients with higher levels of incongruence differed in various sociodemographic (age, educational level, work activity and having children) and psychopathological (all SCL-90-R subscales except anxiety and hostility) characteristics. Using general lineal models, incongruence was found to be the variable with stronger relations with psychopathology even when controlling for diagnosis. Interactions were found between incongruence and diagnosis reflecting a pattern in which patients with functional disorders whose subjective evaluation of functioning is not congruent with that of the clinician, have higher levels of psychopathology than patients with motor disorders. CONCLUSIONS: Incongruence between clinician and self-reported functionality seems to be related to higher levels of psychopathology in patients with functional disorders. These findings underscore the need for routine psychosocial assessment among these patients. Gastroenterologists could use the concept of incongruence and its clinical implications, as a screening tool for psychopathology, facilitating consultation-liaison processes.

An exploratory study comparing psychological profiles and its congruence with clinical performance among patients with functional or motility digestive disorders.

Functional gastrointestinal disorders have been related with different psychological conditions. On the contrary, the role of psychological factors within gastrointestinal motor disorders remains unclear. The objective of this study was to explore the differences and congruence with clinical performance of the psychological profile and subjective functionality among patients diagnosed with functional gastrointestinal disorders and gastrointestinal motor disorders. Using a double-blind design, 56 inpatients from a Gastroenterology Department were included in the study. No major differences were detected between the two groups. However, clinical performance was coherent with subjective physical functioning only among patients diagnosed with gastrointestinal motor disorders. These results may provide useful information for gastroenterologists dealing with patients' complaints not consistent with their clinical profile.

Training professionals' communication and motivation skills to improve spinal cord injury patients' satisfaction and clinical outcomes: Study protocol of the ESPELMA trial.

Acute spinal cord injury leaves patients severely impaired and generates high levels of psychological distress among them and their families, which can cause a less active role in rehabilitation, worse functional recovery, and less perceived satisfaction with the results. Additionally, rehabilitation professionals who deal with this psychological distress could ultimately experience higher stress and more risk of burnout. This article presents the study protocol of the ESPELMA project, aimed to train rehabilitation professionals in the clinical management of acute spinal cord injury-associated psychological distress, and to measure the impact of this training on the patients' perceived satisfaction with treatment.

Biofeedback-guided control of abdominothoracic muscular activity reduces regurgitation episodes in patients with rumination.

BACKGROUND & AIMS: Rumination syndrome is characterized by effortless recurrent regurgitation of recently ingested food into the mouth, with consequent expulsion or re-chewing and swallowing. We investigated whether rumination is under volitional control and can be reversed by behavioral treatment. METHODS: We performed a prospective study of 28 patients who fulfilled the Rome criteria for rumination and had no organic disorders on the basis of a thorough evaluation. The diagnosis of rumination was confirmed by intestinal manometry (abdominal compression associated with regurgitation). Patients were trained to modulate abdominothoracic muscle activity under visual control of electromyographic recordings. Recordings were made after challenge meals, before training (baseline), and during 3 treatment sessions. Outcome was measured by questionnaires administered daily for 10 days before training, immediately after training, and at 1, 3, and 6 months after training. RESULTS: By the end of the 3 sessions, patients had effectively learned to reduce intercostal activity (by 50% ± 2%; P < .001 vs basal) and anterior wall muscle activity (by 30% ± 6%; P < .001 vs basal). Patients reported 27 ± 1 regurgitation episodes/day at baseline and 8 ± 2 episodes/day immediately after treatment. Regurgitation episodes decreased further to 4 ± 1 episodes at 6 months after training. CONCLUSIONS: Rumination is produced by an unperceived somatic response to food ingestion that disrupts abdominal accommodation and can be effectively corrected by biofeedback-guided control of abdominothoracic muscular activity.

Psychosocial factors and antiepileptic drug use related to delayed diagnosis of refractory psychogenic nonepileptic seizures.

OBJECTIVE: We analyzed clinical and psychosocial factors in patients with refractory psychogenic nonepileptic seizures, seeking characteristics that could hasten diagnosis. BACKGROUND: Psychogenic nonepileptic seizures remain a diagnostic challenge. Prognosis is best if patients are treated within 2 years of symptom onset. Psychosocial factors have been shown to provide important information for differential diagnosis. METHODS: Over a year and 1132 consecutive patients, our hospital's Epilepsy Unit suspected 93 patients of having psychogenic nonepileptic seizures and confirmed refractory psychogenic nonepileptic seizures in 67. We referred these patients to our psychiatric consultation unit for detailed diagnostic interviews, and 53 of the patients followed through. Two months after the psychiatric evaluation we gave them a psychiatric intervention, explaining the diagnosis and treating their comorbidities. We also tracked the patients' use of antiepileptic drugs for 3 months, from just before the psychiatric evaluation until a month after they started the intervention. RESULTS: Women, patients with an inadequate primary support group, and patients who had tried many antiepileptic drugs were most likely to have their diagnosis of psychogenic nonepileptic seizures delayed by >2 years after onset. A stepwise logistic regression showed that the 2 best predictors of late diagnosis were lack of availability of a primary support group and patients trying many antiepileptic drugs. CONCLUSIONS: Clinicians evaluating patients with questionable seizures should raise their suspicion of psychogenic nonepileptic seizures especially in female patients with an insufficient primary support group and a history of taking multiple antiepileptic drugs.

Neuropsychological impairment in female patients with chronic fatigue syndrome: a preliminary study.

This study examines neuropsychological impairments associated with chronic fatigue syndrome (CFS) and explores their association with related clinical factors. Sixty-eight women with CFS were assessed with a neuropsychological battery. Raw scores were adjusted for age and gender and were converted to T scores according to normative data extracted from a local sample of 250 healthy subjects. Neuropsychological dysfunction was calculated using summary impairment indexes (proportion of test scores outside normal limits-T score <40-for each cognitive domain). Finally, a linear regression was calculated to identify predictors of cognitive deficit, including intrinsic factors of the disease (level of fatigue and length of illness) and extrinsic factors (emotional factors, age, and education). Approximately 50% of scores showed impairment in attention and motor functioning, and nearly 40% showed impairment in speed information processing and executive functioning. Fatigue predicted attention and executive functioning impairment, and emotional factors predicted verbal memory dysfunction. According to our findings, cognitive dysfunction in CFS could be explained by pathophysiological processes of the disease. One implication of this would be the need to identify homogeneous subgroups of patients with CFS by taking into account common factors, which, in turn, would help to identify more specific cognitive profiles, which could then serve to implement appropriate therapeutic measures accordingly.