Substance use disorders and cooperative research on addictions: Spanish approach as a model.

Substance use disorders (SUD), also named addiction when it is severe, is a chronic brain disorder with serious impact on individual who suffer, the public health and with high burden of disease. They are multitude of mechanisms/factors involved in addiction: from individual characteristics of the person (from genetic to impacts of stress, sex, and age) to social and environmental situation (availability and accessibility of substances, cultural and legal aspects, socio-economical situation) and type of substance of use (pharmacological characteristics) Then, research on Addiction must include different, complementary, and translational perspectives. In this review, we explore the neurobiological, psychosocial, and epidemiological knowledge of substance addiction, and the main role played by pharmacology in the research in this field. In Spain, since 2002, collaborative networks have emerged for comprehensive research on addictions, with the creation of the Addictive Disorders Network (RTA), currently redefined as the Research Network for Primary Care in Addictions (RIAPAd) with the support of the Carlos III Health Institute (Instituto de Salud Carlos III). Basic (including neuropharmacology and behavioral pharmacology), clinical and epidemiological research groups stand out, combining efforts to address prevention, early detection and treatment through interdisciplinary cooperation and the subsequent dissemination of results.

Dysregulation of Plasma Growth Factors and Chemokines in Cocaine Use Disorder: Implications for Dual Diagnosis with Schizophrenia and Antisocial Personality Disorder in an Exploratory Study.

INTRODUCTION: Dual diagnosis in individuals with cocaine use disorders (CUDs) presents a mental health challenge marked by an increased susceptibility to disabling morbidities and premature mortality. Despite extensive research on depression and anxiety, other prevalent comorbidities, such as psychotic and personality disorders, have received less attention. This study explores inflammation-related mediators as potential biomarkers for CUD and dual diagnosis with schizophrenia (SCZ) or antisocial personality disorder (APD). METHODS: This exploratory study included 95 participants, comprising 40 healthy subjects and 55 abstinent patients with CUD. Lifetime CUD was diagnosed either as single diagnosis (CUD group, N = 25) or as a dual diagnosis (DD group. N = 30) with SCZ (CUD+SCZ subgroup) or APD (CUD+APD subgroup). Participants were clinically assessed, and the plasma concentrations of growth factors (i.e., G-CSF, BDNF, and VEGF-A) and chemokines (i.e., CCL11/eotaxin-1, CCL2/MCP-1, and CXCL12/SDF-1) were determined and log(10)-transformed for analysis. RESULTS: Growth factors and chemokines were dysregulated by CUD and psychiatric diagnoses. Specifically, patients in the CUD group exhibited significantly lower concentrations of G-CSF and CCL11/eotaxin-1 than the control group. In contrast, the DD group showed significantly higher concentrations of all analytes than both the CUD and control groups. Additionally, no differences in these analytes were observed between the CUD+SCZ and CUD+APD subgroups within the DD group. Regarding cocaine-related variables, significant associations were identified in the CUD group: an inverse correlation between the age at first cocaine use and the concentrations of BDNF and CCL2/MCP-1; and a positive correlation between the duration of the cocaine abstinence and the concentrations of BDNF and CCL11/eotaxin-1. Lastly, a logistic regression model incorporating all these analytes demonstrated high discriminatory power in distinguishing patients with CUD alone from those with dual diagnosis. CONCLUSIONS: Individuals with dual diagnosis of CUD exhibit elevated concentrations of growth factors and chemokines, distinguishing them from those with CUD alone. It is unclear whether the differences in these inflammatory mediators are specific to the presence of SCZ and APD. The study highlights potential biomarkers and associations, providing valuable insights into the intricate interplay of CUD and psychiatric disorders to enhance clinical diagnosis and therapeutics.

Inhibition of Adult Neurogenesis in Male Mice after Repeated Exposure to Paracetamol Overdose.

Paracetamol, or acetaminophen (N-acetyl-para-aminophenol, APAP), is an analgesic and antipyretic drug that is commonly used worldwide, implicated in numerous intoxications due to overdose, and causes serious liver damage. APAP can cross the blood-brain barrier and affects brain function in numerous ways, including pain signals, temperature regulation, neuroimmune response, and emotional behavior; however, its effect on adult neurogenesis has not been thoroughly investigated. We analyze, in a mouse model of hepatotoxicity, the effect of APAP overdose (750 mg/kg/day) for 3 and 4 consecutive days and after the cessation of APAP administration for 6 and 15 days on cell proliferation and survival in two relevant neurogenic zones: the subgranular zone of the dentate gyrus and the hypothalamus. The involvement of liver damage (plasma transaminases), neuronal activity (c-Fos), and astroglia (glial fibrillar acidic protein, GFAP) were also evaluated. Our results indicated that repeated APAP overdoses are associated with the inhibition of adult neurogenesis in the context of elevated liver transaminase levels, neuronal hyperactivity, and astrogliosis. These effects were partially reversed after the cessation of APAP administration for 6 and 15 days. In conclusion, these results suggest that APAP overdose impairs adult neurogenesis in the hippocampus and hypothalamus, a fact that may contribute to the effects of APAP on brain function.

Sex-based differences in growth-related IGF1 signaling in response to PAPP-A2 deficiency: comparative effects of rhGH, rhIGF1 and rhPAPP-A2 treatments.

BACKGROUND: Children with pregnancy-associated plasma protein-A2 (PAPP-A2) mutations resulting in low levels of bioactive insulin-like growth factor-1 (IGF1) and progressive postnatal growth retardation have improved growth velocity and height following recombinant human (rh)IGF1 treatment. The present study aimed to evaluate whether Pappa2 deficiency and pharmacological manipulation of GH/IGF1 system are associated with sex-specific differences in growth-related signaling pathways. METHODS: Plasma, hypothalamus, pituitary gland and liver of Pappa2ko/ko mice of both sexes, showing reduced skeletal growth, and liver of these mice treated with rhGH, rhIGF1 and rhPAPP-A2 from postnatal day (PND) 5 to PND35 were analyzed. RESULTS: Reduced body and femur length of Pappa2ko/ko mice was associated with increases in: (1) components of IGF1 ternary complexes (IGF1, IGFBP5/Igfbp5, Igfbp3, Igfals) in plasma, hypothalamus and/or liver; and (2) key signaling regulators (phosphorylated PI3K, AKT, mTOR, GSK3ß, ERK1/2 and AMPKα) in hypothalamus, pituitary gland and/or liver, with Pappa2ko/ko females having a more prominent effect. Compared to rhGH and rhIGF1, rhPAPP-A2 specifically induced: (1) increased body and femur length, and reduced plasma total IGF1 and IGFBP5 concentrations in Pappa2ko/ko females; and (2) increased Igf1 and Igf1r levels and decreased Ghr, Igfbp3 and Igfals levels in the liver of Pappa2ko/ko females. These changes were accompanied by lower phospho-STAT5, phospho-AKT and phospho-ERK2 levels and higher phospho-AMPK levels in the liver of Pappa2ko/ko females. CONCLUSIONS: Sex-specific differences in IGF1 system and signaling pathways are associated with Pappa2 deficiency, pointing to rhPAPP-A2 as a promising drug to alleviate postnatal growth retardation underlying low IGF1 bioavailability in a female-specific manner.

Understanding the physiological role of pregnancy-associated plasma protein-A2 (PAPP-A2), a proteinase involved in the insulin-like growth factor-1 (IGF1) availability to regulate growth, could provide insight into new treatments for patients with short stature and skeletal abnormalities. Although progressive postnatal growth retardation in patients with PAPP-A2 mutations can differ between males and females, we do not know the underlying differences in IGF1 system and signaling, and their response to treatment that contribute to growth improvement. The present study examines whether Pappa2 deficiency and pharmacological administration of rhGH, rhIGF1 and rhPAPP-A2 are associated with sex-specific differences in IGF1 ternary complexes and IGF1 signaling pathways. Reduced body and femur length of Pappa2-deficient mice was associated with sex- and tissue-specific alteration of IGF ternary/binary complexes and IGF1 signaling pathways. rhPAPP-A2 treatment induced female-specific increase in body and femur length and reduction in IGF ternary/binary complexes through STAT5-AKT-ERK2-AMPK signaling pathways in liver. The involvement of PAPP-A2 in sex-based growth physiology supports the use of promising drugs to alleviate postnatal growth retardation underlying low IGF1 bioavailability in a female-specific manner.

Clinical features of individuals with laboratory values suggestive of advanced liver fibrosis when first treated for alcohol use disorder.

BACKGROUND: Effective screening for alcohol-associated liver disease is relevant in the context of chronic, excessive alcohol consumption. Patients with alcohol-associated liver disease are often not diagnosed until their liver disease is decompensated. We analyzed the prevalence and associations of Fibrosis-4 index (FIB-4) values suggestive of advanced liver fibrosis in patients referred for their first treatment of alcohol use disorder (AUD). METHODS: We conducted a cross-sectional, multicenter study of noncirrhotic individuals referred for their first AUD treatment between March 2013 and April 2021. We obtained sociodemographic data, substance use characteristics, and blood samples at admission. We considered a FIB-4 value ≥2.67 suggestive of advanced liver fibrosis and used logistic regression analyses to identify features associated with this value. RESULTS: We included 604 patients (67% male), with a median age at admission of 48 years [IQR: 41-56 years]. The median duration of regular alcohol consumption was 21 years [IQR: 18-30 years] and the median alcohol consumption was 105 standard drink units (SDU)/week [IQR: 63-160 SDU/week]. A FIB-4 value ≥ 2.67 was present in 19.3% of cases. These patients reported more frequent binge drinking (75.4% vs. 66%, p = 0.05) than those with FIB-4 values below 2.67. In multivariate analysis, a history of binge drinking (OR 1.9, 95% CI, 1.05-3.47), anemia (OR 2.95, 95% CI, 1.42-6.11), leukopenia (OR 7.46, 95% CI, 2.07-26.8), and total serum bilirubin >1 mg/dL (OR 6.46, 95% CI, 3.57-11.7) were independently associated with FIB-4 values ≥2.67. CONCLUSIONS: One in five patients admitted to treatment for AUD without evidence of decompensated liver disease have FIB-4 values suggestive of advanced liver fibrosis. The presence of a binge drinking history, anemia, leukopenia, and elevated bilirubin levels is associated with high FIB-4 values.

Pharmacotherapeutic value of inflammatory and neurotrophic biomarkers in bipolar disorder: A systematic review.

BACKGROUND: The various pharmacological interventions, ranging from mood stabilizers and antipsychotics to antidepressants, reflect the diff/iculty of treating depressive/manic symptomatology of bipolar disorder (BD). Among a broad range of mechanisms implicated, immune dysregulation may contribute to the increased inflammation that influences the course of BD. Inflammatory, neurotrophic and oxidative stress factors may be identified as promising peripheral biomarkers in brain functioning, perhaps serving as predictors of an effective response to treatment for BD. The present systematic review aimed to examine the evidence supporting the pharmacotherapeutic value of inflammatory and neurotrophic biomarkers in BD. METHODS: PubMed, PsychINFO, Scopus and Web of Science were searched from inception to May 2024 by two independent reviewers. A total of 40 studies with 3371 patients with diagnosis and intervention of BD were selected. RESULTS: Inconsistencies in the effects of pharmacological treatments on the connection between the expected anti-inflammatory response and symptomatologic improvement were identified. Mood stabilizers (lithium), antipsychotics (quetiapine), antidepressants (ketamine) or their combination were described to increase both pro-inflammatory (TNFα, IL-6) and anti-inflammatory (IL-4, IL-8) factors. Other medications, such as memantine and dextromethorphan, autoimmune (infliximab) non-steroidal anti-inflammatory (aspirin, celecoxib) drugs, antidiabetics (pioglitazone), and even dietary supplementation (omega-3), or their combination, clearly decrease inflammatory factors (TNFα, IL-6, IL-1ß, C-reactive protein) and/or increase the neurotrophic factor BDNF in BD patients. CONCLUSION: Inflammation in BD requires further investigation to understand the underlying immunologic mechanism, to identify predictors of treatment response, and to make informed decisions about the use and development of more effective pharmacological interventions for BD.

Plasma Concentrations of High Mobility Group Box 1 Proteins and Soluble Receptors for Advanced Glycation End-Products Are Relevant Biomarkers of Cognitive Impairment in Alcohol Use Disorder: A Pilot Study.

Alcohol use disorder (AUD) is a major component in the etiology of cognitive decline and dementia. Underlying mechanisms by which long-term alcohol abuse causes cognitive dysfunction include excessive oxidative stress and inflammation in the brain, activated by increased reactive oxygen/nitrogen species (ROS/RNS), advanced glycation end-products (AGEs) and high-mobility group box 1 protein (HMGB1). In a pilot study, we examine the potential clinical value of circulating biomarkers of oxidative stress including ROS/RNS, HMGB1, the soluble receptor for AGE (sRAGE), the brain biomarker of aging apolipoprotein D (ApoD), and the antioxidant regulator nuclear factor erythroid 2-related factor 2 (NRF2) as predictive indices for cognitive impairment (CI) in abstinent patients with AUD (n = 25) compared to patients with established Alzheimer's disease (AD, n = 26) and control subjects (n = 25). Plasma concentrations of sRAGE were evaluated with immunoblotting; ROS/RNS with a fluorometric kit; and HMGB1, ApoD, and NRF2 by ELISA. Abstinent AUD patients had higher sRAGE, ROS/RNS (p < 0.05), and ApoD (p < 0.01) concentrations, similar to those of AD patients, and lower NRF2 (p < 0.01) concentrations, compared to controls. These changes were remarkable in AUD patients with CI. HMGB1, and sRAGE correlated positively with duration of alcohol use (rho = 0.398, p = 0.022; rho = 0.404, p = 0.018), whereas sRAGE correlated negatively with periods of alcohol abstinence (rho = -0.340, p = 0.045). A predictive model including ROS/RNS, HMGB1, sRAGE, alcohol use duration, and alcohol abstinence periods was able to differentiate AUD patients with CI (92.3% of correct predictions, ROC-AUC= 0.90) from those without CI. In conclusion, we propose ROS/RNS, HMGB1, and sRAGE as stress biomarkers capable of predicting cognitive impairment in AUD patients.

Alcohol binge drinking induces downregulation of blood-brain barrier proteins in the rat frontal cortex -but not in the hippocampus- that is not prevented by OEA pretreatment.

Alcohol binge drinking promotes neuroinflammation which could be partially mediated by the passage of ABD-induced peripheral inflammatory molecules to the brain parenchyma through the blood-brain barrier. The BBB is sealed by tight junction proteins, which regulate the access of substances to the brain. Whether ABD alters the BBB or not remains controversial. Here, we measured the expression of BBB proteins in frontal cortex and hippocampus after an ABD procedure that was previously shown to induce neuroinflammation in the FC, and checked neuroinflammation in the hippocampus. Oleoylethanolamide is known to inhibit ABD-induced neuroinflammation in rat FC but the mechanisms of action are not clear: whereas OEA protects against alcohol-induced breakdown of the TJ proteins in the gut barrier reducing peripheral inflammation, its effect in the TJ of the BBB remains unknown. Here, we studied whether OEA (5 mg/kg, before each gavage) prevented alcohol-induced BBB dysfunction by measuring the expression of zona-occludens, occludin, and laminin in FC and hippocampus. ABD animals showed reduced laminin and occludin levels in the FC, indicative of BBB dysfunction, which is concordant with previous findings showing ABD-induced neuroinflammation in this brain region. OEA did not prevent ABD-induced changes in the BBB proteins in the FC, suggesting that the OEA main mechanism of action to inhibit neuroinflammation in this brain region is not related to prevention of TJ proteins alteration in the BBB. In the hippocampus, this ABD protocol did not alter BBB protein levels and no markers of neuroinflammation were found elevated.

Niveles plasmáticos de midkina en pacientes con trastorno por uso de cocaína en abstinencia / Plasma midkine levels in patients with cocaine use disorder during abstinence

Diversos estudios preclínicos han sugerido que la midkina endógenapodría jugar un papel modulador clave sobre los efectos neurotóxicosy adictivos de distintas drogas, incluidos los psicoestimulantes. Estahipótesis no ha sido aún explorada en humanos. Como primer pasoen esta dirección, en el presente trabajo hemos medido los nivelesplasmáticos de midkina en 75 pacientes con trastorno por uso decocaína en abstinencia y 26 controles apareados con los anteriorespor sexo, edad e índice de masa corporal. Los pacientes fueronademás divididos en un grupo de abstinencia temprana (menos deun mes, n = 30) y otro de abstinencia tardía (más de un mes, n =45). Se cuantificaron los niveles plasmáticos de midkina de todoslos participantes mediante un ensayo por inmunoabsorción ligadoa enzimas. Los pacientes en abstinencia temprana mostraron unincremento del 60% en su concentración plasmática de midkina conrespecto a los controles que tendió a desaparecer en los pacientes conperiodos de abstinencia más prolongados. Los resultados demuestranque los niveles periféricos de midkina están estrechamenterelacionados con el uso de cocaína y apoyan la idea de que dichacitoquina podría jugar un papel protector limitando la actividadbiológica de los psicoestimulantes. (AU)

Preclinical evidence suggests that endogenous midkine couldplay a key modulatory role on the neurotoxic and addictive effectsof different kinds of drugs of abuse, including psychostimulants.However, this hypothesis has not yet been explored in humans. As afirst approach to progress in this knowledge, we have comparativelystudied plasma midkine levels in 75 patients with cocaine use disorderunder abstinence and 26 control subjects matched for sex, ageand body mass index. Patients were further segmented into earlyabstinent (up to one month of abstinence, n = 30) and late-abstinent(more than one month of abstinence, n = 45). Midkine levels werequantified in plasma samples of all the participants by enzyme-linkedimmunosorbent assays. Early-abstinent patients exhibited a 60%increase of midkine plasma concentration in comparison with thecontrols. This elevation tended to normalize upon the progressionof abstinence. The results obtained demonstrate that peripheralmidkine levels are closely related to cocaine use and are consistentwith the idea that this cytokine could play a protective role by limitingthe biological activity of psychostimulants. (AU)

Trastorno por uso de cocaína y depresión: Cuando el diagnóstico clínico no es suficiente / Cocaine and depressive disorders: When standard clinical diagnosis is insufficient

Antecedentes: El consumo de cocaína es un creciente problema de saluden todo el mundo. Además, los pacientes con trastorno por consumode cocaína (TCC) presentan una alta comorbilidad con el trastornodepresivo mayor (TDM). Estos pacientes pueden presentar dos tipos deTDM: trastorno depresivo mayor primario (TDM-P) y trastorno depresivo mayor inducido por cocaína (TDM-IC). El objetivo de este estudio esevaluar las diferencias en la sintomatología depresiva (TDM-P vs. TDMIC) en los pacientes con TCC para mejorar su tratamiento. Métodos: Sellevó a cabo un análisis secundario en una muestra transversal de 160pacientes que presentaban TCC y algún TDM. La evaluación clínica,así como el diagnóstico diferencial entre TDM-P y TDM-IC, se realizóutilizando la entrevista PRISM. Resultados: Los hombres representaronel 80% de la muestra con una edad media de 38,61 años y el 64,5%sólo tenía estudios primarios. El diagnóstico de TDM-IC (61,3%) fuemás frecuente que el de TDM-P (38,7%). Los pacientes con TDM-ICmostraron una edad de aparición más temprana para el TCC. El 79,4%de los pacientes cumplían criterios para otro trastorno por consumo desustancias. Únicamente el criterio “Cambios en el peso o en el apetito” fueestadísticamente más prevalente (57,1%) en los pacientes con TDM-P.Conclusiones: Existen diferencias en el criterio “Cambios en el peso o en elapetito” entre TDM-P y TDM-IC. Se necesita más investigación a fin deobtener un diagnóstico diferencial entre los dos tipos de depresión yproporcionar un mejor tratamiento para los pacientes con TCC. (AU)

Background: Cocaine use is a growing global health problem and patients with cocaine use disorders (CUD) present several complications, including high rates of major depression. These subjects present two types of major depressive disorder (MDD): primary majordepressive disorder (P-MDD) and cocaine-induced major depressivedisorder (CI-MDD). To improve treatment, it is necessary to distinguish between both types. The aim of this study was to assess the differences in depressive symptomatology criteria (P-MDD vs CI-MDD)in CUD patients. Methods: Secondary data analysis was carried out witha cross-sectional sample of 160 patients presenting CUD and MDD.Clinical assessment was performed using the Psychiatric ResearchInterview for Substance and Mental Disorders (PRISM). A differential diagnosis was obtained between P-MDD and CI-MDD. Results: Menrepresented 80% of the sample, the mean age was 38.61 years, and64.5% had elementary studies. CI-MDD diagnosis (61.3%) was morefrequent than P-MDD (38.7%). There was a younger age of CUD onset in CI-MDD patients. In addition, 79.4% of the patients had anothersubstance use disorder diagnosis. The criterion “Changes in weight orappetite” was more prevalent (57.1%) in P-MDD group. Conclusions:We found differences in the criterion “Changes in weight or appetite”.Further research is needed in this field to establish a differential diagnosis and thus provide better treatment for CUD patients. (AU)

DSM-5 en pacientes que solicitan el primer tratamiento del trastorno por uso de alcohol. Diferencias de sexo en el estudio multicéntrico CohRTA / DSM-5 in patients seeking their first treatment for alcohol use disorder. Sex differences in the multicenter CohRTA study

OBJETIVO: Analizar las diferencias de sexo en los criterios diagnósticos del DSM-5 de los pacientes que solicitan un tratamiento para el trastorno por uso de alcohol (TUA) por primera vez. MÉTODOS: Pacientes incluidos entre enero 2014 y marzo 2016 en el estudio multicéntrico CohRTA de la Red de Trastornos Adictivos. El diagnóstico del TUA se realizó mediante el DSM-5. Además, se recogieron datos sociodemográficos, sobre el consumo de alcohol y otras sustancias, variables clínicas y una analítica general. RESULTADOS: se incluyeron 313 pacientes (74,8% hombres); la edad al inicio del primer tratamiento fue de 48,8 años (desviación estándar (DE): 9,9 años), la edad al inicio del consumo de alcohol de 15,9 años (DE: 3,3 años) y la de inicio del consumo regular de 25,6 años (DE: 9,6 años). Un 69,3% de los pacientes eran fumadores y un 61% tenían antecedentes familiares de TUA. Un 7,7% eran consumidores de cocaína y un 18,2% de cannabis. Las mujeres iniciaron el consumo regular de alcohol más tarde que los hombres (p<,001) y usaban benzodiacepinas con mayor frecuencia (p=,013). Según el DSM-5, el 89,5% de los pacientes presentaban un TUA grave (≥6 criterios). En el análisis ajustado (regresión logística), los hombres tenían mayor probabilidad de presentar el criterio diagnóstico relacionado con el incumplimiento de los deberes fundamentales en el trabajo o en el hogar (OR=1,92, IC95%: 1,06-3,48) y el criterio diagnóstico de consumir alcohol en situaciones de riesgo físico (OR = 3,00, IC95%: 1,65-5,46). DISCUSIÓN: El DSM-5 detecta diferencias de sexo en pacientes que solicitan el primer tratamiento del TUA. El deterioro social y el consumo de alcohol de riesgo son significativamente más frecuentes en hombres

OBJECTIVE: We aimed to analyze sex differences in the DSM-5 criteria among patients admitted to their first treatment of alcohol use disorder (AUD). METHODS: Assessment of AUD was carried out using DSM-5 diagnostic criteria in a multicenter study (CohRTA) within the Spanish Network on Addictive Disorders. Further, baseline questionnaires including socio-demographics, family history, lifetime alcohol consumption and other substance use, as well as clinical and laboratory parameters were obtained during admission. RESULTS: 313 patients (74.8%M) were eligible; mean age at first AUD treatment was 48.8 years (standard deviation (SD): 9.9 years). Age at onset of alcohol use was 15.9 years (SD: 3.3 years) and age at starting regular alcohol consumption was 25.6 years (SD: 9.6 years). Almost 69.3% of patients were tobacco smokers and 61% had family history of AUD. Regarding other substance use, 7.7% were current cocaine users and 18.2% were cannabis users. Women started regular alcohol consumption later than men (p<.001) and used benzodiazepines more frequently (p =.013). According to DSM-5, 89.5% of cases had severe AUD (≥ 6 criteria). In the adjusted analysis (logistic regression), men were more likely to neglect major rules (OR = 1.92, 95%CI: 1.06-3.48) and to have hazardous alcohol use (OR = 3.00, 95%CI: 1.65-5.46). DISCUSSION: DSM-5 detects sex differences in patients seeking their first AUD treatment. Social impairment and risky alcohol use are significantly more frequent in men

Influencia de la infección SARS-Cov2 sobre Enfermedades Neurodegenerativas y Neuropsiquiátricas: ¿Una pandemia demorada? / Impact of SARS-CoV-2 infection on neurodegenerative and neuropsychiatric diseases: a delayed pandemic?

INTRODUCCIÓN: La infección por el coronavirus SARS-CoV2 originada en diciembre de 2019 en la región china de Wuhan ha adquirido proporciones pandémicas. A día de hoy ha ocasionado de más de 1,7 millones de contagios y más de 100.000 muertes en todo el mundo. La investigación científica actual se centra en el mejor conocimiento de la infección aguda y de sus estrategias terapéuticas. Dada la magnitud de la epidemia, planteamos una revisión especulativa sobre las posibles consecuencias en patología neurológica a medio/largo plazo, con especial atención a Enfermedades neurodegenerativas y neuropsiquiátricas con base neuroinflamatoria, teniendo en cuenta la evidencia directa de afectación neurológica a causa de la infección aguda. DESARROLLO: Revisamos de forma sistemática lo conocido sobre los mecanismos patogénicos de la infección por SARS-Cov2, la repercusión de la tormenta de citoquinas sobre el Sistema Nervioso Central y su persistencia en el tiempo y las consecuencias que la neuroinflamación puede tener sobre el Sistema Nervioso Central. CONCLUSIONES: El SARS-CoV2 es un virus neuroinvasivo capaz de provocar una tormenta de citoquinas que podría convertirse en persistente en población seleccionada. Aunque nuestra hipótesis tiene alto componente especulativo, la repercusión que esta situación puede tener en la puesta en marcha y progresión de Enfermedades neurodegenerativas y neuropsiquiátricas con base neuroinflamatoria debe ser considerada como posible germen de una pandemia demorada que podría tener un gran impacto en salud pública a medio o largo plazo. Se hace necesario un estrecho seguimiento de la salud cognitiva y neuropsiquiátrica de los pacientes supervivientes a infección Covid19

INTRODUCTION: SARS-CoV-2 was first detected in December 2019 in the Chinese city of Wuhan and has since spread across the world. At present, the virus has infected over 1.7 million people and caused over 100000 deaths worldwide. Research is currently focused on understanding the acute infection and developing effective treatment strategies. In view of the magnitude of the epidemic, we conducted a speculative review of possible medium-and long-term neurological consequences of SARS-CoV-2 infection, with particular emphasis on neurodegenerative and neuropsychiatric diseases of neuroinflammatory origin, based on the available evidence on neurological symptoms of acute SARS-CoV-2 infection. Development:We systematically reviewed the available evidence about the pathogenic mechanisms of SARS-CoV-2 infection, the immediate and lasting effects of the cytokine storm on the central nervous system, and the consequences of neuroinflammation for the central nervous system.Conclusions:SARS-CoV-2 is a neuroinvasive virus capable of triggering a cytokine storm, with persistent effects in specific populations. Although our hypothesis is highly speculative, the impact of SARS-CoV-2 infection on the onset and progression of neurodegenerative and neuropsychiatric diseases of neuroinflammatory origin should be regarded as the potential cause of a delayed pandemic that may have a major public health impact in the medium to long term. Cognitive and neuropsychological function should be closely monitored in COVID-19 survivors

Pacientes con trastorno por uso de alcohol: resultados iniciales de un registro multicéntrico en la Red de Trastornos Adictivos-RTA. Estudio CohRTA / Patients with alcohol use disorder: initial results from a prospective multicenter registry in the Spanish Network on Addiction Disorders. CohRTA Study

El Programa Alcohol de la Red de Trastornos Adictivos (RTA) requiere de un estudio clínico longitudinal para dar respuesta a preguntas de investigación en el trastorno por uso de alcohol. El proyecto CohRTA es un estudio multicéntrico de investigación cooperativa que se pone en marcha para mejorar la prevención secundaria y el diagnóstico precoz de los procesos patológicos asociados al trastorno por uso de alcohol. Método: estudio observacional en cohorte multicéntrica de pacientes mayores de 18 años que solicitan tratamiento del trastorno por primera vez y autorizan su participación. La información clínica se recoge en una plataforma online diseñada para el estudio y puede ir acompañada de una muestra biológica que se deposita en un biobanco. Se recogen datos basales y prospectivos, sociodemográficos, epidemiológicos, clínicos y de tratamiento. A diciembre de 2015 son 10 los centros proveedores de pacientes y se espera reclutar más de 1.000 pacientes en los próximos años. Resultados: se dispone de 344 pacientes (77% hombres) que cumplen los criterios de inclusión en el estudio y con una edad de 50 años (RIQ: 43-55 años). La edad de inicio de consumo de alcohol fue de 15 años (RIQ: 14-18 años) y un 61% tenían antecedente familiar de trastorno por uso de alcohol. Durante los 30 días previos al inicio del tratamiento los pacientes bebían 12.5 UBE/día (RIQ: 7.1-20 UBE/día), el 72% fumaba tabaco y el 30% consumía cocaína. Conclusiones: Disponer de una cohorte abierta y multicéntrica de pacientes con trastorno por uso de alcohol será útil para analizar las consecuencias del abuso de alcohol, potenciar la investigación traslacional y añadir valor a la investigación clínica y básica del Programa Alcohol dentro de RTA/RETICS. Con una cohorte bien establecida y representativa se espera aumentar la cantidad y calidad científica en relación a las complicaciones del trastorno por uso de alcohol y sus consecuencias clínicas y sociales en España

The Alcohol Program of the Spanish Network on Addictive Disorders-RTA requires a longitudinal study to address different research questions related to alcoholism. The cohort study (CohRTA) focuses on patients seeking treatment for alcohol use disorder, as a multicentre, collaborative research project aimed to improve secondary prevention and early diagnosis of pathological processes associated with the disorder. Methods: multicentre cohort study in adults (>18 years) seeking their first treatment of the disorder. Patients sign an informed consent and data is collected in an online platform specifically designed for the study; patients are also requested to provide biological samples that are stored in a biobank. Baseline and prospective, socio-demographic, epidemiological, clinical and treatment data are collected. Currently there are 10 participating centres that expect to recruit more than 1,000 patients. Results: As of December 2015, 344 patients (77% men) were included. Median age at admission was 50 years (IQR: 43-55 years). Median age at the start of alcohol consumption was 15 years (IQR: 14-18 years) and 61% of cases reported antecedents of alcohol use disorder in the family. During the 30 days prior to admission, alcohol consumption amounted to 12.5 SDU/day (IQR: 7.1-20 SDU/ day), 72% of the patients were tobacco smokers and 30% currently used cocaine. Organising an open cohort of patients with alcohol use disorder may be crucial to better understand the clinical consequences of alcoholism in Spain. This cohort may potentiate quantitative and qualitative research within the Spanish Network on Addictive Disorders-RTA/RETICS. Having a well-established, representative cohort of patients will increase translational research on consequences of alcoholism in our country

Comorbilidad psiquiátrica y valores plasmáticos de 2-acilgliceroles en consumidores de alcohol en tratamiento ambulatorio. Análisis de las diferencias de género / Psychiatric comorbidity and plasma levels of 2-acyl-glycerols in outpatient treatment alcohol users. Analysis of gender differences

La adicción al alcohol se asocia con una elevada comorbilidad psiquiátrica que complica el tratamiento, siendo necesaria una fenotipación clínica objetiva de estos pacientes para optimizar la atención y mejorar el pronóstico. El presente estudio aborda este problema mediante los siguientes objetivos: a) estimar la prevalencia y tipos de comorbilidad psiquiátrica de una muestra de pacientes que buscan tratamiento por uso de alcohol, b) describir las diferencias de género en su presentación y c) analizar los valores plasmáticos de 2-acilgliceroles (incluyendo el endocannabinoide 2-araquidonilglicerol), estudiando su posible valor como biomarcador de alcoholismo y/o comorbilidad psiquiátrica. Para ello se reclutaron 162 pacientes evaluados con la entrevista semiestructurada PRISM, para evaluar la presencia de comorbilidad y su carácter primario o inducido. Los resultados obtenidos indican que la presencia de psicopatología se asoció a un mayor número de criterios de abuso y dependencia de alcohol Se encontraron diferencias de género tanto en la comorbilidad psiquiátrica, especialmente en trastornos del estado de ánimo. La prevalencia de comorbilidad psiquiátrica encontrada a lo largo de la vida fue del 68,5%, destacando los trastornos del estado ánimo (37%), y seguidos por el trastorno por déficit de atención (24,7%, monitorizado específicamente por la entrevista WURS) y los trastornos de ansiedad (17,9%). Entre los trastornos del estado de ánimo y psicóticos fueron más frecuentes los inducidos, mientras que en los trastornos de ansiedad los primarios fueron más prevalentes. Además, se encontraron concentraciones disminuidas significativamente de 2-acilgliceroles en pacientes con trastornos de ansiedad comórbidos diagnosticados en el último año

Alcohol addiction is associated with high psychiatric comorbidity. Objective stratification of patients is necessary to optimize care and improve prognosis. The present study is designed to gain insights into this challenge by addressing the following objectives: a) to estimate the prevalence of psychiatric comorbidities in a sample of outpatients seeking treatment for alcohol use disorder, b) to describe the existence of gender differences and c) to validate 2-acyl-glycerols as biomarkers of alcohol use disorder and/or psychiatric comorbidity. One hundred and sixty-two patients were recruited and evaluated with the semistructured interview PRISM. The presence of psychopathology was associated with a greater number of criteria for alcohol abuse and dependence according to DSM-IV-TR. We found gender differences in psychiatric comorbidity, e.g., mood disorder, as well as in comorbid substance use disorders. The prevalence of lifetime psychiatric comorbidity was 68.5%, with mood disorders the most frequent (37%), followed by attention deficit disorder (24.7%) and anxiety disorders (17.9%). Substance-induced disorders were more frequent in mood and psychotic disorders, whereas the primary disorders were more prevalent in patients with comorbid anxiety disorders. We found that 2-acyl-glycerols were significantly decreased in comorbid anxiety disorders in alcohol dependent patients in the last year, which makes them a potential biomarker for this psychopathological condition

El papel de la dieta materna en la programación metabólica y conductual: revisión de los mecanismos biológicos implicados / The role of maternal diet in metabolic and behavioural programming: review of biologic mechanisms involved

En los últimos años, un importante número de investigaciones se han centrado en el estudio de los efectos de la subnutrición y sobrenutrición durante periodos críticos del desarrollo así como en el riesgo de desarrollar enfermedades metabólicas en etapas posteriores. Adicionalmente, las dietas maternas inadecuadas han sido implicadas en la programación errónea de las funciones cerebrales y ciertos comportamientos. Se han asociado con el proceso de una mala programación diferentes mecanismos tales como modificaciones epigenéticas, excesivo estrés oxidativo o alteraciones hipotalámicas. Estas evidencias apoyan la idea de que la prevención nutricional debe ser considerada desde estadios tempranos del desarrollo que incluyan el periodo preconcepcional. Además, la investigación sobre los mecanismos implicados puede resultar particularmente útil en la búsqueda de terapias eficientes para hacer frente a una mala programación (AU)

Over the last few years, a considerable amount of studies have focused on the effect of undernutrition and overnutrition during critical periods of offspring development and their risk of developing metabolic diseases later in life. Additionally, inadequate maternal diets have been involved in the malprogramming of brain functions and some behaviours. Several mechanisms have been associated with the process of malprogramming such as epigenetics modifications, excessive oxidative stress or hypothalamic alterations. This evidence supports the idea that nutritional prevention strategies must be considered for offspring during early development stages that include the preconceptional period. Additionally, studying involved mechanisms could be particularly useful in the search of efficient therapies against malprogramming (AU)

Adicción a cannabis: bases neurobiológicas y consecuencias médicas / No disponible

La adicción a los preparados de cannabis sativa es un problema relevante en nuestra sociedad, con especial importancia durante la adolescencia. Su fácil disponibilidad y los episodios adversos asociados a su abuso y/o dependencia han incrementado la demanda de tratamiento derivada por su consumo. En los últimos 20 años se ha podido avanzar mucho sobre la farmacología del cannabis y de sus principios activos, moléculas grasas que actúan a través de un sistema de señalización endógeno denominado sistema endocannabinoide implicado en el desarrollo y la plasticidad cerebrales. Su estimulación crónica puede inducir no sólo dependencia y adicción, sino también derivar en consecuencias neurobiológicas que tienen repercusión clínica. Así, por un lado se puede encontrar el incremento de trastornos mentales tanto primarios como inducidos (trastornos del estado de ánimo, trastornos de ansiedad y trastornos psicóticos) y por el otro, alteraciones en los procesos cognitivos (memoria, atención, toma de decisiones, asunción de riesgos, control de impulsos). Estas consecuencias son más graves si el consumo se realiza en la adolescencia. Algunos de estos efectos son permanentes y el conocimiento de los mismos necesario para una correcta atención sanitaria

Addiction to products derived from the plant cannabis sativa has become a relevant problem in western societies. Its prevalence in both teenagers and young adults has grown in the last decade. The problem is aggravated by the availability of plant derivatives with a high THC content. Today, the number of cannabis users requesting medical treatment is growing, as well as the incidence and variety of the adverse effects associated with its chronic consumption. On the other hand, the last 20 years’ research have revealed the hidden pharmacology of the active principles of cannabis. Cannabinoids, the psychoactive chemicals of the plant, exert their pharmacological actions through their interaction with an endogenous signaling system, the endocannabinoid system. This system is involved in brain development, plasticity and repair, and its chronic stimulation can induce not only dependence/addiction, but also result in adverse clinical effects. The negative side of cannabis use has greatest impact in the adolescent period. The main adverse effects of chronic cannabis use include the increase in the incidence of mental disorders (mainly psychosis), as well as alterations in cognitive processes including memory, attention, decision-making, risk behaviors as well as impulsivity. Some of these effects are permanent and information and research on their nature is greatly needed in order to achieve a correct public health approach to cannabis use

Comorbilidad psicopatológica en consumidores de cocaína en tratamiento ambulatorio / Psychopathological comorbidity in cocaine users in outpatient treatment

La adicción a cocaína es un problema de salud creciente y entre sus complicaciones destaca la elevada prevalencia de comorbilidad psicopatológica. La detección temprana de los trastornos psicopatológicos asociados al consumo de cocaína es necesaria para optimizar la asistencia sanitaria y mejorar el pronóstico. El objetivo principal de este estudio es estimar la prevalencia y características de la comorbilidad psicopatológica en una población de sujetos que solicitan atención por uso de cocaína en tratamiento ambulatorio. Se reclutaron 110 consumidores de cocaína por vía nasal evaluados con la entrevista diagnóstica semiestructurada PRISM (entrevista de investigación psiquiátrica para trastornos mentales y por sustancias), que diferencia los trastornos mentales primarios de los inducidos por la droga. Esta población tuvo un 86,4% de hombres y una edad media de 36,5 años. Presentó un uso patológico de cocaína medio de 7 años, y la presencia de psicopatología se asoció a un mayor número de criterios de dependencia de cocaína según el manual DSM-IVTR (manual diagnóstico y estadístico de los trastornos mentales, 4ª edición revisada). La prevalencia de comorbilidad psicopatológica encontrada a lo largo de la vida fue del 61,8%, destacando los trastornos del estado de ánimo (34,5%), seguidos de los trastornos de ansiedad (22,7%) y de los trastornos psicóticos (15,5%). Un 20% presentó trastorno de personalidad antisocial y un 21% trastorno límite de la personalidad. Entre los trastornos del estado de ánimo y psicóticos fueron más frecuentes los inducidos, mientras que en los trastornos de ansiedad los primarios fueron más prevalentes

Cocaine addiction is a growing health problem and among its complications highlights the high prevalence of mental disorders co-occurring with abuse and dependence. This psychopathological comorbidity varies according to the time of consumption and the age of the patient. Early detection of psychopathological disorders associated with drug consumption is necessary to optimize health care and to improve the prognosis. The main aim of the present study was to estimate the prevalence and characteristics of psychopathological comorbidity in a population of subjects seeking outpatient treatment for cocaine use. We recruited 110 subjects using cocaine by nasal insufflations evaluated with the PRISM (Psychiatric Research Interview for Substance and Mental Disorders), a semi-structured diagnostic interview that differentiates primary mental disorders from those induced by the drug. This population presented 86.4% male and had a mean age of 36.5. They displayed a pathological use of cocaine of 7 years and the presence of psychopathology was associated with a higher number of DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders- IV-TR) criteria for substance dependence. The lifetime prevalence of some psychopathological comorbidity was 61.8%, highlighting mood disorders (34.5%), followed by anxiety disorders (22.7%) and psychotic disorders (15.5%). About 20% showed antisocial personality disorder and 21% borderline personality disorder. From among mood and psychotic disorders, the induced disorders were more frequent, while the primary disorders were more prevalent in anxiety