Novel glutamatergic drugs for the treatment of mood disorders

Kyle AB Lapidus, Laili Soleimani, James W MurroughMood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USAAbstract: Mood disorders are common and debilitating, resulting in a significant public health burden. Current treatments are only partly effective and patients who have failed to respond to trials of existing antidepressant agents (eg, those who suffer from treatment-resistant depression [TRD]) require innovative therapeutics with novel mechanisms of action. Although neuroscience research has elucidated important aspects of the basic mechanisms of antidepressant action, most antidepressant drugs target monoaminergic mechanisms identified decades ago. Glutamate, the major excitatory neurotransmitter in the central nervous system, and glutamatergic dysfunction has been implicated in mood disorders. These data provide a rationale for the pursuit of glutamatergic agents as novel therapeutic agents. Here, we review preclinical and clinical investigations of glutamatergic agents in mood disorders with a focus on depression. We begin with discussion of evidence for the rapid antidepressant effects of ketamine, followed by studies of the antidepressant efficacy of the currently marketed drugs riluzole and lamotrigine. Promising novel agents currently in development, including N-methyl-D-aspartate (NMDA) receptor modulators, 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid (AMPA) receptor modulators, and drugs with activity at the metabotropic glutamate (mGlu) receptors are then reviewed. Taken together, both preclinical and clinical evidence exists to support the pursuit of small molecule modulators of the glutamate system as novel therapeutic agents in mood disorders. It is hoped that by targeting neural systems outside of the monoamine system, more effective and perhaps faster acting therapeutics can be developed for patients suffering from these disabling disorders.Keywords: glutamate, mood disorders, major depressive disorder, ketamine, NMDA, AMP

The NAFLD burden on mortality and morbidities in general population: A community-based longitudinal study (NASH-CO study)

International audienceBackground: The impact of non-alcoholic fatty liver disease (NAFLD) on morbidity and mortality has yet to be documented at the general population level. This study aimed to assess whether NAFLD was associated with morbidities and mortality and to estimate its impact on health status and mortality. Methods: The study population consisted of 137 206 participants from Constances cohort. Non-invasive diagnosis of NAFLD and advanced fibrosis was performed using the fatty liver index and Forns index, respectively. Constances data were linked to health care and hospitalization data to identify liver-related events, cardiovascular diseases (CVD), extrahepatic cancers (EHC), chronic kidney disease (CKD) and all-cause mortality. Results: The prevalence of NAFLD was 18.3% in subjects without other chronic liver diseases, among whom 2.7% had fibrosis. NAFLD after IPTW-weighted remained associated with an increased risk of death (HR 1.26, 95% CI 1.01–1.57), hepatic-related complications (HR 2.48, 95% CI 1.99–3.29), CVD (HR 1.42, 95% CI 1.30–1.55), EHC (HR 1.11, 95% CI 1.01–1.28) and CKD (HR 1.81, 95% CI 1.53–2.07) compared to those without chronic liver diseases risk factors (Non-NAFLD). In the trend analysis over the study period of inclusion and compared to Non-NAFLD, NAFLD has shown a fastest growing cause of hepatic events (HR 1.38, 95% CI 1.07–1.76 per year), CVD (HR 1.08, 95% CI 1.03–1.12), CKD (HR 1.16, 95% CI 1.07–1.25), and death (HR 1.39, 95% CI 1.39–1.50). Conclusion: This large community-based cohort showed that NAFLD was associated with excess morbidity and mortality and demonstrated a fastest-growing trend

Lean individuals with NAFLD have more severe liver disease and poorer clinical outcomes (NASH-CO Study)

International audienceApproximately 30% of the worldwide population has at least one risk factor for liver disease. Identifying advanced liver disease before the occurrence of complications remains a difficult challenge in clinical practice, where diagnosis comes too late for many patients, at the time of liver decompensation or palliative hepatocellular carcinoma, with poor short-term prognosis. Noninvasive, blood- or elastography-based tests of liver fibrosis (NITs) have been developed for the early diagnosis of advanced liver fibrosis. Recent population-based studies evaluating the screening of liver fibrosis with these NITs have provided important information on at-risk groups that should be targeted. New measures based on the sequential use of NITs help to better organize the referral of at-risk patients to the liver specialist. However, energizing these measures will require increased awareness of both chronic liver diseases and the use of NITs among non-specialists

Reply : Concerns regarding the use of Fatty Liver Index in studies of lean NAFLD

International audienceNo abstract availabl

Hepatitis C and NAFLD as Main Causes of Liver-Related Morbidity and Mortality in the French General Population: A Nationwide Study (NASH-CO Study)

International audienceBackground: The impact of NAFLD on health status and mortality has yet to be documented at the general population level. This study aimed to assess whether NAFLD was associated with hepatic and extrahepatic diseases and overall mortality, on the one hand, and to estimate its impact on health status and mortality compared to other liver-related diseases such as chronic hepatitis C or alcohol abuse, on the other hand.Methods: The study population consisted of 154,900 participants from the nationwide Constances cohort. Non-invasive diagnosis of NAFLD and advanced fibrosis was performed using the fatty liver index and Forns index, respectively. Constances data were linked to hospitalization data to identify liver-related events, cardiovascular diseases (CVDs), extrahepatic cancers (EHCs), and chronic kidney disease (CKDs). Causal inference methods were used to estimate the impact of NAFLD on morbidity and mortality.Results: The prevalence of NAFLD was 18·3% in subjects without other chronic liver diseases, among whom 2·7% had advanced fibrosis. A history of chronic hepatitis C (HCV) and B (HBV) was observed in 669 (0·4%) and 1311 (0·9%) subjects, respectively, whereas 15,714 (10·1%) individuals were recognized as heavy drinkers. The prevalence of advanced fibrosis was higher in HCV and NAFLD subjects (4·7% vs 2·7% vs 1·7% vs 1·6%, respectively, in HCV, NAFLD, heavy drinkers, and subjects with HBV). HCV remains the leading cause of hepatic-related complications (HR 9·75, 95% CI 6·63–14·33) before NAFLD (HR 2·63, 95% CI 1·96–2·87). NAFLD (HR 1·43, 95% CI 1·25–1·65) is the third leading cause of death behind HCV (HR 2·17, 95% CI 1·25–3·76) and binge drinking (HR 4·50, 95% CI 2·95–6·84). However, NAFLD remains the leading cause of CVD (HR 2·33, 95% CI 1·20–2·78) and CKD (HR 1·89, 95% CI 1·48–2·40).Conclusion: This large general population-based cohort showed that NAFLD was associated with excess morbidity and mortality and demonstrated the fastest-growing trend. It challenges HCV infection in terms of hepatic morbidity and overall mortality

Antibody status and cumulative incidence of SARS-CoV-2 infection among adults in three regions of France following the first lockdown and associated risk factors: a multicohort study

International audienceBackground We aimed to estimate the seropositivity to anti-SARS-CoV-2 antibodies in May–June 2020 after the first lockdown period in adults living in three regions in France and to identify the associated risk factors. Methods Between 4 May 2020 and 23 June 2020, 16 000 participants in a survey on COVID-19 from an existing consortium of three general adult population cohorts living in the Ile-de-France (IDF) or Grand Est (GE) (two regions with high rate of COVID-19) or in the Nouvelle-Aquitaine (NA) (with a low rate) were randomly selected to take a dried-blood spot for anti-SARS-CoV-2 antibodies assessment with three different serological methods (ClinicalTrial Identifier #NCT04392388). The primary outcome was a positive anti-SARS-CoV-2 ELISA IgG result against the spike protein of the virus (ELISA-S). Estimates were adjusted using sampling weights and post-stratification methods. Multiple imputation was used to infer the cumulative incidence of SARS-CoV-2 infection with adjustments for imperfect tests accuracies. Results The analysis included 14 628 participants, 983 with a positive ELISA-S. The weighted estimates of seropositivity and cumulative incidence were 10.0% [95% confidence interval (CI): 9.1%, 10.9%] and 11.4% (95% CI: 10.1%, 12.8%) in IDF, 9.0% (95% CI: 7.7%, 10.2%) and 9.8% (95% CI: 8.1%, 11.8%) in GE and 3.1% (95% CI: 2.4%, 3.7%) and 2.9% (95% CI: 2.1%, 3.8%) in NA, respectively. Seropositivity was higher in younger participants [odds ratio (OR) = 1.84 (95% CI: 1.79, 6.09) in <40 vs 50–60 years old and OR = 0.56 (95% CI: 0.42, 0.74) in ≥70 vs 50–60 years old)] and when at least one child or adolescent lived in the same household [OR = 1.30 (95% CI: 1.11, 1.53)] and was lower in smokers compared with non-smokers [OR = 0.71 (95% CI: 0.57, 0.89)]. Conclusions Seropositivity to anti-SARS-CoV-2 antibodies in the French adult population was ≤10% after the first wave. Modifiable and non-modifiable risk factors were identified

Antibody status and cumulative incidence of SARS-CoV-2 infection among adults in three regions of France following the first lockdown and associated risk factors: a multicohort study

Abstract Background We aimed to estimate the seropositivity to anti-SARS-CoV-2 antibodies in May–June 2020 after the first lockdown period in adults living in three regions in France and to identify the associated risk factors. Methods Between 4 May 2020 and 23 June 2020, 16 000 participants in a survey on COVID-19 from an existing consortium of three general adult population cohorts living in the Ile-de-France (IDF) or Grand Est (GE) (two regions with high rate of COVID-19) or in the Nouvelle-Aquitaine (NA) (with a low rate) were randomly selected to take a dried-blood spot for anti-SARS-CoV-2 antibodies assessment with three different serological methods (ClinicalTrial Identifier #NCT04392388). The primary outcome was a positive anti-SARS-CoV-2 ELISA IgG result against the spike protein of the virus (ELISA-S). Estimates were adjusted using sampling weights and post-stratification methods. Multiple imputation was used to infer the cumulative incidence of SARS-CoV-2 infection with adjustments for imperfect tests accuracies. Results The analysis included 14 628 participants, 983 with a positive ELISA-S. The weighted estimates of seropositivity and cumulative incidence were 10.0% [95% confidence interval (CI): 9.1%, 10.9%] and 11.4% (95% CI: 10.1%, 12.8%) in IDF, 9.0% (95% CI: 7.7%, 10.2%) and 9.8% (95% CI: 8.1%, 11.8%) in GE and 3.1% (95% CI: 2.4%, 3.7%) and 2.9% (95% CI: 2.1%, 3.8%) in NA, respectively. Seropositivity was higher in younger participants [odds ratio (OR) = 1.84 (95% CI: 1.79, 6.09) in &amp;lt;40 vs 50–60 years old and OR = 0.56 (95% CI: 0.42, 0.74) in ≥70 vs 50–60 years old)] and when at least one child or adolescent lived in the same household [OR = 1.30 (95% CI: 1.11, 1.53)] and was lower in smokers compared with non-smokers [OR = 0.71 (95% CI: 0.57, 0.89)]. Conclusions Seropositivity to anti-SARS-CoV-2 antibodies in the French adult population was ≤10% after the first wave. Modifiable and non-modifiable risk factors were identified. </jats:sec