Khalil El-Asmar

Bio: Khalil El-Asmar is an academic researcher from Université Paris-Saclay. The author has contributed to research in topics: SOD2 & Carnitine. The author has an hindex of 1, co-authored 2 publications receiving 1 citations.

SOD2 genetic polymorphism (rs4880) has no impact on 6-month response to antidepressant treatment and inflammatory biomarkers in depressed patients

Abstract: Two thirds of patients suffering from a major depressive episode (MDE) do not reach a complete response with antidepressant drugs. This lack of response is due to several factors, including genetic determinants. Since major depressive disorder is associated with inflammatory and oxidative stress abnormalities, the metabolism of superoxide anions might be involved in non-response to antidepressant drugs. Superoxide anions are metabolized by manganese-dependent superoxide dismutase (SOD2) in the mitochondria. A functional genetic polymorphism (SOD2, rs4880), responsible of a 40% reduction in enzyme activity, is associated with anti-inflammatory response of rosuvastatin. We investigated the association of ala-allele of SOD2 rs4880 and both antidepressant efficacy and inflammatory parameters in patients treated for a MDE with antidepressant drugs. The Hamilton Depression Rating Scale (HDRS) score and levels of plasma CRP and inflammatory cytokines were assessed at baseline, one month (M1), 3 months (M3) and 6 months (M6) after antidepressant treatment. They were compared according to SOD2 genetic polymorphism. Of the 484 patients studied, 361 (74.6%) carried the ala-allele (Ala group), 123 (25.4%) of them had Val/Val genotype (Val/Val group). No significant difference was observed between the Ala and Val/Val groups neither for baseline clinical characteristics, nor for HDRS scores, response/remission rates, plasma CRP and cytokine levels throughout the study. The rs4880 SOD2 genetic polymorphism was not associated with the clinical response and cytokines levels after antidepressant treatment. These data suggest that SOD2 is not a major genetic determinant of antidepressant response. Other genes of the oxidative stress pathways should be explored in further studies.

Plasma acetyl-l-carnitine and l-carnitine in major depressive episodes: a case–control study before and after treatment

Abstract: BACKGROUND Major depressive disorder (MDD) is the main cause of disability worldwide, its outcome is poor, and its underlying mechanisms deserve a better understanding. Recently, peripheral acetyl-l-carnitine (ALC) has been shown to be lower in patients with major depressive episodes (MDEs) than in controls. l-Carnitine is involved in mitochondrial function and ALC is its short-chain acetyl-ester. Our first aim was to compare the plasma levels of l-carnitine and ALC, and the l-carnitine/ALC ratio in patients with a current MDE and healthy controls (HCs). Our second aim was to assess their changes after antidepressant treatment. METHODS l-Carnitine and ALC levels and the carnitine/ALC ratio were measured in 460 patients with an MDE in a context of MDD and in 893 HCs. Depressed patients were re-assessed after 3 and 6 months of antidepressant treatment for biology and clinical outcome. RESULTS As compared to HC, depressed patients had lower ALC levels (p < 0.00001), higher l-carnitine levels (p < 0.00001) and higher l-carnitine/ALC ratios (p < 0.00001). ALC levels increased [coefficient: 0.18; 95% confidence interval (CI) 0.12-0.24; p < 0.00001], and l-carnitine levels (coefficient: -0.58; 95% CI -0.75 to -0.41; p < 0.00001) and l-carnitine/ALC ratios (coefficient: -0.41; 95% CI -0.47 to -0.34; p < 0.00001), decreased after treatment. These parameters were completely restored after 6 months of antidepressant. Moreover, the baseline l-carnitine/ALC ratio predicted remission after 3 months of treatment (odds ratio = 1.14; 95% CI 1.03-1.27; p = 0.015). CONCLUSIONS Our data suggest a decreased mitochondrial metabolism of l-carnitine into ALC during MDE. This decreased mitochondrial metabolism is restored after a 6-month antidepressant treatment. Moreover, the magnitude of mitochondrial dysfunction may predict remission after 3 months of antidepressant treatment. New strategies targeting mitochondria should be explored to improve treatments of MDD.

Oxidative Stress Markers and Antioxidant Enzymes in Children and Adolescents with Depressive Disorder and Impact of Omega-3 Fatty Acids in Randomised Clinical Trial.

Abstract: Oxidative stress (OS) is thought to play a role in mental disorders. However, it is not clear whether the OS is the cause or consequence of the disorder. We investigated markers of oxidative stress (8-isoprostane (8-IsoP-U), lipoperoxides (LP), advanced oxidation protein products (AOPP) and nitrotyrosine (NT)) and antioxidant protection (Trolox equivalent antioxidant capacity (TEAC), activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) in 60 paediatric and adolescent patients with depressive disorder (DD) compared to healthy controls. The patients were divided into two groups (1:1). One group received an emulsion of omega-3 fatty acid (FA), and the other group an emulsion of sunflower oil with omega-6 FA for 12 weeks. The levels of 8-IsoP-U, AOPP and NT were increased, and GPx activity was decreased in patients compared to the controls. We found a significant positive correlation of the Children’s Depression Inventory score with NT and a negative correlation with TEAC, SOD and GPx. NT correlated positively with the baseline omega-6/omega-3 FA ratio and a negatively with SOD. A supplementation with omega-3 FA, but not with omega-6 FA, decreased 8-IsoP-U, AOPP, NT levels and increased TEAC and SOD activity. Our results suggest that NT may play a role in the pathophysiology of DD, while elevated isoprostane is likely caused by the high omega-6/omega-3 FA ratio. Omega-3 FA supplementation reduces oxidative stress in patients with DD. This study was registered with the ISRCTN registry (ISRCTN81655012).

Anti-Inflammatory, Antioxidant, and Neuroprotective Effects of Polyphenols—Polyphenols as an Element of Diet Therapy in Depressive Disorders

Abstract: Depressive disorders can affect up to 350 million people worldwide, and in developed countries, the percentage of patients with depressive disorders may be as high as 10%. During depression, activation of pro-inflammatory pathways, mitochondrial dysfunction, increased markers of oxidative stress, and a reduction in the antioxidant effectiveness of the body are observed. It is estimated that approximately 30% of depressed patients do not respond to traditional pharmacological treatments. However, more and more attention is being paid to the influence of active ingredients in food on the course and risk of neurological disorders, including depression. The possibility of using foods containing polyphenols as an element of diet therapy in depression was analyzed in the review. The possibility of whether the consumption of products such as polyphenols could alleviate the course of depression or prevent the progression of it was also considered. Results from preclinical studies demonstrate the potential of phenolic compounds have the potential to reduce depressive behaviors by regulating factors related to oxidative stress, neuroinflammation, and modulation of the intestinal microbiota.

Major Depressive Disorder and Oxidative Stress: A Review of Peripheral and Genetic Biomarkers According to Clinical Characteristics and Disease Stages

Abstract: Major depressive disorder (MDD) is currently the main cause of disability worldwide, but its pathophysiology remains largely unknown, especially given its high heterogeneity in terms of clinical phenotypes and biological characteristics. Accordingly, its management is still poor. Increasing evidence suggests that oxidative stress, measured on various matrices such as serum, plasma or erythrocytes, has a critical role in MDD. The aim of this narrative review is to identify serum, plasma and erythrocyte biomarkers of oxidative stress in MDD patients according to disease stage and clinical features. Sixty-three articles referenced on PubMed and Embase between 1 January 1991, and 31 December 2022, were included. Modifications to antioxidant enzymes (mainly glutathione peroxidase and superoxide dismutase) in MDD were highlighted. Non-enzymatic antioxidants (mainly uric acid) were decreased in depressed patients compared to healthy controls. These changes were associated with an increase in reactive oxygen species. Therefore, increased oxidative damage products (principally malondialdehyde, protein carbonyl content and 8-hydroxy-2′-deoxyguanosine) were present in MDD patients. Specific modifications could be identified according to disease stages and clinical features. Interestingly, antidepressant treatment corrected these changes. Accordingly, in patients in remission from depression, oxidative stress markers were globally normalized. This narrative review suggests the particular interest of oxidative stress biomarkers for MDD care that may contribute to the heterogeneity of the disease and provide the opportunity to find new therapeutic targets.

Metabolomic profiles of 38 acylcarnitines in major depressive episodes before and after treatment

Abstract: Abstract Background Major depression is associated with changes in plasma L-carnitine and acetyl-L-carnitine. But its association with acylcarnitines remains unclear. The aim of this study was to assess metabolomic profiles of 38 acylcarnitines in patients with major depression before and after treatment compared to healthy controls (HCs). Methods Metabolomic profiles of 38 plasma short-, medium-, and long-chain acylcarnitines were performed by liquid chromatography-mass spectrometry in 893 HCs from the VARIETE cohort and 460 depressed patients from the METADAP cohort before and after 6 months of antidepressant treatment. Results As compared to HCs, depressed patients had lower levels of medium- and long-chain acylcarnitines. After 6 months of treatment, increased levels of medium- and long-chain acyl-carnitines were observed that no longer differed from those of controls. Accordingly, several medium- and long-chain acylcarnitines were negatively correlated with depression severity. Conclusions These medium- and long-chain acylcarnitine dysregulations argue for mitochondrial dysfunction through fatty acid β -oxidation impairment during major depression.

Effectiveness of L-carnitine Supplementation to Sertraline for Treatment of Major Depressive Disorder: A Double-blind Randomized Placebo-controlled Trial

Abstract: Despite the various treatment approaches proposed for major depressive disorder (MDD), the right treatment protocol for different patients is not the same. Supplementation of L-carnitine to antidepressants has been recommended in some studies; however, different results have been reported. This study aimed to evaluate the effectiveness of adding L-carnitine to sertraline in the treatment of patients diagnosed with MDD. This double-blind randomized controlled trial was conducted on 60 patients with MDD. The severity of the depressive disorder, as the primary research outcome, was assessed using the Beck depression inventory. The intervention group received 1000 mg of daily L-carnitine oral capsule along with 100 mg of sertraline; and the control group received a placebo (oral capsule containing 1000 mg of starch), along with 100 mg of sertraline every day. The primary outcome was assessed at baseline, the 3rd, and the 6th week. Although depression score decreased in both groups over time, the difference between the two groups was not significant (P = 0.634). Three patients reported adverse side effects; however, the difference between the two groups was not significant (P = 0.554). Supplementation of L-carnitine to sertraline in patients with MDD did not show a significant effect on the improvement of depression severity.