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

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 ß-oxidation impairment during major depression.

Hereditary transthyretin amyloidosis in middle-aged and elderly patients with idiopathic polyneuropathy: a nationwide prospective study.

BACKGROUND: Hereditary transthyretin amyloidosis (ATTRv) is an adult-onset autosomal dominant disease resulting from TTR gene pathogenic variants. ATTRv often presents as a progressive polyneuropathy, and effective ATTRv treatments are available. METHODS: In this 5 year-long (2017-2021) nationwide prospective study, we systematically analysed the TTR gene in French patients with age >50 years with a progressive idiopathic polyneuropathy. RESULTS: 553 patients (70% males) with a mean age of 70 years were included. A TTR gene pathogenic variant was found in 15 patients (2.7%), including the Val30Met TTR variation in 10 cases. In comparison with patients with no TTR gene pathogenic variants (n = 538), patients with TTR pathogenic variants more often presented with orthostatic hypotension (53 vs. 21%, p = .007), significant weight loss (33 vs 11%, p = .024) and rapidly deteriorating nerve conduction studies (26 vs. 8%, p = .03). ATTRv diagnosis led to amyloid cardiomyopathy diagnosis in 11 cases, ATTRv specific treatment in all cases and identification of 15 additional ATTRv cases among relatives. CONCLUSION: In this nationwide prospective study, we found ATTRv in 2.7% of patients with age >50 years with a progressive polyneuropathy. These results are highly important for the early identification of patients in need of disease-modifying treatments.

More rapid blood interferon α2 decline in fatal versus surviving COVID-19 patients.

Background: The clinical outcome of COVID-19 pneumonia is highly variable. Few biological predictive factors have been identified. Genetic and immunological studies suggest that type 1 interferons (IFN) are essential to control SARS-CoV-2 infection. Objective: To study the link between change in blood IFN-α2 level and plasma SARS-Cov2 viral load over time and subsequent death in patients with severe and critical COVID-19. Methods: One hundred and forty patients from the CORIMUNO-19 cohort hospitalized with severe or critical COVID-19 pneumonia, all requiring oxygen or ventilation, were prospectively studied. Blood IFN-α2 was evaluated using the Single Molecule Array technology. Anti-IFN-α2 auto-Abs were determined with a reporter luciferase activity. Plasma SARS-Cov2 viral load was measured using droplet digital PCR targeting the Nucleocapsid gene of the SARS-CoV-2 positive-strand RNA genome. Results: Although the percentage of plasmacytoid dendritic cells was low, the blood IFN-α2 level was higher in patients than in healthy controls and was correlated to SARS-CoV-2 plasma viral load at entry. Neutralizing anti-IFN-α2 auto-antibodies were detected in 5% of patients, associated with a lower baseline level of blood IFN-α2. A longitudinal analysis found that a more rapid decline of blood IFN-α2 was observed in fatal versus surviving patients: mortality HR=3.15 (95% CI 1.14-8.66) in rapid versus slow decliners. Likewise, a high level of plasma SARS-CoV-2 RNA was associated with death risk in patients with severe COVID-19. Conclusion: These findings could suggest an interest in evaluating type 1 IFN treatment in patients with severe COVID-19 and type 1 IFN decline, eventually combined with anti-inflammatory drugs. Clinical trial registration: https://clinicaltrials.gov, identifiers NCT04324073, NCT04331808, NCT04341584.

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

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.

Pharmacokinetic Model of Tenofovir and Emtricitabine and Their Intracellular Metabolites in Patients in the ANRS 134-COPHAR 3 Trial Using Dose Records.

Tenofovir (TFV) and emtricitabine (FTC) are part of the recommended highly active antiretroviral therapy (ART). Both molecules show a large interindividual pharmacokinetic (PK) variability. Here, we modeled the concentrations of plasma TFV and FTC and their intracellular metabolites (TFV diphosphate [TFV-DP] and FTC triphosphate [FTC-TP]) collected after 4 and 24 weeks of treatment in 34 patients from the ANRS 134-COPHAR 3 trial. These patients received daily (QD) atazanavir (300 mg), ritonavir (100 mg), and a fixed-dose combination of coformulated TFV disoproxil fumarate (300 mg) and FTC (200 mg). Dosing history was collected using a medication event monitoring system. A three-compartment model with absorption delay (Tlag) was selected to describe the PK of, respectively, TFV/TFV-DP and FTC/FTC-TP. TFV and FTC apparent clearances, 114 L/h (relative standard error [RSE] = 8%) and 18.1 L/h (RSE = 5%), respectively, were found to decrease with age. However, no significant association was found with the polymorphisms ABCC2 rs717620, ABCC4 rs1751034, and ABCB1 rs1045642. The model allows prediction of TFV-DP and FTC-TP concentrations at steady state with alternative regimens.

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

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.

[11C]glyburide PET imaging for quantitative determination of the importance of Organic Anion-Transporting Polypeptide transporter function in the human liver and whole-body.

Organic Anion-Transporting Polypeptides (OATPs) are known to control the liver uptake of many drugs. Non-hepatic expression of OATPs has been reported although functional importance for whole-body pharmacokinetics (WBPK) remains unknown. Glyburide is a well described substrate of several hepatic and non-hepatic OATPs. Dynamic whole-body positron emission tomography (DWB-PET) with [11C]glyburide was performed in humans for determination of the importance of OATPs for liver uptake and WBPK. Seven healthy male subjects (24.7 ± 3.2 years) underwent [11C]glyburide PET scan with concomitant blood sampling. All subjects underwent baseline [11C]glyburide PET scan. Five subjects underwent a subsequent [11C]glyburide PET scan after infusion of the potent OATP inhibitor rifampicin (9 mg/kg i.v.). The transfer constant (kuptake) of [11C]glyburide from blood to the liver was estimated using the integration plot method. The tissue exposure of [11C]glyburide was described by the area under the time-activity curve (AUC) and corresponding tissue/blood ratio (AUCR). [11C]glyburide was barely metabolized in both the baseline and rifampicin conditions. Parent (unmetabolized) [11C]glyburide accounted for > 90 % of the plasma radioactivity. Excellent correlation was found between radioactive counting in arterial blood samples and in the image-derived input function, in both the baseline and rifampicin conditions (R2 = 97.9 %, p < 0.01). [11C]glyburide predominantly accumulated in the liver. Rifampicin decreased liver kuptake by 77.3 ± 7.3 %, which increased exposure in blood, kidneys, spleen, myocardium and brain (p < 0.05). No significant change in AUCR was observed except in the liver (p < 0.01). [11C]glyburide benefits from metabolic stability and high sensitivity to OATP inhibition which enables quantitative determination of OATP function. DWB-PET suggests negligible role for non-hepatic OATPs in controlling the tissue distribution of [11C]glyburide.

The association of ARRB1 polymorphisms with response to antidepressant treatment in depressed patients.

Introduction: ß-arrestin 1, a protein encoded by ARRB1 involved in receptor signaling, is a potential biomarker for the response to antidepressant drug (ATD) treatment in depression. We examined ARRB1 genetic variants for their association with response following ATD treatment in METADAP, a cohort of 6-month ATD-treated depressed patients. Methods: Patients (n = 388) were assessed at baseline (M0) and after 1 (M1), 3 (M3), and 6 months (M6) of treatment for Hamilton Depression Rating Scale (HDRS) changes, response, and remission. Whole-gene ARRB1 variants identified from high-throughput sequencing were separated by a minor allele frequency (MAF)≥5%. Frequent variants (i.e., MAF≥5%) annotated by RegulomeDB as likely affecting transcription factor binding were analyzed using mixed-effects models. Rare variants (i.e., MAF<5%) were analyzed using a variant set analysis. Results: The variant set analysis of rare variants was significant in explaining HDRS score changes (T = 878.9; p = 0.0033) and remission (T = -1974.1; p = 0.034). Rare variant counts were significant in explaining response (p = 0.016), remission (p = 0.022), and HDRS scores at M1 (p = 0.0021) and M3 (p=<0.001). rs553664 and rs536852 were significantly associated with the HDRS score (rs553664: p = 0.0055 | rs536852: p = 0.046) and remission (rs553664: p = 0.026 | rs536852: p = 0.012) through their interactions with time. At M6, significantly higher HDRS scores were observed in rs553664 AA homozygotes (13.98 ± 1.06) compared to AG heterozygotes (10.59 ± 0.86; p = 0.014) and in rs536852 GG homozygotes (14.88 ± 1.10) compared to AG heterozygotes (11.26 ± 0.95; p = 0.0061). Significantly lower remitter rates were observed in rs536852 GG homozygotes (8%, n = 56) compared to AG heterozygotes (42%, n = 105) at M6 (p = 0.0018). Conclusion: Our results suggest ARRB1 variants may influence the response to ATD treatment in depressed patients. Further analysis of functional ARRB1 variants and rare variant burden in other populations would help corroborate our exploratory analysis. ß-arrestin 1 and genetic variants of ARRB1 may be useful clinical biomarkers for clinical improvement following ATD treatment in depressed individuals. Clinical Trial Registration: clinicaltrials.gov; identifier NCT00526383.

Astroglial Connexins Inactivation Increases Relapse of Depressive-like Phenotype after Antidepressant Withdrawal.

Studies suggest that astrocytic connexins (Cx) have an important role in the regulation of high brain functions through their ability to establish fine-tuned communication with neurons within the tripartite synapse. In light of these properties, growing evidence suggests a role of Cx in psychiatric disorders such as major depression but also in the therapeutic activity of antidepressant drugs. However, the real impact of Cx on treatment response and the underlying neurobiological mechanisms remain yet to be clarified. On this ground, the present study was designed to evaluate the functional activity of Cx in a mouse model of depression based on chronic corticosterone exposure and to determine to which extent their pharmacological inactivation influences the antidepressant-like activity of venlafaxine (VENLA). On the one hand, our results indicate that depressed mice have impaired Cx-based gap-junction and hemichannel activities. On the other hand, while VENLA exerts robust antidepressant-like activity in depressed mice; this effect is abolished by the pharmacological inhibition of Cx with carbenoxolone (CBX). Interestingly, the combination of VENLA and CBX is also associated with a higher rate of relapse after treatment withdrawal. To our knowledge, this study is one of the first to develop a model of relapse, and our results reveal that Cx-mediated dynamic neuroglial interactions play a critical role in the efficacy of monoaminergic antidepressant drugs, thus providing new targets for the treatment of depression.

Tobacco use is associated with low peripheral beta-arrestin 1 levels in major depression: A preliminary report.

BACKGROUND: Understanding mechanisms associated with depressed smokers is a relevant question given that tobacco use disorder with comorbid major depressive disorder (MDD) has worse outcomes. The beta-arrestin 1 (ARRB1) pathway is a suggested biomarker for major depressive disorder and is involved in both antidepressant mechanism of action and tobacco addiction. We aimed to assess the association between smoking and peripheral ARRB1 expression in participants who exhibited MDD with current major depressive episode (MDE). BASIC PROCEDURES: 61 participants who exhibited MDD with current MDE with a score above 17 on the Hamilton Depression Rating Scale (HDRS), and who were free from antidepressant drug treatment for at least one month before inclusion, were assessed for tobacco use and cigarettes/day. Peripheral ARRB1 expression was assessed by sandwich ELISA from peripheral blood mononuclear cells (PBMC). FINDINGS: In participants who exhibited MDD with current MDE, peripheral ARRB1 expression was lower in tobacco users (n = 20, mean (SD) 4.795 (1.04) ng/mg of total protein) compared to non-tobacco users (n = 41, mean (SD) 6.19 (1.56) ng/mg; FDR p-value= 0.0044). Higher daily tobacco consumption was associated with lower peripheral ARRB1 expression (r = -0.314; FDR p-value=0.037). CONCLUSIONS: Tobacco consumption should be considered in studies of ARRB1 in participants who exhibit MDD. ARRB1 signaling is a new target of interest with a potential clinical implication for people with MDD and tobacco use disorder.

Hydroxychloroquine, Interleukin-6 Receptor Antagonists and Corticoid Treatments of Acute COVID-19 Infection: Psychiatric Symptoms and Mental Disorders 4 Months Later.

Objective: Psychiatric symptoms and mental disorders are common after Coronavirus Disease-19 (COVID-19). Some drugs used to treat acute COVID-19 have psychiatric side effects. We assessed the psychiatric symptoms and mental disorders of patients treated for acute COVID-19 with hydroxychloroquine (HCQ), interleukin-6 receptor antagonists (anti-IL-6), and corticoids (CTC). Methods: We evaluated 177 patients in a day hospital 4 months after acute infection. Results: In a multivariate analysis, HCQ was associated with significant anxiety symptoms (odds ratio [OR] = 5.9, 95% confidence interval [95% CI] = 1.8-20.0, p = 0.003) and mental disorders (OR = 4.1, 95% CI = 1.2-13.9, p = 0.02). In a bivariate analysis with propensity matched cohorts, HCQ was associated with significant anxiety symptoms (9 patients [50.0%] with significant symptoms in the HCQ group versus 15 [20.1%] in the control group, OR = 3.8, 95% CI = 1.3-11.3, p = 0.01). Anti-IL-6 and CTC were not associated with significant psychiatric symptoms or mental disorders. Conclusion: We recommend monitoring psychiatric symptoms, especially anxiety, in patients treated with HCQ during COVID-19 infection. Further studies with larger samples and prospective assessments are needed to confirm our results.

The ERICH3 rs11580409 polymorphism is associated with 6-month antidepressant response in depressed patients.

INTRODUCTION: Major Depressive Disorder (MDD) is the current leading cause of disability worldwide. The effect of its main treatment option, antidepressant drugs (AD), is influenced by genetic and metabolic factors. The ERICH3 rs11580409(A > C) genetic polymorphism was identified as a factor influencing serotonin (5HT) levels in a pharmacometabolomics-informed genome-wide association study. It was also associated with response following AD treatment in several cohorts of depressed patients. OBJECTIVE: Our aim was to analyze the association of the ERICH3 rs11580409(A > C) genetic polymorphism with response following AD treatment and plasma 5HT levels in METADAP, a cohort of 6-month AD-treated depressed patients. METHODS: Clinical (n = 377) and metabolic (n = 150) data were obtained at baseline and after 3 (M3) and 6 months (M6) of treatment. Linear mixed-effects models and generalized logistic mixed-effects models were used to assess the association of the rs11580409 polymorphism with the Hamilton Depression Rating Scale (HDRS) score, response and remission rates, and plasma 5HT levels. RESULTS: The interaction between the ERICH3 rs11580409 polymorphism and time was an overall significant factor in mixed-effects models of the HDRS score (F3,870 = 3.35, P = 0.019). At M6, CC homozygotes had a significantly lower HDRS score compared to A allele carriers (coefficient = -3.50, 95%CI [-6.00--0.99], P = 0.019). No association between rs11580409 and 5HT levels was observed. CONCLUSION: Our results suggest an association of rs11580409 with response following long-term AD treatment. The rs11580409 genetic polymorphism may be a useful biomarker for treatment response in major depression.

Adverse Drug Reactions of Olanzapine, Clozapine and Loxapine in Children and Youth: A Systematic Pharmacogenetic Review.

Children and youth treated with antipsychotic drugs (APs) are particularly vulnerable to adverse drug reactions (ADRs) and prone to poor treatment response. In particular, interindividual variations in drug exposure can result from differential metabolism of APs by cytochromes, subject to genetic polymorphism. CYP1A2 is pivotal in the metabolism of the APs olanzapine, clozapine, and loxapine, whose safety profile warrants caution. We aimed to shed some light on the pharmacogenetic profiles possibly associated with these drugs' ADRs and loss of efficacy in children and youth. We conducted a systematic review relying on four databases, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 recommendations and checklist, with a quality assessment. Our research yielded 32 publications. The most frequent ADRs were weight gain and metabolic syndrome (18; 56.3%), followed by lack of therapeutic effect (8; 25%) and neurological ADRs (7; 21.8%). The overall mean quality score was 11.3/24 (±2.7). In 11 studies (34.3%), genotyping focused on the study of cytochromes. Findings regarding possible associations were sometimes conflicting. Nonetheless, cases of major clinical improvement were fostered by genotyping. Yet, CYP1A2 remains poorly investigated. Further studies are required to improve the assessment of the risk-benefit balance of prescription for children and youth treated with olanzapine, clozapine, and/or loxapine.

Exome sequencing allows detection of relevant pharmacogenetic variants in epileptic patients.

Beyond the identification of causal genetic variants in the diagnosis of Mendelian disorders, exome sequencing can detect numerous variants with potential relevance for clinical care. Clinical interventions can thus be conducted to improve future health outcomes for patients and their at-risk relatives, such as predicting late-onset genetic disorders accessible to prevention, treatment or identifying differential drug efficacy and safety. To evaluate the interest of such pharmacogenetic information, we designed an "in house" pipeline to determine the status of 122 PharmGKB (Pharmacogenomics Knowledgebase) variant-drug combinations in 31 genes. This pipeline was applied to a cohort of 90 epileptic patients who had previously an exome sequencing (ES) analysis, to determine the frequency of pharmacogenetic variants. We performed a retrospective analysis of drug plasma concentrations and treatment efficacy in patients bearing at least one relevant PharmGKB variant. For PharmGKB level 1A variants, CYP2C9 status for phenytoin prescription was the only relevant information. Nineteen patients were treated with phenytoin, among phenytoin-treated patients, none were poor metabolizers and four were intermediate metabolizers. While being treated with a standard protocol (10-23 mg/kg/30 min loading dose followed by 5 mg/kg/8 h maintenance dose), all identified intermediate metabolizers had toxic plasma concentrations (20 mg/L). In epileptic patients, pangenomic sequencing can provide information about common pharmacogenetic variants likely to be useful to guide therapeutic drug monitoring, and in the case of phenytoin, to prevent clinical toxicity caused by high plasma levels.

The MAOA rs979605 Genetic Polymorphism Is Differentially Associated with Clinical Improvement Following Antidepressant Treatment between Male and Female Depressed Patients.

Major depressive disorder (MDD) is the leading cause of disability worldwide. Treatment with antidepressant drugs (ATD), which target monoamine neurotransmitters including serotonin (5HT), are only modestly effective. Monoamine oxidase (MAO) metabolizes 5HT to 5-hydroxy indoleacetic acid (5HIAA). Genetic variants in the X-chromosome-linked MAO-encoding genes, MAOA and MAOB, have been associated with clinical improvement following ATD treatment in depressed patients. Our aim was to analyze the association of MAOA and MAOB genetic variants with (1) clinical improvement and (2) the plasma 5HIAA/5HT ratio in 6-month ATD-treated depressed individuals. Clinical (n = 378) and metabolite (n = 148) data were obtained at baseline and up to 6 months after beginning ATD treatment (M6) in patients of METADAP. Mixed-effects models were used to assess the association of variants with the Hamilton Depression Rating Scale (HDRS) score, response and remission rates, and the plasma 5HIAA/5HT ratio. Variant × sex interactions and dominance terms were included to control for X-chromosome-linked factors. The MAOA rs979605 and MAOB rs1799836 polymorphisms were analyzed. The sex × rs979605 interaction was significantly associated with the HDRS score (p = 0.012). At M6, A allele-carrying males had a lower HDRS score (n = 24, 10.9 ± 1.61) compared to AA homozygous females (n = 14, 18.1 ± 1.87; p = 0.0067). The rs1799836 polymorphism was significantly associated with the plasma 5HIAA/5HT ratio (p = 0.018). Overall, CC/C females/males had a lower ratio (n = 44, 2.18 ± 0.28) compared to TT/T females/males (n = 60, 2.79 ± 0.27; p = 0.047). The MAOA rs979605 polymorphism, associated with the HDRS score in a sex-dependent manner, could be a useful biomarker for the response to ATD treatment.

The GG genotype of the serotonin 4 receptor genetic polymorphism, rs1345697, is associated with lower remission rates after antidepressant treatment: Findings from the METADAP cohort.

BACKGROUND: Pharmacological studies have yielded valuable insights into the role of the serotonin 4 receptor (HTR4) in major depressive episodes (MDE) and response to antidepressant drugs (AD). A genetic association has been shown between HTR4 and susceptibility to mood disorders. Our study aims at assessing the association between the HTR4 genetic polymorphism, rs1345697, and improvement in depressive symptoms and remission after antidepressant treatment in MDE patients. METHODS: 492 depressed patients from the METADAP cohort were treated prospectively for 6 months with ADs. The clinical outcomes according to HTR4 rs1345697 were compared after 1 (M1), 3 (M3), and 6 (M6) months of treatment. Mixed-effects logistic regression and adjusted linear models assessed the association between rs1345697 and 17-item Hamilton Depression Rating Scale (HDRS) score improvement and response/remission. RESULTS: Over the 6 months of treatment, mixed-effects regressions showed lower improvements in HDRS scores (Coefficient=1.52; Confident Interval (CI) 95% [0.37-2.67]; p = 0.009) and lower remission rates (Odds Ratio=2.0; CI95% [1.0-4.1]; p = 0.05) in GG homozygous patients as compared to allele A carriers. LIMITATIONS: The major limitations of our study are the uncertainty of the rs1345697 effect on HTR4 function, the substantial drop-out rate, and the fact that analysis is not based on randomization between polymorphism groups. CONCLUSIONS: In our study, patients who were homozygous carriers of the variant G of the HTR4 rs1345697 had lower depressive symptoms improvement and 2-fold lower remission rates after antidepressant treatment as compared to allele A carriers. Randomization study should be done to confirm these results.

Galaxy Is a Suitable Bioinformatics Platform for the Molecular Diagnosis of Human Genetic Disorders Using High-Throughput Sequencing Data Analysis: Five Years of Experience in a Clinical Laboratory.

BACKGROUND: To date, the usage of Galaxy, an open-source bioinformatics platform, has been reported primarily in research. We report 5 years' experience (2015 to 2020) with Galaxy in our hospital, as part of the "Assistance Publique-Hôpitaux de Paris" (AP-HP), to demonstrate its suitability for high-throughput sequencing (HTS) data analysis in a clinical laboratory setting. METHODS: Our Galaxy instance has been running since July 2015 and is used daily to study inherited diseases, cancer, and microbiology. For the molecular diagnosis of hereditary diseases, 6970 patients were analyzed with Galaxy (corresponding to a total of 7029 analyses). RESULTS: Using Galaxy, the time to process a batch of 23 samples-equivalent to a targeted DNA sequencing MiSeq run-from raw data to an annotated variant call file was generally less than 2 h for panels between 1 and 500 kb. Over 5 years, we only restarted the server twice for hardware maintenance and did not experience any significant troubles, demonstrating the robustness of our Galaxy installation in conjunction with HTCondor as a job scheduler and a PostgreSQL database. The quality of our targeted exome sequencing method was externally evaluated annually by the European Molecular Genetics Quality Network (EMQN). Sensitivity was mean (SD)% 99 (2)% for single nucleotide variants and 93 (9)% for small insertion-deletions. CONCLUSION: Our experience with Galaxy demonstrates it to be a suitable platform for HTS data analysis with vast potential to benefit patient care in a clinical laboratory setting.

Blood microbiota and metabolomic signature of major depression before and after antidepressant treatment: a prospective case-control study.

Background: The microbiota interacts with the brain through the gut-brain axis, and a distinct dysbiosis may lead to major depressive episodes. Bacteria can pass through the gut barrier and be found in the blood. Using a multiomic approach, we investigated whether a distinct blood microbiome and metabolome was associated with major depressive episodes, and how it was modulated by treatment. Methods: In this case-control multiomic study, we analyzed the blood microbiome composition, inferred bacterial functions and metabolomic profile of 56 patients experiencing a current major depressive episode and 56 matched healthy controls, before and after treatment, using 16S rDNA sequencing and liquid chromatography coupled to tandem mass spectrometry. Results: The baseline blood microbiome in patients with a major depressive episode was distinct from that of healthy controls (patients with a major depressive episode had a higher proportion of Janthinobacterium and lower levels of Neisseria) and changed after antidepressant treatment. Predicted microbiome functions confirmed by metabolomic profiling showed that patients who were experiencing a major depressive episode had alterations in the cyanoamino acid pathway at baseline. High baseline levels of Firmicutes and low proportions of Bosea and Tetrasphaera were associated with response to antidepressant treatment. Based on inferred baseline metagenomic profiles, bacterial pathways that were significantly associated with treatment response were related to xenobiotics, amino acids, and lipid and carbohydrate metabolism, including tryptophan and drug metabolism. Metabolomic analyses showed that plasma tryptophan levels are independently associated with response to antidepressant treatment. Limitations: Our study has some limitations, including a lack of information on blood microbiome origin and the lack of a validation cohort to confirm our results. Conclusion: Patients with depression have a distinct blood microbiome and metabolomic signature that changes after treatment. Dysbiosis could be a new therapeutic target and prognostic tool for the treatment of patients who are experiencing a major depressive episode.

Population pharmacokinetic model of blood THC and its metabolites in chronic and occasional cannabis users and relationship with on-site oral fluid testing.

AIMS: To develop a population pharmacokinetic (PP) model of delta-9-tetrahydrocannabinol (THC) and its metabolites in blood and to determine the relationship between blood THC pharmacokinetics and results of on-site oral fluid (OF) testing in chronic (CC) and occasional (OC) cannabis users. METHODS: Fifteen CC (1-2 joints/day) and 15 OC (1-2 joints/week) aged 18-34 years were included, genotyped for their CYP2C9 polymorphisms. Twelve measurements of blood THC, 11-OH-THC and THC-COOH were carried out during the 24-hour period after controlled cross-over random inhalation of placebo, 10 mg or 30 mg of THC. OF tests (DrugWipe® 5S) were performed up to 6 hours and then stopped after two successive negative results. The blood concentrations and their relationship to OF testing results were analysed using a PP approach with NONMEM® and R. RESULTS: A three-compartment model described the pharmacokinetics of THC, with zero-order absorption, and a two-compartment model the metabolites. The fraction of THC converted to 11-OH-THC was 0.27 and the fraction of 11-OH-THC to THC-COOH was 0.86. Smoking 30 mg of THC decreased the THC bioavailability to 0.68 compared to 10 mg. CC showed a 2.41 greater bioavailability than OC, leading to higher Cmax and AUC for the three compounds for the same dose. The best model describing the probability of a positive OF test included THC blood concentration and the group as covariate: for a similar THC blood concentration, a CC was less likely to be positive than an OC. CONCLUSION: OC are more likely to screen positive than CC for a similar blood concentration.