Ketamine metabolism via hepatic CYP450 isoforms contributes to its sustained antidepressant actions.

(R,S)-ketamine (ketamine) has rapid and sustained antidepressant (AD) efficacy at sub-anesthetic doses in depressed patients. A metabolite of ketamine, including (2R,6R)-hydroxynorketamine ((6)-HNKs) has been reported to exert antidepressant actions in rodent model of anxiety/depression. To further understand the specific role of ketamine's metabolism in the AD actions of the drug, we evaluated the effects of inhibiting hepatic cytochrome P450 enzymes on AD responses. We assessed whether pre-treatment with fluconazole (10 and 20 mg/kg, i.p.) 1 hour prior to ketamine or HNKs (10 mg/kg, i.p.) administration would alter behavioral and neurochemical actions of the drugs in male BALB/cJ mice with a highly anxious phenotype. Extracellular microdialysate levels of glutamate and GABA (Gluext, GABAext) were also measured in the medial prefrontal cortex (mPFC). Pre-treatment with fluconazole altered the pharmacokinetic profile of ketamine, by increasing both plasma and brain levels of ketamine and (R,S)-norketamine, while robustly reducing those of (6)-HNKs. At 24 hours post-injection (t24h), fluconazole prevented the sustained AD-like response of ketamine responses in the forced swim test and splash test, as well as the enhanced cortical GABA levels produced by ketamine. A single (2R,6R)-HNK administration resulted in prevention of the effects of fluconazole on the antidepressant-like activity of ketamine in mice. Overall, these findings are consistent with an essential contribution of (6)-HNK to the sustained antidepressant-like effects of ketamine and suggest potential interactions between pharmacological CYPIs and ketamine during antidepressant treatment in patients.

Habenular volume changes after venlafaxine treatment in patients with major depression.

BACKGROUND: Habenula, a hub brain region controlling monoaminergic brain center, has been implicated in major depressive disorder (MDD) and as a possible target of antidepressant response. Nevertheless, the effect of antidepressant drug treatment on habenular volumes remains unknown. The objective of the present research was to study habenular volume change after antidepressant treatment in patients with MDD, and assess whether it is associated with clinical improvement. METHODS: Fifty patients with a current major depressive episode (MDE) in the context of MDD, and antidepressant-free for at least 1 month, were assessed for habenula volume (3T MRI with manual segmentation) before and after a 3 months sequence of venlafaxine antidepressant treatment. RESULTS: A 2.3% significant increase in total habenular volume (absolute volume: P = 0.0013; relative volume: P = 0.0055) and a 3.3% significant increase in left habenular volume (absolute volume: P = 0.00080; relative volume: P = 0.0028) were observed. A significant greater variation was observed in male patients (4.8%) compared to female patients. No association was observed between habenular volume changes and response and remission. Some habenula volume changes were associated with improvement of olfactory pleasantness. CONCLUSION: Habenular volumes increased after 3 months of venlafaxine treatment in depressed patients. Further studies should assess whether cell proliferation and density or dendritic structure variations are implied in these volume changes.

Dietary micronutrients intake and its effect on haemoglobin levels of pregnant women for clinic visit in the Mount Cameroon health area: a cross-sectional study.

Background: Nutritional deficiencies and its consequences such as anaemia are frequent among pregnant women residing in under resource settings. Hence, this study sought to investigate specific dietary micronutrient inadequacy and its effect on maternal haemoglobin levels. Methods: This institution based cross-sectional survey enrolled 1,014 consenting pregnant women consecutively. Data on socio-demographic, economic and antenatal characteristics were recorded using a structured questionnaire. Minimum dietary diversity for women (MDD-W) was assessed using the 24-h recall method and haemoglobin (Hb) concentration (g/dL) determined using a portable Hb metre. Significant levels between associations was set at p < 0.05. Results: Among those enrolled, 40.9% were anaemic while 89.6% had inadequate dietary nutrient intake. In addition, uptake of blood supplements, haem iron, plant and animal-based foods rich in vitamin A were 71.5, 86.2, 35.5 and 12.6%, respectively. Moreover, anaemia prevalence was significantly (p < 0.05) lower in women who took iron-folic acid along with food groups rich in haem iron (38.5%) or both plant and animal vitamin A (29.0%). Besides, mean maternal Hb levels was significantly (p < 0.001) higher in women who consumed haem iron (11.08 ± 1.35) and vitamin A food groups (11.34 ± 1.30) when compared with their counterparts who did not consume haem iron (10.54 ± 1.19) and vitamin A food groups (10.74 ± 1.31). Conclusion: Dietary uptake of foods rich in haem-iron and vitamin A significantly improves Hb levels in Cameroonian pregnant women. Our findings underscore the importance of improving maternal nutritional awareness and counselling during antenatal period to reduce the anaemia burden.

Community engagement and antimalarial drugs medication as the first line of defense in the fight against antimalarial drug resistance in some endemic localities in Cameroon.

Objectives: Malaria burden is primarily owing to resistance of parasites and vectors to frontline drugs and insecticides, respectively. Increasing awareness of factors contributing to parasite resistance to antimalarials within communities is crucial. This study assessed how community knowledge, attitudes, and practices (KAPs) influence factors contributing to antimalarial resistance across four malaria ecological zones in Cameroon. Methods: To accomplish this, structured questionnaires were administered to 980 volunteers from four geographical locations in English or French (the official languages of Cameroon). The data were organized and tested for normality. Spearman rank correlation was used to examine the connection between KAP and malaria. Results: The mean KAP scores were 5.69 ± 1.47, 5.91 ± 1.25, and 5.66 ± 1.84, respectively, on a nine-point scale. Antimalarials commonly used were artemisinin-based combination therapies (37.96%), chloroquine (4.29%), quinine (22.24%), paracetamol (12.96%), and native drugs (19.80%). Up to 49.49% of the participants practiced self-medication, whereas 76.43% bought medications from licensed pharmacies, 10.61% bought from roadside vendors, and 23.57% relied on traditional/herbal medicines. We observed significant and medium positive linear correlations at P <0.01 between knowledge-attitude (r = 0.528), knowledge-practice (r = 0.400), and attitude-practice (r = 0.496). Conclusions: Despite the general fair level of awareness of proper management and use of antimalarial drugs in the communities, the high level of self-medication and gross neglect of certain risk factors that may promote the emergence and spread of drug-resistant parasites is concerning.

Pharmacological Enhancement of Adult Hippocampal Neurogenesis Improves Behavioral Pattern Separation in Young and Aged Mice.

BACKGROUND: Impairments in behavioral pattern separation (BPS)-the ability to distinguish between similar contexts or experiences-contribute to memory interference and overgeneralization seen in many neuropsychiatric conditions, including depression, anxiety, PTSD, dementia, and age-related cognitive decline. While BPS relies on the dentate gyrus and is sensitive to changes in adult hippocampal neurogenesis (AHN), its significance as a pharmacological target has not been tested. METHODS: In this study, we applied a human neural stem cell high-throughput screening cascade to identify compounds that increase human neurogenesis. One compound with a favorable profile, RO6871135, was then tested in BPS in mice. RESULTS: Chronic treatment with RO6871135, 7.5 mg/kg increased AHN and improved BPS in a fear discrimination task in both young and aged mice. RO6871135 treatment also lowered innate anxiety-like behavior, which was more apparent in mice exposed to chronic corticosterone. Ablation of AHN by hippocampal irradiation supported a neurogenesis-dependent mechanism for RO6871135-induced improvements in BPS. To identify possible mechanisms of action, in vitro and in vivo kinase inhibition and chemical proteomics assays were performed. These tests indicated that RO6871135 inhibited CDK8, CDK11, CaMK2a, CaMK2b, MAP2K6, and GSK3b. An analog compound also demonstrated high affinity for CDK8, CaMK2a, and GSK3b. CONCLUSIONS: These studies demonstrate a method for empirical identification and preclinical testing of novel neurogenic compounds that can improve BPS, and points to possible novel mechanisms that can be interrogated for the development of new therapies to improve specific endophenotypes such as impaired BPS.

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.

French National Authority for Health assessment of metabolic surgery for type 2 diabetes remission-A meta-analysis in patients with class I to III obesity.

OBJECTIVE: Randomized controlled trials (RCTs) have demonstrated the superiority of metabolic surgery (MS) over medical therapy (MT) in patients with obesity and type 2 diabetes, leading, to a joint statement in 2016 proposing MS to patients with class I obesity and uncontrolled glycemia. Yet, these RCTs included few patients with class I obesity (body mass index 30-35 kg/m2) and even fewer patients with overweight. Our aim was to provide an updated systematic review (SR) with meta-analysis (MA) of RCTs reporting diabetes remission (DR) after MS in these patients. RESEARCH DESIGN AND METHODS: We included in the SR with MA only RCTs with at least 24-month follow-up found in Medline, Cochrane Library, Embase, and LiSSA between January 2008 and September 2022 comparing DR post-MT versus post-MS. We calculated relative risk (RR) and 95 % confidence intervals (CIs) using the Mantel-Haenszel random-effects approach to examine differences in DR between patients allocated to MS versus MT. RESULTS: DR was significantly higher in MS versus MT after 36 months' follow-up in patients with obesity (RR = 6.65 [95 %CI 2.24;19.79]; I² = 27 %; 5 trials, 404 patients), but also specifically in patients with class I obesity (RR = 5.27 [1.31;21.23]; I² = 0 %; 4 trials, 80 patients). Furthermore, and in line with previous results, all additional MAs performed in patients with obesity in this work favor MS (specifically Roux-en-Y gastric bypass) over MT at 24, 36 (only) and 60 months of follow-up. CONCLUSIONS: Although the data available in patients with class I obesity and type 2 diabetes remains limited, MA shows higher rates of DR after MS compared with MT after 36 months' follow-up in these patients. Consequently, the French National Authority for Health French (HAS) recommends MS for these patients.

A tale of two receptors: simultaneous targeting of NMDARs and 5-HT 4 Rs exerts additive effects against stress.

BACKGROUND: Serotonin (5-HT) receptors and N -methyl-D-aspartate receptors (NMDARs) have both been implicated in the pathophysiology of depression and anxiety disorders. Here, we evaluated whether targeting both receptors through combined dosing of ( R , S )-ketamine, an NMDAR antagonist, and prucalopride, a serotonin type IV receptor (5-HT 4 R) agonist, would have additive effects, resulting in reductions in stress-induced fear, behavioral despair, and hyponeophagia. METHODS: A single injection of saline (Sal), ( R , S )-ketamine (K), prucalopride (P), or a combined dose of ( R , S )-ketamine and prucalopride (K+P) was administered before or after contextual fear conditioning (CFC) stress in both sexes. Drug efficacy was assayed using the forced swim test (FST), elevated plus maze (EPM), open field (OF), marble burying (MB), and novelty-suppressed feeding (NSF). Patch clamp electrophysiology was used to measure the effects of combined drug on neural activity in hippocampal CA3. c-fos and parvalbumin (PV) expression in the hippocampus (HPC) and medial prefrontal cortex (mPFC) was examined using immunohistochemistry and network analysis. RESULTS: We found that a combination of K+P, given before or after stress, exerted additive effects, compared to either drug alone, in reducing a variety of stress-induced behaviors in both sexes. Combined K+P administration significantly altered c-fos and PV expression and network activity in the HPC and mPFC. CONCLUSIONS: Our results indicate that combined K+P has additive benefits for combating stress-induced pathophysiology, both at the behavioral and neural level. Our findings provide preliminary evidence that future clinical studies using this combined treatment strategy may prove advantageous in protecting against a broader range of stress-induced psychiatric disorders.

Dynamics of the Apo µ-Opioid Receptor in Complex with Gi Protein.

Opioid receptors, particularly the µ-opioid receptor (µOR), play a pivotal role in mediating the analgesic and addictive effects of opioid drugs. G protein signaling is an important pathway of µOR function, usually associated with painkilling effects. However, the molecular mechanisms underlying the interaction between the µOR and G protein remain poorly understood. In this study, we employed classical all-atom molecular dynamics simulations to investigate the structural changes occurring with the µOR-G protein complex under two different conditions: with the G protein in the apo form (open) and with the GDP bound G protein (closed, holo form). The receptor was in the apo form and active conformation in both cases, and the simulation time comprised 1µs for each system. In order to assess the effect of the G protein coupling on the receptor activation state, three parameters were monitored: the correlation of the distance between TM3 and TM6 and the RMSD of the NPxxYA motif; the universal activation index (A100); and the χ2 dihedral distribution of residue W2936.48. When complexed with the open G protein, receptor conformations with intermediate activation state prevailed throughout the molecular dynamics, whereas in the condition with the closed G protein, mostly inactive conformations of the receptor were observed. The major effect of the G protein in the receptor conformation comes from a steric hindrance involving an intracellular loop of the receptor and a ß-sheet region of the G protein. This suggests that G-protein precoupling is essential for receptor activation, but this fact is not sufficient for complete receptor activation.

Status of the Multidrug Resistance-1 Gene of Plasmodium falciparum in Four Malaria Epidemiological Strata, Two Decades after the Abolition of Chloroquine as First-Line Treatment for Uncomplicated Malaria in Cameroon.

Drug-resistant malaria parasites pose a threat to global malaria control efforts, and it is important to know the extent of these drug-resistant mutations in each region to determine appropriate control measures. Chloroquine (CQ) was widely used in Cameroon for decades, but its declining clinical efficacy due to resistance prompted health authorities in 2004 to resort to artemisinin-based combination therapy (ACT) as the first-line treatment for uncomplicated malaria. Despite numerous efforts to control malaria, it persists, and the emergence and spread of resistance to ACTs make the development of new drugs or the possible reintroduction of discontinued drugs increasingly urgent. Malaria-positive blood samples were collected from 798 patients on Whatman filter paper to determine the status of resistance to CQ. DNA was extracted by boiling in Chelex and analysis of Plasmodium species. Four hundred P. falciparum monoinfected samples, 100 per study area, were amplified by nested PCR, and allele-specific restriction analysis of Pfmdr1 gene molecular markers was performed. Fragments were analyzed using a 3% ethidium bromide-stained agarose gel. P. falciparum was the most abundant Plasmodium species, accounting for 87.21% of P. falciparum monoinfections only. No infection with P. vivax was detected. The majority of samples contained the wild type for all 3 SNPs evaluated on the Pfmdr1 gene with N86, Y184, and D1246 accounting for 45.50%, 40.00%, and 70.00%, respectively. The most abundant haplotype observed was the Y184D1246 double wild type at 43.70%. The results suggest that P. falciparum is the major infecting species and that P. falciparum species with the susceptible genotype are gradually recapturing the parasite population.

A complex relation between levels of adult hippocampal neurogenesis and expression of the immature neuron marker doublecortin.

We investigated the mechanisms underlying the effects of the antidepressant fluoxetine on behavior and adult hippocampal neurogenesis (AHN). After confirming our earlier report that the signaling molecule ß-arrestin-2 (ß-Arr2) is required for the antidepressant-like effects of fluoxetine, we found that the effects of fluoxetine on proliferation of neural progenitors and survival of adult-born granule cells are absent in the ß-Arr2 knockout (KO) mice. To our surprise, fluoxetine induced a dramatic upregulation of the number of doublecortin (DCX)-expressing cells in the ß-Arr2 KO mice, indicating that this marker can be increased even though AHN is not. We discovered two other conditions where a complex relationship occurs between the number of DCX-expressing cells compared to levels of AHN: a chronic antidepressant model where DCX is upregulated and an inflammation model where DCX is downregulated. We concluded that assessing the number of DCX-expressing cells alone to quantify levels of AHN can be complex and that caution should be applied when label retention techniques are unavailable.

Intrahippocampal injection of a selective blocker of NMDA receptors containing the GluN2B subunit, Ro25-6981, increases glutamate neurotransmission and induces antidepressant-like effects.

Major depressive disorder (MDD) is a serious public health problem, as it is the most common psychiatric disorder worldwide. Antidepressant drugs increase adult hippocampal neurogenesis, which is required to induce some behavioral effects of antidepressants. Adult-born granule cells in the dentate gyrus (DG) and the glutamate receptors subunits 2 (GluN2B) subunit of N-methyl-D-aspartate (NMDA) ionotropic receptors play an important role in these effects. However, the precise neurochemical role of the GluN2B subunit of the NMDA receptor on adult-born GCs for antidepressant-like effects has yet to be elucidated. The present study aims to explore the contribution of the GluN2B-containing NMDA receptors in the ventral dentate gyrus (vDG) to the antidepressant drug treatment using a pharmacological approach. Thus, (αR)-(4-hydroxyphenyl)-(ßS)-methyl-4-(phenylmethyl)-1-piperidinepropanol (Ro25-6981), a selective antagonist of the GluN2B subunit, was acutely administered locally into the ventral DG (vDG, 1 µg each side) following a chronic fluoxetine (18 mg/kg/day) treatment-known to increase adult hippocampal neurogenesis-in a mouse model of anxiety/depression. Responses in a neurogenesis-dependent task, the novelty suppressed feeding (NSF), and neurochemical consequences on extracellular glutamate and gamma-aminobutyric acid (GABA) levels in the vDG were measured. Here, we show a rapid-acting antidepressant-like effect of local Ro25-6981 administration in the NSF independent of fluoxetine treatment. Furthermore, we revealed a fluoxetine-independent increase in the glutamatergic transmission in the vDG. Our results suggest behavioral and neurochemical effects of GluN2B subunit independent of serotonin reuptake inhibition.

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.

Intranasal (R, S)-ketamine delivery induces sustained antidepressant effects associated with changes in cortical balance of excitatory/inhibitory synaptic activity.

In 2019, an intranasal (IN) spray of esketamine SPRAVATO® was approved as a fast-acting antidepressant by drug Agencies US FDA and European EMA. At sub-anesthetic doses, (±)-ketamine, a non-competitive glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, increases the overall excitability of the medial prefrontal cortex (mPFC), an effect being essential for its rapid antidepressant activity. We wondered if this effect of ketamine could come from changes in the balance between neuronal excitation and inhibition (E/I balance) in the mPFC. Here, we performed a preclinical approach to study neurochemical and behavioral responses to a single IN ketamine dose in BALB/cJ mice, a strain more sensitive to stress. By using in vivo microdialysis, we measured cortical E/I balance as the ratio between glutamate to GABA extracellular levels 24 h post-ketamine. We found, for the first time, that E/I balance was shifted in favor of excitation rather than inhibition in the mPFC but more robustly with IN KET than with a single intraperitoneal (IP) dose. Increases in plasma and brain ketamine, norketamine and HNKs levels suggest different metabolic profiles of IP and IN ketamine 30 min post-dose. A significantly larger proportion of ketamine and HNKs in the brain are derived from the IN route 30 min post-dose. It may be linked to the greater magnitude in E/I ratio following IN delivery relative to IP at t24 h. This study suggests that both IP and IN are effective brain delivery methods inducing similar sustained antidepressant efficacy of KET, but the way they induced neurotransmitter changes is slightly different.

Peripheral proteomic changes after electroconvulsive seizures in a rodent model of non-response to chronic fluoxetine.

Major depressive disorder (MDD) is the psychiatric disorder with the highest prevalence in the world. Pharmacological antidepressant treatment (AD), such as selective serotonin reuptake inhibitors [SSRI, i.e., fluoxetine (Flx)] is the first line of treatment for MDD. Despite its efficacy, lack of AD response occurs in numerous patients characterizing Difficult-to-treat Depression. ElectroConvulsive Therapy (ECT) is a highly effective treatment inducing rapid improvement in depressive symptoms and high remission rates of ∼50-63% in patients with pharmaco-resistant depression. Nevertheless, the need to develop reliable treatment response predictors to guide personalized AD strategies and supplement clinical observation is becoming a pressing clinical objective. Here, we propose to establish a proteomic peripheral biomarkers signature of ECT response in an anxio/depressive animal model of non-response to AD. Using an emotionality score based on the analysis complementary behavioral tests of anxiety/depression (Elevated Plus Maze, Novelty Suppressed Feeding, Splash Test), we showed that a 4-week corticosterone treatment (35 µg/ml, Cort model) in C57BL/6JRj male mice induced an anxiety/depressive-like behavior. A 28-day chronic fluoxetine treatment (Flx, 18 mg/kg/day) reduced corticosterone-induced increase in emotional behavior. A 50% decrease in emotionality score threshold before and after Flx, was used to separate Flx-responding mice (Flx-R, n = 18), or Flx non-responder mice (Flx-NR, n = 7). Then, Flx-NR mice received seven sessions of electroconvulsive seizure (ECS, equivalent to ECT in humans) and blood was collected before and after ECS treatment. Chronic ECS normalized the elevated emotionality observed in Flx-NR mice. Then, proteins were extracted from peripheral blood mononuclear cells (PBMCs) and isolated for proteomic analysis using a high-resolution MS Orbitrap. Data are available via ProteomeXchange with identifier PXD037392. The proteomic analysis revealed a signature of 33 peripheral proteins associated with response to ECS (7 down and 26 upregulated). These proteins were previously associated with mental disorders and involved in regulating pathways which participate to the depressive disorder etiology.

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.

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.

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.

In vivo antimalarial activity of a probiotic bacterium Lactobacillus sakei isolated from traditionally fermented milk in BALB/c mice infected with Plasmodium berghei ANKA.

ETHNOPHARMACOLOGICAL RELEVANCE: Milk production, processing and consumption are integral part of traditional practices in Fulani tribe of Cameroon. It has been observed that Fulani are resistant to malaria. Dairy products traditionally processed by Fulani are intensively used in the ritual treatment of malarial, inflammations and behavioural disorders. Many studies have demonstrated that fermented milk is a rich source of probiotic bacteria. However, the antimalarial activity of probiotics isolated from this natural source has not been experimentally tested. AIM OF THE STUDY: Hence, this study was therefore aimed at evaluating the antimalarial activity of a probiotic bacterium Lactobacillus sakei isolated from traditionally fermented milk in mice infected with chloroquine sensitive Plasmodium berghei ANKA. MATERIALS AND METHODS: The probiotic bacterium was isolated from the Cameroonian Mborro Fulani's traditionally fermented milk and identified using the 16S r RNA gene sequencing. The schizontocidal activity of Lactobacillus sakei on established malaria infection was evaluated. Eighty-four healthy young adult Balb/c mice infected with Plasmodium berghei parasite were randomly divided into two sets of seven group of six mice each, and were given three different doses of Lactobacillus sakei, chloroquine and sulfadoxine/pyrimethamine for seven and fourteen days respectively. The level of parasitaemia, body temperature, survival time and haematological parameters were evaluated. RESULTS: The parasite growth inhibition was observed to increase with increasing dose of probiotic bacterium with maximum suppression being 100 % at dose 3 on day 20. Also, the probiotic bacterium significantly prevented body weight loss and was associated with body temperature reduction and prevented (p<0.05) a decrease in haematological parameters compared to that untreated malaria infected mice. CONCLUSION: The results obtained suggest that Lactobacillus sakei is a probiotic bacterium with antimalarial activity in mice infected with chloroquine sensitive Plasmodium berghei.

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.