Therapeutic doses of ketamine acutely attenuate the aversive effect of losses during decision-making.

The discovery of rapid-acting antidepressant, ketamine has opened a pathway to a new generation of treatments for depression, and inspired neuroscientific investigation based on a new perspective that non-adaptive changes in the intrinsic excitatory and inhibitory circuitry might underlie the pathophysiology of depression. Nevertheless, it still remains largely unknown how the hypothesized molecular and synaptic levels of changes in the circuitry might mediate behavioral and neuropsychological changes underlying depression, and how ketamine might restore adaptive behavior. Here, we used computational models to analyze behavioral changes induced by therapeutic doses of ketamine, while rhesus macaques were iteratively making decisions based on gains and losses of tokens. When administered intramuscularly or intranasally, ketamine reduced the aversiveness of undesirable outcomes such as losses of tokens without significantly affecting the evaluation of gains, behavioral perseveration, motivation, and other cognitive aspects of learning such as temporal credit assignment and time scales of choice and outcome memory. Ketamine's potentially antidepressant effect was separable from other side effects such as fixation errors, which unlike outcome evaluation, was readily countered with strong motivation to avoid errors. We discuss how the acute effect of ketamine to reduce the initial impact of negative events could potentially mediate longer-term antidepressant effects through mitigating the cumulative effect of those events produced by slowly decaying memory, and how the disruption-resistant affective memory might pose challenges in treating depression. Our study also invites future investigations on ketamine's antidepressant action over diverse mood states and with affective events exerting their impacts at diverse time scales.

miRNAs in treatment-resistant depression: a systematic review.

BACKGROUND: Treatment-resistant depression (TRD) is a condition in a subset of depressed patients characterized by resistance to antidepressant medications. The global prevalence of TRD has been steadily increasing, yet significant advancements in its diagnosis and treatment remain elusive despite extensive research efforts. The precise underlying pathogenic mechanisms are still not fully understood. Epigenetic mechanisms play a vital role in a wide range of diseases. In recent years, investigators have increasingly focused on the regulatory roles of miRNAs in the onset and progression of TRD. miRNAs are a class of noncoding RNA molecules that regulate the translation and degradation of their target mRNAs via interaction, making the exploration of their functions in TRD essential for elucidating their pathogenic mechanisms. METHODS AND RESULTS: A systematic search was conducted in four databases, namely PubMed, Web of Science, Cochrane Library, and Embase, focusing on studies related to treatment-resistant depression and miRNAs. The search was performed using terms individually or in combination, such as "treatment-resistant depression," "medication-resistant depression," and "miRNAs." The selected articles were reviewed and collated, covering the time period from the inception of each database to the end of February 2024. We found that miRNAs play a crucial role in the pathophysiology of TRD through three main aspects: 1) involvement in miRNA-mediated inflammatory responses (including miR-155, miR-345-5p, miR-146a, and miR-146a-5p); 2) influence on 5-HT transport processes (including miR-674,miR-708, and miR-133a); and 3) regulation of synaptic plasticity (including has-miR-335-5p,has-miR- 1292-3p, let-7b, and let-7c). Investigating the differential expression and interactions of these miRNAs could contribute to a deeper understanding of the molecular mechanisms underlying TRD. CONCLUSIONS: miRNAs might play a pivotal role in the pathogenesis of TRD. Gaining a deeper understanding of the roles and interrelations of miRNAs in TRD will contribute to elucidating disease pathogenesis and potentially provide avenues for the development of novel diagnostic and therapeutic strategies.

Effects of ebselen addition on emotional processing and brain neurochemistry in depressed patients unresponsive to antidepressant medication.

Lithium is an effective augmenting agent for depressed patients with inadequate response to standard antidepressant therapy, but numerous adverse effects limit its use. We previously reported that a lithium-mimetic agent, ebselen, promoted a positive emotional bias-an indicator of potential antidepressant activity in healthy participants. We therefore aimed to investigate the effects of short-term ebselen treatment on emotional processing and brain neurochemistry in depressed patients with inadequate response to standard antidepressants. We conducted a double-blind, placebo-controlled 7-day experimental medicine study in 51 patients with major depressive disorder who were currently taking antidepressants but had an inadequate response to treatment. Participants received either ebselen 600 mg twice daily for seven days or identical matching placebo. An emotional testing battery, magnetic resonance spectroscopy and depression and anxiety rating scales were conducted at baseline and after seven days of treatment. Ebselen did not increase the recognition of positive facial expressions in the depressed patient group. However, ebselen increased the response bias towards fear emotion in the signal detection measurement. In the anterior cingulate cortex, ebselen significantly reduced the concentrations of inositol and Glx (glutamate+glutamine). We found no significant differences in depression and anxiety rating scales between visits. Our study did not find any positive shift in emotional bias in depressed patients with an inadequate response to antidepressant medication. We confirmed the ability of ebselen to lower inositol and Glx in the anterior cingulate cortex. These latter effects are probably mediated through inhibition of inositol monophosphatase and glutaminase respectively.

Quercetin alleviates chronic unpredictable mild stress-induced depression-like behavior by inhibiting NMDAR1 with α2δ-1 in rats.

BACKGROUND: Depression is a serious mental disorder and the most prevalent cause of disability and suicide worldwide. Chronic unpredictable mild stress (CUMS) can lead to a significant acceleration of depression development. Quercetin (Que) is a flavonoid compound with a wide range of pharmacological effects. Recent studies have shown that quercetin can improve CUMS-induced depression-like behavior, but the mechanism of its improvement is still unclear. α2δ-1 is a regulatory subunit of voltage-gated calcium channel, which can interact with N-methyl-D-aspartate receptor (NMDAR) to form a complex. OBJECTIVE: In this study, we found that Que could inhibit the increase of α2δ-1 and NMDAR expression in rat hypothalamus induced by CUMS. In pain, chronic hypertension and other studies have shown that α2δ-1 interacts with the NMDAR to form a complex, which subsequently affects the expression level of NMDAR. Consequently, the present study aimed to investigate the antidepressant effect of Que in vivo and in vitro and to explore its mechanism of action in terms of the interaction between α2δ-1 and NMDAR. METHODS: Rats were randomly exposed to two stressors every day for 4 weeks to establish a CUMS rat model, then sucrose preference test (SPT), forced swimming test (FST), tail suspension test (TST), and open field test (OFT) were performed to detect the behavior of CUMS rats, so as to evaluate whether the CUMS rat model was successfully established and the improvement effect of Que on CUMS-induced depression-like behavior in rats. Experimental techniques such as serum enzyme-linked immunosorbent assay (ELISA), immunofluorescence, Western blot, and co-immunoprecipitation, as well as in vitro experiments, were used to investigate the mechanisms by which Que exerts its antidepressant effects. RESULTS: Behavioral and ELISA test results showed that Que could produce a reduction in the excitability of the hypothalamic-pituitary-adrenal (HPA) axis in CUMS rats and lead to significant improvements in their depressive behavior. Western blot, immunofluorescence, and co-immunoprecipitation experiments showed that Que produced a decrease in NMDAR1 and α2δ-1 expression levels and interfered with α2δ-1 and NMDAR1 binding. In addition, the neural regulation mechanism of Que on antidepressant effect in PC12 cells knocked out α2δ-1 gene was further verified. Cellular experiments demonstrated that Que led to a reversal of up-regulation of NMDAR1 and α2δ-1 expression levels in corticosterone-injured PC12 cells, while Que had no effects on NMDAR1 expression in PC12 cells with the α2δ-1 gene knockout. CONCLUSIONS: Que has a good antidepressant effect and can significantly improve the depression-like behavior caused by CUMS. It exerts antidepressant effects by inhibiting the expression level of α2δ-1, interfering with the interaction between α2δ-1 and NMDAR, and then reducing the excitability of the HPA axis.

Atractylodin ameliorates lipopolysaccharide-induced depressive-like behaviors in mice through reducing neuroinflammation and neuronal damage.

Depression is a psychiatric disorder associated with multiple factors including microglia-mediated neuroinflammation. Although atractylodin exerted a variety of biological activities, however the effect of atractylodin on neuroinflammation-related depression was still unclear. In this study, the lipopolysaccharide (LPS)-induced mouse model was used to explore the antidepressant effects and molecular mechanisms of atractylodin. The results showed that atractylodin increased sugar preference, also reduced immobility time in FST and TST. Further study showed atractylodin reduced the oxidative stress and the activation of microglia in mouse hippocampus, also inhibited the level of cytokine release, especially IL-1ß. The results of western blotting showed that atractylodin significantly inhibited the expression of NLRP3 and pro-IL1ß via inhibition of NF-κB pathway. Our studies showed that atractylodin upregulated BDNF/Akt pathway in mouse hippocampus. Therefore, this study firstly indicated that atractylodin can ameliorate lipopolysaccharide-induced depressive-like behaviors in mice through reducing neuroinflammation and neuronal damage, and its molecular mechanism may be associated with the decrease of the expression of NLRP3 inflammasome and upregulation of BDNF/Akt pathway.

1-(Phenylselanyl)-2-(p-tolyl)indolizine: A selenoindolizine with potential antidepressant-like activity in mice mediated by the modulation of dopaminergic and noradrenergic systems.

1-(Phenylselanyl)-2-(p-tolyl)indolizine (MeSeI) is a selenoindolizine with an antidepressant-like effect in mice by regulation of the serotonergic system. This study investigated the involvement of dopaminergic and noradrenergic systems in the antidepressant-like action of MeSeI. For this purpose, Swiss male mice were pretreated with different antagonists, after 15 min, the MeSeI was administrated by intragastric (i.g.) via; after 30 min, the mouse behavior was assessed in the forced swimming test (FST). The action of MeSeI on the activity of monoamine oxidase (MAO) was determined. The pretreatment of mice with haloperidol (0.05 mg/kg, intraperitoneally, i.p.; non-selective dopamine receptor antagonist), sulpiride (50 mg/kg, i.p.; D2 receptor antagonist), yohimbine (1 mg/kg, i.p.; α2 receptor antagonist), and propranolol (2 mg/kg, i.p.; non-selective ß receptor antagonist), inhibited the anti-immobility action of MeSeI (50 mg/kg, i.g.) in the FST. This blocking effect was not observed when SCH23390 (0.01 mg/kg, i.p.; D1 receptor antagonist), and prazosin (1 mg/kg, i.p.; α1 receptor antagonist) were administered. The coadministration of subeffective doses of bupropion (3 mg/kg. i.g.; dopamine and noradrenaline reuptake inhibitor) and MeSeI (0.5 mg/kg. i.g.) reduced the immobility time in the FST. Furthermore, MeSeI inhibited MAO-A and B activities in vitro and ex vivo tests. These results suggest that MeSeI exerts its antidepressant-like effect via regulation of the D2, α2, and ß1 receptors and the inhibition of MAO-A and B activities. Molecular docking investigations corroborated these results. This study provides comprehensive insights into the antidepressant-like mechanism of MeSeI in mice, suggesting its potential as a novel antidepressant candidate.

Ecocebo: How the interaction between environment and drug effects may improve pharmacotherapy outcomes.

This narrative review describes the research on the effects of the association between environmental context and medications, suggesting the benefit of specific design interventions in adjunction to pharmacotherapy. The literature on Evidence-Based Design (EBD) studies and Neuro-Architecture show how contact with light, nature, and specific physical features of urban and interior architecture may enhance the effects of analgesic, anxiolytics, and antidepressant drugs. This interaction mirrors those already known between psychedelics, drugs of abuse, and setting. Considering that the physical feature of space is a component of the complex placebo configuration, the aim is to highlight those elements of built or natural space that may help to improve drug response in terms of efficacy, tolerability, safety, and compliance. Ecocebo, the integration of design approaches such as EBD and Neuro-Architecture may thus contribute to a more efficient, cost-sensitive, and sustainable pharmacotherapy.

Exosomal miR-1202 mediates Brodmann Area 44 functional connectivity changes in medication-free patients with major depressive disorder: An fMRI study.

Previous large-sample postmortem study revealed that the expression of miR-1202 in brain tissues from Brodmann area 44 (BA44) was dysregulated in patients with major depressive disorder (MDDs). However, the specific in vivo neuropathological mechanism of miR-1202 as well as its interplay with BA44 circuits in the depressed brain are still unclear. Here, we performed a case-control study with imaging-genetic approach based on resting-state functional magnetic resonance imaging (MRI) data and miR-1202 quantification from 110 medication-free MDDs and 102 healthy controls. Serum-derived circulating exosomes that readily cross the blood-brain barrier were isolated to quantify miR-1202. For validation, repeated MR scans were performed after a six-week follow-up of antidepressant treatment on a cohort of MDDs. Voxelwise factorial analysis revealed two brain areas (including the striatal-thalamic region) in which the effect of depression on the functional connectivity with BA44 was significantly dependent on the expression level of exosomal miR-1202. Moreover, longitudinal change of the BA44 connectivity with the striatal-thalamic region in MDDs after antidepressant treatment was found to be significantly related to the level of miR-1202 expression. These findings revealed that the in vivo neuropathological effect of miR-1202 dysregulation in depression is possibly exerted by mediating neural functional abnormalities in BA44-striatal-thalamic circuits.

NSC689857, an inhibitor of Skp2, produces antidepressant-like effects in mice.

We have previously reported that two inhibitors of an E3 ligase S-phase kinase-associated protein 2 (Skp2), SMIP004 and C1, have an antidepressant-like effect in non-stressed and chronically stressed mice. This prompted us to ask whether other Skp2 inhibitors could also have an antidepressant effect. Here, we used NSC689857, another Skp2 inhibitor, to investigate this hypothesis. The results showed that administration of NSC689857 (5 mg/kg) produced an antidepressant-like effect in a time-dependent manner in non-stressed male mice, which started 8 days after drug administration. Dose-dependent analysis showed that administration of 5 and 10 mg/kg, but not 1 mg/kg, of NSC689857 produced antidepressant-like effects in both non-stressed male and female mice. Administration of NSC689857 (5 mg/kg) also induced antidepressant-like effects in non-stressed male mice when administered three times within 24 h (24, 5, and 1 h before testing) but not when administered acutely (1 h before testing). In addition, NSC689857 and fluoxetine coadministration produced additive antidepressant-like effects in non-stressed male mice. These effects of NSC689857 were not associated with the changes in locomotor activity. Administration of NSC689857 (5 mg/kg) also attenuated depression-like behaviors in male mice induced by chronic social defeat stress, suggesting therapeutic potential of NSC689857 in depression. Overall, these results suggest that NSC689857 is capable of exerting antidepressant-like effects in both non-stressed and chronically stressed mice.

Ketamine induces multiple individually distinct whole-brain functional connectivity signatures.

Background: Ketamine has emerged as one of the most promising therapies for treatment-resistant depression. However, inter-individual variability in response to ketamine is still not well understood and it is unclear how ketamine's molecular mechanisms connect to its neural and behavioral effects. Methods: We conducted a single-blind placebo-controlled study, with participants blinded to their treatment condition. 40 healthy participants received acute ketamine (initial bolus 0.23 mg/kg, continuous infusion 0.58 mg/kg/hr). We quantified resting-state functional connectivity via data-driven global brain connectivity and related it to individual ketamine-induced symptom variation and cortical gene expression targets. Results: We found that: (i) both the neural and behavioral effects of acute ketamine are multi-dimensional, reflecting robust inter-individual variability; (ii) ketamine's data-driven principal neural gradient effect matched somatostatin (SST) and parvalbumin (PVALB) cortical gene expression patterns in humans, while the mean effect did not; and (iii) behavioral data-driven individual symptom variation mapped onto distinct neural gradients of ketamine, which were resolvable at the single-subject level. Conclusions: These results highlight the importance of considering individual behavioral and neural variation in response to ketamine. They also have implications for the development of individually precise pharmacological biomarkers for treatment selection in psychiatry. Funding: This study was supported by NIH grants DP5OD012109-01 (A.A.), 1U01MH121766 (A.A.), R01MH112746 (J.D.M.), 5R01MH112189 (A.A.), 5R01MH108590 (A.A.), NIAAA grant 2P50AA012870-11 (A.A.); NSF NeuroNex grant 2015276 (J.D.M.); Brain and Behavior Research Foundation Young Investigator Award (A.A.); SFARI Pilot Award (J.D.M., A.A.); Heffter Research Institute (Grant No. 1-190420) (FXV, KHP); Swiss Neuromatrix Foundation (Grant No. 2016-0111) (FXV, KHP); Swiss National Science Foundation under the framework of Neuron Cofund (Grant No. 01EW1908) (KHP); Usona Institute (2015 - 2056) (FXV). Clinical trial number: NCT03842800.

Ketamine is a widely used anesthetic as well as a popular illegal recreational drug. Recently, it has also gained attention as a potential treatment for depression, particularly in cases that don't respond to conventional therapies. However, individuals can vary in their response to ketamine. For example, the drug can alter some people's perception, such as seeing objects as larger or small than they are, while other individuals are unaffected. Although a single dose of ketamine was shown to improve depression symptoms in approximately 65% of patients, the treatment does not work for a significant portion of patients. Understanding why ketamine does not work for everyone could help to identify which patients would benefit most from the treatment. Previous studies investigating ketamine as a treatment for depression have typically included a group of individuals given ketamine and a group given a placebo drug. Assuming people respond similarly to ketamine, the responses in each group were averaged and compared to one another. However, this averaging of results may have masked any individual differences in response to ketamine. As a result, Moujaes et al. set out to investigate whether individuals show differences in brain activity and behavior in response to ketamine. Moujaes et al. monitored the brain activity and behavior of 40 healthy individuals that were first given a placebo drug and then ketamine. The results showed that brain activity and behavior varied significantly between individuals after ketamine administration. Genetic analysis revealed that different gene expression patterns paired with differences in ketamine response in individuals ­ an effect that was hidden when the results were averaged. Ketamine also caused greater differences in brain activity and behavior between individuals than other drugs, such as psychedelics, suggesting ketamine generates a particularly complex response in people. In the future, extending these findings in healthy individuals to those with depression will be crucial for determining whether differences in response to ketamine align with how effective ketamine treatment is for an individual.

The association between gray matter volume in the hippocampal subfield and antidepressant efficacy mediated by abnormal dynamic functional connectivity.

An abnormality of structures and functions in the hippocampus may have a key role in the pathophysiology of major depressive disorder (MDD). However, it is unclear whether structure factors of the hippocampus effectively impact antidepressant responses by hippocampal functional activity in MDD patients. We collected longitudinal data from 36 MDD patients before and after a 3-month course of antidepressant pharmacotherapy. Additionally, we obtained baseline data from 43 healthy controls matched for sex and age. Using resting-state functional magnetic resonance imaging (rs-fMRI), we estimated the dynamic functional connectivity (dFC) of the hippocampal subregions using a sliding-window method. The gray matter volume was calculated using voxel-based morphometry (VBM). The results indicated that patients with MDD exhibited significantly lower dFC of the left rostral hippocampus (rHipp.L) with the right precentral gyrus, left superior temporal gyrus and left postcentral gyrus compared to healthy controls at baseline. In MDD patients, the dFC of the rHipp.L with right precentral gyrus at baseline was correlated with both the rHipp.L volume and HAMD remission rate, and also mediated the effects of the rHipp.L volume on antidepressant performance. Our findings suggested that the interaction between hippocampal structure and functional activity might affect antidepressant performance, which provided a novel insight into the hippocampus-related neurobiological mechanism of MDD.

Conjugation of sulpiride with a cell penetrating peptide to augment the antidepressant efficacy and reduce serum prolactin levels.

Depression ranks as the fourth most prevalent global disease, with suicide incidents occurring at a younger age. Sulpiride (SUL), an atypical antidepressant drug acting as a dopamine D2 receptor antagonist and possessing anti-inflammatory properties, exhibits limited ability to penetrate the blood brain barrier (BBB). This weak penetration hampers its inhibitory effect on prolactin release in the pituitary gland, consequently leading to hyperprolactinemia. In order to enhance the central nervous system efficacy of sulpiride and reduce serum prolactin levels, we covalently linked sulpiride to VPALR derived from the nuclear DNA repair protein ku70. In vivo study on depressive mice using intraperitoneal injection of VPALR-SUL demonstrated a significant increase in struggle time and total distance compared to those treated with only sulpiride while also reducing serum prolactin concentration. The pharmacokinetic study results showed that VPALR-SUL prolonged half-life and increased bioavailability. In conclusion, VPALR-SUL exhibited potential for enhancing sulpiride transport across the BBB, augmenting its antidepressant effects, and reducing serum prolactin levels. This study laid a foundation for improving sulpiride delivery and developing novel antidepressants.

Acute Dissociation and Ketamine's Antidepressant and Anti-Suicidal Ideation Effects in a Midazolam-Controlled Trial.

OBJECTIVE: We sought to explore relationships of acute dissociative effects of intravenous ketamine with change in depression and suicidal ideation and with plasma metabolite levels in a randomized, midazolam-controlled trial. METHODS: Data from a completed trial in suicidal, depressed participants (n = 40) randomly assigned to ketamine was used to examine relationships between ketamine treatment-emergent dissociative and psychotomimetic symptoms with pre/post-infusion changes in suicidal ideation and depression severity. Nonparametric correlational statistics were used. These methods were also used to explore associations between dissociative or psychotomimetic symptoms and blood levels of ketamine and metabolites in a subset of participants (n = 28) who provided blood samples immediately post-infusion. RESULTS: Neither acute dissociative nor psychotomimetic effects of ketamine were associated with changes in suicidal ideation or depressive symptoms from pre- to post-infusion. Norketamine had a trend-level, moderate inverse correlation with dissociative symptoms on Day 1 post-injection (P = .064; P =.013 removing 1 outlier). Dehydronorketamine correlated with Clinician-Administered Dissociative States Scale scores at 40 minutes (P = .034), 230 minutes (P = .014), and Day 1 (P = .012). CONCLUSION: We did not find evidence that ketamine's acute, transient dissociative, or psychotomimetic effects are associated with its antidepressant or anti-suicidal ideation actions. The correlation of higher plasma norketamine with lower dissociative symptoms on Day 1 post-treatment suggests dissociation may be more an effect of the parent drug.

Psilocybin for dementia prevention? The potential role of psilocybin to alter mechanisms associated with major depression and neurodegenerative diseases.

Major depression is an established risk factor for subsequent dementia, and depression in late life may also represent a prodromal state of dementia. Considering current challenges in the clinical development of disease modifying therapies for dementia, the focus of research is shifting towards prevention and modification of risk factors to alter the neurodegenerative disease trajectory. Understanding mechanistic commonalities underlying affective symptoms and cognitive decline may reveal biomarkers to aid early identification of those at risk of progressing to dementia during the preclinical phase of disease, thus allowing for timely intervention. Adult hippocampal neurogenesis (AHN) is a phenomenon that describes the birth of new neurons in the dentate gyrus throughout life and it is associated with spatial learning, memory and mood regulation. Microglia are innate immune system macrophages in the central nervous system that carefully regulate AHN via multiple mechanisms. Disruption in AHN is associated with both dementia and major depression and microgliosis is a hallmark of several neurodegenerative diseases. Emerging evidence suggests that psychedelics promote neuroplasticity, including neurogenesis, and may also be immunomodulatory. In this context, psilocybin, a serotonergic agonist with rapid-acting antidepressant properties has the potential to ameliorate intersecting pathophysiological processes relevant for both major depression and neurodegenerative diseases. In this narrative review, we focus on the evidence base for the effects of psilocybin on adult hippocampal neurogenesis and microglial form and function; which may suggest that psilocybin has the potential to modulate multiple mechanisms of action, and may have implications in altering the progression from major depression to dementia in those at risk.

Discovering the Potential Value of Coenzyme Q10 as an Adjuvant Treatment in Patients With Depression.

PURPOSE/BACKGROUND: Depressive disorder or mental cold is the most common mental disorder, and depression exists all over the world and in all countries and cultures. The results of several studies have shown that using compounds with antioxidant properties has been fruitful in patients with depression. Coenzyme Q10 (CoQ10) is a fat-soluble antioxidant and exerts its antioxidant effect by directly neutralizing free radicals or reducing tocopherol and preventing the inhibition of mitochondrial activity because of oxidative stress. This study aimed to investigate the effects of oral CoQ10 in patients with depression as an adjunctive treatment. METHODS/PROCEDURES: Sixty-nine patients with moderate and severe depression were randomly divided into 2 CoQ10 groups (36) and placebo (33). The first group of patients received CoQ10 supplements at a dose of 200 mg daily for 8 weeks along with standard interventions and treatments for depression, and the second group received standard treatments for depression along with a placebo. The change in the score of Montgomery-Åsberg Depression Rating Scale depression scale was evaluated 4 and 8 weeks after the intervention. Also, at baseline and 8 weeks later at the end of the study, serum levels of total antioxidant capacity, total thiol groups, nitric oxide, malondialdehyde, and interleukin 6 were assessed. FINDINGS/RESULTS: The changes in the depression score at the end of the study showed that, in the group receiving the CoQ10 supplement after 8 weeks, there was a reduction in depression symptoms, which was statistically significant compared with before the start of the study Meanwhile, no significant changes were observed in the patients of the placebo group in terms of symptom reduction. Compared with baseline and the placebo condition, serum levels of nitric oxide and total thiol groups significantly decreased and increased, respectively. Also, no statistically significant changes were observed for interleukin 6, malondialdehyde, and total antioxidant capacity. IMPLICATIONS/CONCLUSIONS: A dose of 200 mg of CoQ10 supplement daily for 8 weeks can reduce depression and fatigue, as well as improve the quality of life of patients with depression. In addition, CoQ10 can significantly improve inflammation and oxidative stress status in patients with depression.

Biomarker triterpenoids of Centella asiatica as potential antidepressant agents: Combining in vivo and in silico studies.

Although there are various treatments available for depression, some patients may experience resistance to treatment or encounter adverse effects. Centella asiatica (C. asiatica) is an ancient medicinal herb used in Ayurvedic medicine for its rejuvenating, neuroprotective and psychoactive properties. This study aims to explore the antidepressant-like effects of the major constituents found in C. asiatica, i.e., asiatic acid, asiaticoside, madecassic acid, and madecassoside at three doses (1.25, 2.5, and 5 mg/kg, i.p), on the behavioural and cortisol level of unpredictable chronic stress (UCS) zebrafish model. Based on the findings from the behavioural study, the cortisol levels in the zebrafish body after treatment with the two most effective compounds were measured using enzyme-linked immunosorbent assay (ELISA). Furthermore, a molecular docking study was conducted to predict the inhibitory impact of the triterpenoid compounds on serotonin reuptake. The in vivo results indicate that madecassoside (1.25, 2.5, and 5 mg/kg), asiaticoside and asiatic acid (5 mg/kg) activated locomotor behaviour. Madecassoside at all tested doses and asiaticoside at 2.5 and 5 mg/kg significantly decreased cortisol levels compared to the stressed group, indicating the potential regulation effect of madecassoside and asiaticoside on the hypothalamic-pituitary-adrenal axis overactivity. This study highlights the potential benefits of madecassoside and asiaticoside in alleviating depressive symptoms through their positive effects on behaviour and the hypothalamic-pituitary-adrenal (HPA)- axis in a chronic unpredictable stress zebrafish model. Furthermore, the in silico study provided additional evidence to support these findings. These promising results suggest that C. asiatica may be a valuable and cost-effective therapeutic option for depression, and further research should be conducted to explore its potential benefits.

Engeletin alleviates depressive-like behaviours by modulating microglial polarization via the LCN2/CXCL10 signalling pathway.

Microglial polarization and associated inflammatory activity are the key mediators of depression pathogenesis. The natural Smilax glabra rhizomilax derivative engeletin has been reported to exhibit robust anti-inflammatory activity, but no studies to date have examined the mechanisms through which it can treat depressive symptoms. We showed that treatment for 21 days with engeletin significantly alleviated depressive-like behaviours in chronic stress social defeat stress (CSDS) model mice. T1-weighted imaging (T1WI), T2-weighted imaging (T2WI) imaging revealed no significant differences between groups, but the bilateral prefrontal cortex of CSDS mice exhibited significant increases in apparent diffusion coefficient and T2 values relative to normal control mice, with a corresponding reduction in fractional anisotropy, while engeletin reversed all of these changes. CSDS resulted in higher levels of IL-1ß, IL-6, and TNF-a production, enhanced microglial activation, and greater M1 polarization with a concomitant decrease in M2 polarization in the mPFC, whereas engeletin treatment effectively abrogated these CSDS-related pathological changes. Engeletin was further found to suppress the LCN2/C-X-C motif chemokine ligand 10 (CXCL10) signalling axis such that adeno-associated virus-induced LCN2 overexpression ablated the antidepressant effects of engeletin and reversed its beneficial effects on the M1/M2 polarization of microglia. In conclusion, engeletin can alleviate CSDS-induced depressive-like behaviours by regulating the LCN2/CXCL10 pathway and thereby altering the polarization of microglia. These data suggest that the antidepressant effects of engeletin are correlated with the polarization of microglia, highlighting a potential avenue for future design of antidepressant strategies that specifically target the microglia.

Effects of antidepressant on FKBP51 mRNA expression and neuroendocrine hormones in patients with panic disorder.

OBJECTIVE: The purpose of this study was to investigate the effects of escitalopram on the peripheral expression of hypothalamic-pituitary-adrenal (HPA) axis-related genes (FKBP51, HSP90, NR3C1 and POMC) and HPA-axis hormones in patients with panic disorder (PD). METHODS: Seventy-seven patients with PD were treated with escitalopram for 12 weeks. All participants were assessed for the severity of panic symptoms using the Panic Disorder Severity Scale (PDSS). The expression of HPA-axis genes was measured using real-time quantitative fluorescent PCR, and ACTH and cortisol levels were measured using chemiluminescence at baseline and after 12 weeks of treatment. RESULTS: At baseline, patients with PD had elevated levels of ACTH and cortisol, and FKBP51 expression in comparison to healthy controls (all p < 0.01). Correlation analysis revealed that FKBP51 expression levels were significantly positively related to cortisol levels and the severity of PD (all p < 0.01). Furthermore, baseline ACTH and cortisol levels, and FKBP51 expression levels were significantly reduced after 12 weeks of treatment, and the change in the PDSS score from baseline to post-treatment was significantly and positively related to the change in cortisol (p < 0.01). CONCLUSIONS: The results suggest that PD may be associated with elevated levels of ACTH and cortisol, and FKBP51 expression, and that all three biomarkers are substantially decreased in patients who have received escitalopram treatment.

Liraglutide and Naringenin relieve depressive symptoms in mice by enhancing Neurogenesis and reducing inflammation.

Depression is a debilitating mental disease that negatively impacts individuals' lives and society. Novel hypotheses have been recently proposed to improve our understanding of depression pathogenesis. Impaired neuroplasticity and upregulated neuro-inflammation add-on to the disturbance in monoamine neurotransmitters and therefore require novel anti-depressants to target them simultaneously. Recent reports demonstrate the antidepressant effect of the anti-diabetic drug liraglutide. Similarly, the natural flavonoid naringenin has shown both anti-diabetic and anti-depressant effects. However, the neuro-pharmacological mechanisms underlying their actions remain understudied. The study aims to evaluate the antidepressant effects and neuroprotective mechanisms of liraglutide, naringenin or a combination of both. Depression was induced in mice by administering dexamethasone (32 mcg/kg) for seven consecutive days. Liraglutide (200 mcg/kg), naringenin (50 mg/kg) and a combination of both were administered either simultaneously or after induction of depression for twenty-eight days. Behavioral and molecular assays were used to assess the progression of depressive symptoms and biomarkers. Liraglutide and naringenin alone or in combination alleviated the depressive behavior in mice, manifested by decrease in anxiety, anhedonia, and despair. Mechanistically, liraglutide and naringenin improved neurogenesis, decreased neuroinflammation and comparably restored the monoamines levels to that of the reference drug escitalopram. The drugs protected mice from developing depression when given simultaneously with dexamethasone. Collectively, the results highlight the usability of liraglutide and naringenin in the treatment of depression in mice and emphasize the different pathways that contribute to the pathogenesis of depression.

Parental exposure to antidepressants has lasting effects on offspring? A case study with zebrafish.

Fish have common neurotransmitter pathways with humans, exhibiting a significant degree of conservation and homology. Thus, exposure to fluoxetine makes fish potentially susceptible to biochemical and physiological changes, similarly to what is observed in humans. Over the years, several studies demonstrated the potential effects of fluoxetine on different fish species and at different levels of biological organization. However, the effects of parental exposure to unexposed offspring remain largely unknown. The consequences of 15-day parental exposure to relevant concentrations of fluoxetine (100 and 1000 ng/L) were assessed on offspring using zebrafish as a model organism. Parental exposure resulted in offspring early hatching, non-inflation of the swimming bladder, increased malformation frequency, decreased heart rate and blood flow, and reduced growth. Additionally, a significant behavioral impairment was also found (reduced startle response, basal locomotor activity, and altered non-associative learning during early stages and a negative geotaxis and scototaxis, reduced thigmotaxis, and anti-social behavior at later life stages). These behavior alterations are consistent with decreased anxiety, a significant increase in the expression of the monoaminergic genes slc6a4a (sert), slc6a3 (dat), slc18a2 (vmat2), mao, tph1a, and th2, and altered levels of monoaminergic neurotransmitters. Alterations in behavior, expression of monoaminergic genes, and neurotransmitter levels persisted until offspring adulthood. Given the high conservation of neuronal pathways between fish and humans, data show the possibility of potential transgenerational and multigenerational effects of pharmaceuticals' exposure. These results reinforce the need for transgenerational and multigenerational studies in fish, under realistic scenarios, to provide realistic insights into the impact of these pharmaceuticals.