Antidepressant Efficacy Research Articles

Antidepressant Sertraline Synergistically Enhances Paclitaxel Efficacy by Inducing Autophagy in Colorectal Cancer Cells.

Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. It is important to discover new therapeutic regimens for treating CRC. Depression is known to be an important complication of cancer diseases. Repurposing antidepressants into anticancer drugs and exploring the combinational efficacy of antidepressants and chemotherapy are potentially good options for developing CRC treatment regimens. In this study, sertraline, an antidepressant drug, and paclitaxel, an anticancer drug, were chosen to study their antitumor effects in the treatment of colorectal cancer, alone or in combination, and to explore their underlying mechanisms. The data showed that sertraline exerted a dose-dependent cytotoxic effect on MC38 and CT26 colorectal cancer cell lines with IC50 values of 10.53 μM and 7.47 μM, respectively. Furthermore, sertraline synergistically sensitized chemotherapeutic agent paclitaxel efficacy in CRC cells with combination index (CI) values at various concentrations consistently lower than 1. Sertraline remarkably augmented paclitaxel-induced autophagy by increasing autophagosome formation indicated by elevated LC3-II/I ratio and promoting autophagic flux by degrading autophagy cargo receptor SQSTM1/p62, which may explain the synergistically cytotoxic effect of sertraline and paclitaxel combination therapy on CRC cells. This study provides important evidence to support repurposing sertraline as an anticancer agent and suggests a novel combinational regimen for effectively treating CRC as well as in the simultaneous treatment of CRC and depression.

Preliminary Investigation Into the Antidepressant Effects of a Novel Curcumin Analogue (CACN136) In Vitro and In Vivo.

The aim of this study was to develop a novel antidepressant with high activity. Based on the findings of molecular docking, eight novel curcumin analogues were evaluated in vitro to check for antidepressant efficacy. Among them, CACN136 had the strongest antidepressant effect. Firstly, CACN136 had a stronger 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonate) radical ion scavenging ability (IC50: 17.500 ± 0.267μg/mL) compared to ascorbic acid (IC50: 38.858 ± 0.263μg/mL) and curcumin (27.189 ± 0.192μg/mL). Secondly, only CACN136 demonstrated clear protective effects on cells damaged by glutamate and oxidative stress at all concentrations. Finally, only CACN136 showed ASP + inhibition and was more effective than fluoxetine hydrochloride (FLU) at low concentrations. To further confirm the antidepressant effect of CACN136 in vivo, the CUMS model was established. Following 28days of oral administration of CUMS mice, CACN136 increased the central area residence time in the open-field test, significantly increased the sucrose preference rate in the sucrose preference test (P < 0.001) and significantly reduced the immobility period in the tail suspension test (P < 0.0001), all of which were more effective than those of FLU. Subsequent research indicated that the antidepressant properties of CACN136 were linked to a decrease in the metabolism of5-HT and the modulation of oxidative stress levels in vivo. In particular, the activation of the Keap1-Nrf2/BDNF-TrkB signaling pathway by CACN136 resulted in elevated levels of antioxidant enzymes, enhancing the antioxidant capability in mice subjected to CUMS. In conclusion, CACN136 has the potential to treat depression and could be an effective antidepressant.

Antidepressant effects of selective adenosine receptor antagonists targeting the A1 and A2A receptors administered jointly with NMDA receptor ligands: behavioral, biochemical and molecular investigations in mice

BackgroundThe objective of the study was to ascertain the antidepressant potential of the co-administration of NMDA receptor ligands and selective adenosine A1 and A2A receptor antagonists.MethodsThe forced swim test (FST) and spontaneous locomotor activity test were carried out in adult male naïve mice. Before the behavioral testing, animals received DPCPX (a selective adenosine A1 receptor antagonist, 1 mg/kg) or istradefylline (a selective adenosine A2A receptor antagonist, 0.5 mg/kg) in combination with L–701,324 (a potent NMDA receptor antagonist, 1 mg/kg), D–cycloserine (a partial agonist at the glycine recognition site of NMDA receptor, 2.5 mg/kg), CGP 37849 (a competitive NMDA receptor antagonist, 0.3 mg/kg) or MK–801 (a non-competitive NMDA receptor antagonist, 0.05 mg/kg). Additionally, serum BDNF level and the mRNA level of the Adora1, Comt, and Slc6a15 genes in the murine prefrontal cortex were determined.ResultsThe obtained results showed that DPCPX and istradefylline administered jointly with NMDA receptor ligands (except for DPCPX + D–cycloserine combination) produced an antidepressant effect in the FST in mice without enhancement in spontaneous motility of animals. An elevation in BDNF concentration was noted in the D–cycloserine-treated group. Adora1 expression increased with L–701,324, DPCPX + D–cycloserine, and DPCPX + CGP 37849, while D–cycloserine, CGP 37849, and MK–801 led to a decrease. Comt mRNA levels dropped with DPCPX + L–701,324, istradefylline + L–701,324/CGP 37849 but increased with D–cycloserine, MK–801, CGP 37849 and DPCPX + MK–801/ CGP 37849. Slc6a15 levels were reduced by D–cycloserine, DPCPX + L–701,324 but rose with DPCPX + CGP 37849/MK–801 and istradefylline + D–cycloserine/MK–801/CGP 37849.ConclusionOur study suggests that selective antagonists of adenosine receptors may enhance the antidepressant efficacy of NMDA receptor ligands highlighting a potential synergistic interaction between the adenosinergic and glutamatergic systems. Wherein, A2A receptor antagonists are seen as more promising candidates in this context. Given the intricate nature of changes in BDNF levels and the expression of Adora1, Comt, and Slc6a15 seen after drug combinations exerting antidepressant properties, further research and integrative approaches are crucial understand better the mechanisms underlying their antidepressant action.

PH-Sensitive In Situ Gel of Mirtazapine Invasomes for Rectal Drug Delivery: Protruded Bioavailability and Anti-Depressant Efficacy.

The present research emphasizes fabrication alongside the assessment of an innovative nano-vesicular membranous system known as invasomes (NVMs) laden with Mirtazapine for rectal administration. This system could circumvent the confines of orally administered counterparts regarding dose schedules and bioavailability. Mirtazapine invasomes were tailored by amalgamating phospholipid, cineole, and ethanol through a thin-film hydration approach rooted in the Box-Behnken layout. Optimization of composition parameters used to fabricate desired NVMs' physicochemical attributes was undertaken using the Design-Expert® program. The optimal MRZ-NVMs were subsequently transformed to a pH-triggered in situ rectal gel followed by animal pharmacodynamic and pharmacokinetic investigations relative to rectal plain gel and oral suspension. The optimized NVMs revealed a diameter size of 201.3 nm, a z potential of -28.8 mV, an entrapment efficiency of 81.45%, a cumulative release within 12 h of 67.29%, and a cumulative daily permeated quantity of 468.68 µg/cm2. Compared to the oral suspension, pharmacokinetic studies revealed a 2.85- and 4.45-fold increase in calculated rectal bioavailability in circulation and brain, respectively. Pharmacodynamic and immunohistopathology evaluations exposed superior MRZ-NVMs attributed to the orally administered drug. Consequently, rectal MRZ-NVMs can potentially be regarded as a prospective nanoplatform with valuable pharmacokinetics and tolerability assets.

A randomised, open-label, pragmatic pilot comparison of oral and intravenous ketamine in treatment-resistant depression

BackgroundFor depression, ketamine is more conveniently administered by oral than by intravenous (iv) routes. The relative antidepressant efficacy of oral vs iv ketamine is unknown. ObjectivesTo assess the acute efficacy and the persistence of improvement with open-label oral versus iv ketamine in outpatients with treatment-resistant depression (TRD). MethodsAdults with TRD were randomized to oral (N=30) or IV (N=31) ketamine. Oral ketamine was dosed at 150 mg in 50 mL of water, sipped across 15 min. IV ketamine was dosed at 0.5 mg/kg, infused across 40 min. Ketamine sessions (total, 7) were administered on alternate days for 2 weeks. Ongoing antidepressant drugs were continued unchanged. Patients were assessed at baseline, day 14, and day 30. The primary outcome was the endpoint Hamilton Rating Scale for Depression score on day 14. Secondary outcomes were endpoint scores on the Montgomery-Asberg Depression Rating Scale, Beck Depression Inventory, and Clinical Global Impression-Severity of Illness and Improvement. ResultsOverall dropout was lower with oral than with iv ketamine (26.7 % vs 54.8 %; P=0.03). The 2 groups did not differ in depression ratings and in response and remission rates on all instruments on both days 14 and 30. Adverse events such as headache (56.7 % vs 74.2 %) and drowsiness (0.0 % vs 22.6 %) were less common with oral ketamine. ConclusionIn TRD outpatients treated in general hospitals, oral ketamine maybe better accepted and tolerated than iv ketamine. Conclusions about relative efficacy cannot be drawn because of the high dropout rate with iv ketamine.

The Impact of Antidepressants on Gut Microbiome and Depression Management

Depression is a widespread psychiatric disorder that significantly impacts an individual’s quality of life. It affects mental and emotional well-being and has far-reaching consequences on their physical health, relationships, and overall ability to function in daily life. Recent advances in psychiatric research have revealed a connection between the gut-brain axis, a bidirectional communication system linking the brain's emotional and cognitive centers with intestinal functions. Antidepressants, including selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs), are commonly prescribed to alleviate symptoms of depression. However, their influence extends beyond neurotransmitter modulation in the brain to significant effects on gastrointestinal physiology. Antidepressants can alter gut motility, secretion, and microbiota composition, which in turn can influence mood and mental health. This review aims to provide insights into the impact of antidepressants on gut health and their implications for depression treatment. Additionally, it explores the potential of probiotics as an adjunct treatment to enhance the efficacy of antidepressants and mitigate gastrointestinal side effects. Restoring healthy gut microbiota can improve gastrointestinal and mental health outcomes, suggesting a promising avenue for integrated therapeutic approaches.

Metabolic activity of CYP2C19 and CYP2D6 on antidepressant response from 13 clinical studies using genotype imputation: a meta-analysis

Cytochrome P450 enzymes including CYP2C19 and CYP2D6 are important for antidepressant metabolism and polymorphisms of these genes have been determined to predict metabolite levels. Nonetheless, more evidence is needed to understand the impact of genetic variations on antidepressant response. In this study, individual clinical and genetic data from 13 studies of European and East Asian ancestry populations were collected. The antidepressant response was clinically assessed as remission and percentage improvement. Imputed genotype was used to translate genetic polymorphisms to metabolic phenotypes (poor, intermediate, normal, and rapid+ultrarapid) of CYP2C19 and CYP2D6. CYP2D6 structural variants cannot be imputed from genotype data, limiting the determination of metabolic phenotypes, and precluding testing for association with response. The association of CYP2C19 metabolic phenotypes with treatment response was examined using normal metabolizers as the reference. Among 5843 depression patients, a higher remission rate was found in CYP2C19 poor metabolizers compared to normal metabolizers at nominal significance but did not survive after multiple testing correction (OR = 1.46, 95% CI [1.03, 2.06], p = 0.033, heterogeneity I2 = 0%, subgroup difference p = 0.72). No metabolic phenotype was associated with percentage improvement from baseline. After stratifying by antidepressants primarily metabolized by CYP2C19, no association was found between metabolic phenotypes and antidepressant response. Metabolic phenotypes showed differences in frequency, but not effect, between European- and East Asian-ancestry studies. In conclusion, metabolic phenotypes imputed from genetic variants using genotype were not associated with antidepressant response. CYP2C19 poor metabolizers could potentially contribute to antidepressant efficacy with more evidence needed. Sequencing and targeted pharmacogenetic testing, alongside information on side effects, antidepressant dosage, depression measures, and diverse ancestry studies, would more fully capture the influence of metabolic phenotypes.

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 h 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 h post-injection (t24 h), 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.

The effects of brain serotonin deficiency on the behavioral and neurogenesis-promoting effects of voluntary exercise in tryptophan hydroxylase 2 (R439H) knock-in mice

Exercise is known to reduce depression and anxiety symptoms. Although the cellular and molecular mechanisms underlying this effect remain unknown, exercise-induced increases in neurotransmitter release and hippocampal neurogenesis have been hypothesized to play key roles. One neurotransmitter that has been implicated in both antidepressant-like effects and the regulation of hippocampal neurogenesis is serotonin (5-HT). Complete loss of function of the brain 5-HT synthesis enzyme (tryptophan hydroxylase 2, Tph2) has been reported to prevent exercise-induced increases in neurogenesis and to block a subset of antidepressant-like responses to selective serotonin reuptake inhibitors (SSRIs), but whether partial loss of Tph2 function blocks the behavioral and neurogenic effects of exercise has not been established. This study used four tests that are predictive of antidepressant efficacy to determine the impact of 5-HT deficiency on responses to exercise in male and female mice. Our results demonstrate that low 5-HT impairs the behavioral effects of exercise in females in the forced swim and novelty-suppressed feeding tests. However, genetic reductions in 5-HT synthesis did not significantly impact exercise-induced alterations in cellular proliferation or immature neuron production in the hippocampus in either sex. These findings highlight the importance of brain 5-HT in mediating behavioral responses to exercise and suggest that individual differences in brain 5-HT synthesis could influence sensitivity to the mental health benefits of exercise. Furthermore, the observed disconnect between neurogenic and behavioral responses to exercise suggests that increased neurogenesis is unlikely to be the primary driver of the behavioral effects of exercise observed here.

Establishment of a predictive model for antidepressant efficacy based on machine learning

Establishment of a predictive model for antidepressant efficacy based on machine learning

Sex-specific GABAergic microcircuits that switch vulnerability into resilience to stress and reverse the effects of chronic stress exposure.

Clinical and preclinical studies have identified somatostatin (SST)-positive interneurons as key elements that regulate the vulnerability to stress-related psychiatric disorders. Conversely, disinhibition of SST neurons in mice results in resilience to the behavioral effects of chronic stress. Here we established a low-dose chronic chemogenetic protocol to map these changes in positively and negatively motivated behaviors to specific brain regions. AAV-hM3Dq mediated chronic activation of SST neurons in the prelimbic cortex (PLC) had antidepressant drug-like effects on anxiety- and anhedonia-related motivated behaviors in male but not female mice. Analogous manipulation of the ventral hippocampus (vHPC) had such effects in female but not male mice. Moreover, activation of SST neurons in the PLC of male and the vHPC of female mice resulted in stress resilience. Activation of SST neurons in the PLC reversed prior chronic stress-induced defects in motivated behavior in males but was ineffective in females. Conversely, activation of SST neurons in the vHPC reversed chronic stress-induced behavioral alterations in females but not males. Quantitation of c-Fos+ and FosB+ neurons in chronic stress-exposed mice revealed that chronic activation of SST neurons leads to a paradoxical increase in pyramidal cell activity. Collectively, these data demonstrate that GABAergic microcircuits driven by dendrite targeting interneurons enable sex- and brain-region-specific neural plasticity that promotes stress resilience and reverses stress-induced anxiety- and anhedonia-like motivated behavior. Our studies provide a mechanistic rationale for antidepressant efficacy of dendrite-targeting, low-potency GABAA receptor agonists, independent of sex and despite striking sex differences in the relevant brain substrates.

Neural Circuit Mechanisms of Sinisan formula for the Treatment of adolescent Depression: prefrontal cortex to dorsal raphe nucleus

Ethnopharmacological relevanceSinisan formula (SNSF), documented in the classic books Shanghan Lun, is known for its ability to regulate liver-qi and treat depression. However, its underlying mechanism, particularly its effects on dynamic real-time neuron activity and circuits remains to be fully elucidated. Aim of the studyThis study aimed to investigate the antidepressant effect of SNSF and its central nervous system mechanism on depression-like behaviors, focusing on the prefrontal cortex (PFC) to dorsal raphe nucleus (DRN) neural circuit in a stress-induced adolescent animal model. Materials and methodsSNSF comprised four herbs, the root of Bupleurum chinense DC., the root of Paeonia lactiflora Pall., the fruit of Citrus aurantium L., the rhizome of Glycyrrhiza uralensis Fisch., in equal propotions. The adolescent depression animal model was induced by maternal separation (MS) and chronic restraint stress (CRS). In-vivo multichannel physiological electrodes were implanted into the PFC on PND 28 and animals were recorded 5 times during PND 35–46. From PND 47, the behavioral tests were performed to evaluate the antidepressant efficacy of SNSF. Subsequently, brain tissue was collected for Western blot and immunofluorescence staining analysis. Retro virus was injected into the DRN to explore sources of projections received by serotonergic (5-HTergic) neurons. And the PFC-to-DRN circuit was activated or inhibited through chemogenetic techniques to investigate the effects of SNSF on depression-like behaviors. ResultsAdministration of SNSF for 18 days effectively alleviated depression-like behaviors in MS&CRS adolescent mice. The PFC emerged as the primary glutamatergic projection source of the DRN5−HT neurons. Following SNSF administration for 13/15/18 days, there was an increase in the firing rate of excitatory neurons and excitatory/inhibitory (E/I) ratio in the PFC. MS&CRS stress let to a reduction in the density of 5-HT+ and CaMKII + neurons in the DRN, accompanied by an increase in the density of GAD + neurons in the DRN, while SNSF administration reversed the alterations. Chemogenetic activation of the PFC-to-DRN circuit rescued the depression-like behaviors induced by MS&CRS, whereas suppression of this circuit attenuated the antidepressant effect of SNSF. ConclusionsSNSF significantly mitigated depression-like behaviors in MS&CRS mice. SNSF exerts its antidepressant effects by increasing the E/I ratio in the PFC and enhancing glutamatergic projections from the PFC to the DRN.

Impact of vortioxetine on depressive symptoms moderated by symptoms of anxiety in persons with post-COVID-19 condition: A secondary analysis

ObjectiveRecovery from a COVID-19 infection can lead to post-COVID-19 condition (PCC), which causes a multitude of debilitating symptoms that negatively affect an individual's health-related quality of life, including depressive and anxiety symptoms. We aim to examine the mediatory effects of anxiety on depressive symptoms in persons with PCC receiving vortioxetine. MethodsWe performed a post-hoc analysis of a randomized, double-blinded, placebo-controlled clinical trial investigating vortioxetine treatment on cognitive functioning in persons with PCC. Anxiety and depressive symptoms were measured by the 7-Item Generalized Anxiety Disorder (GAD-7) Scale and the 16-Item Quick Inventory of Depressive Symptomatology (QIDS-SR-16), respectively. ResultsBased on data of 147 participants, GAD-7 scores were significantly positively associated with QIDS-SR-16 scores (β=0.038, 95 % CI [0.029,0.047], p < 0.001). After adjusting for covariates, a significant group (χ2=176.786, p < 0.001), time (χ2=8.914, p = 0.003), and treatment x time x GAD-7 score interaction (χ2=236.483, p < 0.001) effect was observed. Vortioxetine-treated participants had a significant difference in overall change in depressive symptoms (mean difference=-3.15, SEM=0.642, 95 % CI [-4.40,-1.89], p < 0.001). ConclusionAnxiety symptoms were significantly associated with depressive symptoms in persons with PCC. Antidepressant efficacy on ameliorating depressive symptoms is dependent on improving anxiety symptoms, underscoring significant implications in improving treatment efficacy and patient quality of life.

Optimizing and Predicting Antidepressant Efficacy in Patients with Major Depressive Disorder Using Multi-Omics Analysis and the Opade AI Prediction Tools.

According to the World Health Organization (WHO), major depressive disorder (MDD) is the fourth leading cause of disability worldwide and the second most common disease after cardiovascular events. Approximately 280 million people live with MDD, with incidence varying by age and gender (female to male ratio of approximately 2:1). Although a variety of antidepressants are available for the different forms of MDD, there is still a high degree of individual variability in response and tolerability. Given the complexity and clinical heterogeneity of these disorders, a shift from "canonical treatment" to personalized medicine with improved patient stratification is needed. OPADE is a non-profit study that researches biomarkers in MDD to tailor personalized drug treatments, integrating genetics, epigenetics, microbiome, immune response, and clinical data for analysis. A total of 350 patients between 14 and 50 years will be recruited in 6 Countries (Italy, Colombia, Spain, The Netherlands, Turkey) for 24 months. Real-time electroencephalogram (EEG) and patient cognitive assessment will be correlated with biological sample analysis. A patient empowerment tool will be deployed to ensure patient commitment and to translate patient stories into data. The resulting data will be used to train the artificial intelligence/machine learning (AI/ML) predictive tool.

Efficacy and safety of perioperative application of esketamine on postoperative depression: a meta-analysis of randomized controlled studies.

Postoperative depression has a profound impact on patients' postoperative rehabilitation and overall quality of life. Preventing postoperative depression is of significant value because conventional antidepressants have a slow onset of action. Esketamine showed prompt and sustained antidepressant efficacy. Nevertheless, the safety and effectiveness of perioperative esketamine in preventing postoperative depression are still unknown. The purpose of this meta-analysis was to assess the safety and effectiveness of perioperative intravenous esketamine in relation to its ability to prevent postoperative depression. Randomized controlled trials were searched in the following databases: Web of Science, Cochrane Central Registry of Controlled Trials, PubMed, and Embase. The primary outcome assessed is the postoperative depression scores. Postoperative pain ratings and adverse effects constituted secondary outcomes. Subgroup analyses were carried out on the basis of multiple variables, including the absence or presence of preoperative depression, the mode of esketamine administration, the dosage of esketamine, and the type of anesthesia. A total of 16 studies encompassed 1161 patients who received esketamine intervention, whereas 1106 patients served as controls. Esketamine was efficacious in reducing postoperative depression scores when administered perioperatively, and the esketamine group maintained a lower postoperative depression score than the control group more than four weeks after surgery. Esketamine effectively alleviated postoperative pain scores without increasing the occurrence of postoperative nausea and vomiting, dizziness, drowsiness, nightmares, and dissociation. The administration of esketamine during the perioperative has the potential to decrease postoperative depression and pain scores without increasing the incidence of adverse effects.

Efficacy and dose-response relationships of antidepressants in the acute treatment of major depressive disorders: a systematic review and network meta-analysis.

The optimal antidepressant dosages remain controversial. This study aimed to analyze the efficacy of antidepressants and characterize their dose-response relationships in the treatments of major depressive disorders (MDD). We searched multiple databases, including the Embase, Cochrane Central Register of Controlled Trials, PubMed, and Web of Science, for the studies that were conducted between January 8, 2016, and April 30, 2023. The studies are double-blinded, randomized controlled trials (RCTs) involving the adults (≥18years) with MDD. The primary outcomes were efficacy of antidepressant and the dose-response relationships. A frequentist network meta-analysis was conducted, treating participants with various dosages of the same antidepressant as a single therapy. We also implemented the model-based meta-analysis (MBMA) using a Bayesian method to explore the dose-response relationships. The network meta-analysis comprised 135,180 participants from 602 studies. All the antidepressants were more effective than the placebo; toludesvenlafaxine had the highest odds ratio (OR) of 4.52 (95% confidence interval [CI]: 2.65-7.72), and reboxetine had the lowest OR of 1.34 (95%CI: 1.14-1.57). Moreover, amitriptyline, clomipramine, and reboxetine showed a linear increase in effect size from low to high doses. The effect size of toludesvenlafaxine increased significantly up to 80mg/day and subsequently maintained the maximal dose up to 160mg/day while the predictive curves of nefazodone were fairly flat in different dosages. Although most antidepressants were more efficacious than placebo in treating MDD, no consistent dose-response relationship between any antidepressants was observed. For most antidepressants, the maximum efficacy was achieved at lower or middle prescribed doses, rather than at the upper limit.

Antidepressants in the acute treatment of post-traumatic stress disorder in adults: a systematic review and meta-analysis.

Currently, there are few pharmacotherapy options for clinicians treating post-traumatic stress disorder (PTSD), and antidepressants are usually the medication of choice. This meta-analysis aimed to review the efficacy of antidepressants in the acute treatment of PTSD in adults while investigating the contribution of study design and placebo response to the findings of these studies. Randomized, double-blind, placebo-controlled clinical trials that compared antidepressants with placebo for acute treatment of PTSD were selected. Standardized mean difference (SMD) in change in Clinician-Administered PTSD Scale scores were pooled after examining for heterogeneity. A random-effects meta-analysis was performed. Twenty-nine antidepressant-placebo comparisons, involving 4575 subjects, were analyzed. The SMD among all studies was 0.25, a small to medium effect size, lower than that in studies of antidepressants in adult major depressive disorder. The SMDs for low and high mean placebo responses, were 0.27 and 0.22, respectively. The overall SMD for paroxetine studies was in the moderate range (0.43) and that for sertraline studies was in the small range (0.12). Our findings suggest that antidepressants have modest efficacy in alleviating PTSD symptoms. Patient-level meta-analyses are required to further explore the potential clinical relevance of sertraline for PTSD.

Genetic ablation of the isoform γ of PI3K decreases antidepressant efficacy of ketamine in male mice

About one-third of major depressive disorder (MDD) patients demonstrate unresponsiveness to classic antidepressants, and even the clinical efficacy of fast-acting drugs such as ketamine varies significantly among patients with treatment-resistant depression. Nevertheless, the lack of suitable animal models that mimic a possible ketamine-resistant phenotype challenges the understanding of resistance to drug treatment. In this study, we showed that PI3Kγ knock-out (KO) mice do not respond to classical doses of ketamine and classical antidepressants. PI3Kγ KO mice were unresponsive to both the rapid and sustained antidepressant-like effects of a single dose of ketamine in the forced swimming test. Additionally, they were unresponsive to the antidepressant-like effects induced by the tricyclic antidepressant imipramine and the selective serotonin reuptake inhibitor fluoxetine. However, acute pharmacological inhibition of PI3Kγ did not block the antidepressant-like effect of ketamine, showing that a chronic deficiency of the PI3Kγ-mediated pathway is necessary for the effects of classic doses of ketamine and antidepressants. Therefore, we propose that PI3Kγ participates in the antidepressant activity and is likely implicated in the neurobiology and phenotype observed in patients with MDD who demonstrate treatment resistance.

The N-methyl-d-aspartate receptor hypothesis of ketamine's antidepressant action: evidence and controversies.

Substantial clinical evidence has unravelled the superior antidepressant efficacy of ketamine: in comparison to traditional antidepressants targeting the monoamine systems, ketamine, as an N-methyl-d-aspartate receptor (NMDAR) antagonist, acts much faster and more potently. Surrounding the antidepressant mechanisms of ketamine, there is ample evidence supporting an NMDAR-antagonism-based hypothesis. However, alternative arguments also exist, mostly derived from the controversial clinical results of other NMDAR inhibitors. In this article, we first summarize the historical development of the NMDAR-centred hypothesis of rapid antidepressants. We then classify different NMDAR inhibitors based on their mechanisms of inhibition and evaluate preclinical as well as clinical evidence of their antidepressant effects. Finally, we critically analyse controversies and arguments surrounding ketamine's NMDAR-dependent and NMDAR-independent antidepressant action. A better understanding of ketamine's molecular targets and antidepressant mechanisms should shed light on the future development of better treatment for depression. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Effect of oral tryptamines on the gut microbiome of rats—a preliminary study

Background Psilocybin and related tryptamines have come into the spotlight in recent years as potential therapeutics for depression. Research on the mechanisms of these effects has historically focused on the direct effects of these drugs on neural processes. However, in addition to such neural effects, alterations in peripheral physiology may also contribute to their therapeutic effects. In particular, substantial support exists for a gut microbiome-mediated pathway for the antidepressant efficacy of other drug classes, but no prior studies have determined the effects of tryptamines on microbiota. Methods To address this gap, in this preliminary study, male Long Evans rats were treated with varying dosages of oral psilocybin (0.2 or 2 mg/kg), norbaeocystin (0.25 or 2.52 mg/kg), or vehicle and their fecal samples were collected 1 week and 3 weeks after exposure for microbiome analysis using integrated 16S ribosomal DNA sequencing to determine gut microbiome composition. Results We found that although treatment with neither psilocybin nor norbaeocystin significantly affected overall microbiome diversity, it did cause significant dose- and time-dependent changes in bacterial abundance at the phylum level, including increases in Verrucomicrobia and Actinobacteria, and decreases in Proteobacteria. Conclusion and Implications These preliminary findings support the idea that psilocybin and other tryptamines may act on the gut microbiome in a dose- and time-dependent manner, potentially identifying a novel peripheral mechanism for their antidepressant activity. The results from this preliminary study also suggest that norbaeocystin may warrant further investigation as a potential antidepressant, given the similarity of its effects to psilocybin.