Hippocampal PPARα Plays a Role in the Pharmacological Mechanism of Vortioxetine, a Multimodal-Acting Antidepressant.
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ABSTRACT:
SUBMITTER: Wang Y
PROVIDER: S-EPMC8239178 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background and objectiveThe identification and quantification of potential drug-drug interactions is important for avoiding or minimizing the interaction-induced adverse events associated with specific drug combinations. Clinical studies in healthy subjects were performed to evaluate potential pharmacokinetic interactions between vortioxetine (Lu AA21004) and co-administered agents, including fluconazole (cytochrome P450 [CYP] 2C9, CYP2C19 and CYP3A inhibitor), ketoconazole (CYP3A and P-glycoprotein inhibitor), rifampicin (CYP inducer), bupropion (CYP2D6 inhibitor and CYP2B6 substrate), ethinyl estradiol/levonorgestrel (CYP3A substrates) and omeprazole (CYP2C19 substrate and inhibitor).MethodsThe ratio of central values of the test treatment to the reference treatment for relevant parameters (e.g., area under the plasma concentration-time curve [AUC] and maximum plasma concentration [C max]) was used to assess pharmacokinetic interactions.ResultsCo-administration of vortioxetine had no effect on the AUC or C max of ethinyl estradiol/levonorgestrel or 5'-hydroxyomeprazole, or the AUC of bupropion; the 90 % confidence intervals for these ratios of central values were within 80-125 %. Steady-state AUC and C max of vortioxetine increased when co-administered with bupropion (128 and 114 %, respectively), fluconazole (46 and 15 %, respectively) and ketoconazole (30 and 26 %, respectively), and decreased by 72 and 51 %, respectively, when vortioxetine was co-administered with rifampicin. Concomitant therapy was generally well tolerated; most adverse events were mild or moderate in intensity.ConclusionDosage adjustment may be required when vortioxetine is co-administered with bupropion or rifampicin.
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Project description:Current antidepressants still display unsatisfactory efficacy and a delayed onset of therapeutic action. Here we show that the pharmacological blockade of serotonin 7 (5-HT(7)) receptors produced a faster antidepressant-like response than the commonly prescribed antidepressant fluoxetine. In the rat, the selective 5-HT(7) receptor antagonist SB-269970 counteracted the anxiogenic-like effect of fluoxetine in the open field and exerted an antidepressant-like effect in the forced swim test. In vivo, 5-HT(7) receptors negatively regulate the firing activity of dorsal raphe 5-HT neurons and become desensitized after long-term administration of fluoxetine. In contrast with fluoxetine, a 1-week treatment with SB-269970 did not alter 5-HT firing activity but desensitized cell body 5-HT autoreceptors, enhanced the hippocampal cell proliferation, and counteracted the depressive-like behavior in olfactory bulbectomized rats. Finally, unlike fluoxetine, early-life administration of SB-269970, did not induce anxious/depressive-like behaviors in adulthood. Together, these findings indicate that the 5-HT(7) receptor antagonists may represent a new class of antidepressants with faster therapeutic action.
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Project description:In addition to its role as a neuronal energy substrate and signaling molecule involved in synaptic plasticity and memory consolidation, recent evidence shows that lactate produces antidepressant effects in animal models. However, the mechanisms underpinning lactate's antidepressant actions remain largely unknown. In this study, we report that lactate reverses the effects of corticosterone on depressive-like behavior, as well as on the inhibition of both the survival and proliferation of new neurons in the adult hippocampus. Furthermore, the inhibition of adult hippocampal neurogenesis prevents the antidepressant-like effects of lactate. Pyruvate, the oxidized form of lactate, did not mimic the effects of lactate on adult hippocampal neurogenesis and depression-like behavior. Finally, our data suggest that conversion of lactate to pyruvate with the concomitant production of NADH is necessary for the neurogenic and antidepressant effects of lactate.
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Project description:BackgroundFor many patients with major depressive disorder (MDD) adequate treatment remains elusive. Neuroimaging techniques received attention for their potential use in guiding and predicting response, but were rarely investigated in real-world psychiatric settings.AimsTo identify structural and functional Magnetic Resonance Imaging (MRI) biomarkers associated with antidepressant response in a real-world clinical sample.MethodsWe studied 100 MDD inpatients admitted to our psychiatric ward, treated with various antidepressants upon clinical need. Hamilton Depression Rating Scale percentage decrease from admission to discharge was used as a measure of response. All patients underwent 3.0 T MRI scanning. Grey matter (GM) volumes were investigated both in a voxel-based morphometry (VBM), and in a regions of interest (ROI) analysis. In a subsample of patients, functional resting-state connectivity patterns were also explored.ResultsIn the VBM analysis, worse response was associated to lower GM volumes in two clusters, encompassing the left hippocampus and parahippocampal gyrus, and the right superior and middle temporal gyrus. Investigating ROIs, lower bilateral hippocampi and amygdalae volumes predicted worse treatment outcomes. Functional connectivity in the right temporal and parahippocampal gyrus was also associated to response.ConclusionOur results expand existing literature on the relationship between the structure and function of several brain regions and treatment response in MDD. While we are still far from routine use of MRI biomarkers in clinical practice, we confirm a possible role of these techniques in guiding treatment choices and predicting their efficacy.
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Project description:Ketamine has been demonstrated to be a rapid-onset and long-lasting antidepressant, but its underlying molecular mechanisms remain unclear. Recent studies have emerged microRNAs as important modulators for depression treatment. In this study, we report that miR-98-5p is downregulated in the prefrontal cortex and hippocampus of mice subjected to chronic social stress, while overexpressing it by its agonist alleviates depression-like behaviors. More importantly, we demonstrate that miR-98-5p is upregulated by ketamine administration, while inhibition of it by its antagonist blocks the antidepressant effect of ketamine. Our data implicate a novel molecular mechanism underlying the antidepressant effect of ketamine, and that therapeutic strategies targeting miR-98-5p could exert beneficial effects for depression treatment.
| S-EPMC8417029 | biostudies-literature
Project description:Fasting is a physiological stress that elicits well-known metabolic adaptations, however, little is known about the role of stress-responsive tumor suppressors in fasting. Here, we have examined the expression of several tumor suppressors upon fasting in mice. Interestingly, p21 mRNA is uniquely induced in all the tissues tested, particularly in liver and muscle (>10 fold), and this upregulation is independent of p53. Remarkably, in contrast to wild-type mice, p21-null mice become severely morbid after prolonged fasting. The defective adaptation to fasting of p21-null mice is associated to elevated energy expenditure, accelerated depletion of fat stores, and premature activation of protein catabolism in the muscle. Analysis of the liver transcriptome and cell-based assays revealed that the absence of p21 partially impairs the transcriptional program of PPARα, a key regulator of fasting metabolism. Finally, treatment of p21-null mice with a PPARα agonist substantially protects them from their accelerated loss of fat upon fasting. We conclude that p21 plays a relevant role in fasting adaptation through the positive regulation of PPARα.
| S-EPMC5056372 | biostudies-literature
Project description:Current pharmacotherapies for depression exhibit slow onset, side effects and limited efficacy. Therefore, identification of novel fast-onset antidepressants is desirable. GLO1 is a ubiquitous cellular enzyme responsible for the detoxification of the glycolytic byproduct methylglyoxal (MG). We have previously shown that MG is a competitive partial agonist at GABA-A receptors. We examined the effects of genetic and pharmacological inhibition of GLO1 in two antidepressant assay models: the tail suspension test (TST) and the forced swim test (FST). We also examined the effects of GLO1 inhibition in three models of antidepressant onset: the chronic FST (cFST), chronic mild stress (CMS) paradigm and olfactory bulbectomy (OBX). Genetic knockdown of Glo1 or pharmacological inhibition using two structurally distinct GLO1 inhibitors (S-bromobenzylglutathione cyclopentyl diester (pBBG) or methyl-gerfelin (MeGFN)) reduced immobility in the TST and acute FST. Both GLO1 inhibitors also reduced immobility in the cFST after 5 days of treatment. In contrast, the serotonin reuptake inhibitor fluoxetine (FLX) reduced immobility after 14, but not 5 days of treatment. Furthermore, 5 days of treatment with either GLO1 inhibitor blocked the depression-like effects induced by CMS on the FST and coat state, and attenuated OBX-induced locomotor hyperactivity. Finally, 5 days of treatment with a GLO1 inhibitor (pBBG), but not FLX, induced molecular markers of the antidepressant response including brain-derived neurotrophic factor (BDNF) induction and increased phosphorylated cyclic-AMP response-binding protein (pCREB) to CREB ratio in the hippocampus and medial prefrontal cortex (mPFC). Our findings indicate that GLO1 inhibitors may provide a novel and fast-acting pharmacotherapy for depression.
| S-EPMC5608625 | biostudies-literature
Project description:The dentate gyrus (DG) of the hippocampus is one of major targets for antidepressant treatments. Our recent research has revealed that selective serotonin reuptake inhibitor (SSRI) treatment causes a long-lasting change in the phenotypes of mature dentate granule neurons to immature state in adult mouse DG. However, it is unknown whether this M-bM-^@M-^\dematurationM-bM-^@M-^] of DG is a common effect of antidepressant treatments and what mechanisms underlie it. Using electroconvulsive stimulation (ECS), a model of highly effective and fast-acting antidepressant therapy, here we show that neural stimulation via ECS induces rapid and lasting dematuration of granule neurons in DG. A single or few times of stimulation transiently reduced mature marker expression and mature synaptic functions. Repetitive stimulation converted this transient dematuration into a stable form lasting more than 1 month. Dematured granule neurons showed higher excitability, and an increase in GABA-mediated inhibition by the benzodiazepine diazepam prevented the lasting maintenance phase of dematuration without affecting the initial induction phase. Our study suggests that dematuration of DG is a common cellular mechanism underlying effects of different types of antidepressant treatments, and demonstrate a novel role for excitation/inhibition balance in bidirectional regulation of the state of neuronal maturation in the adult brain. Mice were decapitated after the 11 times of ECS (or Sham) or 4 weeks treatment of fluoxetine (or vehicle) at a dose of 22 mg/kg. The brains were sliced and the frequency facilitation of mossy fiber synapse was measured in each sample. The samples which exhibited low frequency facilitation were selected to be used as dematured DG (n = 3) and the dentate gyrus was dissected from each sample. Total RNA was extracted by using an RNeasy micro kit (Qiagen) and the samples of the same groups were put together. From each group, 100 ng of total RNA was amplified with 3M-bM-^@M-^YIVT Express kit (Affymetrix, Inc., Santa Clara, CA, USA). All samples were hybridized to the GeneChip mouse genome 430A 2.0 array (Affymetrix, Inc.), and the microarray suite 5.0 of the Affymetrix gene chip operating software was used for the analysis of the GeneChip data.
2014-04-01 | E-GEOD-54307 | biostudies-arrayexpress
Project description:How rapid-acting antidepressants (RAADs), such as ketamine, induce immediate and sustained improvements in mood in patients with major depressive disorder (MDD) is poorly understood. A core feature of MDD is the prevalence of cognitive processing biases associated with negative affective states, and the alleviation of negative affective biases may be an index of response to drug treatment. Here, we used an affective bias behavioral test in rats, based on an associative learning task, to investigate the effects of RAADs. To generate an affective bias, animals learned to associate two different digging substrates with a food reward in the presence or absence of an affective state manipulation. A choice between the two reward-associated digging substrates was used to quantify the affective bias generated. Acute treatment with the RAADs ketamine, scopolamine, or psilocybin selectively attenuated a negative affective bias in the affective bias test. Low, but not high, doses of ketamine and psilocybin reversed the valence of the negative affective bias 24 hours after RAAD treatment. Only treatment with psilocybin, but not ketamine or scopolamine, led to a positive affective bias that was dependent on new learning and memory formation. The relearning effects of ketamine were dependent on protein synthesis localized to the rat medial prefrontal cortex and could be modulated by cue reactivation, consistent with experience-dependent neural plasticity. These findings suggest a neuropsychological mechanism that may explain both the acute and sustained effects of RAADs, potentially linking their effects on neural plasticity with affective bias modulation in a rodent model.
| S-EPMC7615567 | biostudies-literature
Project description:Mood disorders are recurrent/chronic diseases with variable clinical remission rates. Available antidepressants are not effective in all patients and often show a relevant response latency, with a range of adverse events, including weight gain and sexual dysfunction. Novel rapid agents were developed with the aim of overcoming at least in part these issues. Novel drugs target glutamate, gamma-aminobutyric acid, orexin, and other receptors, providing a broader range of pharmacodynamic mechanisms, that is, expected to increase the possibility of personalizing treatments on the individual clinical profile. These new drugs were developed with the aim of combining a rapid action, a tolerable profile, and higher effectiveness on specific symptoms, which were relatively poorly targeted by standard antidepressants, such as anhedonia and response to reward, suicidal ideation/behaviours, insomnia, cognitive deficits, and irritability. This review discusses the clinical specificity profile of new antidepressants, namely 4-chlorokynurenine (AV-101), dextromethorphan-bupropion, pregn-4-en-20-yn-3-one (PH-10), pimavanserin, PRAX-114, psilocybin, esmethadone (REL-1017/dextromethadone), seltorexant (JNJ-42847922/MIN-202), and zuranolone (SAGE-217). The main aim is to provide an overview of the efficacy/tolerability of these compounds in patients with mood disorders having different symptom/comorbidity patterns, to help clinicians in the optimization of the risk/benefit ratio when prescribing these drugs.
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