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Ecotoxicology and Environmental Safety Aug 2023Mirtazapine is a commonly prescribed antidepressant and has been found widespread in aquatic environments. However, its toxicities to aquatic organisms has rarely been...
Mirtazapine is a commonly prescribed antidepressant and has been found widespread in aquatic environments. However, its toxicities to aquatic organisms has rarely been explored. Herein, we conducted a comprehensive study on the developmental effects of mirtazapine on early life stages of zebrafish at environmentally relevant concentrations (3.9 ng/L and 43.5 ng/L). Out of the endpoints measured, spontaneous contraction of embryos at 24 h post fertilization (hpf) and hatching rate and heart rate of embryos at 50 hpf and 56 hpf, respectively, were significantly affected. In light-dark transition behavior test, mirtazapine significantly reduced the swimming frequency and swimming speed of embryos at both concentrations of 3.9 ng/L and 43.5 ng/L. Furthermore, the total swimming distances in dark conditions were also significantly reduced. Transcriptomic analysis was further conducted. It demonstrated that the decreased neural activities in embryos may be associated with altered epinephrine and neuregulin signaling. The present results fill a data gap regarding the exposure of fish to mirtazapine at environmentally relevant concentrations and provide new insights into the neurotoxic mechanisms of mirtazapine exposure.
PubMed: 37567106
DOI: 10.1016/j.ecoenv.2023.115335 -
Cancers Jul 2023This study compared mirtazapine with megestrol in the management of cancer-related anorexia-cachexia syndrome in patients with advanced cancer. A randomized,...
Mirtazapine versus Megestrol in the Treatment of Anorexia-Cachexia Syndrome in Patients with Advanced Cancer: A Randomized, Double-Blind, Controlled Phase II Clinical Trial.
This study compared mirtazapine with megestrol in the management of cancer-related anorexia-cachexia syndrome in patients with advanced cancer. A randomized, double-blind, controlled clinical trial involving patients with advanced cancer and anorexia-cachexia syndrome was performed. Participants received mirtazapine 30 mg/day or megestrol 320 mg/day for eight weeks. The primary endpoint was the effect of mirtazapine on weight gain and the secondary endpoints were its effect on appetite, muscle strength, physical performance, body composition, adverse events, and medication adherence. Linear regression model with mixed effects was applied and a significance level of 5% was adopted. Fifty-two patients were randomized. Mean age was 65.8 ± 8.4 years. There was weight gain in 52% of the participants in the megestrol group and in 38% in the mirtazapine group after four weeks ( = 0.040). Appetite improved in 92% of the participants in the megestrol group and in 56% in the mirtazapine group after eight weeks ( = 0.007). In the sub-analysis by sex, women showed improvement in appetite ( < 0.001) and weight gain ( < 0.005) in the mirtazapine group, which was not observed in men. Mirtazapine appears to be inferior to megestrol in weight and appetite improvement. However, there may be a difference in the therapeutic response between sexes.
PubMed: 37509249
DOI: 10.3390/cancers15143588 -
Ecotoxicology and Environmental Safety Sep 2023A novel method for simultaneous separation and detection of the racemates and the enantiomers of common chiral antidepressants in wastewater matrix was developed by...
Simultaneous separation and determination of several chiral antidepressants and their enantiomers in wastewater by online heart-cutting two-dimensional liquid chromatography.
A novel method for simultaneous separation and detection of the racemates and the enantiomers of common chiral antidepressants in wastewater matrix was developed by online heart-cutting two-dimensional liquid chromatography (2D-LC) coupled to solid-phase extraction (SPE). Screening of chiral stationary phases (CSPs) and chromatographic conditions was investigated for complete enantioseparation to be compatible with RP-HPLC in 1st D-LC. Using methanol-0.1 % (v/v) ammonia solution as mobile phase, a 2D-LC system was configured by reversed mode with a combination of C18 column and the serially CPS columns as 2D-LC stationary phases respectively. The target analytes could achieve satisfactory transformation between 2D-LCs with transfer rate of 90.57-98.58 %. By means of freeze-drying and SPE, three antidepressants in wastewater were greatly preconcentrated under the optimized conditions, improving the method performance. The racemates and the enantiomers of mirtazapine, bupropion and fluoxetine exhibited good linearity in the range of 0.10-30.00 ng/mL (R≥0.9986), and LODs and LOQs ranged in 0.0183-0.0549 ng/mL and 0.0661-0.1831 ng/mL, respectively. By this way, the method was successfully applied to simultaneous determination of the racemates and the enantiomers of mirtazapine, bupropion and fluoxetine in wastewater samples. Among them, three samples contained bupropion at level of 0.401-0.822 ng/mL, and mirtazapine at level of 0.328 and fluoxetine at level of 0.381 ng/mL were detected respectively in the other two samples. The enantiomers were at level of 0.140-0.189 ng/mL for mirtazapine, 0.182-0.419 ng/mL for bupropion and 0.179-0.204 ng/mL for fluoxetine, respectively. The proposed method providing an efficient approach to monitoring chiral drugs and their enantiomers in wastewater, facilitating to pollution assessment of chiral drugs in the environment and regional survey of illicit abuse in drug control.
Topics: Wastewater; Fluoxetine; Bupropion; Mirtazapine; Tandem Mass Spectrometry; Water Pollutants, Chemical; Antidepressive Agents; Chromatography, High Pressure Liquid; Stereoisomerism
PubMed: 37506440
DOI: 10.1016/j.ecoenv.2023.115302 -
Journal of Affective Disorders Oct 2023MicroRNAs (miRNAs) and circulating cell-free mitochondrial DNA (ccf-mtDNA) have attracted interest as biological markers of affective disorders. In response to stress,... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
MicroRNAs (miRNAs) and circulating cell-free mitochondrial DNA (ccf-mtDNA) have attracted interest as biological markers of affective disorders. In response to stress, it is known that miRNAs in mitochondria diffuse out of the cytoplasm alongside mtDNA; however, this process has not yet been identified. We hypothesized that miRNAs derived from specific cell nuclei cause mitochondrial damage and mtDNA fragmentation under MDD-associated stress conditions.
METHODS
A comprehensive analysis of the plasma miRNA levels and quantification of the plasma ccf-mtDNA copy number were performed in 69 patients with depression to determine correlations and identify genes and pathways interacting with miRNAs. The patients were randomly assigned to receive either selective serotonin reuptake inhibitors (SSRI) or mirtazapine. Their therapeutic efficacy over four weeks was evaluated in relation to miRNAs correlated with ccf-mtDNA copy number.
RESULTS
The expression levels of the five miRNAs showed a significant positive correlation with the ccf-mtDNA copy number after correcting for multiple testing. These miRNAs are involved in gene expression related to thyroid hormone synthesis, the Hippo signaling pathway, vasopressin-regulated water reabsorption, and lysine degradation. Of these five miRNAs, miR-6068 and miR-4708-3p were significantly associated with the SSRI and mirtazapine treatment outcomes, respectively.
LIMITATIONS
This study did not show comparison with a healthy group.
CONCLUSIONS
The expression levels of specific miRNAs were associated with ccf-mtDNA copy number in untreated depressed patients; moreover, these miRNAs were linked to antidepressant treatment outcomes. These findings are expected to lead to the elucidation of new pathological mechanism of depression.
Topics: Humans; MicroRNAs; DNA, Mitochondrial; Depressive Disorder, Major; Mirtazapine; Depression; Cell-Free Nucleic Acids; Mitochondria; Selective Serotonin Reuptake Inhibitors
PubMed: 37467797
DOI: 10.1016/j.jad.2023.07.073 -
NPJ Parkinson's Disease Jul 2023Depressive symptoms in Parkinson's disease (PD) are multifactorial and are partly linked to the underlying dopaminergic deficit. However, at least a subset of PD...
Depressive symptoms in Parkinson's disease (PD) are multifactorial and are partly linked to the underlying dopaminergic deficit. However, at least a subset of PD patients may exhibit an unspecific depressive reaction to chronic illness. Here, we compared the prevalence and severity of depressive symptoms in PD patients and disease controls (DC). PD patients reported depressive symptoms at similar frequencies as DC but were on antidepressants, especially Mirtazapine, more frequently. Still, in both groups, a high proportion of patients with clinically significant depressive symptoms was not receiving medication. Diagnosis and treatment of depressive symptoms both in PD and DC should be improved.
PubMed: 37452071
DOI: 10.1038/s41531-023-00551-8 -
International Journal of Molecular... Jul 2023About 30% of major depression disorder patients fail to achieve remission, hence being diagnosed with treatment-resistant major depression (TRD). Opium had been largely...
About 30% of major depression disorder patients fail to achieve remission, hence being diagnosed with treatment-resistant major depression (TRD). Opium had been largely used effectively to treat depression for centuries, but when other medications were introduced, its use was discounted due to addiction and other hazards. In a series of previous studies, we evaluated the antinociceptive effects of eight antidepressant medications and their interaction with the opioid system. Mice were tested with a hotplate or tail-flick after being injected with different doses of mianserin, mirtazapine, trazodone, venlafaxine, reboxetine, moclobemide, fluoxetine, or fluvoxamine to determine the effect of each drug in eliciting antinociception. When naloxone inhibited the antinociceptive effect, we further examined the effect of the specific opioid antagonists of each antidepressant drug. Mianserin and mirtazapine (separately) induced dose-dependent antinociception, each one yielding a biphasic dose-response curve, and they were antagonized by naloxone. Trazodone and venlafaxine (separately) induced a dose-dependent antinociceptive effect, antagonized by naloxone. Reboxetine induced a weak antinociceptive effect with no significant opioid involvement, while moclobemide, fluoxetine, and fluvoxamine had no opioid-involved antinociceptive effects. Controlled clinical studies are needed to establish the efficacy of the augmentation of opiate antidepressants in persons with treatment-resistant depression and the optimal dosage of drugs prescribed.
Topics: Animals; Mice; Analgesics, Opioid; Mianserin; Venlafaxine Hydrochloride; Fluvoxamine; Mirtazapine; Fluoxetine; Reboxetine; Trazodone; Moclobemide; Depression; Antidepressive Agents; Naloxone; Dose-Response Relationship, Drug
PubMed: 37446323
DOI: 10.3390/ijms241311142 -
International Journal of Clinical... Oct 2023Pharmacogenetics (PGx), especially in regard to CYP2D6, is gaining more importance in routine clinical settings. Including phenoconversion effects (PC) in result...
BACKGROUND
Pharmacogenetics (PGx), especially in regard to CYP2D6, is gaining more importance in routine clinical settings. Including phenoconversion effects (PC) in result interpretation could maximize its potential benefits. However, studies on genetics of pharmacokinetic genes including the functional enzyme status are lacking.
AIM
The retrospective analyses of clinical routine data aimed to investigating how the CYP2D6 functional enzyme status affects serum concentrations and metabolite-to-parent ratios of seven common psychotropic drugs and allows an evaluation of the relevance of this information for patient care.
METHOD
Two patient cohorts (total n = 316; 44.2 ± 15.4 years) were investigated for the CYP2D6 functional enzyme status and its associations with drug exposure and metabolism of venlafaxine, amitriptyline, mirtazapine, sertraline, escitalopram, risperidone and quetiapine.
RESULTS
We found an increase in intermediate and poor metabolizers, as well as a decrease in normal metabolizers of CYP2D6 when including PC. Moreover, we found associations between amitriptyline exposure with the phenoconversion-corrected activity score of CYP2D6 (Spearman correlation; p = 0.03), and risperidone exposure with CYP2D6 functional enzyme status (Kruskal-Wallis test; p = 0.01), as well as between metabolite-to-parent ratio of venlafaxine and risperidone with CYP2D6 functional enzyme status (Kruskal-Wallis test; p < 0.001; p = 0.05).
CONCLUSION
The data stress the relevance of PC-informed PGx in psychopharmacological treatment and suggest that PC should be included in PGx result interpretation when PGx is implemented in routine clinical care, especially before initiating amitriptyline- or risperidone-treatment, to start with a dose adequate to the respective CYP2D6 functional enzyme status. Moreover, PGx and therapeutic drug monitoring should be used complementary but not alternatively.
Topics: Humans; Antipsychotic Agents; Cytochrome P-450 CYP2D6; Retrospective Studies; Risperidone; Pharmacogenetics; Venlafaxine Hydrochloride; Amitriptyline; Genotype; Phenotype; Antidepressive Agents
PubMed: 37166747
DOI: 10.1007/s11096-023-01588-8 -
Advances in Clinical and Experimental... Oct 2023Psychosis is a very common feature of Alzheimer's disease (AD) that can emerge as the neurodegenerative disease progresses. The 5-hydroxytryptamine (5-HT2A) receptors... (Meta-Analysis)
Meta-Analysis
Efficacy and safety of negative allosteric modulators of 5-hydroxytryptamine 2A receptors in the treatment of Alzheimer's disease psychosis: A systematic review and meta-analysis.
BACKGROUND
Psychosis is a very common feature of Alzheimer's disease (AD) that can emerge as the neurodegenerative disease progresses. The 5-hydroxytryptamine (5-HT2A) receptors are located postsynaptically to serotonergic neurons in the frontal cortex and mediate both excitatory and inhibitory neurotransmissions. However, the effectiveness and tolerance of negative modulators of 5-HT2A receptors in Alzheimer's disease psychosis (ADP) are uncertain.
OBJECTIVES
To detect the negative modulators of the 5-HT2A receptor as a cure for ADP.
MATERIAL AND METHODS
The primary outcome indicator was the total Neuropsychiatric Inventory (NPI) score. Other prognostic indicators included Mini-Mental State Examination (MMSE), the Katz Index of Independence in Activities of Daily Living (KATZ), the discontinuation rate, and adverse events.
RESULTS
Compared to placebo, 5-HT2A inverse agonists significantly reduced the NPI total score, the KATZ and the MMSE score. The pooled odds ratio (OR) was 1.64 (95% confidence interval (95% CI): 1.01-2.65) and the heterogeneity variance was estimated at Tau2 = 0.52 with an I2 value of 90%, a χ2 value of 111.31, p = 0.04, and z-value of 2.01. The risk difference (RD) between the 5-HT2A receptor negative modulators and placebo groups was 0.12 (95% CI: 0.00-0.24) and the heterogeneity was estimated at Tau2 = 0.03, χ2 value of 127.23, degrees of freedom (df) value of 9, I2 value of 93%, z-value of 1.92, and p-value of 0.01 (<0.05).
CONCLUSION
Our results suggest that negative modulators of 5-HT2A receptors are beneficial and well-tolerated in the treatment of ADP.
Topics: Humans; Alzheimer Disease; Serotonin; Neurodegenerative Diseases; Activities of Daily Living; Drug Inverse Agonism; Receptor, Serotonin, 5-HT2A; Psychotic Disorders
PubMed: 37166012
DOI: 10.17219/acem/161159 -
Journal of Affective Disorders Aug 2023The choice of antidepressants for initial pharmacological treatment of depression in older adults and associated patients' characteristics are understudied. We aimed to...
Do sociodemographic and clinical factors affect the selection of initial antidepressant treatment for depression in older adults? Results from a nationwide descriptive study in Denmark.
BACKGROUND
The choice of antidepressants for initial pharmacological treatment of depression in older adults and associated patients' characteristics are understudied. We aimed to describe the first selected antidepressant (first-choice) for depression in older adults (≥65 years) and whether patients' sociodemographic and clinical characteristics influence selecting an alternative first-choice (any other antidepressant than the nationally recommended first-choice sertraline) in Denmark.
METHODS
Register-based cross-sectional study including all older adults who redeemed their first antidepressant prescription for depression at community pharmacies in Denmark in 2015-2019. We analyzed the effect of patients' characteristics on the first-choice antidepressant selection using multinomial logistic regression.
RESULTS
Among 34,337 older adults with a first antidepressant-prescription, over two-thirds filled alternative first-choice antidepressants than sertraline (28.9 %): escitalopram or citalopram (30.3 %) or mirtazapine (34.4 %). Socially disadvantaged older adults (e.g., with short educational attainment, being single, or of non-western ethnicity) and clinically vulnerable older adults (e.g., having somatic diagnoses and hospital contacts) were more likely to use alternative first-choice antidepressants.
LIMITATIONS
Information on prescribers and in-hospital medications was not included in this study.
CONCLUSIONS
Further investigation of the first antidepressant selection and its impact on depression treatment outcomes in older adults is necessary. Moreover, for older patients, national guidelines on depression treatment should be more specific.
ARTICLE SUMMARY
Antidepressant selection for initial pharmacological treatment of depression in older adults can be difficult due to comorbidity, polypharmacy, and age-related changes in pharmacokinetics and pharmacodynamics. Real-world evidence/knowledge on first-choice antidepressant selection and associated user characteristics are rare. This Danish register-based cross-sectional study found over two-thirds of older adults filled alternative antidepressants (primarily escitalopram/citalopram or mirtazapine) than nationally recommended first-choice sertraline for depression treatment and identified wide-ranging sociodemographic and clinical factors influencing the first antidepressant selection.
Topics: Humans; Aged; Sertraline; Citalopram; Depression; Mirtazapine; Escitalopram; Cross-Sectional Studies; Antidepressive Agents; Denmark
PubMed: 37146907
DOI: 10.1016/j.jad.2023.04.110 -
Drug Delivery and Translational Research Sep 2023The solid dispersion technique is the most effective and widely used approach for increasing the solubility and release of drugs that have low water solubility....
The solid dispersion technique is the most effective and widely used approach for increasing the solubility and release of drugs that have low water solubility. Mirtazapine (MRT) is an atypical antidepressant used to treat severe depression. MRT has a low oral bioavailability (about 50%) due to its low water solubility (BCS class II). The study's goal was to determine optimum conditions for incorporating MRT into various polymer types utilizing the solid dispersion (SD) technique, with the goal of selecting the most suitable formula with the optimal aqueous solubility, loading efficiency, and dissolution rate. The D-optimal design was used to pick the optimal response. The optimum formula was subjected to physicochemical evaluation by Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and scanning electron microscopy (SEM). In vivo bioavailability study was conducted on white rabbits' plasma samples. MRT-SDs were prepared by the solvent evaporation method using Eudragit (RL-100, RS-100, E-100, L-100-55), PVP K-30, and PEG 4000 with different drug/polymer percentages (33.33%, 49.99%, and 66.66%). Results showed that the optimum formula obtained using PVP K-30 at a drug percentage of 33.33% gave a loading efficiency of 100.93%, an aqueous solubility of 0.145 mg/ml, and a dissolution rate of 98.12% after 30 min. These findings demonstrated promising enhancement of MRT properties and increasing its oral bioavailability by 1.34-fold more than plain drug.
Topics: Animals; Rabbits; Spectroscopy, Fourier Transform Infrared; Mirtazapine; Chemistry, Pharmaceutical; Biological Availability; Polymers; Povidone; X-Ray Diffraction; Solubility; Water; Calorimetry, Differential Scanning; Drug Carriers
PubMed: 36940079
DOI: 10.1007/s13346-023-01316-9