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Scientific Reports Oct 2023Esketamine provides an immediate and noticeable antidepressant effect, although the underlying molecular processes are yet unclear. Irisin induced by aerobic exercise...
Esketamine provides an immediate and noticeable antidepressant effect, although the underlying molecular processes are yet unclear. Irisin induced by aerobic exercise has been implicated in the alleviation of depressive symptoms, whether irisin expression responds to the administration of esketamine remains unknown. In this study, we found that irisin was reduced in the hippocampus and peripheral blood of chronic unpredictable mild stress (CUMS) mice, whereas the irisin level was rescued by esketamine treatment. The reduction of PGC-1α expression (transcriptional regulator of irisin gene expression) in the CUMS mice was rescued by esketamine treatment, PGC-1α knockdown significantly reduced the irisin level induced by esketamine. Additionally, FNDC5/irisin-knockout mice developed more severe depressant-like behaviors than wild-type mice under CUMS stimulation, with an attenuated the antidepressant effect of esketamine. Further research indicated that irisin-mediated modulation of esketamine on depressive-like behaviors in CUMS mice involved the ERK1/2 pathway. Overall, the PGC-1α/irisin/ERK1/2 signaling activation may be a new mechanism underlying the antidepressant activity of esketamine, denoting that irisin may be a promising therapeutic target for the treatment of depression.
Topics: Animals; Mice; Antidepressive Agents; Depression; Fibronectins; Hippocampus; MAP Kinase Signaling System; Mice, Knockout; Muscle, Skeletal
PubMed: 37789092
DOI: 10.1038/s41598-023-43684-9 -
Frontiers in Endocrinology 2023Dysfunction in the hypothalamic-pituitary-adrenal axis has been associated with depressive and anxiety disorders. Little is known about the risk for these disorders...
BACKGROUND
Dysfunction in the hypothalamic-pituitary-adrenal axis has been associated with depressive and anxiety disorders. Little is known about the risk for these disorders among individuals with congenital adrenal hyperplasia (CAH), a form of primary adrenal insufficiency.
OBJECTIVE
We investigated the prevalence of depressive and anxiety disorders and antidepressant prescriptions in two large healthcare databases of insured children, adolescents, and young adults with CAH in the United States.
METHODS
We conducted a retrospective cohort study using administrative data from October 2015 through December 2019 for individuals aged 4-25 years enrolled in employer-sponsored or Medicaid health plans.
RESULTS
Adjusting for age, the prevalence of depressive disorders [adjusted prevalence ratio (aPR) = 1.7, 95% confidence interval (CI): 1.4-2.0, p<0.001], anxiety disorders [aPR = 1.7, 95% CI: 1.4-1.9, p<0.001], and filled antidepressant prescriptions [aPR = 1.7, 95% CI: 1.4-2.0, p<0.001] was higher among privately insured youth with CAH as compared to their non-CAH peers. Prevalence estimates were also higher among publicly insured youth with CAH for depressive disorders [aPR = 2.3, 95% CI: 1.9-2.9, p<0.001], anxiety disorders [aPR = 2.0, 95% CI: 1.6-2.5, p<0.001], and filled antidepressant prescriptions [aPR = 2.5, 95% CI: 1.9-3.1, p<0.001] as compared to their non-CAH peers.
CONCLUSIONS
The elevated prevalence of depressive and anxiety disorders and antidepressant prescriptions among youth with CAH suggests that screening for symptoms of depression and anxiety among this population might be warranted.
Topics: United States; Adolescent; Humans; Child; Young Adult; Adrenal Hyperplasia, Congenital; Hypothalamo-Hypophyseal System; Retrospective Studies; Pituitary-Adrenal System; Anxiety Disorders; Antidepressive Agents; Prescriptions
PubMed: 37664854
DOI: 10.3389/fendo.2023.1129584 -
Cellular and Molecular Neurobiology Jul 2023Depression is the most common mental illness characterized by anhedonia, avolition and loss of appetite and motivation. The majority of conventional antidepressants are... (Review)
Review
Depression is the most common mental illness characterized by anhedonia, avolition and loss of appetite and motivation. The majority of conventional antidepressants are monoaminergic system selective inhibitors, yet the efficacies are not sufficient. Up to 30% of depressed patients are resistant to treatment with available antidepressants, underscoring the urgent need for development of novel therapeutics to meet clinical needs. Recent years, compounds acting on the glutamate system have attracted wide attention because of their strong, rapid and sustained antidepressant effects. Among them, selective inhibitors of metabotropic glutamate receptors 2 and 3 (mGluR2/3) have shown robust antidepressant benefits with fewer side-effects in both preclinical and clinical studies. Thus, we here attempt to summarize the antidepressant effects and underlying mechanisms of these inhibitors revealed in recent years as well as analyze the potential value of mGluR2/3 selective inhibitors in the treatment of depression.
Topics: Humans; Antidepressive Agents; Mental Disorders
PubMed: 36443586
DOI: 10.1007/s10571-022-01310-8 -
Naunyn-Schmiedeberg's Archives of... May 2024Mirtazapine (MTZ) is an antidepressant drug with an exceptional pharmacological profile. It also has an excellent safety and tolerability profile. The present review... (Review)
Review
Mirtazapine (MTZ) is an antidepressant drug with an exceptional pharmacological profile. It also has an excellent safety and tolerability profile. The present review provides a pharmacological update on MTZ and summarizes the research findings of MTZ's effects on different diseases. MTZ is hypothesized to have antidepressant effects because of the synergy between noradrenergic and serotonergic actions and is effective in treating major depressive disorder and depression associated with epilepsy, Alzheimer's disease, stroke, cardiovascular disease, and respiratory disease. In cancer patients, MTZ significantly reduced sadness, nausea, sleep disruption, and pain and improved quality of life. Also, it has promising effects on Parkinson's disease, schizophrenia, dysthymia, social anxiety disorder, alcohol dependency, posttraumatic stress disorder, panic disorder, pain syndromes, obsessive-compulsive disorder, and sleep disorders. Additionally, MTZ is potentially therapeutic in different situations associated with depression, such as liver, kidney, cardiovascular, respiratory, infertility, heavy metal-induced neurotoxicity, and pruritus. Potent antioxidative, anti-inflammatory, and anti-apoptotic bioactivities mediate these promising effects. These positive outcomes of the scientific investigations motivate more and more clinical trials for a golden exceptional antidepressant in different conditions.
Topics: Humans; Mirtazapine; Animals; Antidepressive Agents; Antidepressive Agents, Tricyclic
PubMed: 37943296
DOI: 10.1007/s00210-023-02818-6 -
Psychiatry Research Sep 2023Treatment-resistant depression (TRD) represents a severe clinical condition with high social and economic costs. Esketamine Nasal Spray (ESK-NS) has recently been...
Treatment-resistant depression (TRD) represents a severe clinical condition with high social and economic costs. Esketamine Nasal Spray (ESK-NS) has recently been approved for TRD by EMA and FDA, but data about predictors of response are still lacking. Thus, a tool that can predict the individual patients' probability of response to ESK-NS is needed. This study investigates sociodemographic and clinical features predicting responses to ESK-NS in TRD patients using machine learning techniques. In a retrospective, multicentric, real-world study involving 149 TRD subjects, psychometric data (Montgomery-Asberg-Depression-Rating-Scale/MADRS, Brief-Psychiatric-Rating-Scale/BPRS, Hamilton-Anxiety-Rating-Scale/HAM-A, Hamilton-Depression-Rating-Scale/HAMD-17) were collected at baseline and at one month/T1 and three months/T2 post-treatment initiation. We trained three different random forest classifiers, able to predict responses to ESK-NS with accuracies of 68.53% at T1 and 66.26% at T2 and remission at T2 with 68.60% of accuracy. Features like severe anhedonia, anxious distress, mixed symptoms as well as bipolarity were found to positively predict response and remission. At the same time, benzodiazepine usage and depression severity were linked to delayed responses. Despite some limitations (i.e., retrospective study, lack of biomarkers, lack of a correct interrater-reliability across the different centers), these findings suggest the potential of machine learning in personalized intervention for TRD.
Topics: Humans; Antidepressive Agents; Retrospective Studies; Depression; Reproducibility of Results; Depressive Disorder, Treatment-Resistant; Machine Learning; Treatment Outcome
PubMed: 37574600
DOI: 10.1016/j.psychres.2023.115378 -
BMJ Open Jan 2024Literature surrounding the association between antidepressant use during pregnancy and miscarriage is conflicting. We aimed to conduct a systematic review and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Literature surrounding the association between antidepressant use during pregnancy and miscarriage is conflicting. We aimed to conduct a systematic review and meta-analysis of studies among pregnant women regarding the association between exposure to antidepressants during pregnancy and the risk of miscarriage, compared with pregnant women not exposed to antidepressants.
DESIGN
We conducted a systematic review and meta-analysis of non-randomised studies.
DATA SOURCES
We searched Medline, Embase and PsychINFO up to 6 August 2023.
ELIGIBILITY CRITERIA AND OUTCOMES
Case-control, cohort and cross-sectional study designs were selected if they compared individuals exposed to any antidepressant class during pregnancy to comparator groups of either no antidepressant use or an alternate antidepressant.
DATA EXTRACTION AND SYNTHESIS
Effect estimates were extracted from selected studies and pooled using a random-effects meta-analysis. Risk of bias (RoB) was assessed using the Risk of Bias in Non-Randomised Studies of Interventions (ROBINS-I) tool, and heterogeneity assessed using the I statistic. Subgroup analyses were used to explore antidepressant classes and the impact of confounding by indication.
RESULTS
1800 records were identified from the search, of which 29 were included in the systematic review and meta-analysis. The total sample included 5 671 135 individuals. Antidepressant users initially appeared to have a higher risk of miscarriage compared with unexposed individuals from the general population (summary effect estimate: 1.24, 95% CI 1.18 to 1.31, I=69.2%; number of studies (n)=29). However, the summary estimate decreased when comparing against unexposed individuals with maternal depression (1.16, 1.04 to 1.31; I=58.6%; n=6), suggesting confounding by indication may be driving the association. 22 studies suffered from serious RoB, and only two of the 29 studies were deemed at moderate RoB.
CONCLUSIONS
After accounting for maternal depression, there is little evidence of any association between antidepressant use during pregnancy and miscarriage. Instead, the results indicate the biasing impact of confounding by indication.
Topics: Humans; Female; Pregnancy; Abortion, Spontaneous; Cross-Sectional Studies; Antidepressive Agents
PubMed: 38272551
DOI: 10.1136/bmjopen-2023-074600 -
Journal of Clinical PsychopharmacologyThe purpose of this study was to review the association between the SLC6A4 5-HTTLPR polymorphism and antidepressant (AD)-associated treatment emergent mania (TEM) in... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The purpose of this study was to review the association between the SLC6A4 5-HTTLPR polymorphism and antidepressant (AD)-associated treatment emergent mania (TEM) in bipolar disorder alongside starting a discussion on the merits of developing risk stratification models to guide when not to provide AD treatment for bipolar depression.
METHODS
Studies that examined the association between clinical and genetic risk factors, specifically monoaminergic transporter genetic variation, and TEM were identified. A meta-analysis was performed using the odds ratio to estimate the effect size under the Der-Simonian and Laird model.
RESULTS
Seven studies, referencing the SLC6A4 5-HTTLPR polymorphism and TEM (total N = 1578; TEM+ =594, TEM- = 984), of 142 identified articles were included. The time duration between the start of the AD to emergence of TEM ranged from 4 to 12 weeks. There was a nominally significant association between the s allele of the 5-HTTLPR polymorphism and TEM (odds ratio, 1.434; 95% confidence interval, 1.001-2.055; P = 0.0493; I2 = 52%). No studies have investigated norepinephrine or dopamine transporters.
CONCLUSION
Although the serotonin transporter genetic variation is commercially available in pharmacogenomic decision support tools, greater efforts, more broadly, should focus on complete genome-wide approaches to determine genetic variants that may contribute to TEM. Moreover, these data are exemplary to the merits of developing risk stratification models, which include both clinical and biological risk factors, to guide when not to use ADs in bipolar disorder. Future studies will need to validate new risk models that best inform the development of personalized medicine best practices treating bipolar depression.
Topics: Humans; Antidepressive Agents; Bipolar Disorder; Mania; Pharmacogenetics; Polymorphism, Genetic; Serotonin Plasma Membrane Transport Proteins
PubMed: 37683232
DOI: 10.1097/JCP.0000000000001747 -
European Psychiatry : the Journal of... Feb 2024Hyponatremia (hypoNa) is a potentially serious adverse event of antidepressant treatment. Previous research suggests the risk of drug-induced hyponatremia differs... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Hyponatremia (hypoNa) is a potentially serious adverse event of antidepressant treatment. Previous research suggests the risk of drug-induced hyponatremia differs between antidepressants. This meta-analysis sought to determine the risk of antidepressant-induced hypoNa, stratified by different compounds and classes.
METHODS
A PRISMA-compliant systematic search of Web of Science and PubMed databases was performed from inception until Jan 5, 2023, for original studies reporting incidences or risks of hypoNa in adults using antidepressants. We modelled random-effects meta-analyses to compute overall event rates and odds ratios of any and clinically relevant hypoNa for each compound and class, and ran head-to-head comparisons based on hypoNa event rates. We conducted subgroup analyses for geriatric populations and sodium cut-off value. The study is registered with PROSPERO, CRD42021269801.
RESULTS
We included 39 studies (n = 8,175,111). Exposure to antidepressants was associated with significantly increased odds of hypoNa (k = 7 studies, OR = 3.160 (95%CI 1.911-5.225)). The highest event rates were found for SNRIs (7.44%), SSRIs (5.59%), and TCAs (2.66%); the lowest for mirtazapine (1.02%) and trazodone (0.89%). Compared to SSRIs, SNRIs were significantly more likely (k = 10, OR = 1.292 (1.120 - 1.491), p < 0.001) and mirtazapine significantly less likely (k = 9, OR = 0.607 (0.385 - 0.957), p = 0.032) to be associated with hypoNa.
CONCLUSION
Our meta-analysis demonstrated that, while no antidepressant can be considered completely risk-free, for hypoNa-prone patients mirtazapine should be considered the treatment of choice and SNRIs should be prescribed more cautiously than SSRIs and TCAs.
Topics: Adult; Humans; Aged; Selective Serotonin Reuptake Inhibitors; Mirtazapine; Serotonin and Noradrenaline Reuptake Inhibitors; Hyponatremia; Antidepressive Agents
PubMed: 38403888
DOI: 10.1192/j.eurpsy.2024.11 -
Journal of Nanobiotechnology Oct 2023Brain-derived neurotrophic factor (BDNF) with neuronic development and function is a promising therapeutic agent for treating depressive disorder, according to the...
BACKGROUND
Brain-derived neurotrophic factor (BDNF) with neuronic development and function is a promising therapeutic agent for treating depressive disorder, according to the neurotrophin hypothesis. However, the delivery of BDNF into the brain is not easy as these large protein molecules cannot efficiently cross the blood-brain barrier (BBB) and easily suffer oxidative damage in vivo. Therefore, the quercetin-based alginate nanogels (quercetin nanogels) loaded with BDNF have been developed, which could efficiently bypass the BBB via the nose-to-brain pathway and protect BDNF from oxidative damage, providing an effective route for the therapy of depressive disorders by intranasal delivery.
RESULTS
Quercetin nanogels exhibited uniform size distribution, excellent biocompatibility, and potent antioxidant and anti-inflammatory activities. Quercetin nanogels in the thermosensitive gel achieved sustained and controlled release of BDNF with non-Fick's diffusion, exhibited rapid brain distribution, and achieved nearly 50-fold enhanced bioavailability compared to oral quercetin. Quercetin nanogels as a therapeutic drug delivery carrier exerted antidepressant effects on reserpine-induced rats, effectively delivered BDNF to reverse despair behavior in stress-induced mice, and exhibited antidepressant effects on chronic mild unpredictable stimulation (CUMS) rats. These antidepressant effects of BDNF-Quercetin nanogels for CUMS rats are associated with the regulation of the glutamatergic system, PI3K-Akt, and BDNF-TrkB signaling pathway.
CONCLUSIONS
In this study, we provide a promising strategy for brain delivery of BDNF for treating depressive disorders, effectively achieved through combining quercetin nanogels and intranasal administration.
Topics: Rats; Mice; Animals; Quercetin; Brain-Derived Neurotrophic Factor; Depression; Nanogels; Alginates; Phosphatidylinositol 3-Kinases; Antidepressive Agents; Hippocampus; Disease Models, Animal
PubMed: 37848975
DOI: 10.1186/s12951-023-02150-4 -
Annual Review of Medicine Jan 2024Major depressive disorder (MDD) is a leading cause of suicide in the world. Monoamine-based antidepressant drugs are a primary line of treatment for this mental... (Review)
Review
Major depressive disorder (MDD) is a leading cause of suicide in the world. Monoamine-based antidepressant drugs are a primary line of treatment for this mental disorder, although the delayed response and incomplete efficacy in some patients highlight the need for improved therapeutic approaches. Over the past two decades, ketamine has shown rapid onset with sustained (up to several days) antidepressant effects in patients whose MDD has not responded to conventional antidepressant drugs. Recent preclinical studies have started to elucidate the underlying mechanisms of ketamine's antidepressant properties. Herein, we describe and compare recent clinical and preclinical findings to provide a broad perspective of the relevant mechanisms for the antidepressant action of ketamine.
Topics: Humans; Ketamine; Depression; Depressive Disorder, Major; Antidepressive Agents; Amines
PubMed: 37729028
DOI: 10.1146/annurev-med-051322-120608