Norepinephrine Reuptake Inhibitor Research Articles

A Study on Tapentadol Misuse and Abuse among Heroin Users Attending a Deaddiction Center in Kashmir

Abstract Background: Tapentadol is a powerful opioid receptor agonist and a norepinephrine reuptake inhibitor, making it a centrally acting analgesic. In India, where the government is trying to combat an ongoing opioid crisis, the lack of scheduling of tapentadol creates an easy opportunity for its misuse. We aim to analyze the demographic and clinical characteristics of heroin users who also abuse tapentadol concurrently through our cross-sectional study done at the drug-deaddiction center situated at the community center of SMHS Hospital, Srinagar, Kashmir. Material and Methods: It was a cross-sectional study done at the Community Centre of SMHS hospital Srinagar, which houses the drug deaddiction centre run by the Psychiatry Department of GMC(Government Medical College) Srinagar. From 1st June 2023 until 30th November 2023, we gathered data for our investigation. After gaining informed consent, all the first-time heroin-dependent patients at the deaddiction facility who admitted to using tapentadol were included in the study. Patients’ age, sex, marital status, family composition, and level of education were analysed in accordance with a predefined proforma. In addition, the modified Kuppuswamy scale was used to categorise patients based on their socioeconomic status. Parameters such as the pattern of tapentadol use, the route of heroin use, and the comparison of the psychoactive effects of tapentadol and heroin were recorded using a proforma to create a clinical profile of such patients. Results: Our sample comprised 100 participants. The prevalence of tapentadol abuse among heroin users in our study came out to be 16%. The average age of our study participants was 25.11 ± 2.99 years. The vast majority of our patients were male (97%). The vast majority (58%) of our participants were from lower socioeconomic status. Ninety-eight percent of our subjects used oral tapentadol while there were 2 (2%) instances of intravenous tapentadol use. The majority of participants used the “Tapal” brand (60%). Tapentadol was mainly obtained either through a chemist’s shop (35%) (with or without a prescription) or through a friend (37%). Half of the subjects (50%) obtained tapentadol for the purpose of managing heroin withdrawal. Thirty-five percent of participants used tapentadol in a dependent manner, while the remaining 65% either misused or abused the drug. Conclusion: The continued heroin usage crisis, lenient tapentadol procurement regulations, and the use of nonevidence-based drugs for the treatment of opioid use disorder all contribute to the problem of tapentadol abuse in our region.

Prevalence of Antidepressant Prescription in Adolescents Newly Diagnosed with Depression in Germany.

Depression is the most common mental illness in the world, found in nearly three in ten adolescents globally. This study aims to evaluate the prevalence of antidepressant prescriptions and the types of antidepressant therapy administered among adolescents diagnosed with depression in Germany. This retrospective cohort study, based on data provided by 30 child and adolescent psychiatrists, included adolescents aged 13-17 years with an initial diagnosis of depression between 2010 and 2022 (index date) documented in the IQVIATM Disease Analyzer database. Kaplan-Meier curves were used to investigate the one-year cumulative incidence of antidepressant prescriptions stratified by age, sex, and depression severity. Multivariable Cox regression analyses were used to assess the association between age, sex, depression severity, co-diagnoses, and antidepressant drug prescription. A total of 6338 adolescents (mean age: 16 years, 67% female, 59% with moderate depression) were available. The cumulative incidence of antidepressant prescriptions was 61% and increased with age from 13 years old to 17 years old. Fluoxetine was the most prescribed drug, followed by Sertraline, Escitalopram, Serotonin and Norepinephrine reuptake inhibitors, herbal medications, and Mirtazapine. Obsessive-compulsive disorder and eating disorders were found to be significantly associated with antidepressant prescriptions within the spectrum of co-diagnosed conditions. Higher age, depression severity, and a co-diagnosis of an obsessive-compulsive disorder or eating disorder were significantly positively associated with antidepressant prescriptions in adolescents. Fluoxetine was the most frequently prescribed drug for depression.

Evaluation of akathisia in patients receiving selective serotonin reuptake inhibitors/serotonin and noradrenaline reuptake inhibitors.

Akathisia is an underestimated but disturbing extrapyramidal side effect of antidepressants, which could reduce treatment compliance in mood disorders. This study aimed to investigate the frequency and risk factors in patients treated with selective serotonin reuptake inhibitors/serotonin and noradrenaline reuptake inhibitors (SSRI/SNRI). In addition, we assessed the impact of akathisia on the quality of life (QoL). Patients were aged between 18 and 75 years, receiving an SSRI/SNRI for 4-8 weeks, and were diagnosed with anxiety, depression, or obsessive-compulsive disorder. The Barnes Akathisia Rating Scale was used to assess the severity of the akathisia. QoL was evaluated using the Short Form 36 (SF-36) questionnaire. Akathisia was observed in 25% (50/198) of patients. Smokers and younger patients were more frequent among patients with akathisia. Physical functioning, physical role, vitality, and mental health domains of the SF-36 were reduced in the presence of akathisia. In conclusion, our results suggest that akathisia is not a rare side effect of SSRI/SNRI in patients with mood disorders, especially in smokers and younger patients. In addition, akathisia may reduce treatment compliance owing to a reduction in QoL. Further investigations are needed to confirm the risk factors, frequency, and consequences of treatment compliance for SSRI/SNRI-induced akathisia in patients with mood disorders.

Estimating the benefit of esketamine nasal spray versus real-world treatment on patient-reported functional remission: results from the ICEBERG study.

Treatment resistant depression (TRD) affects approximately 10-30% of patients with major depressive disorder, and most patients with TRD do not respond to real-world treatments (RWT). Treatment with esketamine nasal spray (NS) plus a selective serotonin or serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) has significant long-term clinical benefit over RWT in patients with TRD. However, the impact on patient-reported function remains to be determined. The ICEBERG analysis was an indirect treatment comparison performed using data from two studies of patients with TRD: SUSTAIN-2 (esketamine NS; NCT02497287) and the European Observational TRD Cohort (EOTC; RWT; NCT03373253; clinicaltrials.gov). Here, patient-reported functional remission, assessed using the Sheehan Disability Scale (SDS), was defined as SDS ≤6 at Month 6. Analyses were conducted using propensity score re-weighting and multivariable models based on 18 covariates. At Month 6, the probability of functional remission in esketamine NS-treated patients from SUSTAIN-2 (n=512) was 25.6% (95% confidence interval [CI] 21.8-29.4), while the adjusted probability for RWT patients from the EOTC (n=184) was 11.5% (95% CI 6.9-16.1; relative risk: 2.226 [95% CI 1.451-3.416]; p=0.0003). In the total combined population (N=696), patients who did not achieve clinical response or remission had a low probability of achieving functional remission (5.84% and 8.76%, respectively). However, for patients who did achieve clinical response or remission, the probability of achieving functional remission was greater (43.38% and 54.15%, respectively), although many still did not achieve this status. For patients with TRD, esketamine NS had a significant functional benefit versus RWT after 6 months of treatment. Irrespective of treatment, achievement of clinical response or remission was insufficient to attain functional remission. Nevertheless, clinical remission increased the likelihood of achieving functional remission, further supporting an important role for clinical remission in for the path towards functional recovery.

The effect of atomoxetine efficacy on freezing of gait in patient with Parkinson’s disease: a double-blinded randomized clinical trial

Introduction: Freezing of gait (FOG) is a debilitating symptom experienced by many individuals with Parkinson’s disease, characterized by an abrupt and transient inability to initiate or continue locomotion. Despite extensive research, effective pharmacological interventions targeting FOG remain elusive. Atomoxetine, a selective norepinephrine reuptake inhibitor, has shown promise in alleviating FOG in small-scale studies. However, the efficacy of atomoxetine in larger cohorts remains underexplored. Objectives: This study aims to assess the impact of atomoxetine on Parkinson’s disease-related FOG in a larger study population than currently reported in the literature. Patients and Methods: This randomized clinical trial was performed in Golestan Hospital, Ahvaz, Iran, in 2022. The participants were divided into group A comprising 16 patients subjected to atomoxetine treatment, and group B consisting of 16 patients administered a placebo. Three scheduled visits were conducted. Freezing of Gait Questionnaire (FOGQ) scores was documented during each visit. Results: The mean age of all participants was 62.4 ± 8.3 years, with no significant intergroup age disparity and no statistically significant gender-based distinctions between the two groups. The average disease duration in the atomoxetine group was 8.2 ± 3.1 years, while in the placebo group, it was 7.2 ± 3.4 years, with no significant divergence between the two groups. The study findings indicated no significant distinction in FOGQ scores between the treatment and placebo groups. Conclusion: Though atomoxetine did not significantly improve improvement in freezing of the gait of studied patients with Parkinson’s disease, it may cause a modest improvement in the gait freezing of some patients. Trial Registration: The trial protocol was approved by the Iranian Registry of Clinical Trials (identifier: IRCT20211008052695N1; https://irct.behdasht.gov.ir/trial/59643, ethical code; #IR.AJUMS.HGOLESTAN. REC.1400.026).

Comparison of the Effect of Selective Serotonin and Norepinephrine Reuptake Inhibitors on Bone Mineral Density with Selective Serotonin Reuptake Inhibitors and Healthy Controls

Purpose: This study investigated the association between selective serotonin reuptake inhibitor (SSRI) and selective serotonin and norepinephrine reuptake inhibitor (SNRI) use and the risk of decreased bone mineral density in postmenopausal women.Methods: Sixty-three patients diagnosed with GAD (Generalized Anxiety Disorder) were treated with venlafaxine or duloxetine from the SNRI group, and sixty patients treated with SSRIs were enrolled. Social demographic features, the Hamilton Anxiety Scale (HAS) results, and the Hamilton Depression Scale (HDS) scores of all the patients were assessed. The BMD (bone mineral density) of the patients was measured by dual-energy X-ray absorptiometry (DXA) at the femoral and lumbar regions. The BMD of the patients was compared with that of 40 healthy controls.Results: Bone measurements in the SNRI and SSRI users were similar to those of the healthy controls. However, osteopenic values were observed in the SSRI users, while normal bone density was found in the SNRI users. Also, the bone mineral densities were compared between patients using duloxetine and venlafaxine with healthy controls, showing similar T-score and Z-score values with no significant differences compared to the control group. However, while the lumbar region T-scores of those using duloxetine were within normal values, they were within the osteopenia range of venlafaxine and healthy controls.Conclusion: SNRIs may have a lower risk of developing osteoporosis than SSRIs. Of the SNRIs, duloxetine appears to be safer than venlafaxine. Further randomized controlled studies are warranted to determine whether SNRI use is risky.

Mastering Ejaculation Challenges Through Comprehensive Strategies: A Case Report

Background This case report explores the successful management of psychogenic anejaculation in a 31-year-old poultry farmer. Despite an 8-year history of anejaculation during intercourse, the patient achieved ejaculation during masturbation. Initial pharmacological intervention with duloxetine, a selective serotonin and norepinephrine reuptake inhibitor, provided partial success. To address persisting challenges, dual sex therapy and sensate focus therapy were introduced, based on the work of Masters and Johnson. The integrated approach proved effective, leading to successful ejaculation and the conception of the patient's wife. This case emphasizes the necessity of a comprehensive approach to psychological anejaculation, combining pharmacological and psychotherapeutic interventions for successful outcomes.

Post-marketing safety profile of solriamfetol: A real-world disproportionality analysis using FDA adverse event reporting system (FAERS) database

Solriamfetol is a selective dopamine and noradrenalin reuptake inhibitor applied in adult patients with excessive daytime sleepiness (EDS) associated with narcolepsy or obstructive sleep apnea (OSA). However, the post-marketing safety profile of solriamfetol in large number of people was unrevealed. The purpose of our study is to unravel solriamfetol's adverse events (AEs) in real-world to refine medication safety using Food and Drug Administration Adverse Event Reporting System (FAERS) database. We derived the data associated with solriamfetol from FAERS between 2019 and 2023, and removed the duplicated entries. We evaluated the disproportionality of solriamfetol's AEs by reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN) and the multi-item gamma Poisson shrinker (MGPS). Among 8,846,085 AE reports, 1659 recorded solriamfetol as the ‘primary suspected (PS)’. 74 significant disproportionality preferred terms (PTs) were retained across 27 organ systems. Moreover, 16 unexpected AEs not mentioned in the FDA label of solriamfetol were identified. Our findings provided the post-marketing safety profile of solriamfetol, highlighting potential solriamfetol's AEs. Further researches are significant to define the causality between solriamfetol and newly identified AEs.

The Impact of Antidepressants on COVID-19 and Post-Acute COVID-19 Syndrome: A Scoping-Review Update

On May 20, 2024, this systematic scoping review in PUBMED identified 1016 articles related to AD and COVID-19, Long COVID and SARS-COV-2. These included 10 retrospective "large scale" studies (> 20000 chart reviews), 8 prospective clinical trials (plus 4 regarding Long COVID), 11 placebo-controlled randomized (RCT) (plus 2 regarding Long COVID) and 15 meta-analyses. COVID-19: Retrospective studies with cohorts taking AD primarily for psychiatric comorbidities or chronic pain conditions directly prior to SARS-COV-2 infection described that this substance class (most studied: Selective Serotonin Re-Uptake Inhibitors (SSRI) and Selective Serotonin Noradrenaline Re-Uptake Inhibitors (SSNRI)) were associated with (i) significantly fewer SARS-COV-2 infections and (ii) a milder course of COVID-19 ("COVID-19 protection"). Ten of the 11 RCTs found regarding COVID-19 tested fluvoxamine, as this old AD appeared suitable as a prophylactic agent against severe COVID-19, taking into account its in vitro potency against the progression of intracellular sepsis cascades. Therefore, most (12 out of 15) meta-analyses also referred to fluvoxamine. They found (iii) a significant (40-70% reduction) in mortality, intubation and hospitalization rates when fluvoxamine was used as an add-on to standard therapy for mild to moderate COVID-19. When this AD was used in the early stages of the disease, it was more successful than when it was given later in advanced, severe COVID-19 (e.g. severe pneumonia, final sepsis stages). A dose dependency was observed: 2x50 mg fluvoxamine over 15 days was less effective than 2x100 or even 3x100 mg with an adverse event profile still at the placebo level. Direct comparisons with drugs approved for COVID-19 do not yet exist. A first indirect meta-analytical comparison showed an advantage of paxlovid or molnupiravir versus fluvoxamine against the development of severe COVID-19: risk reduction of 95% (I2 = N/A, but only one study) or 78% (I2=0) versus 5+-5% (I2=48). However, an add-on of fluvoxamine was still significantly more efficacious than symptom-oriented standard therapy alone. Long COVID: A common Long COVID phenotype with dominant anxiety and depression symptoms, which responds to AD, relaxation therapy and/or psychotherapy, has now been identified. Casuistics report positive effects of AD on fatigue, cognitive and autonomic dysfunctions. A first large prospective open-label RCT has just shown significantly more favourable courses, less viral load and less pro-inflammatory cytokines in the treatment of mild to moderate COVID-19 with fluvoxamine versus standard treatment, also with regard to the subsequent development of neuropsychiatric and pulmonary Long COVID or fatigue. Overall, there is promising evidence of a preventive effect of AD (especially fluvoxamine) against progression to severe COVID-19 and against the development of Long COVID. It is likely, that the entire AD substance class could be effective here. This assumption is based on the results of retrospective large scale studies, but awaits verification by better controlled studies. The potential effectiveness/efficacy (currently low and moderate confidence of the evidence for the entire substance class and specifically fluvoxamine, respectively) of fluvoxamine as an add-on against COVID-19 and possibly also directly against Long COVID could stimulate similar projects in other infectious diseases that also have the potential to pose a lasting threat to the health of those affected. We consider the evidence to date to be sufficient to be able to emphasize a possible positive effect of these substances in the psychoeducation of patients with COVID-19 or Long COVID who are already receiving AD for other conditions - especially also against the symptoms associated with the viral disease or its consequences. In regions where neither vaccines nor antiviral agents currently approved for the prevention or treatment of COVID-19 are available, AD and in particular fluvoxamine would be a cost-effective alternative to protect against a severe course, even if this AD appears to have a smaller effect against COVID-19 than the currently approved antiviral agents, but with presumably better tolerability. A direct comparative clinical trial with approved antiviral agents is still pending and should be positive to further open the door for a guideline-based recommendation of fluvoxamine (or perhaps even AD) for COVID-19 or its aftermath.

Antinociceptive activity of transdermal nanostructured surfactant-based systems containing duloxetine hydrochloride

Duloxetine hydrochloride (DLX) is a serotonin and norepinephrine reuptake inhibitor that is effective in the treatment of chronic pain. However, the drug has several adverse reactions and extensive hepatic first-pass effect. This study aimed at developing surfactant-based formulations such as liquid crystals (LCs) and evaluating the influence of the formulations on DLX skin permeation and in vivo antinociceptive activity. Thereafter, the formulations were obtained using PEG-40 Hydrogenated Castor Oil, Tween 80, licuri oil and water. The systems selected showed isotropy, high viscosity and rheology suggestive of LCs. The systems presented ability to permeate DLX through the skin. ATR-FTIR demonstrated that formulations promoted lipid disorganization and modification of protein conformation, facilitating the drug diffusion through the stratum corneum. Moreover, the formulation loaded with DLX showed high antinociceptive activity in mice (tests of acetic acid-induced abdominal writhing, formalin and tail immersion) via the transdermal route. The antinociceptive activity was close to that of morphine (i.p.). In conclusion, the LC obtained proved to be a promising system for transdermal delivery of DLX and pain management.

Smoking cessation pharmacotherapy; varenicline or bupropion?

Tobacco smoking is a worldwide health problem and one of the leading causes of premature deaths in last years. As there are lots of researches focusing on cessation strategies with attention to pharmacotherapy and behavioral counseling, the aim of this study was to compare two of the first-line FDA-approved pharmacotherapies for smoking cessation; varenicline and bupropion. This writing is an overview of researches published in Pubmed database from 2012 to 2022 with "Varenicline" and "Bupropion" as key words. Among the researches that were found, 24 articles were selected which mainly focused on comparison of these two medicines. Varenicline and bupropion are known as non-nicotinic pharmacotherapy and have been used in addition to nicotine replacement therapy for smoking cessation. Varenicline is partial agonist for α4β2 nicotinic acetyl choline receptors while bupropion, classified as an atypical antidepressant, is actually a norepinephrine and dopamine reuptake inhibitor. Although these treatments can result in some adverse effects including nausea, insomnia, anxiety, irritability, fatigue and abnormal dreams, their efficacy in reduction of craving and also maintenance of abstinence is well been studied and approved by FDA. Moreover, adverse effects are usually mild to moderate clinical symptoms which can be tolerated and also easily managed and prevented in cases. The efficacy and tolerability of varenicline and bupropion as treatments for smoking cessation is well understood. However, studies have shown that varenicline seems to be more effective in maintaining of abstinence and also reducing craving than bupropion and NRT.

Evaluation of inhibitory actions of antidepressants on muscarinic receptors assessed by a binding assay in the mouse cerebral neocortex

We investigated the inhibitory effects of 32 antidepressants on [3H]N-methylscopolamine ([3H]NMS)-specific binding in the mouse cerebral neocortex to determine which antidepressants should be recommended for patients with Alzheimer's disease (AD). Of those tested, nine antidepressants (10−4 M) exhibited less inhibitory effect on [3H]NMS-specific binding (<35%): tianeptine (a tricyclic); trazodone (a serotonin 5-HT2A blocker); sulpiride (a dopamine D2 blocker); fluvoxamine (a selective serotonin reuptake inhibitor (RI)); milnacipran, levomilnacipran, venlafaxine, and desvenlafaxine (serotonin and noradrenaline RIs); and bupropion (a noradrenaline and dopamine RI). Therefore, these antidepressants show little anticholinergic effect in the brain and are recommended for use in patients with AD.

Noradrenergic modulation of saccades in Parkinson's disease.

Noradrenaline is a powerful modulator of cognitive processes, including action decisions underlying saccadic control. Changes in saccadic eye movements are common across neurodegenerative diseases of ageing, including Parkinson's disease. With growing interest in noradrenergic treatment potential for non-motor symptoms in Parkinson's disease, the temporal precision of oculomotor function is advantageous to assess the effects of this modulation. Here, we studied the effect of 40 mg atomoxetine, a noradrenaline reuptake inhibitor, in 19 people with idiopathic Parkinson's disease using a single dose, randomized double-blind, crossover, placebo-controlled design. Twenty-five healthy adult participants completed the assessments to provide normative data. Participants performed prosaccade and antisaccade tasks. The latency, velocity and accuracy of saccades, and resting pupil diameter, were measured. Increased pupil diameter on the drug confirmed its expected effect on the locus coeruleus ascending arousal system. Atomoxetine altered key aspects of saccade performance: prosaccade latencies were faster and the saccadic main sequence was normalized. These changes were accompanied by increased antisaccade error rates on the drug. Together, these findings suggest a shift in the speed-accuracy trade-off for visuomotor decisions in response to noradrenergic treatment. Our results provide new evidence to substantiate a role for noradrenergic modulation of saccades, and based on known circuitry, we advance the hypothesis that this reflects modulation at the level of the locus coeruleus-superior colliculus pathway. Given the potential for noradrenergic treatment of non-motor symptoms of Parkinson's disease and related conditions, the oculomotor system can support the assessment of cognitive effects without limb-motor confounds on task performance.

Assessing the prevalence of Beers medication utilization in the Medicare Part D population in 2020.

Medication utilization has been increasing in the U.S. year-over-year for several decades. As older adults take more medications, there is a higher risk of them being exposed to drug-drug or drug-disease interactions. The American Geriatrics Society in 2019 updated their Beers Criteria for Potentially Inappropriate Medication (PIM) Use in Older Adults. The objective of this study was to assess the prevalence of utilization of medications included in the 2019 Beers Criteria. An analysis was conducted using the Medicare Part D Provider Utilization and Payment Data Public Use File for calendar-year 2020. Medications identified in the 2019 Beers Criteria were applied to the analysis. Two categories of medications were assessed: (1) "Avoid" and (2) "Use With Caution." In 2020, 56 million prescriptions were dispensed to Medicare patients 65 years and older that are recommended to be avoided without exception (4.7% of all prescriptions) totaling $957 million in medication costs. The most utilized medication classes in this category were benzodiazepines (25,949,994 prescriptions), "Z-drugs" (6,204,909 prescriptions), long-acting sulfonylureas (5,306,577 prescriptions), 1st-generation antihistamines (5,049,289 prescriptions), and tricyclic antidepressants (4,190,062 prescriptions). Additionally, 135 million prescriptions were dispensed to Medicare beneficiaries 65 years and older for medications which the Beers Criteria states to use caution (11.3% of all prescriptions) exceeding $2.85 billion in medication costs. The most utilized medications for this category were diuretics (74,599,126 prescriptions), selective serotonin reuptake inhibitors (30,033,121 prescriptions), serotonin and norepinephrine reuptake inhibitors (11,858,968 prescriptions), tramadol (11,450,878 prescriptions), and mirtazapine (5,737,304 prescriptions). Even with the existence of the AGS Beers Criteria for PIM Use in Older Adults and its continued updated versions, 16% of medications dispensed to Medicare Part D were potentially inappropriate. Future studies are needed to assess if this has led to worsened outcomes among older adults who utilized these PIM.

IMPACT OF PROLONGED USE OF ANTIDEPRESSANTS ON NEUROPLASTICITY

Antidepressants are widely used in the treatment of depressive and anxiety disorders and are essential for the management of these conditions. However, the impact of prolonged use of these drugs on neuroplasticity - the brain’s ability to reorganize itself, forming new neural connections - has been a topic of growing interest and debate in the scientific community. This abstract addresses the effects of prolonged use of antidepressants on neuroplasticity, considering their implications for long-term mental health. The aim of this paper is to examine and synthesize the scientific evidence on the impact of long-term use of antidepressants on neuroplasticity, with a focus on how these changes can influence the effectiveness of treatment and the long-term prognosis of patients. This study conducts a literature review on the long-term effects of antidepressants on neuroplasticity, investigating both the therapeutic potentials and the associated risks. The review focuses on how neuroplasticity can influence treatment outcomes, tolerance to antidepressants, and the impacts on specific populations, such as the elderly and individuals with hormonal variations. Antidepressants, especially selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs), have been shown to influence neuroplasticity in several ways. Pre-clinical and clinical studies suggest that prolonged use of these drugs can promote neurogenesis, particularly in the hippocampus, an area of the brain crucial for memory and learning. This neurogenic effect is associated with an improvement in depressive symptoms and the brain’s ability to adapt to new challenges. In addition, antidepressants appear to increase the expression of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), which plays a vital role in the survival and growth of neurons. The increase in BDNF levels may contribute to the restoration of synaptic connectivity, which is often compromised in patients with depression. However, there is controversy about the long-term effects of continuous use of these drugs on neuroplasticity. Some studies suggest that, despite the initial benefits, prolonged use can lead to a “rigidity” in brain plasticity, making it difficult to adapt to new treatments or therapeutic strategies. In addition, the impact on other areas of the brain, such as the prefrontal cortex, which is involved in decision-making and emotional control, is still poorly understood and requires further research. These findings raise questions about the optimal duration of treatment with antidepressants and the need for continuous monitoring of patients’ long-term mental health. Neuroplasticity may be a crucial factor in individual response to treatment and the possibility of relapse or development of resistance to treatment. Therefore, the prolonged use of antidepressants has a significant impact on neuroplasticity, initially promoting neurogenic effects and an increase in synaptic connectivity, which can improve depressive symptoms. However, the long-term effects still need to be better understood, especially with regard to the possible “rigidity” in brain plasticity and the implications for ongoing treatment. To maximize the benefits and minimize the risks, it is essential that treatment with antidepressants is carefully monitored, with attention to changes in neuroplasticity over time. More research is needed to elucidate the underlying mechanisms and guide clinical practice towards more effective and safer strategies for the management of depression and other related disorders.

Implication of locus coeruleus dysfunction in Prader–Willi syndrome: Insights from a mouse model

Prader–Willi syndrome (PWS) is a multisystemic disorder. Notably, many characteristic symptoms of PWS are correlated with locus coeruleus norepinephrine system (LC-NE) dysfunction, including impairment in arousal, learning, pain modulation, and stress-induced negative affective states. Although electrophysiological experiments in necdin-deficient mice, an established PWS animal model, have revealed decreased spontaneous neuronal firing activity in the LC and impaired excitability, the behavioral phenotypes related to LC-NE dysfunction remain unexplored. In this study, heterozygous necdin-deficient mice (B6.Cg-Ndntm1ky) were bred from wild-type (WT) females to generate WT (+m/+p) and heterozygous (+m/−p) animals. Compared to WT mice, Ndn + m/−p mice demonstrated impaired visual-spatial memory in the Y-maze test, reduced social interaction, impaired sexual recognition, and shorter falling latency on the Rotarod. Using the open field test (OFT) and elevated plus maze (EPM), we observed similar locomotion activity of Ndn + m/−p and WT mice, but Ndn + m/−p mice were less anxious. After acute restraint, Ndn + m/−p mice exhibited significant impairment in stress-induced anxiety. Additionally, the plasma norepinephrine surge following exposure to acute restraint stress was also impaired. Pretreatment with atomoxetine, a norepinephrine reuptake inhibitor aimed to enhance LC function, restored Ndn + m/−p mice to exhibit a normal response to acute restraint stress. Furthermore, by employing chemogenetic approaches to facilitate LC neuronal firing, post-stress anxious responses were also partially rescued in Ndn + m/−p mice. These data strongly suggest that LC dysfunction is implicated in the pathogenesis of stress-related neuropsychiatric symptoms in PWS. Manipulation of LC activity may hold therapeutic potential for patients with PWS.

Practical diagnosis and treatment of premenstrual syndrome and premenstrual dysphoric disorder by psychiatrists and obstetricians/gynecologists in Japan.

To investigate and compare the diagnoses and treatment of premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) from the perspectives of psychiatrists and obstetricians/gynecologists (OB/GYNs) in Japan. Between December 2021 and February 2022, a web-based survey was conducted among the members of the Japanese Association of Neuro-Psychiatric Clinics. Data from 262 psychiatrists who responded to the aforementioned survey were compared with data from 409 OB/GYNs from a survey conducted in 2021 among members of the Japanese Society of Obstetrics and Gynecology. Overall, 79.8% of psychiatrists and 97.3% of OB/GYNs were involved in practicing PMS/PMDD diagnosis and treatment. Most psychiatrists believed that PMS should be treated by OB/GYNs (74.4%) and PMDD by psychiatrists (75.6%). Only vague medical interviews were conducted by 86.6% of psychiatrists, and only 9.7% maintained a two-cycle symptom diary. Psychiatrists mostly prescribed selective serotonin/serotonin and noradrenaline reuptake inhibitor (SSRI/SNRI) continuous dosing (91.1%), followed by Kampo medicines, especially Kamishoyosan (73.3%); only 2.8% chose oral contraceptive pills, unlike OB/GYNs, while SSRI continuous (32.8%) and luteal phase dosing (20.6%) and Kampo medicine (42.1%) were the most common first-line treatments. Lifestyle guidance was prescribed by 63.6% of psychiatrists, followed by cognitive behavioral therapy (13.8%) and the symptom diary observation method (11.1%), which were similar to OB/GYNs' choices. Many Japanese psychiatrists and OB/GYNs do not base PMS/PMDD diagnoses on prospective monitoring methods using specific diagnostic criteria and therefore do not provide evidence-based treatment. Moreover, a tendency of being biased toward treatments in which the department specialized was observed.

Gepirone: A New Extended-Release Oral Selective Serotonin Receptor Agonist for Major Depressive Disorder

Objective: To evaluate the safety, efficacy, and tolerability of gepirone (Exxua) in the treatment of adult patients with major depressive disorder. Data Sources: A literature search was performed through PubMed, Embase, and PsycINFO using the following terms: Exxua, gepirone, depression, major depressive disorder, anxiety, and anxiety disorders. Study Selection and Data Extraction: Articles that were selected included English-language dominant studies, or studies that could be translated into English by the authors, with terms associated with the safety, efficacy, and/or tolerability of gepirone. Data Synthesis: Gepirone exhibits its antidepressant activity through agonism of 5HT1A serotonin receptors. Phase 3 clinical trials showed that gepirone at a dose of 20 to 80 mg was proven to be effective in the treatment of major depressive disorder in adult patients. Common adverse effects reported in clinical trials included dizziness, nausea, headache, fatigue, and insomnia. Conclusion: This review evaluates the pharmacokinetic, pharmacologic, efficacy, and safety profile of gepirone and includes a discussion on its place in therapy for the treatment of major depressive disorder. Most clinical guidelines recommend second-generation antidepressants consisting of selective serotonin reuptake inhibitors or serotonin norepinephrine reuptake inhibitors as first-line therapy options. Gepirone is expected to receive greater clinical relevance and recommendations when compared to other azapirone medications (buspirone) within practice guidelines. Gepirone could be considered as either an alternative option for patients failing first-line therapies or for initial use to avoid unwanted side effects of other therapy options in the treatment of adult patients with major depressive disorder.

Zygotic Exposure to Venlafaxine Disrupts the Circadian Locomotor Activity Behaviour in Zebrafish Larvae.

The antidepressant venlafaxine, a selective serotonin and norepinephrine reuptake inhibitor, is commonly prescribed to treat major depressive disorder and is found at high concentrations in the aquatic environment. Concerns have been raised related to the health of aquatic organisms in response to this nontargeted pharmaceutical exposure. For instance, we previously demonstrated that exposure to venlafaxine perturbs neurodevelopment, leading to behavioural alterations in zebrafish (Danio rerio). We also observed disruption in serotonin expression in the pineal and raphe, regions critical in regulating circadian rhythms, leading us to hypothesize that zygotic exposure to venlafaxine disrupts the circadian locomotor rhythm in larval zebrafish. To test this, we microinjected zebrafish embryos with venlafaxine (1 or 10 ng) and recorded the locomotor activity in 5-day-old larvae over a 24-h period. Venlafaxine deposition reduced larval locomotor activity during the light phase, but not during the dark phase of the diurnal cycle. The melatonin levels were higher in the dark compared to during the light photoperiod and this was not affected by embryonic venlafaxine deposition. Venlafaxine exposure also did not affect the transcript abundance of clock genes, including clock1a, bmal2, cry1aand per2, which showed a clear day/night rhythmicity. A notable finding was that exposure to luzindole, a melatonin receptor antagonist, decreased the locomotor activity in the control group in light, whereas the activity was higher in larvae raised from the venlafaxine-deposited embryos. Overall, zygotic exposure to venlafaxine disrupts the locomotor activity of larval zebrafish fish during the day, demonstrating the capacity of antidepressants to disrupt the circadian rhythms in behaviour. Our results suggest that disruption in melatonin signalling may be playing a role in the venlafaxine impact on circadian behaviour, but further investigation is required to elucidate the possible mechanisms in larval zebrafish.

Efficacy and Safety of TAS-303 in Female Patients With Stress Urinary Incontinence: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial.

We aimed to evaluate the therapeutic efficacy and safety of TAS-303, a highly selective noradrenaline reuptake inhibitor, in Japanese women with stress urinary incontinence (SUI). A double-blind, placebo-controlled, phase 2 study randomized women with SUI symptoms to once-daily oral administration of TAS-303 18 mg or placebo for 12 weeks. The primary endpoint was percent change from baseline to Week 12 in mean SUI episode frequency per 24 hours (SUIEF) in the per-protocol set. The secondary endpoints were the proportion of patients with ≥ 50% reduction in mean SUIEF, incontinence episode frequency, incontinence amount, health-related quality of life, and safety in the full analysis set. In total, 231 patients were randomized to TAS-303 (n = 116) or placebo (n = 115). At Week 12, TAS-303 had superior efficacy to placebo, with a least squares mean percent change in mean SUIEF of -57.7% vs -46.9%, respectively, in the per-protocol set (least squares mean difference -10.8%; P = .036). TAS-303 showed some evidence of improved incontinence episode frequency, incontinence amount, and health-related quality of life (although not statistically significant) at Week 12 vs placebo in the full analysis set. The between-group difference in SUIEF improvement was more clearly confirmed in patients with ≥ 2 SUI episodes daily at baseline. All adverse events (AEs) with TAS-303 were mild or moderate; there were no serious AEs, AEs leading to discontinuation, or nervous system- or gastrointestinal-related (eg, nausea or vomiting) adverse drug reactions. Once-daily TAS-303 18 mg showed superior efficacy to placebo for the treatment of SUI in Japanese women, with an adequate safety profile. ClinicalTrials.gov: NCT04512053; Japan Registry of Clinical Trials: jRCT2080225307 (JapicCTI-205403 before site integration).