Norepinephrine Reuptake Inhibitor Research Articles

Heterogeneity in Antidepressant Treatment and Major Depressive Disorder Outcomes Among Clinicians

While abundant work has examined patient-level differences in antidepressant treatment outcomes, little is known about the extent of clinician-level differences. Understanding these differences may be important in the development of risk models, precision treatment strategies, and more efficient systems of care. To characterize differences between outpatient clinicians in treatment selection and outcomes for their patients diagnosed with major depressive disorder across academic medical centers, community hospitals, and affiliated clinics. This was a longitudinal cohort study using data derived from electronic health records at 2 large academic medical centers and 6 community hospitals, and their affiliated outpatient networks, in eastern Massachusetts. Participants were deidentified clinicians who billed at least 10 International Classification of Diseases, Ninth Revision (ICD-9) or Tenth Revision (ICD-10) diagnoses of major depressive disorder per year between 2008 and 2022. Data analysis occurred between September 2023 and January 2024. Heterogeneity of prescribing, defined as the number of distinct antidepressants accounting for 75% of prescriptions by a given clinician; proportion of patients who did not return for follow-up after an index prescription; and proportion of patients receiving stable, ongoing antidepressant treatment. Among 11 934 clinicians treating major depressive disorder, unsupervised learning identified 10 distinct clusters on the basis of ICD codes, corresponding to outpatient psychiatry as well as oncology, obstetrics, and primary care. Between these clusters, substantial variability was identified in the proportion of selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, and tricyclic antidepressants prescribed, as well as in the number of distinct antidepressants prescribed. Variability was also detected between clinician clusters in loss to follow-up and achievement of stable treatment, with the former ranging from 27% to 69% and the latter from 22% to 42%. Clinician clusters were significantly associated with treatment outcomes. Groups of clinicians treating individuals diagnosed with major depressive disorder exhibit marked differences in prescribing patterns as well as longitudinal patient outcomes defined by electronic health records. Incorporating these group identifiers yielded similar prediction to more complex models incorporating individual codes, suggesting the importance of considering treatment context in efforts at risk stratification.

Central nervous system active medication use in Medicare enrollees receiving home health care: association with chronic pain and anxiety level.

No comparative effectiveness data exist on nonopioid analgesics and nonbenzodiazepine anxiolytics to treat pain with anxiety. We examined the relationship between drug class and central nervous system (CNS) active drug polypharmacy on pain and anxiety levels in Medicare enrollees receiving home health (HH) care. This retrospective cohort study included enrollees with diagnoses and 2+ assessments of pain and anxiety between HH admission and discharge. Three sets of linear regression difference-in-reduction analyses assessed the association of pain or anxiety reduction with number of drugs; drug type; and drug combinations in those with daily pain and daily anxiety. Logistic regression analysis assessed the effect of medication number and class on less-than-daily pain or anxiety at HH discharge. A sensitivity analysis using multinomial regression was conducted with a three-level improvement to further determine clinical significance. Of 85,403 HH patients, 43% received opioids, 27% benzodiazepines, 26% gabapentinoids, 32% selective serotonin reuptake inhibitors, and 8% serotonin and norepinephrine reuptake inhibitors (SNRI). Furthermore, 75% had depression, 40% had substance use disorder diagnoses, and 6.9% had PTSD diagnoses. At HH admission, 83%, 35%, and 30% of patients reported daily pain, daily anxiety, and both, respectively. Central nervous system polypharmacy was associated with worse pain control and had no significant effect on anxiety. For patients with daily pain plus anxiety, pain was best reduced with one medication or any drug combination without opioid/benzodiazepine; anxiety was best reduced with combinations other than opiate/benzodiazepine. Gabapentinoids or SNRI achieved clinically meaningful pain control. Selective serotonin reuptake inhibitors provided clinically meaningful anxiety relief.

Insulin resistance, clinical presentation and resistance to selective serotonin and noradrenaline reuptake inhibitors in major depressive disorder

BackgroundThe understanding of mechanisms underlying non-response to antidepressants is limited. The latest data highlights the role of insulin resistance (IR) in major depressive disorder (MDD) pathophysiology, presentation, and treatment efficacy. This work aimed to assess IR in MDD and explore the relationships between IR, MDD presentation and non-response to selective serotonin and noradrenaline reuptake inhibitors (SNRI).Methods67 MDD individuals: 36 responsive (MDD T[+]), 31 non-responsive (MDD T[−]) to SNRI and 30 healthy controls were recruited. The treatment response criteria were: Clinical Global Impression Scale-Improvement score of 1 or 2 after ≥ 8 weeks of treatment. Participants were assessed by physician and self-report tools measuring depression, anhedonia, anxiety, bipolarity, sleep quality. Blood samples were collected to assess fasting glucose and insulin levels and calculate HOMA-IR (homeostasis model assessment of insulin resistance).ResultsMDD T[-] vs. MDD T[+] had significantly higher body mass index, insulin levels, and HOMA-IR. MDD T[-] presented higher levels of depressed mood, appetite/weight changes, loss of interest, energy, overall depressive symptoms, and sleep impairment; some evaluations suggested higher anhedonia and anxiety in MDD T[-] vs. MDD T[+]. Insulin and IR were weakly but significantly correlated with the severity of psychomotor symptoms, energy level, thoughts of death/suicide, self-criticism, appetite/weight, depressed mood symptoms, sleep problems. IR was weakly but significantly correlated with anhedonia.ConclusionIR appears to be linked to depressive symptoms characteristic of the “metabolic” MDD subtype, such as psychomotor changes, energy level, anhedonia, sleep problems, appetite/weight changes, state and trait anxiety, sleep quality, and non-response to SNRI.

High rate of potentially inappropriate medication use in older people: a case–control study

Annually, 172 million fall events cause temporary or permanent impairment in older adults, and this number is increasing. Contributing factors that increase the risk for falls include age, polypharmacy, and malnutrition. This study evaluated medications mainly included in the EU(7)-PIM (potentially inappropriate medication) list. From March 21, 2022, to July 6, 2022, 945 patients who experienced a fall and visited the Department of Emergency Medicine at the Albert Szent-Györgyi Health Centre of the University of Szeged in Hungary. Data from 886 patients were collected (study group). The control group included 1364 patient data collected from three general practice in Hungary. The use of ≥ 2 EU(7)-PIM drugs was found to be associated with increased risk for falls (adjusted odds ratio [AOR], 1.38; 95% confidence interval [CI] 1.01–1.88). Piracetam (AOR, 1.81; 95% CI, 1.28–2.57) and trimetazidine (AOR, 1.62; 95% CI, 1.17–2.24) were associated with increased risk for falls. Doxazosin was associated with a low risk for falls (AOR, 0.59; 95% CI, 0.41–0.86). Tiapride (AOR, 3.54; 95% CI, 1.75–7.17), gliclazide (AOR, 1.57; 95% CI, 1.02–2.43), and vinpocetine (AOR, 1.95; 95% CI, 1.29–2.95) are not included in the EU(7)-PIM list; however, they are associated with increased risk for falls. Long-acting benzodiazepines (AOR, 1.79; 95% CI, 1.20–2.68), antidepressants (AOR, 1.89; 95% 95% CI, 1.37–2.61), serotonin–norepinephrine reuptake inhibitor (AOR, 2.82; 95% CI, 1.41–5.67; p < 0.01), and selective serotonin reuptake inhibitor (AOR, 1.88; 95% CI, 1.24–2.85) were also associated with increased risk for falls. However, Z-drugs were associated with a low risk for falls (AOR, 0.57; 95% CI, 0.36–0.92). With the help of this tool, trimetazidine and piracetam are filtered as EU(7)-PIM drugs associated with increased risk for falls.

Risk of stress cardiomyopathy associated with selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors: a real-world pharmacovigilance analysis

Selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are reported to cause stress cardiomyopathy (SC). This study evaluated the association between SSRI/SNRI use and the occurrence of cardiomyopathy in the publicly available U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database. Disproportionate analysis and likelihood ratio tests were used to identify risk associated with SSRIs or SNRIs and the incidence of SC, using data from between from 2012 to 2022 acquired from the FAERS database. The study identified 132 individual case safety reports (ICSRs) of SC associated with SSRIs or SNRIs. Venlafaxine (48%) and fluoxetine (27%) were the most common antidepressants of the ICSRs. Approximately 80% of SC cases were reported in females, with individuals aged 45–65 years identified as a high-risk population. Both venlafaxine (ratio-scale information component [RSIC] 2.54, 95% CI 2.06–3.04) and fluoxetine (RSIC 3.20, 95% CI 2.31–4.47) were associated with SC, with likelihood ratio estimates of 3.55 (p = 0.02) for venlafaxine and 4.82 (p = 0.008) for fluoxetine. The median time to cardiomyopathy onset was 20 days, with hospitalization reported in 48.33% of patients. Venlafaxine and fluoxetine were associated with SC risk, particularly in middle-aged women. Caution should be exercised when using SSRIs or SNRIs combined with other serotonergic medications.

Safety and tolerability of esketamine nasal spray versus quetiapine extended release in patients with treatment resistant depression

In ESCAPE-TRD (NCT04338321), esketamine nasal spray (NS) significantly increased the probability of remission at Week 8, and of being relapse-free through Week 32 after remission at Week 8, versus quetiapine extended release (XR) in patients with treatment resistant depression (TRD). Here, we explore the time course, burden and consequences of treatment emergent adverse events (TEAEs) in the phase IIIb ESCAPE‑TRD trial. Patients with TRD were randomised 1:1 to esketamine NS or quetiapine XR, dosed per label alongside an ongoing selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor. In this secondary publication, safety analyses (comprising patients who received ≥1 dose of study treatment) included incidence, severity and durations (Kaplan‑Meier method) of TEAEs, and subsequent dispositional changes. P values were not adjusted for multiple testing. 336 patients were randomised to esketamine NS and 340 to quetiapine XR; 334 and 336 received ≥1 dose of study treatment, respectively. TEAEs were significantly more common with esketamine NS than quetiapine XR (91.9 % versus 78.0 %; p < 0.001), but were typically mild/moderate and transient in nature: a greater proportion resolved on the same-day (92.0 % versus 12.1 %) and lead to treatment discontinuation in significantly fewer patients (4.2 % versus 11.0 %, respectively; p < 0.001). The proportion of days spent with TEAEs was significantly lower with esketamine NS than quetiapine XR (median: 11.9 % versus 21.3 %; p < 0.001). Although more frequent with esketamine NS, TEAEs were typically transient and mild, with discontinuation less likely versus quetiapine XR. Data were consistent with established safety profiles, with no new safety signals identified. Alongside greater efficacy, the demonstrably more favourable tolerability profile of esketamine NS versus quetiapine XR further supports its use for TRD.

Development of Two Green and High-Throughput Microwell Spectrometric Platforms for Determination of Reboxetine, the First FDA-Approved Selective Noradrenaline Reuptake Inhibitor Antidepressant Drug.

Reboxetine (RBX) is the first FDA-approved antidepressant drug of the selective noradrenaline reuptake inhibitors class. There is a serious need for a convenient analytical tool for the quantitation of RBX in its dosage form. This study aims toward the development and validation of two green and high-throughput microwell spectrometric platforms for the pharmaceutical analysis of RBX. The two platforms, abbreviated as MW-AB and MW-FL, involved microwell-based analysis assisted with a multifunction microplate plate reader for measuring absorbance and fluorescence signals, respectively. The MW-AB and MW-FL platforms involved the formation of colored and fluorescent derivatives upon the reaction of RBX with oxidized pyrocatechol reagent (OPC) and tetracyanoquinodimethane (TCNQ), respectively. The absorbance of colored RBX-OPC derivative at 520 nm, and the fluorescence of RBX-TCNQ charge transfer complex at 283 and 484 nm for excitation and emission, respectively. The optimum conditions of both reactions were established, their molar ratios were determined, and reaction mechanisms were postulated. Both platforms were optimized and validated according to the guidelines of the International Council on Harmonization. The limits of quantitation were 19.6 µg/mL and 27 ng/mL for MW-AB and MW-FL, respectively. Both platforms were applied with excellent reliability to the quantitation of RBX content in Edranox® tablets and their drug uniformity. The greenness levels of both platforms were assessed by two comprehensive tools, and the results confirmed the high level of greenness for both platforms. Both platforms involved one-step reactions, adapted microwell analysis, and simultaneous handling of large number of samples. Therefore, they have the advantages of greenness and high-throughput analysis. The proposed two platforms are valuable tools for the rapid quantitation of RBX.

Serotonergic and dopaminergic neurons in the dorsal raphe are differentially altered in a mouse model for parkinsonism

Parkinson’s disease (PD) is characterized by motor impairments caused by degeneration of dopamine neurons in the substantia nigra pars compacta. In addition to these symptoms, PD patients often suffer from non-motor comorbidities including sleep and psychiatric disturbances, which are thought to depend on concomitant alterations of serotonergic and noradrenergic transmission. A primary locus of serotonergic neurons is the dorsal raphe nucleus (DRN), providing brain-wide serotonergic input. Here, we identified electrophysiological and morphological parameters to classify serotonergic and dopaminergic neurons in the murine DRN under control conditions and in a PD model, following striatal injection of the catecholamine toxin, 6-hydroxydopamine (6-OHDA). Electrical and morphological properties of both neuronal populations were altered by 6-OHDA. In serotonergic neurons, most changes were reversed when 6-OHDA was injected in combination with desipramine, a noradrenaline (NA) reuptake inhibitor, protecting the noradrenergic terminals. Our results show that the depletion of both NA and dopamine in the 6-OHDA mouse model causes changes in the DRN neural circuitry.

Serotonergic and dopaminergic neurons in the dorsal raphe are differentially altered in a mouse model for parkinsonism.

Parkinson's disease (PD) is characterized by motor impairments caused by degeneration of dopamine neurons in the substantia nigra pars compacta. In addition to these symptoms, PD patients often suffer from non-motor comorbidities including sleep and psychiatric disturbances, which are thought to depend on concomitant alterations of serotonergic and noradrenergic transmission. A primary locus of serotonergic neurons is the dorsal raphe nucleus (DRN), providing brain-wide serotonergic input. Here, we identified electrophysiological and morphological parameters to classify serotonergic and dopaminergic neurons in the murine DRN under control conditions and in a PD model, following striatal injection of the catecholamine toxin, 6-hydroxydopamine (6-OHDA). Electrical and morphological properties of both neuronal populations were altered by 6-OHDA. In serotonergic neurons, most changes were reversed when 6-OHDA was injected in combination with desipramine, a noradrenaline (NA) reuptake inhibitor, protecting the noradrenergic terminals. Our results show that the depletion of both NA and dopamine in the 6-OHDA mouse model causes changes in the DRN neural circuitry.

Obtainment of prescribed analgesics among patients with Lyme neuroborreliosis; a nationwide, population-based matched cohort study

BackgroundRadicular pain is the most predominant symptom among adults with Lyme neuroborreliosis (LNB) but the duration preceding and following diagnosis remains unknown. We aimed to investigate whether patients with LNB have increased obtainment of analgesics before and after diagnosis and for how long. MethodsWe performed a nationwide, population-based, matched cohort study (2009–2021). all Danish residents with LNB (positive Borrelia burgdorferi intrathecal antibody index test and cerebrospinal fluid pleocytosis) were included. To form a comparison cohort, individuals from the general population were randomly extracted and matched 10:1 to patients with LNB on age and sex. Outcomes were obtainment of simple analgesics, antiepileptics, tricyclic antidepressants, serotonin and noradrenaline reuptake inhibitors, tramadol, and other opioids. We calculated monthly and six-monthly proportions of individuals with obtainment of analgesics and absolute risk differences. Results1,056 patients with LNB and 10,560 comparison cohort members were included. An increased proportion of patients with LNB obtained analgesics from 3 months before study inclusion, especially simple analgesics, tramadol, and other opioids. Within the 0–1-month period after study inclusion, patients with LNB most frequently obtained simple analgesics (15 %), antiepileptics (11 %), and tramadol (10 %). Thereafter, obtainment of analgesics declined within a few months. A slightly larger proportion of patients with LNB obtained antiepileptics up to 2.5 years after diagnosis. ConclusionsUp to 3 months preceding diagnosis, LNB was preceded by increased obtainment of analgesics, which suggests diagnostic delay. Importantly, most patients with LNB did not obtain analgesics after the immediate disease course, although obtainment remained more frequent up to 2.5 years after.

Therapeutic Approaches for Treatment and Management of Depressive Disorder: A Comprehensive Review

Depression, which is associated with high levels of cognitive and functional activity, melancholy, reduced activity, difficulty understanding, failure to focus, dietary abnormalities, sleep disturbances, and emotions of feelings of sadness, suicidal thoughts, and lack of hope are symptoms of a psychoneurotic disorder. It is a common and recurring disorder with a high morbidity and death rate throughout the world. Despite advances in depression treatment, such as selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), there remain several unmet clinical requirements in terms of effectiveness and adverse effects. These requirements range from enhanced to decreased side effects like emesis and erectile problems in treatment-resistant patients. There are a variety of combination therapies available to meet these needs. Several combination medicines and novel strategies have been found, all of which have the potential to improve one or so more areas. The kinds of targets and methods being used are extremely diverse. Therapeutic approaches, on the one hand, provide the benefits of SSRIs while including alternative routes in an attempt to improve efficacy or reduce undesirable effects. Neurotrophins (BDNF, IGF) are more novel targets on the other end of the spectrum, based on the most recent research suggesting antidepressants enhance neurogenesis. Antidepressants act by blocking many proteins, such as neurotransmitter transporters and G-protein coupled receptor families, in the brain. Some of the computational approaches that are useful for uncovering drug action mechanisms and are important for drug development are molecular docking, molecular dynamics, and drug candidates.

Microstructural properties of attention-related white matter tracts are associated with the renewal effect of extinction

The tendency to show the renewal effect of extinction appears as an intra-individually stable, reproducible processing strategy associated with differential patterns of BOLD activation in hippocampus, iFG and vmPFC, as well as differential resting-state functional connectivity between prefrontal regions and the dorsal attention network. Also, pharmacological modulations of the noradrenergic system that influence attentional processing have partially different effects upon individuals with (REN) and without (NoREN) a propensity for renewal. However, it is as yet unknown whether REN and NoREN individuals differ regarding microstructural properties in attention-related white matter (WM) regions, and whether such differences are related to noradrenergic processing. In this diffusion tensor imaging (DTI) analysis we investigated the relation between microstructural properties of attention-related WM tracts and ABA renewal propensity, under conditions of noradrenergic stimulation by means of the noradrenergic reuptake inhibitor atomoxetine, compared to placebo.Fractional anisotropy (FA) was higher in participants with noradrenergic stimulation (ATO) compared to placebo (PLAC), the effect was predominantly left-lateralized and based on the comparison of ATO REN and PLAC REN participants. In REN participants of both treatment groups, FA in several WM tracts showed a positive correlation with the ABA renewal level, suggesting higher renewal levels were associated with higher microstructural integrity. These findings point towards a relation between microstructural properties of attention-related WM tracts and the propensity for renewal that is not specifically dependent on noradrenergic processing.

Growing evidence of pharmacotherapy effectiveness in managing attention-deficit/hyperactivity disorder in young children with or without autism spectrum disorder: a minireview.

Many children with autism spectrum disorder (ASD) also have attention-deficit/hyperactivity disorder (ADHD). ADHD in children is associated with increased risk of negative outcomes, and early intervention is critical. Current guidelines recommend psychosocial interventions such as behavioral training as the first line of therapy in managing ADHD symptoms in children with or without ASD. Where symptoms are refractory to these interventions, medications such as stimulants, α2-adrenergic agonist inhibitors, selective norepinephrine reuptake inhibitors, and second-generation antipsychotics are recommended. However, these pharmacotherapies do not have regulatory approval for use in children of preschool age, and evidence on their safety and efficacy in this population has historically been very limited. Since publication of the current guidelines in 2020, several new randomized controlled trials and real-world studies have been published that have investigated the efficacy and tolerability of these medications in preschool children with ADHD, with or without comorbid ASD. Here, we provide a review of the key findings of these studies, which suggest that there is growing evidence to support the use of pharmacological interventions in the management of ADHD in preschool children with comorbid ASD.

MODL-12. REPURPOSING SSRI/SNRI TARGETING NEUROTRANSMITTER SIGNALING TO SENSITIZE DMG TO CDK9 INHIBITORS

Abstract BACKGROUND Diffuse Midline Glioma (DMG) comprise a subset of aggressive pediatric brain tumors with few effective therapies. Cyclin-dependent kinase 9 inhibitors (CDK9i) like zotiraciclib (ZTR) are in clinical trials for adult and pediatric glioma, but resistance frequently develops. In this study, we find that co-treatment with CDK9i and brain penetrant, FDA-approved drugs targeting neurotransmitter signaling alters DMG transcription and reduces DMG growth and tumorigenesis. METHODS We conducted drug screens to assess DMG response to a sub-threshold dose of ZTR combined with a library of ~220 bioactive and FDA-approved compounds. Combinatorial effects of CDK9i+SSRI/SNRI treatment were confirmed through in vitro dose curve studies and in orthotopic DMG xenograft models. We identified downstream targets of CDK9i+SSRI/SNRI treatment through phospho-proteomic profiling, RNAseq analysis, immunofluorescence staining, and Western blotting. RESULTS Our targeted drug screens identified SSRIs (selective serotonin reuptake inhibitors) and SNRIs (serotonin and norepinephrine reuptake inhibitors) that increase DMG sensitivity to a low dose of zotiraciclib (ZTR). Follow-up studies confirm that combinations of structurally distinct CDK9i (ZTR, AZD4573) and SSRI/SNRI (sertraline, duloxetine) synergistically reduce DMG growth in neurospheres, induce the apoptotic marker cleaved caspase 3, and reduce the expression of proliferation markers. Additional proteogenomic analyses define downstream targets of CDK9i+SSRI co-treatment, including differential phosphorylation of chromatin regulators and RNA Polymerase 2 (Pol2)-associated elongation factors and splicing machinery. Further RNAseq studies reveal robust transcriptional changes induced by CDK9i+SSRI treatment characterized by altered expression of developmental and synaptic signaling genes. Finally, pilot pre-clinical studies find that CDK9i+SSRI treatment reduces tumor growth and increases progression free survival in a DMG xenograft model. CONCLUSIONS We have identified synergistic CDK9i+SSRI drug combinations that can be applied to alter malignant gene regulation and reduce DMG growth in vitro and in xenografts. These studies provide a basis for a drug-repurposing strategy to combine SSRI/SNRI and CDK9 inhibitors for DMG treatment.

Formulation and evaluation of sustained release floating tablets of venlafaxine using natural polymers

Over the past three decades, oral controlled-release dosage forms have been developed due to their therapeutic advantages, such as ease of administration, patient compliance, and flexibility in formulation. However, this approach has faced physiological difficulties, such as the inability to contain and position the controlled drug delivery system within the desired region of the gastrointestinal tract (GIT) due to variable gastric emptying and motility. Venlafaxine is an antidepressant and a serotonin and norepinephrine reuptake inhibitor (SNRI). Its active metabolite, desvenlafaxine, works by blocking the reuptake of serotonin and norepinephrine, which are key neurotransmitters in mood regulation. Gastroretentive dosage forms can stay in the gastric region for several hours and significantly prolong the gastric residence time of drugs. Natural materials have been extensively used in drug delivery because they are readily available, cost-effective, eco-friendly, capable of many chemical modifications, potentially degradable, and compatible due to their natural origin. Keywords: Sustained Release Floating Tablets, Venlafaxine,

Adolescent stress differentially modifies dopamine and norepinephrine release in the medial prefrontal cortex of adult rats

Adolescent stress (AS) has been associated with higher vulnerability to psychiatric disorders such as schizophrenia, depression, or drug dependence. Moreover, the alteration of brain catecholamine (CAT) transmission in the medial prefrontal cortex (mPFC) has been found to play a major role in the etiology of psychiatric disturbances. We investigated the effect of adolescent stress on CAT transmission in the mPFC of freely moving adult rats because of the importance of this area in the etiology of psychiatric disorders, and because CAT transmission is the target of a relevant group of drugs used in the therapy of depression and psychosis. We assessed basal dopamine (DA) and norepinephrine (NE) extracellular concentrations (output) by brain microdialysis in in the mPFC of adult rats that were exposed to chronic mild stress in adolescence. To ascertain the role of an altered release or reuptake, we stimulated DA and NE output by administering either different doses of amphetamine (0.5 and 1.0 mg / kg s.c.), which by a complex mechanism determines a dose dependent increase in the CAT output, or reboxetine (10 mg/kg i.p.), a selective NE reuptake inhibitor. The results showed the following: (i) basal DA output in AS rats was lower than in controls, while no difference in basal NE output was observed; (ii) amphetamine, dose dependently, stimulated DA and NE output to a greater extent in AS rats than in controls; (iii) reboxetine stimulated NE output to a greater extent in AS rats than in controls, while no difference in stimulated DA output was observed between the two groups. These results show that AS determines enduring effects on DA and NE transmission in the mPFC and might lead to the occurrence of psychiatric disorders or increase the vulnerability to drug addiction.

Antidepressant-related microstructural changes in the external capsule.

Several magnetic resonance imaging (MRI) studies have reported that antidepressant medications are strongly linked to brain microstructural alterations. Notably, external capsule alterations have been reported to be a biological marker for therapeutic response. However, prior studies did not investigate whether a change in the neurite density or directional coherence of white matter (WM) fibers underlies the observed microstructural alterations. This MRI-based case-control study examined the relationship between patients' current use of antidepressant medications and advanced measurements of external capsule WM microstructure derived from multishell diffusion imaging using neurite orientation dispersion and density imaging (NODDI). The study compared a group of thirty-five participants who were taking antidepressant medications comprising selective serotonin reuptake inhibitors (SSRIs) (n = 25) and serotonin and norepinephrine reuptake inhibitors (SNRIs) with a control group of thirty-five individuals matched in terms of age, sex, race, and atherosclerotic cardiovascular risk factors. All participants were selected from the Dallas Heart Study phase 2, a multi-ethnic, population-based cohort study. A series of multiple linear regression analyses were conducted to predict microstructural characteristics of the bilateral external capsule using age, sex, and antidepressant medications as predictor variables. There was significantly reduced neurite density in the bilateral external capsules of patients taking SSRIs. Increased orientation dispersion in the external capsule was predominantly seen in patients taking SNRIs. Our findings suggest an association between specific external capsule microstructural changes and antidepressant medications, including reduced neurite density for SSRIs and increased orientation dispersion for SNRIs.

Norepinephrine Reuptake Inhibition, an Emergent Treatment for Neurogenic Orthostatic Hypotension.

The NET (norepinephrine transporter) is situated in the prejunctional plasma membrane of noradrenergic neurons. It is responsible for >90% of the norepinephrine uptake that is released in the autonomic neuroeffector junction. Inhibitors of this cell membrane transporter, known as norepinephrine reuptake inhibitors (NRIs), are commercially available for the treatment of depression and attention deficit hyperactivity disorder. These agents increase norepinephrine levels, potentiating its action in preganglionic and postganglionic adrenergic neurons, the latter through activation of α-1 adrenoreceptors. Previous studies found that patients with neurogenic orthostatic hypotension can improve standing blood pressure and reduce symptoms of neurogenic orthostatic hypotension after a single administration of the selective NRI atomoxetine. This effect was primarily observed in patients with impaired central autonomic pathways with otherwise normal postganglionic sympathetic fibers, known as multiple system atrophy. Likewise, patients with normal or high norepinephrine levels may benefit from NRIs. The long-term efficacy of NRIs for the treatment of neurogenic orthostatic hypotension-related symptoms is currently under investigation. In summary, an in-depth understanding of the pathophysiology of neurogenic orthostatic hypotension resulted in the discovery of a new therapeutic pathway targeted by NRI.

Medical treatment of pediatric obesity

Background: The increasing prevalence of pediatric obesity over the past few decades has become a serious public health concern. Quarantine measures during the coronavirus disease pandemic have led to an increase in childhood obesity rates. Children with obesity are at greater risk for type 2 diabetes, hypertension, dyslipidemia, polycystic ovary syndrome, obstructive sleep apnea, and adult obesity. Lifestyle modification therapy is the firstline treatment for pediatric obesity. Pharmacotherapy is the next logical treatment option in patients in whom lifestyle modifications alone are ineffective.Current Concepts: Anti-obesity medications for pediatric obesity include metformin, orlistat, glucagon-like peptide-1 agonists, phentermine, and phentermine/topiramate combination. Metformin, a medication used for type 2 diabetes has not been approved for treatment of pediatric obesity. Orlistat, a lipase inhibitor, prevents fat absorption from the human diet. Liraglutide, a glucagon-like peptide-1 agonist, is associated with decreased gastric emptying, increased satiety, and appetite suppression. Phentermine, a norepinephrine reuptake inhibitor, is approved by the Food and Drug Administration for short-term treatment of patients aged &gt;16 years. Phentermine/topiramate is a combination of the conventional anti-obesity medication, phentermine and an antiepileptic agent, topiramate that is commonly associated with weight loss as an adverse effect.Discussion and Conclusion: Anti-obesity treatment may serve as the next logical therapeutic option for pediatric obesity. However, sufficient lifestyle modification therapy should be attempted before considering medication, and anti-obesity medications should preferably be used in combination with lifestyle modifications. Monitoring growth and pubertal development during anti-obesity treatment is essential to ensure healthy development of children and adolescents.

Efficacy of Duloxetine With Arthrocentesis in the Management of TMJ Internal Derangement.

Temporomandibular joint (TMJ) arthrocentesis is one of the most commonly used non-invasive surgical interventions in the treatment of refractory pain and dysfunction associated with internal derangement. Several adjunctive therapies have been used in combination with arthrocentesis in an attempt to increase its efficacy and long-term maintenance. Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor which is used in different chronic pain conditions. This study aimed to assess the efficacy of duloxetine in combination with arthrocentesis compared with arthrocentesis alone. Twenty-eight patients with chronic TMJ pain were included and randomly allocated into 2 groups (control and study groups). The control group included patients who underwent TMJ arthrocentesis only, and the study group included patients who underwent arthrocentesis followed by giving duloxetine (30mg) orally twice daily for 3 months. Pain, maximum mouth opening, and level of anxiety and depression were assessed preoperatively and followed at regular intervals of 1 week, 1 month, 3 months, and 6 months postoperatively. Pain was significantly reduced in both groups at all postoperative intervals and was significantly lower in the study group than the control group at 6 months. Maximum mouth opening increased significantly in both groups, but the difference between them was not significant. Level of anxiety and depression was significantly decreased in both groups, with no statistically significant difference between them. The results of this study indicate that duloxetine in combination with arthrocentesis may provide effective and long-term pain control; however, its use is associated with a higher risk of adverse events.