Norepinephrine Reuptake Inhibitor Research Articles

A phase 3, multicenter, double-blind, randomized, placebo-controlled clinical trial to verify the efficacy and safety of ansofaxine (LY03005) for major depressive disorder

Major depressive disorder (MDD) is the most prevalent form of depression and is becoming a great challenge for public health and medical practice. Although first-line antidepressants offer therapeutic benefits, about 35% of depressed patients are not adequately treated, creating a substantial unmet medical need. A multicenter, double-blind, randomized, placebo-controlled phase 3 clinical trial was conducted in patients with MDD in China to assess the efficacy and safety of ansofaxine (LY03005), a potential triple reuptake inhibitor of serotonin, norepinephrine, and dopamine. Eligible 588 MDD patients were included and randomly assigned (1:1:1) to 8-week treatment with ansofaxine 80 mg/day(n = 187), ansofaxine 160 mg/day(n = 186), or placebo(n = 185). The primary efficacy endpoint was the Montgomery-Åsberg Depression Rating Scale (MADRS) total score change from baseline to the end of the study. Safety indexes included adverse events, vital signs, physical examination, laboratory tests, 12-lead electrocardiogram (ECG), and evaluation of suicide tendency and sexual function. Significant differences were found in mean changes in MADRS total score at week 8 in the two ansofaxine groups (80 mg, −20.0; 160 mg, −19.9) vs. placebo (−14.6; p < 0.0001). All doses of ansofaxine were generally well-tolerated. Treatment-emergent adverse events (TEAEs) were reported by 137 (74.46%) patients in ansofaxine 80 mg group, 144 (78.26%) patients in ansofaxine 160 mg and 125 (67.93%) patients in the placebo group. The incidence of treatment-related adverse events (TRAEs) was 59.2% (109 patients), 65.22% (120 patients) in the 80, 160 mg ansofaxine groups, and 45.11% (83 patients) in the placebo group. The initial results of this trial indicate that ansofaxine at both the 80 mg/day and 160 mg/day was effective and safe in adult patients with MDD. ClinicalTrials.gov Identifier: NCT04853407.

Latest updates on the serotonergic system in depression and anxiety.

Psychiatric disorders are among the leading causes of global health burden, with depression and anxiety being the most disabling subtypes. The two common disorders, depression and anxiety, usually coexist and are pathologically polygenic with complicated etiologies. Current drug-based therapies include selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, and 5-hydroxytryptamine partial agonists. However, these modalities share common limitations, such as slow onset and low efficacy, which is why potential mechanistic insights for new drug targets are needed. In this review, we summarize recent advances in brain localization, pathology, and therapeutic mechanisms of the serotonergic system in depression and anxiety.

Strategy for the management and prevention of psycho-emotional disorders in the GP’s practice

Psycho-emotional disorders, such as anxiety disorders, acute and chronic stress, are significant risk factors for the development and complicated course of both major cardiovascular and other common chronic non-communicable diseases. The psycho-emotional disorders significantly reduce patients’ motivation and adherence to lifestyle changes and drug therapy, significantly worse quality of life, increase the risk of disability and healthcare system expenditures. The topicality of the issues of diagnosis and management of psycho-emotional disorders in the general practitioner’s practice is caused, on the one hand, by high rates of these disorders in patients with cardiovascular and other chronic diseases, deterioration in quality of life and an increase in adverse outcomes, and on the other hand, inadequate awareness of the risks associated with the sphere of psycho-emotional status in patients. The management of psycho-emotional disorders includes both pharmacological and non-pharmacological treatments. Antidepressants that fall into the class of selective serotonin or serotonin and norepinephrine reuptake inhibitors are the first-line drugs used for the treatment of most of the disorders discussed. However, prescription of these drugs requires to take into account a wide range of possible side effects in patients with chronic diseases, including CVDs. Drugs that have fast onsets of sedative and anti-anxiety action, also known as tranquilizers, are more widely used in real-world clinical practice. Tofisopam is the most promising from this group of drugs in therapeutic and cardiological practice. The efficacy and safety of tofisopam have been studied in numerous studies in patients with chronic non-communicable diseases and a wide range of anxiety disorders, including the long-term use of the drug.

Adult attention deficit hyperactivity disorder: a comprehensive review.

Attention deficit hyperactivity disorder (ADHD) is a common childhood disorder, with only 2-3% prevalence into adulthood. The epidemiology and proposed causes of ADHD are multifactorial, including genetic, prenatal and environmental influences. The diagnosis of ADHD is often complicated by masking coping mechanisms, an overlap of symptoms with other, more commonly diagnosed disorders. Traditionally, it has been treated with stimulant medications. Non-stimulant options often target norepinephrine and dopamine regulation and are preferred in cases of comorbid substance use disorder, anxiety and other complicating factors, due to an improved side-effect profile and patient preference. They include atomoxetine and viloxazine. The latter, Viloxazine, in the form of extended-release capsules, is the first novel, non-stimulant option approved for adults with ADHD, in the past two decades. Its therapeutic effects are predominantly produced by its action as a norepinephrine reuptake inhibitor and may also modulate the serotonergic system. Viloxazine is relatively safe and effective in treating other disorders such as depression, anxiety, epilepsy and substance use disorder. Its pharmacokinetics includes metabolization by CYP enzymes. As antiepileptics inhibit CYP1A2, therefore, a special consideration would be needed, when co-administering with anti-epileptic drugs. Similarly, individuals with liver or cardiovascular disease and a personal or family history of bipolar disorder require close monitoring, while on this medication. A thorough review of the history, mechanism of action, pharmacokinetics and drug-drug interactions has been presented here, with special attention on treatment in adults with comorbid conditions. This study conducted an all-language literature search on Medline, Cochrane, Embase, and Google Scholar until December 2022. The following search strings and Medical Subject Headings (MeSH) terms were used: "Viloxazine," "ADHD," "Stimulants," and "adult ADHD." We explored the literature on the growing knowledge of Viloxazine. A thorough review of the history, mechanism of action, pharmacokinetics, and drug-drug interactions are reviewed here with special attention on treatment in adults with comorbid conditions.

Antidepressants

Tricyclic antidepressants possess anticholinergic, alpha 1 anti-adrenergic, and H1 antihistaminic properties, and an overdose affects patients' quality of life, which has led to the development of novel antidepressant drugs. Selective serotonin reuptake inhibitors (SSRIs) are non-sedating drugs that selectively reuptake serotonin and are effective against anxiety. Adverse effects of SSRIs include gastrointestinal disturbances, sexual dysfunction, and bleeding tendency. Serotonin noradrenaline reuptake inhibitors (SNRIs) are non-sedating agents that are expected to improve volition. SNRIs are effective against chronic pain, although they are associated with gastrointestinal symptoms, tachycardia, and elevated blood pressure. Mirtazapine is a sedative drug used in patients with anorexia and insomnia. However, drowsiness and weight gain are known adverse effects of this medication. Vortioxetine is a non-sedative drug associated with gastrointestinal symptoms; however, insomnia and sexual dysfunction are less common.

Frequency of antidepressant use and clinical characteristics of children and adolescents undergoing polysomnography: an observational study

BackgroundAntidepressants are increasingly used in children for various psychiatric disorders but also for sleep disorders such as insomnia; however, it is currently unknown how many children undergoing polysomnography (PSG) are taking anti-depressants. The aims were: to determine the frequency of use of antidepressants in paediatric patients referred for PSG, to identify the most common antidepressants used, to investigate the reasons for their use, and to analyse the PSG parameters found in children taking antidepressants.MethodAn observational cross-sectional retrospective chart review of all children undergoing PSG at Seattle Children’s Hospital from 6/14/2020 to 12/8/2022 was carried out. Clinical features (such as diagnosis, especially psychiatric), sleep disorders (such as insomnia and restless sleep), and class of antidepressant used [selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCA), or atypical antidepressants], and PSG parameters were collected for further analysis.ResultsAmong 3,371 patients who underwent PSG during the study, 367 children were selected who were taking one antidepressant only (154 boys and 213 girls, mean age was 13.7 ± years 3.69). A significantly decreased sleep stage N3 was found in girls, who were older than boys. Children with insomnia had longer sleep latency than children without, but more N3. There was a prolonged rapid eye movement (REM) sleep latency in children with attention-deficit/hyperactivity disorder and children with autism. REM latency was longer and REM percentage smaller in children taking SNRIs. Periodic leg movement index ≥ 5/hour was found in a higher number of children taking SSRIs or SNRIs (24.9%) than in subjects taking TCA or atypical antidepressants (13.3%) (chi-square 5.29, p = 0.013).ConclusionsChild and adolescent psychiatrists should question about the effects on sleep (both positive and negative) after initiating therapy with antidepressant medications.

Successful use of extracorporeal life support and hemadsorption in the context of venlafaxine intoxication requiring cardiopulmonary resuscitation: a case report

Venlafaxine is a serotonin and noradrenalin reuptake inhibitor prescribed as an antidepressant. Overdose clinically manifests with neurological, cardiovascular and gastrointestinal abnormalities based on, amongst others, serotonin syndrome and can be life-threatening due to cardiovascular collapse. Besides immediate decontamination via gastric lavage and inhibition of enteral absorption through active charcoal, successful hemadsorption with CytoSorb® has been reported. We present the case of a 17-year-old female who required extracorporeal life support (ECLS) for cardiovascular collapse as a result of life-threatening venlafaxine intoxication. Serial serum blood concentrations of venlafaxine/desmethylvenlafaxine on admission at a tertiary hospital (approx. 24 h after ingestion) and subsequently 6 h and 18 h thereafter, as well as on days 2 and 4, were measured. CytoSorb® was initiated 6 h after admission and changed three times over 72 h. The initial blood concentration of venlafaxine/desmethylvenlafaxine was 53.52 µmol/l. After 6 h, it declined to 30.7 µmol/l and CytoSorb® was initiated at this point. After 12 h of hemadsorption, the blood level decreased to 9.6 µmol/l. On day 2, it was down to 7.17 µmol/l and decreased further to 3.74 µmol/l. Additional continuous renal replacement therapy using CVVHD was implemented on day 5. The combination of hemadsorption, besides traditional decontamination strategies along maximal organ supportive therapy with ECLS, resulted in the intact neurological survival of the highest venlafaxine intoxication reported in the literature to date. Hemadsorption with CytoSorb® might help to reduce blood serum levels of venlafaxine. Swift clearance of toxic blood levels may support cardiovascular recovery after life-threatening intoxications.

Evidence of Sympathetic Overactivity in Subjects with REM Behavior Disorder at Risk for Parkinson’s Disease (P6-13.002)

<h3>Objective:</h3> To evaluate sympathetic nervous system (SNS) activity in subjects with REM sleep behavior disorder (RBD) at risk of Parkinson’s disease, using imaging and autonomic functions markers. <h3>Background:</h3> While the nature of RBD is not completely understood, there is evidence that enhancement of noradrenergic activity may play a causative role, as suggested by evidence of persistent tonic discharge of locus coeruleus (LC) and RBD-triggering action of selective norepinephrine reuptake inhibitors. <h3>Design/Methods:</h3> Subjects &gt;50 years old with RBD with at least one pre-motor PD symptom (hyposmia, constipation, depression) were tested with a battery of autonomic evaluations including SCOPA-AUT questionnaire, cardiac MIBG scintigraphy, Heart Rate Variability (HRV) and neuromelanin sensitive MRI (NSMRI) of LC and substantia nigra (SN). Analyzed variables included: 1) for MIBG, late heart/mediastinum (H/M) ratio and washout ratio (WR); 2) for HRV, time and frequency domain measures; 3) for NSMRI, contrast-to-noise ratio (CNR) between LC and pons and between substantia nigra (SN) and cerebral peduncles. Results were compared with available normative ranges. <h3>Results:</h3> 14 subjects (11M, age 66.2±8.2) were enrolled. Average total SCOPA-AUT score was increased (12.1±6.7 vs 8.8±5.4), with gastrointestinal (2.4±2.1 vs 1.4±1.6), urinary (5.4±2.7 vs 3.9±2.4) and cardiovascular (0.86±1.10 vs 0.3±0.6) scores above normal ranges. MIBG late H/M ratio was reduced (1.45±0.31) with increased WR (33.0±14.8). HRV results showed enhanced sympathetic and low parasympathetic activity both in time (SDNN 106.8±73.2ms; RMSSD 21.9±10.9ms; PNN50% 6.7±8.4%) and frequency domain (LF/HF 3.4±1.8). NMSMRI showed high LC CNR (right 3.26±1.9 vs 2.08±0.5; left 2.95±0.9 vs 2.79±0.5). SN CNR was high (Medial 6.24±1.9 vs 4.57±0.8; Central 6.26±1.6 vs 3.43±0.6; Lateral 3.44±2.1 vs 3.05±0.5) and MDS-UPDRS motor scores were low (2.9±3.3). <h3>Conclusions:</h3> RBD subjects at risk for PD show abnormal autonomic scores, which appears to be driven by SNS overactivity, as suggested by increased MIBG WR, elevated LF/HF HRV ratios and increased LC and SN NSMRI signal. <b>Disclosure:</b> Dr. Tagliati has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Abbott. Dr. Tagliati has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Boston Scientific. Dr. Tagliati has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Supernus. Dr. Tagliati has received personal compensation in the range of $500-$4,999 for serving as a Consultant for NeuroDerm. Dr. Tagliati has received publishing royalties from a publication relating to health care. Dr. Gregorio has nothing to disclose. Dr. Maghzi has nothing to disclose. Gloria Obialisi has nothing to disclose. Dr. Hogg has nothing to disclose. Dr. Malatt has nothing to disclose. Dr. Tan has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Allergan. Dr. Artal has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Jazz Pharmaceuticals. Dr. Artal has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Private Parties. The institution of Dr. Artal has received research support from Jazz Pharma. The institution of Dr. Artal has received research support from Axsome. The institution of Dr. Artal has received research support from Suven. Dr. Shehata has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbott. Brian Renner has nothing to disclose. The institution of Dr. Sati has received research support from National Multiple Sclerosis Society. The institution of Dr. Sati has received research support from National Institutes of Health. Dr. Sati has received publishing royalties from a publication relating to health care.

The use of antidepressants in neurological practice

Antidepressants are widely used in neurological practice, and their use in stroke, Alzheimer's disease, depression with cognitive impairment, Parkinson's disease, multiple sclerosis, chronic back pain and chronic migraine is discussed. Antidepressants are used in the presence of severe depressive symptoms, which are observed in 20–30% of neurological patients. The effect of antidepressants is higher in case of combination with recurrent depression. Presence of episodes of depression before the development of a neurological disease, history of effectiveness of antidepressants, hereditary burden of affective disorders, characteristic daily dynamics of symptoms with typical impaired sleep architecture indicate the likelihood of a combined affective disorder. Final establishment of a psychiatric diagnosis is possible with a consultation of a neurological patient by a psychiatrist, but in clinical practice this is realistic only in a small number of patients. The most commonly used antidepressants are selective serotonin reuptake inhibitors, selective serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants in low or medium doses, the duration of their administration is usually at least 3-6 months. In neurological diseases, the effectiveness of only some drugs has been noted, many antidepressants have not been studied in neurological diseases, but this does not exclude their effectiveness. When prescribing antidepressants, it is necessary to take into account possible drug interactions and avoid those combinations that may cause adverse reactions. It is advisable to use antidepressants in complex therapy in combination with an educational program, cognitive behavioral therapy and kinesiotherapy. Many questions regarding the efficacy and safety of treatment, the choice of the optimal antidepressant, its dosage and duration of use require further study.

The effect of triple reuptake inhibitor toludesvenlafaxine on neurological function in cerebral ischemic rats.

Purpose: The aim is to investigate the effect of toludesvenlafaxine (Tdv), a reuptake inhibitor of serotonin, norepinephrine, and dopamine, on the neurological function in cerebral ischemic rats and the underlying mechanisms. Material and Methods: Middle cerebral artery occlusion/reperfusion (MCAO/R) model was induced in rats and the neuroprotective effects of Tdv were evaluated by infarct size, Garcia test, and beam walking test. Neuronal apoptosis in the peri-infarct area was observed by TUNEL staining. And the apoptosis-related proteins were evaluated with Western blotting. The role of CREB pathway in effect of Tdv was also investigated using Western blotting and immunofluorescence. Results: In the MCAO/R model, administration of Tdv reduced the infarct size, promoted neural functional recovery, decreased the expression of Bax and Caspase-3, and increased the expression of Bcl-2 and BDNF. In addition, Tdv reduced neuronal apoptosis in the peri-infarct area. Tdv increased the expression of phosphorylated CREB. The application of the specific CREB inhibitor, compound 666-15, could reverse the anti-ischemic cerebral injury of Tdv in MCAO/R rats. Conclusion: Tdv ameliorated cerebral ischemic injury through reducing neuronal apoptosis and increasing the expression of BDNF via the activation of CREB pathway.

Duloxetine in Reducing Catheter-Related Bladder Discomfort: A Prospective, Randomized, Double-Blind, Placebo-Controlled Study.

The excessive desire to void with discomfort in the supra-pubic region, which is experienced postoperatively by patients who underwent urinary catheterization, is known as catheter-related bladder discomfort. In this study, we evaluated duloxetine, a selective serotonin and norepinephrine reuptake inhibitor, in preventing catheter-related bladder discomfort. Around 64 adults (18-60 years), of either sex, with American Society of American Society of Anesthesiologists (ASA) physical status I and II, scheduled to undergo elective gastrointestinal carcinoma surgeries under general anesthesia were analyzed in the final assessment of 2 comparative groups C and D of 32 patients each. Group D received 1 ranitidine tablet of 150 mg and 1 duloxetine tablet of 60 mg, while group C patients received 2 tablets of ranitidine of 75 mg 2 hours prior to induction. A 16 F Foley catheter was used to catheterize bladder intra-operatively, and 10 mL of distilled water was used to fill the balloon. At 0, 1, 2, and 6 hours, the catheter-related bladder discomfort was evaluated, and categorized into none, mild, moderate, and severe. The study drug's adverse effects, if any, were reported. At all-time intervals, group D had lower incidence and severity of catheterrelated bladder discomfort than group C (P < .05). Compared to group C, patients in group D had a higher incidence of nausea, dizziness, and vomiting; nevertheless, the difference was statistically insignificant (P > .05). Duloxetine of 60 mg given orally 2 hours before induction decreases the incidence and severity of catheter-related bladder discomfort.

Administration of serotonin and norepinephrine reuptake inhibitors tends to have less ocular surface damage in a chronic stress-induced rat model of depression than selective serotonin reuptake inhibitors

Depressed patients who medicate with selective serotonin reuptake inhibitors (SSRIs) often report ocular dryness. Epidemiological studies have found that serotonin and norepinephrine reuptake inhibitors (SNRIs) are not risk factors for dry eye in depressed patients. However, the effect of SNRIs on the ocular surface is unknown. A depression rat model was induced by chronic unpredictable mild stress (CUMS), and SNRIs or SSRIs were administered to the rats for 3 or 6 weeks. The levels of norepinephrine (NE) and serotonin in tear fluid were tested by ELISA. The corneal fluorescence and lissamine green staining were used to evaluate ocular surface damage. NE and/or serotonin were administered to human corneal epithelial cells in vitro. RNA sequencing (RNA-seq) analysis was performed to investigate the mRNA expression profiles. Tear NE levels were higher in the SNRIs group, and ocular surface inflammation and apoptosis were significantly reduced compared to the SSRIs group. RNA-Seq indicated that NE significantly activate MAPK signaling pathway. NE can inhibit serotonin-induced activation of the NF-κB signaling pathway through α-1 adrenergic receptors and promotes the proliferation of corneal epithelial cells through activation of the MAPK signaling pathway. SNRIs administration have less ocular surface damage than SSRIs. NE protects human corneal epithelial cells from damage, and reduce inflammation on the ocular surface via activating the MAPK signaling pathway. SNRIs might be used as an appropriate treatment for depression-related DED.

Teaching NeuroImages: Sleep-onset REM period during routine EEG

A 76-year-old incarcerated man presented with word-finding difficulties and underwent a routine EEG. Shortly after reaching stage N2 sleep, EEG showed brisk lateral eye movements with concurrent sawtooth waves (figure), indicating sleep-onset REM period (SOREMP). Normal REM sleep is reached 90–120 minutes after sleep onset. SOREMP is an abnormal EEG finding thought to be suggestive of narcolepsy. However, it may also be present in 3.9% of the general population1 and is normal in infants. It is also associated with severe sleep deprivation, obstructive sleep apnea, and alcohol or medication (selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors) withdrawal. In the inpatient setting, it is usually caused by sleep deprivation.2

Abstract 6464: Antidepressant use and lung cancer risk and mortality: A meta-analysis of observational studies

Abstract Objectives: Recent preclinical studies suggested potential anticancer effects of antidepressant (AD) use in multiple cancers, but the effect on lung cancer in human studies remains unclear. This meta-analysis examined the effect of AD use on lung cancer incidence and mortality. Methods: Web of Science, Medline, CINAHL, and PsycINFO databases were searched to identify eligible studies published by June 2022. We conducted a meta-analysis using a random effects model to estimate pooled risk ratio (RR) and 95% confidence interval (CI) for comparing those with AD use and non-use. Heterogeneity was examined using Cochran’s Q test and inconsistency I2 statistics. The methodological quality of selected studies was assessed using the Newcastle-Ottawa Scale for observational studies. Results: The meta-analysis, including 11 publications involving 1913172 participants, showed that AD use significantly increased lung cancer risk by 11% (RR= 1.11; 95% CI= 1.01, 1.22; I2= 74.3%; n= 6); however, all-cause mortality was not affected by AD use (RR= 1.05; 95% CI= 0.68, 1.58; I2= 90.1%; n= 4) while lung cancer-specific mortality could be reduced by 32% from onse study. Subgroup analysis showed that serotonin and norepinephrine reuptake inhibitors (SNRIs) were associated with an increased lung cancer risk (RR= 1.38; 95% CI= 1.07, 1.78), but selective serotonin reuptake inhibitors (RR= 1.05; 95% CI=0.91, 1.21) and tricyclic antidepressants (RR= 1.09; 95% CI=0.95, 1.26) were not. In addition, variations in the definition of AD use could be the source of heterogeneity of observed effects. The quality of selected studies was good (n= 5) to fair (n= 6). Conclusions: Evidence suggests that AD use was associated with an elevated risk of lung cancer but not with all-cause mortality. More research is needed to precisely estimate the effect of AD use on lung cancer-specific mortality. (Funding: University of Central Florida Center for Behavioral Health Research and Training; Registration: PROSPERO; registration number: CRD42022350719) Citation Format: Eunkyung Lee, David Li, Yongho Park, Alice Rodriguez-Fuguet, Xiaochuan Wang, Wen Cai Zhang. Antidepressant use and lung cancer risk and mortality: A meta-analysis of observational studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6464.

Effects of Viloxazine ER (Qelbree®) on Weight and Height Trajectories: Interim Results From a Long-term, Open-Label Extension Trial in Pediatric ADHD

AbstractIntroductionStimulant medications and the norepinephrine reuptake inhibitor, atomoxetine, contain warnings regarding potential for slowing of growth (weight and height) in children and recommend monitoring of growth when using these medications for pediatric ADHD. Viloxazine ER (viloxazine extended-release capsules; Qelbree®), is a nonstimulant medication, FDA-approved for ADHD in adults and children (≥6 years of age). Viloxazine ER has pharmacologic differences from other approved ADHD medications and might not affect growth in the same manner as other therapies. A safety analysis was conducted to determine viloxazine ER effects on growth and weight trajectories in pediatric ADHD patients with long-term use.MethodsData were evaluated from five DBPC, phase 2 and 3 clinical trials and an ongoing long-term, open-label extension (OLE) trial (NCT02736656). Viloxazine ER doses during the trials ranged from 100–400 mg/day (age 6–11 yrs) or 100–600 mg/day (age 12–17 yrs). Height and weight were evaluated pretreatment in both DB and OLE every 3 months during the OLE, and converted into percentile values and corresponding z-scores using Centers for Disease Control (CDC) normal growth curves to evaluate growth trajectories. The incidence of weight- and growth-related adverse events (AEs) terms were also evaluated.ResultsAt the time of data cut (31 July 2019), 1097 subjects had received at least one dose of viloxazine ER in the OLE (66% male, mean (SD) age 10.8 (3.06), 59% age 6–11, mean (SD) BMI 18.8 (3.42) kg/m2, height 146.7 (17.46) cm, weight 42.1 (16.01) kg. During the OLE, mean (SE) z-scores for height and weight were between -1 and 1 for all timepoints, indicating growth measures within a normal range compared with expected values. Similar results were observed when weight and height were analyzed by sex and by age categories. Growth data were available for 338 subjects at 12 months. Among these subjects, the mean (SD) change from baseline in weight-for-age z-score was -0.2 (0.5) and height-for-age z-score was -0.14 (1.1). Adverse events relevant to weight and growth in the DB trials (incidence ≥ 1%) included (viloxazine ER [100–600 mg/day] n=1117 vs. placebo n=487): decreased appetite (8.1% vs. 0.8%), nausea (5.1% vs. 2.7%), vomiting (4.7% vs. 1.4%), weight increase (0.4% vs. 1.2%) and weight decrease (1.3% vs. 0.4%), and increased appetite (0.2% vs. 1.2%). During the OLE weight-and growth-related AEs reported for ≥ 1% of subjects were: decreased appetite 5.8%, vomiting 2.7%, nausea 2.4%, weight decreased 2.3%, and weight increased 2.0%.ConclusionsOver time, pediatric subjects taking viloxazine ER, on average, maintained normal weight and height relative to the CDC’s child growth charts. However, because Qelbree may affect weight, it is recommended that healthcare providers check patient weight before starting and while using viloxazine ER.FundingSupernus Pharmaceuticals, Inc.

Preclinical Pharmacology of Solriamfetol: Potential Mechanisms for Wake Promotion

AbstractIntroductionSolriamfetol is a wake-promoting agent (WPA) approved for the treatment of excessive daytime sleepiness associated with narcolepsy and obstructive sleep apnea. The wake-promoting mechanism of solriamfetol may result from dopamine and norepinephrine reuptake inhibition. Preclinical pharmacology studies were conducted to further elucidate the molecular targets activated by solriamfetol and compare them to that of known WPAs and traditional stimulants.MethodsIn vitro binding and functional studies were conducted in a panel of cell lines or membrane preparations expressing transmembrane receptors and monoamine transporters to measure the activity of solriamfetol, comparator WPAs, and traditional stimulants. Electrophysiology studies were conducted in slice preparations from mouse ventral tegmental area (VTA). Studies to measure locomotor activity and wake-promoting effects were conducted in mice.ResultsIn vitro functional studies showed agonist activity of solriamfetol at human, mouse, and rat TAAR1 receptors. hTAAR1 EC50 values (10–16 μM) were within the clinically observed therapeutic solriamfetol plasma concentration range and overlapped with the observed DAT/NET inhibitory potencies of solriamfetol in vitro. TAAR1 agonist activity was unique to solriamfetol; neither the WPA modafinil nor the DAT/NET inhibitor bupropion had TAAR1 agonist activity. Solriamfetol (1–10 μM) dose-dependently inhibited the firing frequency of dopaminergic VTA neurons in mouse brain slices, similar to known TAAR1 agonists; however, these effects were inhibited by a D2 antagonist, suggesting a DAT-mediated effect. Unlike traditional stimulants, solriamfetol did not increase locomotor activity in naive mice, but inhibited the increase in locomotor activity in DAT knockout mice.ConclusionsPreclinical studies have identified agonist activity at the TAAR1 receptor and, possibly, lower potency agonist activity at 5-HT1A receptors as potential pharmacological targets for solriamfetol, in addition to its activity as a DAT/NET inhibitor. Given the current understanding of TAAR1 agonists as modulators of monoamine transmission with potential wake-promoting effects in multiple preclinical species, agonist activity at the hTAAR1 receptor may represent an additional pharmacological target underlying the wake-promoting effects for solriamfetol, in addition to its DNRI activity.FundingAxsome Therapeutics, Jazz Pharmaceuticals

Viloxazine Increases Cortical Serotonin Without Inhibiting Serotonin Reuptake at Doses Used to Treat ADHD

AbstractBackgroundMost FDA-approved ADHD treatments increase norepinephrine (NE) and dopamine (DA); however, our prior preclinical studies of the non-stimulant ADHD treatment viloxazine ER (Qelbree®) demonstrated that viloxazine also increases serotonin (5-HT). A prior microdialysis study showed increases in NE, DA, and 5-HT in the rat prefrontal cortex (PFC); however, the 50 mg/kg dose resulted in supratherapeutic plasma concentrations. Viloxazine is a moderate affinity selective NE reuptake inhibitor, structurally different than traditional SSRI antidepressants. Viloxazine has negligible activity at the serotonin reuptake transporter (SERT), suggesting viloxazine has a different mechanism of 5-HT PFC elevation than SSRIs. The current microdialysis study was undertaken to further characterize if viloxazine affects 5-HT and its 5-HIAA metabolite at therapeutically relevant plasma concentrations. Results are compared to similar microdialysis studies of SSRIs.MethodsRats were implanted with I-shaped microdialysis probes connected to a microperfusion pump, delivering artificial cerebrospinal fluid, in the PFC. After a 2-hour baseline period, viloxazine (1, 3, 10, or 30 mg/kg) was administered (ip). Dialysate samples were collected from the interstitial fluid (ISF) of the PFC before and after dosing. LC-MS/MS was used to determine the dialysate concentrations of viloxazine and viloxazine-induced changes in NE, 5-HT, and their respective metabolites, DHPG and 5-HIAA. Viloxazine plasma concentrations were also measured.Animal research was approved by the Institutional Animal Care and Use Committee and conducted in accordance with the National Research Council’s Guide for the Care and Use of Laboratory Animals.ResultsViloxazine administration resulted in significant dose-dependent increases in ISF NE levels and corresponding decreases in DHPG (NE metabolite) at all doses tested, reflecting viloxazine’s activity as a NET inhibitor. Viloxazine treatment also resulted in a dose-dependent elevation of ISF 5-HT levels in the PFC. Of the doses tested, 30 mg/kg was found to be clinically relevant as it induced ISF concentrations approximating unbound plasma concentrations in pediatric ADHD patients. At this dose, 5-HT levels were significantly increased over baseline and higher than vehicle levels. Coincident changes in 5-HIAA concentrations were not observed, reaffirming viloxazine’s lack of activity as a SERT inhibitor.ConclusionViloxazine induced dose-dependent increases in NE and 5-HT in the PFC, a critical target region for ADHD therapies. At clinically relevant viloxazine plasma concentrations, 5-HT was increased in the PFC. Unlike SSRIs, which correspondingly decrease the 5-HT metabolite in the PFC (indicating serotonin reuptake inhibition), viloxazine did not affect 5-HIAA levels. Thus, viloxazine increases cortical 5-HT levels by a different mechanism than SSRIs. Whether 5-HT effects aid in viloxazine therapeutic efficacy in ADHD is yet unknown.FundingSupernus Pharmaceuticals, Inc.

Duloxetine for Postoperative Pain Control Following Knee or Hip Replacement: A Systematic Review and Meta-Analysis.

Duloxetine is a Food and Drug Administration-approved selective norepinephrine reuptake inhibitor for treating depression, anxiety, fibromyalgia, and neuropathic and chronic musculoskeletal pain. This meta-analysis aims to evaluate the efficacy of duloxetine in reducing pain and postoperative opioid use following lower extremity total joint arthroplasty. A literature search was performed, identifying randomized controlled trials investigating duloxetine for pain management after total hip and total knee arthroplasty. Data from the visual analog scale (VAS) for pain during movement and at rest were extracted for postoperative days (PODs) 1, 3, 7, and 14, as well as postoperative week 6 and postoperative month 3. Opioid use data were obtained at 24, 48 and 72 hours. All data were analyzed using inverse variance with random effects and presented as weighted mean difference. Eight unique studies were identified and included, 7 of which were analyzed quantitatively. Duloxetine decreased postoperative opioid consumption at 48 and 72 hours. For VAS for pain at rest, significantly reduced pain was reported by duloxetine-treated patients at POD 3, POD 7, and postoperative week 6. For VAS for pain at movement, significantly reduced pain was reported by duloxetine-treated patients at POD1, POD 3, POD 7, POD 14, postoperative week 6, and postoperative month3. Duloxetine appears to decrease postoperative pain and opioid consumption following total joint arthroplasty. However, definitive conclusions are limited by small sample size and study heterogeneity. While there is a need for follow-up studies to determine the optimal dose, duration, and patient population, strong preliminary data provide robust support for future large-scale efficacy studies.

Hypoactive Sexual Desire and Other Sexual Dysfunctions Caused by Psychotropic Drugs and Anticonvulsants

Currently, there are a huge number of drugs. Every year their number increases and their number is in the tens of thousands, which makes it possible to speak of a “pharmaceutical explosion”. In addition to its main therapeutic effect, each of the drugs has side effects, which, in particular, may affect the sexual sphere. This article discusses the literature on the side effects of psychotropic drugs and anticonvulsants, which can lead to hypoactive sexual desire and other sexual dysfunctions. The side effects on sexual functions of tranquilizers, antipsychotics (traditional and newer), antidepressants of various groups (tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, as well as newer antidepressants), mood stabilizers and anticonvulsants are considered. The degree of influence of neuroleptics and antidepressants on sexual function is discussed depending on the dose, duration of administration, belonging to one or another chemical class. It is noted that some drugs from these groups can have a stronger negative effect on sexual functions, others have a moderate or weak effect, and still others not only do not have such an effect, but even increase sexual desire and other sexual functions. Therefore, before starting to take one or another drug from these groups, one should evaluate the state of sexual functions and, in case of their violation, prescribe such drugs that have the same therapeutic effect, but when they are used, there is no risk of adverse effects on the sexual sphere. These drugs (for example, antidepressants) should be prescribed as a substitute even in cases where a drug with an antidepressant effect was previously taken, which led to sexual dysfunctions.

Trends in Pain Medication Use in Patients With Type 2 Diabetes: NHANES 2005–2018

The aim of this research was to compare pain medication use trends among adults with and without type 2 diabetes in the US. This cross-sectional study used data of adults with and without (type 2) diabetes from the National Health and Nutrition Examination Survey waves 2005–2018. Use of pain medication including opioids, prescription nonsteroidal anti-inflammatory drugs, gabapentinoids, serotonin norepinephrine reuptake inhibitors, skeletal muscle relaxants, and headache treatment agents was compared by diabetes status and within select social determinants of health and clinical factors. Adults with type 2 diabetes were twice as likely to be prescribed pain medications compared to those without a diabetes diagnosis (16.2% vs 8.6%). Females and those with a history of smoking or arthritis were more likely to be on pain medications. Opioid use was the most prevalent regardless of diabetes status, and use was twice as high among those with diabetes (10.8% vs 5.5%). Patients with type 2 diabetes in the US are twice as likely to be prescribed pain medications overall as well as opioids compared with those without diabetes. Clinical guideline recommendations are necessary to find pharmacologic and nonpharmacologic nociceptive pain management specific for patients with diabetes.