Background: Viloxazine was historically described as a norepinephrine reuptake inhibitor (NRI). Since NRIs have previously demonstrated efficacy in attention deficit/hyperactivity disorder (ADHD), viloxazine underwent contemporary investigation in the treatment of ADHD. Its clinical and safety profile, however, was found to be distinct from other ADHD medications targeting norepinephrine reuptake. Considering the complexity of neuropsychiatric disorders, understanding the mechanism of action (MoA) is an important differentiating point between viloxazine and other ADHD medications and provides pharmacology-based rationale for physicians prescribing appropriate therapy. Methods: Viloxazine was evaluated in a series of in vitro binding and functional assays. Its effect on neurotransmitter levels in the brain was evaluated using microdialysis in freely moving rats. Results: We report the effects of viloxazine on serotoninergic (5-HT) system. In vitro, viloxazine demonstrated antagonistic activity at 5-HT 2B and agonistic activity at 5-HT 2C receptors, along with predicted high receptor occupancy at clinical doses. In vivo, viloxazine increased extracellular 5-HT levels in the prefrontal cortex (PFC), a brain area implicated in ADHD. Viloxazine also exhibited moderate inhibitory effects on the norepinephrine transporter (NET) in vitro and in vivo, and elicited moderate activity at noradrenergic and dopaminergic systems. Conclusion: Viloxazine's ability to increase 5-HT levels in the PFC and its agonistic and antagonistic effects on certain 5-HT receptor subtypes, which were previously shown to suppress hyperlocomotion in animals, indicate that 5-HT modulating activity of viloxazine is an important (if not the predominant) component of its MoA, complemented by moderate NET inhibition. Supported by clinical data, these findings suggest the updated psychopharmacological profile of viloxazine can be best explained by its action as a serotonin norepinephrine modulating agent (SNMA).

Viloxazine has a long history of clinical use in Europe as an antidepressant, and has recently been repurposed into an extended-release form for the treatment of attention-deficit/hyperactivity disorder in the USA. An immediate-release formulation was approved for the treatment of depression in the UK in 1974, and was subsequently marketed there and in several European countries for 30 years with no major safety concerns. In contrast to first-generation antidepressants (e.g., tricyclic antidepressants, monoamine oxidase inhibitors), viloxazine was associated with a relatively low risk for cardiotoxicity. Gastrointestinal symptoms were the most commonly reported side effects. The therapeutic effects of viloxazine are thought to be primarily the result of its action as a norepinephrine reuptake inhibitor, although in vitro and preclinical in vivo animal data suggest that viloxazine may also impact the serotoninergic system. This review summarizes the evolving knowledge of viloxazine based on information from previously published preclinical and clinical investigations, and acquired unpublished historical study reports from both open-label and blinded controlled clinical trials. We review the chemical properties, mechanism of action, safety, and tolerability across these studies, and discuss the contemporary rationale for the development of this agent as an extended-release oral formulation for the treatment of attention-deficit/hyperactivity disorder.

Proper drug categorization enables clinicians to readily identify the agents most appropriate for patients in need. Currently, patients with maladaptive aggression do not all always fall into a single existing diagnostic or treatment category. Such is the case for those with impulsive aggression (IA). IA is an associated feature of numerous neuropsychiatric disorders, and can be described as eruptive, aggressive behavior or a 'short fuse'. Although agents from a broad spectrum of drug classes have been used to treat maladaptive aggression, few have been tested distinctly in patients with IA, and there is no drug specifically indicated by the US Food and Drug Administration (US FDA) for IA. Further, current treatments often fail to sufficiently treat IA symptomatology. These issues create an unclear and inadequate treatment path for patients. Here we will propose the establishment of a class of anti-maladaptive aggression agents to begin addressing this clinical issue. The development of such a class would unify the various drugs currently used to treat maladaptive aggression and streamline the treatment approach towards IA. As an important case example of the range of candidate drugs that could fit into a new anti-maladaptive aggression agent category, we will review an investigational IA pharmacotherapy. SPN-810 (extended-release molindone) is currently being investigated as a novel treatment for children with IA and ADHD. Based on these studies we will review how SPN-810 may be well suited for a new, anti-maladaptive aggression drug class and more precisely, a proposed subgroup of IA modulators. The goal of this review is to begin improving the identification of and therapeutic approach for maladaptive aggression as well as IA through more precise anti-maladaptive aggression agent categorization.

Objective: To establish the validity and reliability of a provisional 30-item impulsive aggression (IA) diary in children (ages 6-12 years, inclusive) with attention-deficit/hyperactivity disorder (ADHD). Methods: The provisional 30-item IA diary was administered for 14 days to parents of children with ADHD and IA symptoms (n = 103). Key inclusion criteria: confirmed ADHD diagnosis; signs of IA as measured by a Retrospective-Modified Overt Aggression Scale (R-MOAS) score ‡20 and an Aggression Questionnaire score of-2 to-5. Analyses included inter-item correlations, exploratory factor analysis (EFA), item response theory (IRT) modeling, internal consistency, test-retest reliability (TRT), concurrent validity (estimated by correlation between the IA diary and the R-MOAS/Nisonger Child Behavior Rating Form), and known-groups methods. Results: The prevalence rates of 15 (50.0%) items were found to be too low (<1%) for analysis; three items with prevalence rates £1% were retained, as content validity was deemed high by clinical experts. The remaining 12 behavior items had prevalence rates of 2.7%-73.6%. EFA and IRT models confirmed two subdomains in the IA diary included within a general domain of IA behavior frequency, yielding a single total behavioral frequency score (TBFS). Internal consistency was high for this TBFS (marginal reliability = 0.86 and a = 0.73). TRT for the TBFS, based on the intraclass correlation coefficient, was 0.8. Concurrent validity of TBFS with R-MOAS ranged from r = 0.49 to r = 0.62. Conclusion: The final 15-item IA diary is a reliable, psychometrically validated IA measurement tool that will allow clinicians and researchers to assess the frequency of IA behavior.

This is the first case report using 3D cone beam computed tomography-based image guidance for the placement of an intrathecal catheter through a bony fusion mass. This technique appears to be a viable option for IDDS implantation in patients with difficult anatomy.

No abstract

Syncope and palpitations are common complaints that all physicians confront during daily clinical practice. Single center and multicenter cohort studies have found that syncope accounts for 1%-3% of emergency department evaluations and that palpitations are the primary symptom for approximately 16% of patients who arrive at an outpatient clinic with a cardiac complaint. For both conditions, women make up approximately 60% of the cohorts. In general, the evaluation of both syncope and palpitations can be challenging because of the heterogeneity of causes and, consequently, the variability of clinical outcomes, ranging from a single isolated event with no effect on morbidity and mortality to the first sign of a potentially life-threatening problem and sudden cardiac death. For all women with syncope or palpitations, the history, physical examination, and a baseline electrocardiogram (ECG) form the basis of the initial workup and focus on identifying patients with cardiovascular abnormalities who are at the highest risk for sudden cardiac death. More advanced tests must be chosen using a problem-specific approach, but generally, documentation of the cardiac rhythm during symptoms is critical for all patients with syncope or palpitations. Although the diagnostic testing strategy is generally similar for men and women, gender-related differences in treatment response have been identified. Antiarrhythmic medications, such as dofetilide and sotalol, that prolong the QT interval are more likely to be associated with proarrhythmia in women. In addition, higher complication rates for invasive cardiac procedures, such as device implantation, are observed in women.

Objective This study aimed to investigate the effectiveness of repeat cooled radiofrequency ablation (CRFA) in chronic posterior sacroiliac joint (SIJ) pain. Design The electronic records of 41 adult patients who had successful CRFA were reviewed for duration of pain relief and utilization of medical care for six months before and after each CRFA procedure. Setting Academic, tertiary medical center. Patients Forty-one adult patients who had CRFA for chronic posterior SIJ pain. Results A repeat ipsilateral CRFA ablation procedure provided 9.0 months of pain relief compared with 5.5 months after the first CRFA procedure (P = 0.0378). The total number of medical treatments decreased after the first CRFA procedure (from 343 to 201). The medical cost decreased by 51.0% after the first CRFA and by 70.4% after the repeated CRFA procedure. Conclusions Using repeated nonsurgical, minimally invasive approach, CRFA relieves chronic posterior SIJ pain and reduces patients’ utilization of medical services.