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Characterization of Viloxazine Effects on Cortical Serotonin Neurotransmission at Doses Relevant for ADHD Treatment
- Jennie Garcia-Olivares, Brittney Yegla, Jami Earnest, Vladimir Maletic, ChungPing Yu
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- Journal:
- CNS Spectrums / Volume 28 / Issue 2 / April 2023
- Published online by Cambridge University Press:
- 14 April 2023, p. 235
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Introduction
Most ADHD treatments are thought to be effective due to augmentation of dopamine (DA) and norepinephrine (NE). Our prior preclinical studies found that the ADHD treatment, viloxazine, may augment serotonin (5-HT) in addition to NE and DA; however, it was unclear if these effects occurred at clinically relevant concentrations. To further understand these potential 5-HT effects, we conducted a series of experiments with two objectives: 1) Can we confirm and better elucidate the previously observed serotonergic effects of viloxazine and determine if they occur at clinically relevant concentrations? 2) Are these effects observed in species with close physiology to humans?
MethodsObjective 1: The affinity of viloxazine for human isoforms of 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT7 receptors was assessed via cell-based binding assays. Viloxazine agonism of 5-HT2C and antagonism at 5-HT7 was elucidated with IP1, Ca2+, β-arrestin, internalization, and cAMP assays in cells expressing human receptor isoforms. A microdialysis study was conducted in rats to determine the relationship between viloxazine concentrations in the interstitial fluid (ISF) and changes in NE, DA, 5-HT, and their metabolite concentrations in the prefrontal cortex (PFC). Objective 2: A PET imaging study using a 5-HT2A/2C radioligand agonist, [11C]CIMBI-36, is being conducted in non-human primates (NHPs) to evaluate if viloxazine binds these receptors and/or increases 5-HT release.
Animal research was approved by animal care and use committees. Animals were cared for according to international standards.
ResultsObjective 1: Cell-based assays to measure viloxazine affinity for NET, 5-HT2B, 5-HT2C, and 5-HT7 found Ki values of 0.14, 0.65, 0.84, 1.90 μM respectively. These values were lower than therapeutically relevant rat ISF concentrations (3.5 ± 1.6 μM) approximating pediatric ADHD patients unbound plasma concentrations (2.1-3.3 μM), indicating receptor recruitment. Binding affinity and functional activity assays found viloxazine had negligible activity for 5-HT2A and SERT at therapeutic concentrations. Viloxazine 5-HT2C agonism activated Gq-protein signaling (EC50=1.6 μM, Ca2+ assay), but not β-arrestin or internalization pathways (EC50 values >150 μM). Viloxazine 5-HT7 antagonism decreased Gs-protein signaling (IC50 =6.7 μM). The microdialysis study found that at therapeutically relevant ISF concentrations, 5-HT levels were significantly increased over baseline; no changes were seen in the 5-HIAA metabolite, indicating 5-HT increase is not due to 5-HT reuptake inhibition. Objective 2: PET imaging studies are ongoing.
ConclusionsTo date, our experiments to further elucidate the potential 5-HT effects of viloxazine have shown that the previously observed effects of viloxazine on 5-HT receptors and its augmentation of 5-HT in rat PFC occur at clinically relevant concentrations. Further exploration is needed to ascertain if these effects occur in NHPs and are relevant to ADHD.
FundingSupernus Pharmaceuticals, Inc.
Healthcare Provider Perspectives on Bipolar I Disorder Screening and the Rapid Mood Screener (RMS), a Pragmatic, New Tool
- Michael E. Thase, Stephen M. Stahl, Roger S. McIntyre, Tina Matthews-Hayes, Mehul Patel, Amanda Harrington, Vladimir Maletic, William clay Jackson, Eduard Vieta
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- Journal:
- CNS Spectrums / Volume 26 / Issue 2 / April 2021
- Published online by Cambridge University Press:
- 30 April 2021, p. 181
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Introduction
Although mania is the hallmark symptom of bipolar I disorder (BD-I), most patients initially present for treatment with depressive symptoms. Misdiagnosis of BD-I as major depressive disorder (MDD) is common, potentially resulting in poor outcomes and inappropriate antidepressant monotherapy treatment. Screening patients with depressive symptoms is a practical strategy to help healthcare providers (HCPs) identify when additional assessment for BD-I is warranted. The new 6-item Rapid Mood Screener (RMS) is a pragmatic patient-reported BD-I screening tool that relies on easily understood terminology to screen for manic symptoms and other BD-I features in <2 minutes. The RMS was validated in an observational study in patients with clinically confirmed BD-I (n=67) or MDD (n=72). When 4 or more items were endorsed (“yes”), the sensitivity of the RMS for identifying patients with BP-I was 0.88 and specificity was 0.80; positive and negative predictive values were 0.80 and 0.88, respectively. To more thoroughly understand screening tool use among HCPs, a 10-minute survey was conducted.
MethodsA nationwide sample of HCPs (N=200) was selected using multiple HCP panels; HCPs were asked to describe their opinions/current use of screening tools, assess the RMS, and evaluate the RMS versus the widely recognized Mood Disorder Questionnaire (MDQ). Results were reported by grouped specialties (primary care physicians, general nurse practitioners [NPs]/physician assistants [PAs], psychiatrists, and psychiatric NPs/PAs). Included HCPs were in practice <30 years, spent at least 75% of their time in clinical practice, saw at least 10 patients with depression per month, and diagnosed MDD or BD in at least 1 patient per month. Findings were reported using descriptive statistics; statistical significance was reported at the 95% confidence interval.
ResultsAmong HCPs, 82% used a tool to screen for MDD, while 32% used a tool for BD. Screening tool attributes considered to be of the greatest value included sensitivity (68%), easy to answer questions (66%), specificity (65%), confidence in results (64%), and practicality (62%). Of HCPs familiar with screening tools, 70% thought the RMS was at least somewhat better than other screening tools. Most HCPs were aware of the MDQ (85%), but only 29% reported current use. Most HCPs (81%) preferred the RMS to the MDQ, and the RMS significantly outperformed the MDQ across valued attributes; 76% reported that they were likely to use the RMS to screen new patients with depressive symptoms. A total of 84% said the RMS would have a positive impact on their practice, with 46% saying they would screen more patients for bipolar disorder.
DiscussionThe RMS was viewed positively by HCPs who participated in a brief survey. A large percentage of respondents preferred the RMS over the MDQ and indicated that they would use it in their practice. Collectively, responses indicated that the RMS is likely to have a positive impact on screening behavior.
FundingAbbVie Inc.
Management of Painful Physical Symptoms Associated With Depression and Mood Disorders
- Thomas N. Wise, Lesley M. Arnold, Vladimir Maletic, David L. Ginsberg
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- Journal:
- CNS Spectrums / Volume 10 / Issue S19 / December 2005
- Published online by Cambridge University Press:
- 06 November 2014, pp. 1-16
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Depression is a common, recurring illness that continues to be underdiagnosed and undertreated in both psychiatric and primary care settings. It is increasingly being recognized that painful physical symptoms, which commonly exist comorbid with depressive disorders, play a role in complicating diagnosis of depression. Patients tend to discuss physical pain with primary care physicians and emotional pain with psychiatrists, often oblivious to the fact that both may be aspects of one disorder. Those who present with somatic complaints are three times less likely to be accurately diagnosed than patients with psychosocial complaints. However, thorough evaluation of mood and anxiety disorders in primary care is sparse due to the limited time primary care physicians can spend with each patient. Better recognition and treatment of both physical and emotional symptoms associated with mood disorders may increase a patient's chance of achieving remission, which is the optimum therapeutic goal.
Abnormalities of serotonin and noradrenaline are strongly associated with depression and are thought to play a role in pain perception. Brain-derived neurotrophic factor, which is increased with antidepressant treatment, appears to influence regulation of mood and perception of pain. Clinical evidence indicates that dual-acting agents may have an advantage in modulating pain over those agents that increase either serotonin or noradrenaline alone. The novel dual-acting agents, such as venlafaxine and duloxetine, are better tolerated than tricyclic antidepressants and monoamine oxidase inhibitors. These agents have demonstrated efficacy in depression and in diabetic neuropathic pain independently. Therefore, unless otherwise stated, all inferences to studies of pain in this monograph refer to neuropathic pain in nondepressed patients.