- The Atxn7-overexpressing mice showed hyperactivity and impulsivity which were ameliorated by atomoxetine treatment: A possible animal model of the hyperactive-impulsive phenotype of ADHD. [Journal Article]
- PNProg Neuropsychopharmacol Biol Psychiatry 2018 Aug 17
- Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental disorder characterized by varying levels of hyperactivity, inattention, and impulsivity. Patients with ADHD are o...
Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental disorder characterized by varying levels of hyperactivity, inattention, and impulsivity. Patients with ADHD are often classified as (1) predominantly hyperactive-impulsive, (2) predominantly inattentive, and (3) combined type. There is a growing interest in developing specific animal models that would recapitulate specific clinical forms of ADHD, with the goal of developing specific therapeutic strategies. In our previous study, we have identified Ataxin-7 (Atxn7) as a hyperactivity-associated gene. Here, we generated an Atxn7 overexpressing (Atxn7 OE) mice to investigate whether increased Atxn7 expression in the brain correlates with ADHD-like behaviors. Quantitative real-time polymerase chain reaction and immunofluorescence confirmed overexpression of the Atxn7 gene and protein in the prefrontal cortex (PFC) and striatum (STR) of the Atxn7 OE mice. The Atxn7 OE mice displayed hyperactivity and impulsivity, but not inattention. Interestingly, treatment with the ADHD drug, atomoxetine (3 mg/kg, intraperitoneal), attenuated ADHD-like behaviors and reduced Atxn7 gene expression in the PFC and STR of these mice. These findings suggest that Atxn7 plays a role in the pathophysiology of ADHD, and that the Atxn7 OE mice can be used as an animal model of the hyperactive-impulsive phenotype of this disorder. Although confirmatory studies are warranted, the present study provides valuable information regarding the potential genetic underpinnings of ADHD.
- [Supervised off-label prescribing of methylphenidate in adult ADHD]. [Journal Article]
- EEncephale 2018 Aug 16
- CONCLUSIONS: When an off-label prescription is being considered, it must comply with the basic rules of good clinical practice, and the benefit/risk ratio should be constantly reassessed. The proposed multidisciplinary framework, adapted to the characteristics of adult ADHD and the pharmacological properties of methylphenidate, appears to be an interesting strategy to meet the requirements of the good clinical practice. The complementary assessments carried out and the collegial framework allow enhancing the patient's follow-up and minimize the drug risk, particularly in the psychiatric, addictive and cardiovascular adverse events. Finally, this framework could also help the monitoring of other off-label treatments for ADHD, such as atomoxetine or guanfacine.
- Physiologically based pharmacokinetic modelling of atomoxetine with regard to CYP2D6 genotypes. [Journal Article]
- SRSci Rep 2018 Aug 17; 8(1):12405
- Atomoxetine is a norepinephrine reuptake inhibitor indicated in the treatment of attention-deficit/hyperactivity disorder. It is primarily metabolized by CYP2D6 to its equipotent metabolite, 4-hydrox...
Atomoxetine is a norepinephrine reuptake inhibitor indicated in the treatment of attention-deficit/hyperactivity disorder. It is primarily metabolized by CYP2D6 to its equipotent metabolite, 4-hydroxyatomoxetine, which promptly undergoes further glucuronidation to an inactive 4-HAT-O-glucuronide. Clinical trials have shown that decreased CYP2D6 activity leads to substantially elevated atomoxetine exposure and increase in adverse reactions. The aim of this study was to to develop a pharmacologically based pharmacokinetic (PBPK) model of atomoxetine in different CYP2D6 genotypes. A single 20 mg dose of atomoxetine was given to 19 healthy Korean individuals with CYP2D6*wt/*wt (*wt = *1 or *2) or CYP2D6*10/*10 genotype. Based on the results of this pharmacokinetic study, a PBPK model for CYP2D6*wt/*wt individuals was developed. This model was scaled to those with CYP2D6*10/*10 genotype, as well as CYP2D6 poor metabolisers. We validated this model by comparing the predicted pharmacokinetic parameters with diverse results from the literature. The presented PBPK model describes the pharmacokinetics after single and repeated oral atomoxetine doses with regard to CYP2D6 genotype and phenotype. This model could be utilized for identification of appropriate dosages of atomoxetine in patients with reduced CYP2D6 activity to minimize the adverse events, and to enable personalised medicine.
- Incidence of Heart Failure and Cardiomyopathy Following Initiation of Medications for Attention-Deficit/Hyperactivity Disorder: A Descriptive Study. [Journal Article]
- JCJ Clin Psychopharmacol 2018 Aug 10
- CONCLUSIONS: Heart failure/cardiomyopathy rates were not higher over 3 years of ADHD medication use compared with shorter-term treatment. In older age groups, lower rates later in treatment could reflect depletion of patients predisposed to the outcome if they develop it soon after starting treatment.
- Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis. [Journal Article]
- LPLancet Psychiatry 2018 Aug 07
- CONCLUSIONS: Our findings represent the most comprehensive available evidence base to inform patients, families, clinicians, guideline developers, and policymakers on the choice of ADHD medications across age groups. Taking into account both efficacy and safety, evidence from this meta-analysis supports methylphenidate in children and adolescents, and amphetamines in adults, as preferred first-choice medications for the short-term treatment of ADHD. New research should be funded urgently to assess long-term effects of these drugs.
- Using ADHD Medications to Treat Coexisting ADHD and Reading Disorders: A Systematic Review. [Review]
- CPClin Pharmacol Ther 2018 Jul 27
- Attention-deficit/hyperactivity disorder (ADHD), the most common pediatric neurobehavioral disorder, frequently presents with co-existing reading disorders (RD). Despite this, it is unclear whether m...
Attention-deficit/hyperactivity disorder (ADHD), the most common pediatric neurobehavioral disorder, frequently presents with co-existing reading disorders (RD). Despite this, it is unclear whether medication improves symptoms and function in children with comorbid ADHD and RD. We present a systematic review of studies investigating the effects of ADHD medications on ADHD symptoms, academic outcomes, and neuropsychological measures in this important group. This article is protected by copyright. All rights reserved.
- Amplification and Suppression of Distinct Brain-wide Activity Patterns by Catecholamines. [Journal Article]
- JNJ Neurosci 2018 Jul 23
- The widely projecting catecholaminergic (norepinephrine and dopamine) neurotransmitter systems profoundly shape the state of neuronal networks in the forebrain. Current models posit that the effects ...
The widely projecting catecholaminergic (norepinephrine and dopamine) neurotransmitter systems profoundly shape the state of neuronal networks in the forebrain. Current models posit that the effects of catecholaminergic modulation on network dynamics are homogenous across the brain. However, the brain is equipped with a variety of catecholamine receptors with distinct functional effects and heterogeneous density across brain regions. Consequently, catecholaminergic effects on brain-wide network dynamics might be more spatially specific than assumed. We tested this idea through the analysis of functional magnetic resonance imaging (fMRI) measurements performed in humans (19 females, 5 males) at 'rest' under pharmacological (atomoxetine-induced) elevation of catecholamine levels. We used a linear decomposition technique to identify spatial patterns of correlated fMRI signal fluctuations that were either increased or decreased by atomoxetine. This yielded two distinct spatial patterns, each expressing reliable and specific drug effects. The spatial structure of both fluctuation patterns resembled the spatial distribution of the expression of catecholamine receptor genes: α1 norepinephrine receptors (for the fluctuation pattern: placebo > atomoxetine), 'D2-like' dopamine receptors (pattern: atomoxetine > placebo), and β norepinephrine receptors (for both patterns, with correlations of opposite sign). We conclude that catecholaminergic effects on the forebrain are spatially more structured than traditionally assumed and at least in part explained by the heterogeneous distribution of various catecholamine receptors. Our findings link catecholaminergic effects on large-scale brain networks to low-level characteristics of the underlying neurotransmitter systems. They also provide key constraints for the development of realistic models of neuromodulatory effects on large-scale brain network dynamics.SIGNIFICANCE STATEMENTThe catecholamines norepinephrine and dopamine are an important class of modulatory neurotransmitters. Because of the widespread and diffuse release of these neuromodulators, it has commonly been assumed that their effects on neural interactions are homogenous across the brain. Here, we present results from the human brain that challenge this view. We pharmacologically increased catecholamine levels and imaged the effects on the spontaneous covariations between brain-wide fMRI signals at 'rest'. We identified two distinct spatial patterns of covariations: one that was amplified and another that was suppressed by catecholamines. Each pattern was associated with the heterogeneous spatial distribution of the expression of distinct catecholamine receptor genes. Our results provide novel insights into the catecholaminergic modulation of large-scale human brain dynamics.
- Drugs and Lactation Database (LactMed) [BOOK]
- BOOKNational Library of Medicine (US): Bethesda (MD)
- There is no published experience with atomoxetine during breastfeeding, although reports from the manufacturer found no serious advese effects in two breastfed infants. An alternate drug may be prefe...
There is no published experience with atomoxetine during breastfeeding, although reports from the manufacturer found no serious advese effects in two breastfed infants. An alternate drug may be preferred, especially while nursing a newborn or preterm infant.
- Orthostatic Hypotension in the Hypertensive Patient. [Journal Article]
- AJAm J Hypertens 2018 Jul 02
- Orthostatic hypotension (OH) is an important and common medical problem, particularly in the frail elderly with multiple comorbidities and polypharmacy. OH is an independent risk factor for falls and...
Orthostatic hypotension (OH) is an important and common medical problem, particularly in the frail elderly with multiple comorbidities and polypharmacy. OH is an independent risk factor for falls and overall mortality. Hypertension is among the most common comorbidities associated with OH, and its presence complicates the management of these patients because treatment of one can worsen the other. However, there is evidence that uncontrolled hypertension worsens OH so that both should be managed. The limited data available suggest that angiotensin receptor blockers and calcium channel blockers are preferable antihypertensives for these patients. Patients with isolated supine hypertension can be treated with bedtime doses of short-acting antihypertensives. Treatment of OH in the hypertensive patients should focus foremost on the removal of drugs that can worsen OH, including ones that are easily overlooked, such as tamsulosin, tizanidine, sildenafil, trazodone, and carvedilol. OH and postprandial hypotension can be prevented with abdominal binders and acarbose, respectively, without the need to increase baseline blood pressure. Upright blood pressure can be improved by harnessing residual sympathetic tone with atomoxetine, which blocks norepinephrine reuptake in nerve terminals, and pyridostigmine, which facilitates cholinergic neurotransmission in autonomic ganglia. Oral water bolus acutely but transiently increases blood pressure in autonomic failure patients. If traditional pressor agents are needed, midodrine and droxidopa can be used, administered at the lowest dose and frequency that improves symptoms. Management of OH in the hypertensive patient is challenging, but a management strategy based on understanding the underlying pathophysiology can be effective in most patients.
New Search Next
- Pharmacological treatment for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders. [Review]
- CDCochrane Database Syst Rev 2018 06 26; 6:CD007990
- CONCLUSIONS: Following an updated search of potentially relevant studies, we found no new studies that matched our inclusion criteria and thus our conclusions have not changed.Methylphenidate, clonidine, guanfacine, desipramine, and atomoxetine appear to reduce ADHD symptoms in children with tics though the quality of the available evidence was low to very low. Although stimulants have not been shown to worsen tics in most people with tic disorders, they may, nonetheless, exacerbate tics in individual cases. In these instances, treatment with alpha agonists or atomoxetine may be an alternative. Although there is evidence that desipramine may improve tics and ADHD in children, safety concerns will likely continue to limit its use in this population.