Guanfacine Extended Release Research Articles

Development and Validation of A High-Performance Liquid Chromatography- Mass Spectroscopy Assay for the Bioequivalence Study of Guanfacine Extended Release (GXR) Tablet in Human Plasma

Abstract: Guanfacine, an α2-adrenergic (α2A) agonist long indicated to treat hypertension, is now being used to treat attention deficit hyperactivity disorder (ADHD) in adolescents. A simple rapid high performance liquid chromatography-mass spectrometry (HPLC-MS/MS) method to detect and quantify guanfacine provides a basis for studying its bioequivalence and pharmacokinetics in human plasma. This assay involves quantitation of guanfacine using its stable isotope labeled internal standard (IS) guanfacine-13C-15N3, without impact of ion suppression in plasma matrix. Electrospray ionization (ESI) in positive mode and multiple reaction monitoring (MRM) were used for guanfacine and guanfacine-13C-15N3 at the transitions m/z 246.1→60.1 and m/z 250.0→159.1 respectively. The sample preparation is optimized in this method with an accurate and simple protein precipitation method employing methanol. Linearity was demonstrated over within the range of 0.0500-10.0 ng/mL for guanfacine in plasma with correlation coefficients greater than 0.99. The method showed excellent reproducibility, Aaccuracy (Relative Error) of the method ranged from -2.897.2% to 108.98.9% even at the the lower limit of quantification (LLOQ), and total precision, expressed as the coefficient of variation, was between 1.6% and 10.5%. The average recoveries of guanfacine at three spiked levels of 0.150, 1.00 and 7.50 ng/mL waswere 103.93%, 97.91% and 100.22%, respectively. The validated method was applied successfully to a bioequivalence study of a fixed-dose of extended-release guanfacine hydrochloride (GXR) tablet (Test formulation) and Intuniv® (Reference formulation) in Chinese healthy subjects, 42 subjects under fasting condition and 30 subjects under feeding condition. Pharmacokinetic parameters were calculated using DAS 3.2.8, and 90% confidence intervals (CIs) of AUC0-t, AUC0-∞ and Cmax for guanfacine were all within 80.00-125.00%, suggesting that the two formulations were bioequivalent in terms of rate and extent of absorption.

Noradrenergic Add-on Therapy with Extended-Release Guanfacine in Alzheimer’s Disease (NorAD): study protocol for a randomised clinical trial and COVID-19 amendments

BackgroundGuanfacine is a α2A adrenergic receptor agonist approved for treating attention deficit hyperactivity disorder (ADHD). It is thought to act via postsynaptic receptors in the prefrontal cortex, modulating executive functions including the regulation of attention. Attention is affected early in Alzheimer’s disease (AD), and this may relate to pathological changes within the locus coeruleus, the main source of noradrenergic pathways within the brain. Given that cholinergic pathways, also involved in attention, are disrupted in AD, the combination of noradrenergic and cholinergic treatments may have a synergistic effect on symptomatic AD. The primary objective of the NorAD trial is to evaluate the change in cognition with 12 weeks of treatment of extended-release guanfacine (GXR) against a placebo as a combination therapy with cholinesterase inhibitors in participants with mild to moderate Alzheimer’s disease.Methods/designNorAD is a 3-month, single-centre, randomised, double-blind, placebo-controlled, phase III trial of extended-release guanfacine (GXR) in participants with mild to moderate Alzheimer’s disease. A total of 160 participants will be randomised to receive either daily guanfacine or placebo in combination with approved cholinesterase treatment for 12 weeks. The primary outcome is the change in cognition, as measured by the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), from baseline to follow-up in the treatment group compared to the placebo group. Secondary outcomes include the change in additional cognitive measures of attention (Tests of Attention: Trails A and B, digit-symbol substitution, Test of Everyday Attention and CANTAB-RVP), neuropsychiatric symptoms (Neuropsychiatric Inventory), caregiver burden (Zarit Burden Interview) and activities of daily living (Alzheimer’s Disease Co-operative Study – Activities of Daily Living Inventory). From July 2020, observation of change following cessation of treatment is also being assessed.DiscussionThere is strong evidence for early noradrenergic dysfunction in Alzheimer’s disease. The NorAD trial aims to determine whether guanfacine, a noradrenergic alpha-2 agonist, improves attention and cognition when used in addition to standard cholinergic treatment.Trial registrationClinicalTrials.govNCT03116126. Registered on 14 April 2017EudraCT: 2016-002598-36

Evaluating the pharmacokinetics of extended release viloxazine in the treatment of children with attention-deficit/hyperactivity disorder

ABSTRACT Introduction Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder of childhood and impacts function negatively in multiple settings. Current treatments include stimulants, which inhibit the reuptake of dopamine and norepinephrine, a nonstimulant norepinephrine reuptake inhibitor (NRI) atomoxetine, and alpha-2 agonists clonidine extended release (ER) and guanfacine ER. Despite the effectiveness of these medications some patients do not respond to available drugs or may experience tolerability issues that hinder their use. Areas covered Viloxazine, a serotonin norepinephrine modulating agent, was used outside of the United States (U.S.) as an effective antidepressant for several decades, but its use fell out of favor due to the need for multiple daily dosing. An ER viloxazine formulation was recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of ADHD. The efficacy, pharmacokinetics and metabolism of viloxazine and viloxazine ER are reviewed. Expert opinion Viloxazine ER is the first nonstimulant approved to treat ADHD in more than a decade. Although they have not been directly compared, the effect size of viloxazine ER is less than has been observed for stimulants. However, its pharmacokinetic properties and tolerability make viloxazine ER a useful addition to the collection of FDA approved ADHD treatments.

Delayed Signs and Symptoms of Extended Release Guanfacine Overdose in Two Adolescent Patients: Implications of Monitoring on the Psychiatry Unit

Guanfacine is a selective alpha-2a adrenoreceptor agonist that with overdose can cause symptoms ranging from mild sedation to coma, respiratory depression, hyporeflexia, hypotonia, bradycardia, and hypotension. Despite a well-defined and predictable toxidrome, variations can be seen based on multiple factors including age, quantity ingested, organ functions, coingestions, time since ingestion, and specific dosage form. Here, we describe two cases of delayed presentation of extended release guanfacine toxicity and highlight the variations encountered in the toxidrome presentation. These cases bring to attention the importance of maintaining a high suspicion for such atypical presentations, keeping in mind the limitations of managing these complications on an inpatient psychiatric unit.

A retrospective medical chart review of clinical outcomes in children and adolescents with attention-deficit/hyperactivity disorder treated with guanfacine extended-release in routine Canadian clinical practice

ObjectiveThis study evaluated clinical outcomes in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) treated with the α2-adrenoceptor agonist guanfacine extended-release (GXR) in routine Canadian clinical practice.MethodsThis retrospective chart review focused on patients with ADHD aged 6–17 years initiating treatment with GXR as monotherapy or adjunctive therapy. Patients were followed for up to 12 months after GXR initiation and, if they had received prior ADHD pharmacotherapy, for 12 months before GXR initiation. The primary outcome was change in ADHD symptoms and functionality based on physician assessments, classified as improvement, no change, or worsening relative to the time of GXR initiation. Treatment-emergent adverse events (TEAEs) were evaluated. Clinical outcomes were also analyzed post hoc according to whether GXR treatment was received as monotherapy or adjunctive therapy, and by select psychiatric comorbidities. Exploratory analyses were conducted in patients who had received prior ADHD pharmacotherapy to evaluate clinical outcomes after initiating GXR.ResultsImprovements in ADHD symptoms were reported for 232/330 (70.3%) patients. Functional improvements in school performance and home life were reported for 213/330 (64.5%) and 209/330 (63.3%) patients, respectively. The most frequent TEAEs (≥ 5%) were somnolence, headache, insomnia, presyncope, and decreased appetite. Improvements in ADHD symptoms were observed when GXR was received as either monotherapy (35/60 [58.3%]) or adjunctive therapy (197/270 [73.0%]). Improvements in ADHD symptoms and functionality were observed in the majority of patients with select psychiatric comorbidities. Among patients who had experienced worsening of symptoms with prior ADHD pharmacotherapy, 44/54 (81.5%) experienced symptom improvement, 33/44 (75.0%) who had previously experienced worsening of school performance improved, and 34/48 (70.8%) who had previously experienced worsening of home life improved.ConclusionIn Canadian routine clinical practice, most children and adolescents with ADHD treated with GXR experienced improvements in ADHD symptoms and in functionality both at school and at home.

Visualizing Neuropharmacological Effects of Guanfacine Extended Release in Attention Deficit Hyperactivity Disorder Using Functional Near-Infrared Spectroscopy.

Objective: In the current study, we explored the neural substrate for acute effects of guanfacine extended release (GXR) on inhibitory control in school-aged children with attention deficit hyperactivity disorder (ADHD), using functional near-infrared spectroscopy (fNIRS). Methods: Following a GXR washout period, 12 AD HD children (6-10 years old) performed a go/no-go task before and 3 h after GXR or placebo administration, in a randomized, double-blind, placebo-controlled, crossover design study. In the primary analysis, fNIRS was used to monitor the right prefrontal cortical hemodynamics of the participants, where our former studies showed consistent dysfunction and osmotic release oral system-methylphenidate (OROS-MPH) and atomoxetine hydrochloride (ATX) elicited recovery. We examined the inter-medication contrast, comparing the effect of GXR against the placebo. In the exploratory analysis, we explored neural responses in regions other than the right prefrontal cortex (PFC). Results: In the primary analysis, we observed no significant main effects or interactions of medication type and age in month (two-way mixed ANCOVA, Fs < 0.20, all ps > .05). However, in the post-hoc analysis, we observed significant change in the oxy-Hb signal in the right angular gyrus (AG) for inter-medication (one sample t-test, p < 0.05, uncorrected, Cohen's d = 0.71). Conclusions: These results are different from the neuropharmacological effects of OROS-MPH and ATX, which, in an upregulated manner, reduced right PFC function in ADHD children during inhibitory tasks. This analysis, while limited by its secondary nature, suggested that the improved cognitive performance was associated with activation in the right AG, which might serve as a biological marker to monitor the effect of GXR in the ADHD children.

Efficacy and Safety of Medication for Attention-Deficit Hyperactivity Disorder in Children and Adolescents with Common Comorbidities: A Systematic Review.

IntroductionComorbid psychiatric conditions in children and adolescents with attention-deficit hyperactivity disorder (ADHD) occur frequently, complicate management, and are associated with substantial burden on patients and caregivers. Very few systematic reviews have assessed the efficacy and safety of medications for ADHD in children and adolescents with comorbidities. Of those that were conducted, most focused on a particular comorbidity or medication. In this systematic literature review, we summarize the efficacy and safety of treatments for children and adolescents with ADHD and comorbid autism spectrum disorders, oppositional defiant disorder, Tourette’s disorder and other tic disorders, generalized anxiety disorder, and major depressive disorder.MethodsWe searched MEDLINE, Embase, and ClinicalTrials.gov (to October 2019) for studies of patients (aged < 18 years) with an ADHD diagnosis and the specified comorbidities treated with amphetamines, methylphenidate and derivatives, atomoxetine (ATX), and guanfacine extended-release (GXR). For efficacy, placebo-controlled randomized controlled trials (RCTs) or meta-analyses of RCTs were eligible for inclusion; for safety, all study types were eligible. The primary efficacy outcome measure was ADHD Rating Scale IV (ADHD-RS-IV) total score.ResultsOf 2177 publications/trials retrieved, 69 were included in this systematic literature review (5 meta-analyses, 37 placebo-controlled RCTs, 16 cohort studies, 11 case reports). A systematic narrative synthesis is provided because insufficient data were retrieved to combine ADHD-RS-IV total scores or effect sizes. Effect sizes for ADHD-RS-IV total scores were available for ten RCTs and ranged from 0.46 to 1.0 for ATX and from 0.92 to 2.0 for GXR across comorbidities. The numbers and types of adverse events in children with comorbidities were consistent with those in children without comorbidities, but treatment should be individualized to ensure children can tolerate the lowest effective dose.ConclusionLimited information is available from placebo-controlled RCTs on the efficacy (by ADHD-RS-IV) or safety of medication in children with ADHD and psychiatric comorbidities. Further studies are required to support evidence-based drug selection for these populations.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40120-021-00249-0.

Evaluating Guanfacine Hydrochloride in the Treatment of Attention Deficit Hyperactivity Disorder (ADHD) in Adult Patients: Design, Development and Place in Therapy.

Attention-deficit/hyperactivity disorder (ADHD) is characterized by age-inappropriate and impairing levels of inattention, hyperactivity, or impulsivity, or a combination of these characteristics. It is estimated to affect around 4% of adults worldwide. In the past few decades, prescriptions for ADHD drugs (psychostimulants and non-psychostimulants) have increased significantly. However, the efficacy and safety of adult ADHD medications remains controversial. Guanfacine extended-release (GXR) is a non-psychostimulant ADHD drug that is a selective α2A-adrenergic receptor agonist, first approved for treatment of adult ADHD in Japan in June 2019. Our aim was to provide an overview of GXR pharmacology and review the studies on efficacy and safety that have been conducted in adults with ADHD. The beneficial actions of guanfacine are thought to be attributed to the strengthening of prefrontal cortical network connections, which regulate attention, emotion, and behavior via the activity at post-synaptic α2A receptors. Current evidence of GXR efficacy and safety suggests that GXR is an effective monotherapy treatment option for adults with ADHD.

Safety and efficacy of guanfacine extended-release in adults with attention-deficit/hyperactivity disorder: an open-label, long-term, phase 3 extension study

BackgroundTo assess the safety and efficacy of long-term administration of guanfacine extended-release (GXR) in adults with attention-deficit/hyperactivity disorder (ADHD).MethodsIn this open-label, long-term, phase 3 extension study in Japan, 150 patients transitioned from a double-blind trial, and 41 newly enrolled patients received once daily GXR (starting dose 2 mg/day, maintenance dose 4–6 mg/day) for 50 weeks. Primary outcome measures were the frequency and nature of treatment-emergent adverse events (TEAEs); secondary outcome measures included the change from week 0 in ADHD Rating Scale IV with Adult Prompts (ADHD-RS-IV; Japanese version) total and subscale scores, Conners’ Adult ADHD Rating Scales (CAARS), Clinical Global Impression-Improvement (CGI-I) and Patient Global Impression-Improvement (PGI-I) scales, and quality of life (QoL) and executive functioning measures.ResultsOf all patients, 94.2% (180/191) reported ≥1 TEAE and 19.9% (38/191) discontinued because of a TEAE. Most TEAEs were mild to moderate in severity; there were two serious TEAEs and no deaths. Commonly reported TEAEs (≥10% of patients) were somnolence, thirst, nasopharyngitis, decreased blood pressure, postural dizziness, bradycardia, malaise, constipation, and dizziness. Mean changes from week 0 in ADHD-RS-IV total and subscale scores and CAARS subscale scores were significantly improved in former placebo or GXR patients and new patients at last observation (p < .0001), and the percentage of patients with very much or much improved CGI-I and PGI-I scores increased.ConclusionsThere were no major safety concerns during long-term GXR administration in adults with ADHD. After long-term treatment, patients had significant improvements from baseline in ADHD symptoms, QoL, and executive functioning.Trial registrationJapan Primary Registries Network (https://rctportal.niph.go.jp/en/): JapicCTI-163232, registered 04/21/2016.

Functional impairment outcomes in clinical trials of different ADHD medications: post hoc responder analyses and baseline subgroup analyses

Several recent phase 3 clinical trials of attention-deficit/hyperactivity disorder (ADHD) medications have used the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P). Here, we assess WFIRS-P response in individual patients in two pivotal trials of lisdexamfetamine dimesylate (LDX) and guanfacine extended release (GXR). We also analysed pooled WFIRS-P data from seven phase 3 studies of ADHD medications to shed light on factors associated with baseline functional impairment. The proportion of patients with a change in WFIRS-P score that exceeded the minimal important difference (MID) criteria for response was greater for LDX than placebo in the Family, Learning and School, and Risky Activities domains, and was greater for GXR than placebo in the Social Activities, Learning and School, and Family domains. Responders had significantly worse baseline scores in all WFIRS-P domains (all p < 0.001) than non-responders. In the pooled analyses, baseline WFIRS-P scores in all domains were significantly worse in participants with oppositional defiant disorder (ODD) than in those without ODD. Having combined type or hyperactive-impulsive type ADHD, being enrolled into a study in Europe, being male and being younger also had modest negative effects on baseline WFIRS-P scores. The present analysis of WFIRS-P response shows that previously reported group-level improvements in WFIRS-P functional impairment score translated into clinically relevant improvements in many individual participants. Functional impairment is a diverse and subjective construct that is influenced by multiple factors. Optimal management of individuals with ADHD should involve monitoring improvements in functioning and quality of life, as well as symptomatic improvement.

Efficacy of Guanfacine Extended Release in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder and Comorbid Oppositional Defiant Disorder.

To assess the efficacy of the non-stimulant guanfacine extended release (GXR) on attention-deficit/hyperactivity disorder (ADHD) symptoms in children and adolescents, with and without comorbid oppositional defiant disorder (ODD). Data were derived from 4 phase 3, randomized, placebo-controlled trials of dose-optimized GXR monotherapy, in which at least 10% of participants had a diagnosis of comorbid ODD. SPD503-312 and SPD503-316 were 10- to 13-week studies of GXR (1-7 mg/d). SPD503-314 and SPD503-307 were 8-week studies of GXR (1-4 mg/d). Efficacy was assessed using the ADHD Rating Scale IV (ADHD-RS-IV) total scores. In total, 1,084 participants were included (SPD503-312 and SPD503-316, n = 537; SPD503-314, n = 333; and SPD503-307, n = 214). GXR was associated with significant improvements in ADHD core symptoms at endpoint in participants with and without ODD (p < 0.01 in all studies). Placebo-adjusted least-squares mean (95% confidence interval) changes from baseline to endpoint in the ADHD-RS-IV total scores in participants with and without ODD were -8.6 (-14.4, -2.8) and -7.3 (-9.5, -5.0) in the pooled data from SPD503-312 and SPD503-316, -12.6 (-19.6, -5.7) and -8.7 (-11.8, -5.5) in SPD503-314, and -12.7 (-17.3, -8.1) and -11.8 (-19.3, -4.4) in SPD503-307, respectively. The corresponding effect sizes were 0.688 and 0.598 in SPD503-312 and SPD503-316, 0.876 and 0.729 in SPD503-314, and 0.962 and 0.842 in SPD503-307. The findings demonstrate the efficacy of GXR for treating ADHD in children and adolescents with comorbid ODD.

Evaluation of the current data on guanfacine extended release for the treatment of ADHD in children and adolescents

ABSTRACTIntroduction: Attention-deficit/hyperactivity disorder (ADHD) commonly occurs in children, adolescents, and adults. Although symptoms of ADHD often respond robustly to treatment with stimulants (amphetamine or methylphenidate), not all patients are appropriate candidates for treatment with these drugs. Guanfacine extended-release (GXR) is a non-stimulant alternative drug approved for the treatment of ADHD in the United States (U.S.), Canada, and Europe.Areas covered: The chemistry, pharmacokinetics, mechanism of action and dosage of GXR are presented. Efficacy and safety data obtained in clinical trials with subjects aged 6–17 years for both GXR monotherapy and use in combination with stimulants are described. Meta-analyses comparing GXR to other drugs are presented. MedWatch surveillance data collected for GXR since approval in the U.S. are also discussed.Expert opinion: Although GXR is effective for the treatment of ADHD and has a different side effect profile than stimulants, it is not as impressive in reducing symptoms. Despite the availability of multiple pharmacological treatments for ADHD, there remains an unmet need for formulations as potent as stimulants but with fewer adverse effects. Several pharmacological agents for ADHD treatment are in development. It is not clear that any of these compounds will replace currently available formulations as first-line alternatives.

Treatment Patterns, Health Care Resource Utilization, and Health Care Cost Associated with Atypical Antipsychotics or Guanfacine Extended Release in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder in Quebec, Canada.

Objective: To assess treatment patterns, health care resource utilization, and health care costs associated with use of atypical antipsychotics (AAPs) or the nonstimulant guanfacine extended release (GXR) after stimulant therapy for attention-deficit/hyperactivity disorder (ADHD). In Canada, GXR is approved as a monotherapy for children and adolescents with ADHD or as an adjunct to stimulants, and AAPs are commonly used off-label as an adjunct to stimulants.Methods: Health care claims data (January 1, 2007 to March 31, 2016) from Quebec's provincial health plan were assessed for individuals with ADHD, 6–17 years of age, who received ≥1 stimulant followed by a first AAP or GXR prescription (index medication), without a diagnosis for which AAPs are indicated.Results: Overall, 1327 individuals were included (AAPs, 1098; GXR, 229). Rates of discontinuation, augmentation, or switching of the index medication did not differ between AAPs and GXR during the first follow-up year. Discontinuation rates were significantly lower with GXR than with AAPs during the second year (22.0% vs. 35.9%; p = 0.03). GXR and AAPs resulted in similar increases in total health care cost. In GXR users, the increase in prescription drug cost after 6 months was higher than in AAP users, whereas the increase in overall medical cost was higher with AAPs than GXR, owing to more psychiatric department visits.Conclusions: In children and adolescents with ADHD who used AAPs or GXR after stimulants, secondary treatment changes were similar with both treatments after 1 year, but discontinuation rates were significantly lower with GXR than with AAPs in the second year. The greater increase in prescription cost with GXR was balanced by a greater increase in overall medical costs with AAPs, resulting in no overall difference in total health care cost between the two treatments.

Guanfacine extended-release for cannabis use disorder: a pilot feasibility trial

ABSTRACT Background: Currently, there are no established pharmacotherapies for cannabis use disorders (CUDs). As a long-acting alpha-2-adrenergic receptor agonist, guanfacine extended-release (G-XR) could be useful in the treatment of CUDs by mitigating withdrawal and improving behavioral control. Objectives: To evaluate the feasibility and tolerability of G-XR as a treatment for CUDs. Methods: In an eight-week open-label outpatient pilot trial, we evaluated the safety and tolerability of G-XR in 22 cannabis dependent individuals. Using 2 different titration schedules, G-XR was gradually titrated to a dose of 4 mg or the highest dose tolerated. All participants received standard medication management. Results: Retention at week eight was 41%. Average daily amount of cannabis use (in grams: F1,86 = 8.74, p = .004; in dollars: F1,86 = 16.67, p < .0001) and cannabis using days (F1,86 = 7.67, p = .007) significantly reduced over the course of study participation. There were no significant differences between the titration schedules on emergence of side effects (Fisher exact test, p = .378) or retention (Log-Rank Test X2 1 = 0.021, p = .886). A total of 3 participants achieved 3 weeks or greater of total abstinence. Conclusions: G-XR is a feasible treatment for CUDs, and should be evaluated further in an efficacy trial.

Cardiovascular Effects of Drugs Used to Treat Attention-Deficit/Hyperactivity Disorder Part 2: Impact on Cardiovascular Events and Recommendations for Evaluation and Monitoring.

A variety of psychostimulant and nonpsychostimulant medications have proven to be successful in reducing inattention, impulsivity, and hyperactivity in individuals with attention-deficit/hyperactivity disorder (ADHD). Psychostimulants used to treat ADHD include methylphenidate and related drugs and various amphetamine preparations. Nonpsychostimulant medications used to treat ADHD include atomoxetine and 2 α-2 adrenergic agonists: guanfacine extended-release and clonidine extended-release. The psychostimulants and atomoxetine have been shown, on average, to increase heart rate by 3-10 beats/min, systolic blood pressure by 3-8 mm Hg, and diastolic BP by 2-14 mm Hg. These drugs may also delay ventricular repolarization. The α-2 adrenergic agonists may reduce heart rate and BP. For these reasons, there is concern about the safety of psychostimulant and nonpsychostimulant medications in patients with ADHD. Studies in healthy children adolescents and adults have not consistently shown a disproportionately high risk of major adverse cardiovascular (CV) outcomes, including sudden unexpected death. Those with underlying CV disease have, in general, tolerated these drugs well. Certain high-risk groups have been identified who may benefit from cardiology consultation prior to drug initiation. Several American and Canadian professional societies have published guidelines for CV evaluation, management, and monitoring of patients with ADHD who are candidates for pharmacotherapy.

Cardiovascular Effects of Drugs Used to Treat Attention-Deficit/Hyperactivity Disorder: Part 1: Epidemiology, Pharmacology, and Impact on Hemodynamics and Ventricular Repolarization.

Attention-deficit/hyperactivity disorder (ADHD) is a clinical syndrome characterized by persistent inattention, impulsivity, and hyperactivity. It is most commonly encountered in children and adolescents but may persist into adulthood. A variety of psychostimulant and nonpsychostimulant medications have proven to be successful in reducing inattention, impulsivity, and hyperactivity in those with ADHD. Psychostimulants used to treat ADHD include methylphenidate and related drugs and various amphetamine preparations. Non-psychostimulant medications used to treat ADHD include atomoxetine and two alpha-2 adrenergic agonists: guanfacine extended-release and clonidine extended-release. The psychostimulants and atomoxetine have been shown, on average, to increase heart rate by 3-10 beats/min, systolic blood pressure by 3-8 mm Hg, and diastolic blood pressure by 2-14 mm Hg. These drugs may also delay ventricular repolarization. The alpha-2 adrenergic agonists may reduce heart rate and blood pressure. For these reasons, there is concern about the safety of psychostimulant and nonpsychostimulant medications in patients with ADHD. In part 1 of this review, we discuss the epidemiology and natural history of ADHD, describe the pharmacology of drugs used to treat ADHD, and discuss in detail studies assessing the effects of ADHD drugs on blood pressure, heart or pulse rate, and electrocardiographic indices of ventricular repolarization.

Guanfacine Extended Release for the Reduction of Aggression, Attention-Deficit/Hyperactivity Disorder Symptoms, and Self-Injurious Behavior in Prader-Willi Syndrome-A Retrospective Cohort Study.

Objective: To examine the role of Guanfacine Extended Release (GXR) in the management of behavioral disturbances in patients with Prader-Willi Syndrome (PWS). Methods: Twenty from a total of 27 individuals with genetically confirmed PWS, 6-26 years of age, with the following symptoms were identified: significant aggression/agitation, skin picking, and/or symptoms of attention-deficit/hyperactivity disorder (ADHD). Response to GXR for the above noted symptoms was categorized as improved, worsened, or unchanged, while assessing for side effects and tolerability. Results: Eleven of the 20 individuals reported skin-picking, 17 reported aggression/agitation, and 16 reported symptoms of ADHD. Nine (81.8%), 14 (82.3%), and 15 (93.7%) individuals showed an improvement in skin-picking, aggression/agitation, and ADHD, respectively, while on GXR treatment. Two patients with prior complaints of psychotic symptoms did not respond to GXR. Of note, no abnormal weight gain or significant adverse reaction was observed in this group, while on GXR. Conclusions: In this study, GXR demonstrated improvement in symptoms of skin picking, aggression/agitation, and ADHD in patients with PWS. GXR was not effective in reducing psychosis or agitation related to psychotic symptoms. Future studies are warranted to further establish the utility of GXR in PWS patients.

WHAT WE KNOW—AND DON'T KNOW—ABOUT THE PSYCHOSOCIAL IMPACT OF PSYCHIATRIC GENETIC INFORMATION

The present study investigated whether symptom reduction in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) treated with guanfacine extended release (GXR) can be explained by sedative effects of the medication. Data from four double-blind, randomized, placebo-controlled, phase 3 trials of GXR monotherapy (1–7 mg/day; morning administration) in children (aged 6–12 years) and adolescents (aged 13–17 years) with ADHD were analyzed post hoc. Two studies used forced-dose titration and two used flexible-dose titration. Efficacy was determined using ADHD Rating Scale IV (ADHD-RS-IV) scores. Sedative treatment-emergent adverse events (TEAEs) included somnolence, sedation and hypersomnia. The proportion of responders (≥ 30% reduction in ADHD-RS-IV total score) increased from weeks 1 to 4 and remained stable to study endpoint. Sedative TEAEs generally peaked at the first week in which the target dose was achieved and then declined. In subgroup analyses, significant placebo-adjusted improvements in ADHD-RS-IV total scores were observed in participants without any sedative TEAEs in the forced-dose and flexible-dose studies (nominal p < 0.001). In addition, GXR was associated with significant improvements in both inattentive and hyperactive–impulsive symptoms, as assessed by the ADHD-RS-IV subscale scores (nominal p < 0.001) and by the ADHD-RS-IV total score in participants with different ADHD subtypes (nominal p < 0.05). Thus, the efficacy of GXR in children and adolescents with ADHD is not primarily due to sedation, although some contribution to symptom reduction cannot be excluded, especially early in treatment when rates of sedative TEAEs are at their highest.

Distinguishing the efficacy and sedative effects of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder

The present study investigated whether symptom reduction in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) treated with guanfacine extended release (GXR) can be explained by sedative effects of the medication. Data from four double-blind, randomized, placebo-controlled, phase 3 trials of GXR monotherapy (1–7 mg/day; morning administration) in children (aged 6–12 years) and adolescents (aged 13–17 years) with ADHD were analyzed post hoc. Two studies used forced-dose titration and two used flexible-dose titration. Efficacy was determined using ADHD Rating Scale IV (ADHD-RS-IV) scores. Sedative treatment-emergent adverse events (TEAEs) included somnolence, sedation and hypersomnia. The proportion of responders (≥ 30% reduction in ADHD-RS-IV total score) increased from weeks 1 to 4 and remained stable to study endpoint. Sedative TEAEs generally peaked at the first week in which the target dose was achieved and then declined. In subgroup analyses, significant placebo-adjusted improvements in ADHD-RS-IV total scores were observed in participants without any sedative TEAEs in the forced-dose and flexible-dose studies (nominal p < 0.001). In addition, GXR was associated with significant improvements in both inattentive and hyperactive–impulsive symptoms, as assessed by the ADHD-RS-IV subscale scores (nominal p < 0.001) and by the ADHD-RS-IV total score in participants with different ADHD subtypes (nominal p < 0.05). Thus, the efficacy of GXR in children and adolescents with ADHD is not primarily due to sedation, although some contribution to symptom reduction cannot be excluded, especially early in treatment when rates of sedative TEAEs are at their highest.

A randomized, placebo-controlled trial of extended-release guanfacine in children with autism spectrum disorder and ADHD symptoms: an analysis of secondary outcome measures.

In a prior report, we showed that extended-release guanfacine (GEXR) is safe and effective for children with autism spectrum disorder (ASD) accompanied by ADHD symptoms. Here, we examine the impact of GEXR on oppositional behavior, anxiety, repetitive behavior, and sleep disturbance. Sixty-two subjects with ASD (53 boys, 9 girls; ages 5-14 years) were randomly assigned to GEXR (n = 30) or placebo (n = 32) for 8 weeks. Outcomes include the Home Situation Questionnaire-Modified for ASD (HSQ-ASD), Anxiety scale of the Child and Adolescent Symptom Inventory (CASI), Children's Yale-Brown Obsessive-Compulsive Scale-Modified for ASD (CYBOCS-ASD), and Children's Sleep Habits Questionnaire (CSHQ). A repeated measures linear mixed model was used to determine the effects of treatment group and time on HSQ scores. For other measures, change from baseline was evaluated with Analysis of Covariance (ANCOVA).After 8 weeks of treatment, parent ratings of oppositional behavior on the HSQ declined by 44% (per item mean from 3.4 to 1.9) in the GEXR group compared to 12% (from 3.3 to 2.9) for placebo (p = 0.004). Repetitive behavior on the CYBOCS-ASD showed a significantly greater decline in GEXR-treated participants compared to placebo (24% vs. <1%, p = 0.01). No group differences were observed on CASI Anxiety or CSHQ (p = 0.64 and 0.75, respectively). GEXR was effective in reducing oppositional behavior and, more modestly, repetitive behavior. GEXR was not superior to placebo for anxiety, though baseline anxiety ratings were low. GEXR did not significantly improve sleep habits. Future studies could focus on repetitive behavior or anxiety, symptoms with limited treatment options.