Guanfacine for the Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents with Down Syndrome: A Retrospective Chart Review.

Study Design: Retrospective case series. Objectives: The objective of this study was to provide naturalistic data on the use of guanfacine for the treatment of attention-deficit/hyperactivity disorder (ADHD) in a clinically referred sample of youth with Down syndrome (DS). Methods: The medical records of children and adolescents with DS who received guanfacine for the treatment of ADHD from a multidisciplinary neurodevelopmental disorder clinic between September 1, 2011, and September 10, 2021, were reviewed. Demographic and clinical characteristics, guanfacine dose and treatment duration, and adverse effects were recorded. Clinical Global Impression Scale (CGI) scores for ADHD symptom severity (S) and improvement (I) were retrospectively assigned by a child and adolescent psychiatrist based on review of the clinic notes. Response to guanfacine was defined as completion of at least 12 weeks of treatment and a Clinical Global Impression Improvement subscale rating ≤2 (1 = "very much improved" or 2 = "much improved"). Results: Twenty-one patients were eligible for inclusion, of whom 17 (81%) completed at least 12 weeks of guanfacine. Ten of the 21 patients (48%; 95% confidence interval [CI]: 28%-68%) responded to treatment. The median time on guanfacine treatment covered by the clinic notes was 50.4 weeks, with a range of 0.3 weeks to 7.5 years. Thirteen patients (62%) remained on guanfacine at the time of their most recent clinic note. Nine patients had adverse events documented in their clinic notes (43%; 95% CI: 24%-63%), most commonly sleepiness (n = 7) and constipation (n = 2). Conclusion: About half of patients with DS responded to guanfacine for the treatment of ADHD and many tolerated long-term use. Study limitations primarily relate to the retrospective nature of the study and small sample size.

Activating astrocytic α2A adrenoceptors in hippocampus reduces glutamate toxicity to attenuate sepsis-associated encephalopathy in mice.

BACKGROUND: Glutamate metabolism disorder is an important mechanism of sepsis-associated encephalopathy (SAE). Astrocytes regulate glutamate metabolism. In septic mice, α2A adrenoceptor (α2A-AR) activation in the central nervous system provides neuroprotection. α2A-ARs are expressed abundantly in hippocampal astrocytes. This study was performed to determine whether hippocampal astrocytic α2A-AR activation confers neuroprotection against SAE and whether this protective effect is astrocyte specific and achieved by the modulation of glutamate metabolism. METHODS: Male C57BL/6 mice with and without α2A-AR knockdown were subjected to cecal ligation and puncture (CLP). They were treated with intrahippocampal guanfacine (an α2A-AR agonist) or intraperitoneal dexmedetomidine in the presence or absence of dihydrokainic acid [DHK; a glutamate transporter 1 (GLT-1) antagonist] and/or UCPH-101 [a glutamate/aspartate transporter (GLAST) antagonist]. Hippocampal tissue was collected for the measurement of astrocyte reactivity, GLT-1 and GLAST expression, and glutamate receptor subunit 2B (GluN2B) phosphorylation. In vivo real-time extracellular glutamate concentrations in the hippocampus were measured by ultra-performance liquid chromatography tandem mass spectrometry combined with microdialysis, and in vivo real-time hippocampal glutamatergic neuron excitability was assessed by calcium imaging. The mice were subjected to the Barnes maze and fear conditioning tests to assess their learning and memory. Golgi staining was performed to assess changes in the hippocampal synaptic structure. In vitro, primary astrocytes with and without α2A-AR knockdown were stimulated with lipopolysaccharide (LPS) and treated with guanfacine or dexmedetomidine in the presence or absence of 8-bromo- cyclic adenosine monophosphate (8-Br-cAMP, a cAMP analog). LPS-treated primary and BV2 microglia were also treated with guanfacine or dexmedetomidine. Astrocyte reactivity, PKA catalytic subunit, GLT-1 an GLAST expression were determined in primary astrocytes. Interleukin-1ß, interleukin-6 and tumor necrosis factor-alpha in the medium of microglia culture were measured. RESULTS: CLP induced synaptic injury, impaired neurocognitive function, increased astrocyte reactivity and reduced GLT-1 and GLAST expression in the hippocampus of mice. The extracellular glutamate concentration, phosphorylation of GluN2B at Tyr-1472 and glutamatergic neuron excitability in the hippocampus were increased in the hippocampus of septic mice. Intraperitoneal dexmedetomidine or intrahippocampal guanfacine administration attenuated these effects. Hippocampal astrocytes expressed abundant α2A-ARs; expression was also detected in neurons but not microglia. Specific knockdown of α2A-ARs in hippocampal astrocytes and simultaneous intrahippocampal DHK and UCPH-101 administration blocked the neuroprotective effects of dexmedetomidine and guanfacine. Intrahippocampal administration of DHK or UCPH-101 alone had no such effect. In vitro, guanfacine or dexmedetomidine inhibited astrocyte reactivity, reduced PKA catalytic subunit expression, and increased GLT-1 and GLAST expression in primary astrocytes but not in primary astrocytes that received α2A-AR knockdown or were treated with 8-Br-cAMP. Guanfacine or dexmedetomidine inhibited microglial reactivity in BV2 but not primary microglia. CONCLUSIONS: Our results suggest that neurocognitive protection against SAE after hippocampal α2A-AR activation is astrocyte specific. This protection may involve the inhibition of astrocyte reactivity and alleviation of glutamate neurotoxicity, thereby reducing synaptic injury. The cAMP/protein kinase A (PKA) signaling pathway is a potential cellular mechanism by which activating α2A-AR modulates astrocytic function.

QT-Interval Prolongation Associated with Supratherapeutic Guanfacine Concentration: A Case Report.

INTRODUCTION: Guanfacine, an alpha-2 adrenergic agonist, is used to treat attention deficit hyperactivity disorder (ADHD). Although cardiovascular effects including hypotension and bradycardia are common adverse effects of guanfacine, the effect of guanfacine on QT intervals remains unclear. The association between the serum concentration of guanfacine and its toxicity has also not been fully investigated. CASE REPORT: This is a case of a 21-year-old woman with ADHD who developed repeated presyncope 1 day before admission. She was taking 3 mg of extended-release guanfacine and 50 mg of sertraline. On admission, she had bradycardia and hypotension. An electrocardiogram (ECG) showed a QT interval of 0.68 s and a QTcF interval of 0.648 s. The QT intervals were manually measured and corrected by the Fridericia formula (QTcF = QT/RR1/3). Although she denied taking an overdose of guanfacine and other drugs, we suspected guanfacine toxicity. The serum guanfacine concentration was 13.0 ng/mL on admission and decreased to 3.2 ng/mL on day 1 and 0.4 ng/mL on day 2. Changes in QTcF intervals and her vital signs correlated with serum guanfacine concentrations. CONCLUSION: Supratherapeutic serum guanfacine concentrations may induce QT prolongation.

Effect of ion pair strategy on transdermal delivery of guanfacine: Which factor dominates drug permeation?

Ion pair is an effective chemical approach to promoting drug transdermal permeation, and the traditional interpretation for its enhanced permeation effect is mainly attributed to counterions altering the physicochemical properties of the drug (lipophilicity, melting point, etc.). In this work, guanfacine (GFC), a non-stimulant for anti-attention deficit and hyperactivity disorder (ADHD), was used as a model drug, and several organic or inorganic acids were designed thereby successfully constructing ion pairs. The transdermal permeation ability of ion pairs through isolated porcine skin was observed and ranked as follows: guanfacine caprylate (GFC-CA) > GFC > guanfacine laurate (GFC-LA) > guanfacine fumarate (GFC-FA) > guanfacine hydrochloride (GFC-HA) > guanfacine palmitate (GFC-PA). The effect of key physicochemical properties (octanol-water partition coefficient, molecular volume, melting point) on the transdermal permeation rate of the model drug was analyzed in detail. In addition, GFC-CA was observed to alter the lipid structure of the skin, suggesting the traditional explanation of the action of ion pair may be inadequate and underrated, and ion pair may also enhance permeation by disrupting skin structure. The intriguing phenomenon is expected to provide a novel approach to achieving precise transdermal drug delivery.

A case of pulmonary edema due to guanfacine intoxication with measurement of serum guanfacine concentrations.

Guanfacine hydrochloride extended-release (GXR) is used to treat attention deficit hyperactivity disorder. It is a selective α2A-adrenorecepor agonist that was reported to cause QT prolongation and hypotension in the event of overdosing. We report the case of a 17-year-old man who took 226 tablets of GXR 3 mg for attempted suicide. He was found complaining of dyspnea, and emergency medical services were called. When the patient was transferred to our hospital, his Glasgow coma scale was 12 (E4V3M5). He was agitated and hypoxemic. He was intubated for invasive mechanical ventilation under sedation. His chest X-ray and computed tomography scan showed pulmonary edema. Transthoracic echocardiography showed markedly reduced cardiac function. His serum guanfacine concentration peaked on day 3 after admission. His pulmonary edema improved quickly after a decrease in serum guanfacine concentration, but cardiac decompensation persisted for about 1 month. This case reveals that the decline in cardiac function after guanfacine intoxication is prolonged even after its serum concentration has decreased.

An adolescent boy with kleptomania and attention-deficit hyperactivity disorder treated with methylphenidate and guanfacine: A case report.

We present the case of a patient, a boy of 16 years of age at initial presentation, with kleptomania, an impulse disorder characterized by an impulse to steal unneeded items, and attention-deficit hyperactivity disorder (ADHD). The patient's parents reported that he would frequently impulsively steal items and money that he did not need. Cognitive and physical assessments revealed no abnormalities, and the patient had no history of substance abuse. The patient was diagnosed with kleptomania and ADHD. The patient was started on Osmotic Release Oral System Methylphenidate (OROS-MPH), a medication commonly used to treat ADHD, and experienced improvement in ADHD symptoms and stealing behavior. At 19 years of age, it was discovered that the patient's behavioral symptoms were uncontrolled during times of the day when the blood concentration of MPH was likely to have waned. After starting an additional dose of guanfacine at night, his symptoms during these times of day improved. While existing research is not definitive, there may be a connection between ADHD and kleptomania. Further, there are some reports that treatment of ADHD with MPH also reduced stealing behavior, aligning with our present findings. We discuss the potential mechanisms behind these improvements and further present the first evidence of the efficacy of guanfacine in the treatment of kleptomania.

[Attention deficit hyperactivity: pharmacotherapy through life]. / Déficit de atención con hiperactividad: farmacoterapia a través de la vida.

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder of biological origin with a 70 to 80% genetic basis, which affects 5% of children and adolescents and 2.5% of adults, whose main symptoms are inattention, hyperactivity, and impulsivity. For many years it was thought that it only affected children; currently in the DSM 5 it is accepted that it can be diagnosed in adolescents and adults. Treatment must be individualized, the main objectives are to improve the core symptoms of people with ADHD, and their quality of life. The therapeutic approach is psychological, behavioral, and pharmacological. Medications are classified as stimulants and nonstimulants, with stimulants such as methylphenidate, lisdexamfetamine, and dexamphetamine being the first line. Non-stimulants include guanfacine and atomoxetine. Treatment is essential because it improves the quality of life of the person at the family, educational, work, and social levels.

El Trastorno por déficit de atención con hiperactividad (TDAH) es un trastorno del neurodesarrollo de origen biológico con una base genética del 70 al 80%, que afecta al 5% de niños y adolescentes y a un 2.5% de los adultos, cuyos síntomas principales son la inatención, hiperactividad e impulsividad. Por muchos años se pensó que afectaba solo a los niños; actualmente en el DSM 5 se acepta que se puede diagnosticar en adolescentes y adultos. El tratamiento debe ser individualizado, los objetivos principales son mejorar los síntomas centrales de las personas con TDAH, y su calidad de vida. El abordaje terapéutico es psicológico, conductual y farmacológico. Los medicamentos se clasifican en estimulantes y no estimulantes, siendo los de primera línea los estimulantes tales como el metilfenidato, lisdexanfetamina y dexanfetamina. Entre los no estimulantes se cuentan a la guanfacina y atomoxetina. El tratamiento es fundamental porque mejora la calidad de vida de la persona a nivel familiar, educativo, laboral y social.

Therapeutics for Substance-Using Women: The Need to Elucidate Sex-Specific Targets for Better-Tailored Treatments.

In the last decade, alcohol consumption in the US has risen by 84% in women compared with 35% in men. Furthermore, research has shown that sex- and gender-related differences may disadvantage women in terms of developing a range of psychological, cognitive, and medical problems considerably earlier in their drinking history than men, and despite consuming a similar quantity of substances. While this "telescoping" process has been acknowledged in the literature, a concomitant understanding of the underlying biobehavioral mechanisms, and an increase in the development of specific treatments tailored to women, has not occurred. In the current chapter we focus on understanding why the need for personalized, sex-specific medications is imperative, and highlight some of the potential sex-specific gonadal and stress-related adaptations underpinning the accelerated progress from controlled to compulsive drug and alcohol seeking in women. We additionally discuss the efficacy of these mechanisms as novel targets for medications development, using exogenous progesterone and guanfacine as examples. Finally, we assess some of the challenges faced and progress made in terms of developing innovative medications in women. We suggest that agents such as exogenous progesterone and adrenergic medications, such as guanfacine, may provide some efficacy in terms of attenuating stress-induced craving for several substances, as well as improving the ability to emotionally regulate in the face of stress, preferentially in women. However, to fully leverage the potential of these therapeutics in substance-using women, greater focus needs to the placed on reducing barriers to treatment and research by encouraging women into clinical trials.

Percutaneous Ultrasound-Guided Tenotomy of the Iliotibial Band for Trochanteric Pain Syndrome: A Longitudinal Observational Study With One-Year Durability Results.

BACKGROUND: Upper lateral hip pain is a common complaint in adults and is referred to as greater trochanteric pain syndrome (GTPS) and is more prevalent among older women. This is a debilitating condition that could result in lower physical activity and quality of life, and higher unemployment rate. GTPS is a clinical diagnosis, and many cases improve with conservative medical management (CMM). However, there is still a gap between patients not responding to CMM and those who are not good surgical candidates. Thus, percutaneous ultrasound tenotomy (PUT) may be a valuable treatment option to limit this gap. OBJECTIVES: Demonstration of the one-year pain and functional outcomes, including sit to stand. SETTING: Academic tertiary care medical center. METHODS: Forty-eight consecutive patients with refractory trochanteric pain due to iliotibial band (ITB) tendinopathy. Fifty-six hips were treated; 8 patients underwent bilateral procedures. Electronic medical record review of consecutive patients who underwent ITB TENEX® was performed at Montefiore Medical Center from December 2019 to December 2021. Institutional guidelines recommended TENEX® for greater trochanteric pain refractory to conservative treatment and ultrasound (US) confirmed ITB tendinopathy (hypoechogenicity or thickened tendon > 6 mm). Pain level, as well as sit-to-stand, side-lying, and walking tolerance levels were evaluated at baseline preprocedure visit and one-year visit. Follow-up was performed by independent practitioners and corroborated by chart review. RESULTS: Numeric Rating Scale (NRS-11) improved by 4 points across all patients. Seventy percent of patients endorsed pain relief at one-year visit. Median preprocedure NRS-11 was 9. The reported median NRS-11at one year was 5 (Wilcoxon signed rank NRS-11 demonstrated a Z score of -6.042 with P < 0.001). One-year analysis among all patients revealed 57%, 78%, and 66% improvement in side-lying, sit-to-stand, and walking tolerance levels, respectively. LIMITATIONS: We believe that our results must be confirmed with a randomized control trial with a control arm and more patients included. CONCLUSIONS: PUT of the ITB using the TENEX® tissue remodeling device could be a safe and effective treatment for ITB tendinopathy-associated GTPS.

Nonstimulant Medications for Attention-Deficit/Hyperactivity Disorder (ADHD) in Adults: Systematic Review and Meta-analysis.

BACKGROUND: For some adults with Attention-Deficit/Hyperactivity Disorder (ADHD), nonstimulants need to be considered either as a monotherapy or as an adjunct to stimulants. OBJECTIVES: The objectives of this systematic review and meta-analysis were to assess the efficacy, acceptability, and tolerability of nonstimulants in adults with ADHD. METHODS: Data sources, searches, and study selection were based on a previously published network meta-analysis of randomized clinical trials (RCTs) by Cortese at al. (Lancet Psychiatry 5(9):727-738, 2018), which we updated in March 2022. Specifically, we searched PubMed, BIOSIS Previews, CINAHL, the Cochrane Central Register of Controlled Trials, EMBASE, ERIC, MEDLINE, PsycINFO, OpenGrey, Web of Science Core Collection, ProQuest Dissertations and Theses (UK and Ireland), ProQuest Dissertations and Theses (abstracts and international), and the WHO International Trials Registry Platform, including ClinicalTrials.gov for double-blind RCTs with a placebo arm, lasting at least one week, including adults with a diagnosis of ADHD based on DSM-III, DSM-III-R, DSM-IV(TR), DSM-5 or ICD-9- or 10, and reporting data on efficacy, tolerability (drop-out due to side effects) and acceptability (drop-out due to any cause) of guanfacine, clonidine, or atomoxetine. Additionally, we searched for RCTs of viloxazine extended release (ER), approved for ADHD in 2021. Random-effects meta-analyses were conducted, and the risk of bias for individual RCTs was assessed using the Cochrane Risk of Bias tool. RESULTS: We included 18 studies in the meta-analyses (4308 participants) plus one additional study in the narrative synthesis (374 participants). The meta-analysis showed that atomoxetine (15 RCTs) (Hedge's g = - 0.48, 95% CI [- 0.64; - 0.33]), guanfacine (two RCTs) (Hedge's g = - 0.66, 95% CI [- 0.94; - 0.38]) and viloxazine ER (one RCT) were significantly more efficacious than placebo. Atomoxetine was less well tolerated than placebo, while tolerability of guanfacine and viloxazine ER could not be meta-analysed, since only one study, for each medication, reported on it. CONCLUSIONS: All investigated nonstimulants were more efficacious in the treatment of ADHD in adults, than placebo, while the placebo had better acceptability and tolerability. PROTOCOL: https://osf.io/5vnmt/?view_only=2bf87ed12ba94645babedceeee4c0120 .

Targeting C/EBPα overcomes primary resistance and improves the efficacy of FLT3 inhibitors in acute myeloid leukaemia.

The outcomes of FLT3-ITD acute myeloid leukaemia (AML) have been improved since the approval of FLT3 inhibitors (FLT3i). However, approximately 30-50% of patients exhibit primary resistance (PR) to FLT3i with poorly defined mechanisms, posing a pressing clinical unmet need. Here, we identify C/EBPα activation as a top PR feature by analyzing data from primary AML patient samples in Vizome. C/EBPα activation limit FLT3i efficacy, while its inactivation synergistically enhances FLT3i action in cellular and female animal models. We then perform an in silico screen and identify that guanfacine, an antihypertensive medication, mimics C/EBPα inactivation. Furthermore, guanfacine exerts a synergistic effect with FLT3i in vitro and in vivo. Finally, we ascertain the role of C/EBPα activation in PR in an independent cohort of FLT3-ITD patients. These findings highlight C/EBPα activation as a targetable PR mechanism and support clinical studies aimed at testing the combination of guanfacine with FLT3i in overcoming PR and enhancing the efficacy of FLT3i therapy.

Guanfacine for the Treatment of Attention-Deficit Hyperactivity Disorder: An Updated Systematic Review and Meta-Analysis.

Background: Non-stimulant guanfacine is a common second-line medication for attention-deficit hyperactivity disorder (ADHD). Numerous randomized controlled trials (RCTs) have explored the efficacy of guanfacine in ADHD treatment. This meta-analysis combined data from selected RCTs to analyze the efficacy and safety of guanfacine in treating ADHD. Methods: RCTs were identified from published sources through searches in PubMed, Cochrane Library, Web of Science, and Embase (up to February 2022), defining the Clinical Global Impression of Improvement (CGI-I) treatment response score of ≤2 as the primary outcome. Subgroup analysis was performed with a bound treatment duration of 10 weeks. Safety was defined by treatment-emergent adverse events (TEAEs). Results: Twelve out of 332 studies with 2653 participants were included. All studies compared guanfacine with placebos. Guanfacine was significantly more effective in treating ADHD (Risk Ratio [RR] 1.78, 95% CI: 1.59-2.01). In the <10 weeks subgroup, the efficacy in the guanfacine group compared with the placebo group was 58.5% versus 29.4%, respectively (RR 1.97, 95% CI: 1.71-2.26). In the >10 weeks subgroup, the efficacy in the guanfacine group compared with the placebo group was 63.6% versus 39.7%, respectively (RR 1.57, 95% CI: 1.37-1.79). Both subgroups lacked heterogeneity (I2 = 0), and a funnel plot showed a low publication bias risk. Around 80% of participants in the guanfacine group experienced at least one TEAE, compared with 66.5% in the placebo group (RR 1.23, 95% CI: 1.14-1.32), with low heterogeneity (I2 = 46, p = 0.05). The most common TEAEs in the guanfacine group were somnolence (38.6%), headaches (20.5%), and fatigue (15.2%). Conclusions: Guanfacine is safe and effective for treating ADHD, with no serious adverse events. Guanfacine should be considered as an effective treatment option where effectiveness or tolerability of the central nervous system stimulant is of concern. There is stronger evidence of efficacy for children; more clinical studies are needed for adults.

Guanfacine inhibits interictal epileptiform events and sodium currents in prefrontal cortex pyramidal neurons.

BACKGROUND: Guanfacine (an alpha-2A receptor agonist) is a commonly used drug with recognized efficacy in the treatment of attention deficit hyperactivity disorder (ADHD). This study aimed to assess the effects of guanfacine on short-lasting (interictal) epileptiform discharges in cortical neurons. Moreover, we assessed the effects of guanfacine on voltage-gated sodium currents. METHODS: We conducted patch-clamp recordings in prefrontal cortex pyramidal neurons obtained from young rats. Interictal epileptiform events were evoked in cortical slices in a zero magnesium proepileptic extracellular solution with an elevated concentration of potassium ions. RESULTS: Interictal epileptiform discharges were spontaneous depolarisations, which triggered action potentials. Guanfacine (10 and 100 µM) inhibited the frequency of epileptiform discharges. The effect of guanfacine on interictal events persisted in the presence of alpha-2 adrenergic receptor antagonist idazoxan. The tested drug inhibited neuronal excitability. Tonic NMDA currents were not influenced by guanfacine. Recordings from dispersed neurons showed that the tested drug (10 and 100 µM) inhibited persistent and fast inactivating voltage-gated sodium currents. CONCLUSIONS: This study shows that guanfacine inhibits interictal discharges in cortical neurons independently of alpha-2A adrenergic receptors. This effect may be mediated by voltage-gated sodium currents. Inhibition of interictal activity by guanfacine may be of clinical importance because interictal events often occur in patients with ADHD and may contribute to symptoms of this disease.

Inhibition of norepinephrine signaling during a sensitive period disrupts locus coeruleus circuitry and emotional behaviors in adulthood.

Deficits in arousal and stress responsiveness are a feature of numerous psychiatric disorders including depression and anxiety. Arousal is supported by norepinephrine (NE) released from specialized brainstem nuclei, including the locus coeruleus (LC) neurons into cortical and limbic areas. During development, the NE system matures in concert with increased exploration of the animal's environment. While several psychiatric medications target the NE system, the possibility that its modulation during discreet developmental periods can have long-lasting consequences has not yet been explored. We used a chemogenetic strategy in mice to reversibly inhibit NE signaling during brief developmental periods and then evaluated any long-lasting impact of our intervention on adult NE circuit function and on emotional behavior. We also tested whether developmental exposure to the α2 receptor agonist guanfacine, which is commonly used in the pediatric population and is not contraindicated during pregnancy and nursing, recapitulates the effect seen with the chemogenetic strategy. Our results reveal that postnatal days 10-21 constitute a sensitive period during which alterations in NE signaling lead to changes in baseline anxiety, increased anhedonia, and passive coping behaviors in adulthood. Disruption of NE signaling during this sensitive period also caused altered LC autoreceptor function, along with circuit specific changes in LC-NE target regions at baseline, and in response to stress. Our findings indicate an early critical role for NE in sculpting brain circuits that support adult emotional function. Interfering with this role by guanfacine and similar clinically used drugs can have lasting implications for mental health.

An ensemble recruited by α2a-adrenergic receptors is engaged in a stressor-specific manner in mice.

α2a-adrenergic receptor (α2a-AR) agonists are candidate substance use disorder therapeutics due to their ability to recruit noradrenergic autoreceptors to dampen stress system engagement. However, we recently found that postsynaptic α2a-ARs are required for stress-induced reinstatement of cocaine-conditioned behavior. Understanding the ensembles recruited by these postsynaptic receptors (heteroceptors) is necessary to understand noradrenergic circuit control. We utilized a variety of approaches in FosTRAP (Targeted Recombination in Active Populations) mice to define an ensemble of cells activated by the α2a-AR partial agonist guanfacine ("Guansembles") in the bed nucleus of the stria terminalis (BST/BNST), a region key to stress-induced reinstatement of drug seeking. We define BNST "Guansembles" and show they differ from restraint stress-activated cells. Guanfacine produced inhibition of cAMP-dependent signaling in Guansembles, while chronic restraint stress increased cAMP-dependent signaling. Guanfacine both excited and inhibited aspects of Guansemble neuronal activity. Further, while some stressors produced overall reductions in Guansemble activity, active coping events during restraint stress and exposure to unexpected shocks were both associated with Guansemble recruitment. Using viral tracing, we define a BNST Guansemble afferent network that includes regions involved in the interplay of stress and homeostatic functions. Finally, we show that activation of Guansembles produces alterations in behavior on the elevated plus maze consistent with task-specific anxiety-like behavior. Overall, we define a population of BNST neurons recruited by α2a-AR signaling that opposes the behavioral action of canonical autoreceptor α2a-AR populations and which are differentially recruited by distinct stressors. Moreover, we demonstrate stressor-specific physiological responses in a specific neuronal population.

Patterns of attention deficit hyperactivity disorder medicine use in the era of new non-stimulant medicines: A population-based study among Australian children and adults (2013-2020).

BACKGROUND AND AIMS: New therapeutic options such as lisdexamfetamine and guanfacine have recently become available for the treatment of attention deficit hyperactivity disorder. We described contemporary patterns of attention deficit hyperactivity disorder medicine use among children, adolescents and adults in Australia. METHODS: This population-based study used dispensing data for a 10% random sample of Australian residents between July 2012 and December 2020. We estimated the annual prevalence and incidence of attention deficit hyperactivity disorder medicines, second-line guanfacine use and examined concurrent medicine use of both stimulants and non-stimulants. We followed incident users for up to 5 years and analysed treatment persistence using a novel proportion of people covered method. Analyses were stratified by attention deficit hyperactivity disorder medicine, sex and age group; young children (0-5 years), children (6-12 years), adolescents (13-17 years), young adults (18-24 years) and adults (⩾25 years). RESULTS: We observed a twofold increase in the overall prevalence of attention deficit hyperactivity disorder medicine use between 2013 and 2020, from 4.9 to 9.7 per 1000 persons. Incident use also increased across all age groups and both sexes, with the most pronounced increases among adolescent females (from 1.4 to 5.3 per 1000 persons). Stimulant treatment persistence after 5 years was highest among those initiating treatment as young children (64%) and children (69%) and lowest among those initiating treatment in adolescence (19%). Concurrent use of stimulants and non-stimulants was more common among males and younger age groups. Most children (87%) initiating guanfacine had prior dispensings of attention deficit hyperactivity disorder medicines. CONCLUSION: We observed increasing attention deficit hyperactivity disorder medicine use in Australia, especially among young females. Nevertheless, treatment rates remain lower than the estimated prevalence of attention deficit hyperactivity disorder across all subpopulations. Poor long-term treatment persistence in adolescence may warrant improved clinical monitoring of attention deficit hyperactivity disorder in patients transitioning from paediatric to adult care. Reassuringly, use of newly approved guanfacine appeared to be in accordance with guidelines among children.

Methylphenidate, Guanfacine, and Combined Treatment Effects on Electroencephalography Correlates of Spatial Working Memory in Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: The combination of d-methylphenidate and guanfacine (an α-2A adrenergic agonist) may be an effective alternative to either agent as monotherapy in children with attention-deficit/hyperactivity disorder (ADHD). This study investigated the neural mechanisms underlying medication effects using cortical source analysis of electroencephalography (EEG) data. METHOD: A total of 172 children with ADHD (aged 7-14; 118 boys) completed an 8-week randomized, double-blind, comparative study with 3 treatment arms: d-methylphenidate, guanfacine, or their combination. EEG modulations of brain oscillations at baseline and end point were measured during a spatial working memory task from cortical sources localized within the anterior cingulate (midfrontal) and primary visual cortex (midoccipital), based on previously reported ADHD and control differences. Linear mixed models examined treatment effects on EEG and performance measures. RESULTS: Combined treatment decreased midoccipital EEG power across most frequency bands and task phases. Several midoccipital EEG measures also showed significantly greater changes with combined treatment than with monotherapies. D-methylphenidate significantly increased midoccipital theta during retrieval, while guanfacine produced only trend-level reductions in midoccipital alpha during maintenance and retrieval. Task accuracy improved with combined treatment, was unchanged with d-methylphenidate, and worsened with guanfacine. Treatment-related changes in midoccipital power correlated with improvement in ADHD severity. CONCLUSION: These findings show that combined treatment ameliorates midoccipital neural activity associated with treatment-related behavioral improvements and previously implicated in visuo-attentional deficits in ADHD. Both monotherapies had limited effects on EEG measures, with guanfacine further showing detrimental effects on performance. The identified midoccipital EEG profile may aid future treatment monitoring for children with ADHD. CLINICAL TRIAL REGISTRATION INFORMATION: Single Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder (Project1); https://clinicaltrials.gov/; NCT00429273. DIVERSITY & INCLUSION STATEMENT: We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure sex and gender balance in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. We actively worked to promote sex and gender balance in our author group.

Electrophysiological and Clinical Predictors of Methylphenidate, Guanfacine, and Combined Treatment Outcomes in Children With Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: The combination of d-methylphenidate and guanfacine (an α-2A agonist) has emerged as a potential alternative to either monotherapy in children with attention-deficit/hyperactivity disorder (ADHD), but it is unclear what predicts response to these treatments. This study is the first to investigate pretreatment clinical and electroencephalography (EEG) profiles as predictors of treatment outcome in children randomized to these different medications. METHOD: A total of 181 children with ADHD (aged 7-14 years; 123 boys) completed an 8-week randomized, double-blind, comparative study with d-methylphenidate, guanfacine, or combined treatments. Pretreatment assessments included ratings on ADHD, anxiety, and oppositional behavior. EEG activity from cortical sources localized within midfrontal and midoccipital regions was measured during a spatial working memory task with encoding, maintenance, and retrieval phases. Analyses tested whether pretreatment clinical and EEG measures predicted treatment-related change in ADHD severity. RESULTS: Higher pretreatment hyperactivity-impulsivity and oppositional symptoms and lower anxiety predicted greater ADHD improvements across all medication groups. Pretreatment event-related midfrontal beta power predicted treatment outcome with combined and monotherapy treatments, albeit in different directions. Weaker beta modulations predicted improvements with combined treatment, whereas stronger modulation during encoding and retrieval predicted improvements with d-methylphenidate and guanfacine, respectively. A multivariate model including EEG and clinical measures explained twice as much variance in ADHD improvement with guanfacine and combined treatment (R2= 0.34-0.41) as clinical measures alone (R2 = 0.14-.21). CONCLUSION: We identified treatment-specific and shared predictors of response to different pharmacotherapies in children with ADHD. If replicated, these findings would suggest that aggregating information from clinical and brain measures may aid personalized treatment decisions in ADHD. CLINICAL TRIAL REGISTRATION INFORMATION: Single Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder; https://clinicaltrials.gov; NCT00429273.

Therapeutic Approaches for ADHD by Developmental Stage and Clinical Presentation.

Attention Deficit Hyperactivity Disorder is a neurodevelopmental disorder with three presentations: inattentive, hyperactive/impulsive and combined. These may represent an independent disease entity. Therefore, the therapeutic approach must be focused on their neurobiological, psychological and social characteristics. To date, there is no comprehensive analysis of the efficacy of different treatments for each presentation of ADHD and each stage of development. This is as narrative overview of scientific papers that summarize the most recent findings and identify the most effective pharmacological and psychosocial treatments by ADHD presentation and age range. Evidence suggests that methylphenidate is the safest and most effective drug for the clinical management of children, adolescents and adults. Atomoxetine is effective in preschoolers and maintains similar efficacy to methylphenidate in adults, whereas guanfacine has proven to be an effective monotherapy for adults and is a worthy adjuvant for the management of cognitive symptoms. The psychosocial treatments with the best results in preschoolers are behavioral interventions that include training of primary caregivers. In adolescents, the combination of cognitive and cognitive-behavioral therapies has shown the best results, whereas cognitive-behavioral interventions are the most effective in adults. Pharmacological and psychosocial treatments must be adjusted to the ADHD presentation and its neurocognitive characteristics through the patient's development.