Noradrenergic Agents Research Articles

Attention-Deficit/Hyperactivity Disorder In Children and Adolescents

Among the neurobehavioral disorders that children and adolescents most frequently seek treatment for is ADHD. ADHD frequently has long-lasting effects that persist into adulthood, including noticeable symptoms. Co-occurring disorders such as disruptive, mood, anxiety, and substance abuse are frequently linked to ADHD. Reviewing symptoms and impairments helps establish the clinical diagnosis of ADHD. Data from neuropsychology, neurochemistry, neuroimaging, and genetics all support the disorder's biological basis. When diagnosing and treating ADHD, all facets of the patient's life must be taken into account. Individual, family, and educational support are all part of multimodal treatment. ADHD and comorbid conditions benefit from both medication and psychotherapy alone. Throughout the lifespan, pharmacotherapy—which includes stimulants, noradrenergic agents, alpha agonists, and antidepressants—is essential to the long-term management of ADHD.

Pharmacotherapy to Improve Cognitive Functioning After Acquired Brain Injury: AMeta-Analysis and Meta-Regression.

Cognitive impairments, common sequelae of acquired brain injury (ABI), significantly affect rehabilitation and quality of life. Currently, there is no solid evidence-base for pharmacotherapy to improve cognitive functioning after ABI, nevertheless off-label use is widely applied in clinical practice. This meta-analysis and meta-regression aims to quantitatively aggregate the available evidence for the effects of pharmacological agents used in the treatment of cognitive impairments following ABI. We conducted a comprehensive search of Embase, Medline Ovid, and Cochrane Controlled Trials Register databases for randomized controlled and crossover trials. Meta-analytic effects were calculated for each pharmaceutical agent and targeted neuromodulator system. Cognitive outcome measures were aggregated across cognitive domains. Of 8,216 articles, 41 studies (4,434 patients) were included. The noradrenergic agent methylphenidate showed a small, significant positive effect on cognitive functioning in patients with traumatic brain injury (TBI; k = 14, d = 0.34, 95% confidence interval: 0.12-0.56, P = 0.003). Specifically, methylphenidate was found to improve cognitive functions related to executive memory, baseline speed, inhibitory control, and variability in responding. The cholinergic drug donepezil demonstrated a large effect size, albeit based on a limited number of studies (k = 3, d = 1.68, P = 0.03). No significant effects were observed for other agents. Additionally, meta-regression analysis did not identify significant sources of heterogeneity in treatment response. Our meta-analysis supports the use of methylphenidate for enhancing cognitive functioning in patients with TBI. Although donepezil shows potential, it warrants further research. These results could guide clinical decision making, inform practice guidelines, and direct future pharmacotherapeutic research in ABI.

One Month Dosing of Atomoxetine plus Oxybutynin in Obstructive Sleep Apnea: A Randomized, Placebo-controlled Trial.

Rationale: The combination of noradrenergic and antimuscarinic agents has recently been shown to improve upper-airway function and reduce obstructive sleep apnea (OSA) severity in short-term (⩽1 wk) proof-of-concept studies. Objectives: To determine the safety, tolerability, and potential efficacy of longer term use of different doses of the noradrenergic agent atomoxetine combined with the antimuscarinic oxybutynin (ato-oxy). Methods: Thirty-nine people with predominantly severe OSA received 80/5 mg ato-oxy, 40/5 mg ato-oxy, 40/2.5 mg ato-oxy, or placebo nightly for 30 days in a double-blind, randomized, parallel design. Participants completed three in-laboratory sleep studies (baseline, Night 1, and Night 30) to assess efficacy. Vital signs and objective measures of alertness and memory were assessed. In men, potential effects on prostate function were assessed using the International Prostate Symptom Score at baseline and Night 30. Potential adverse events were assessed during in-laboratory visits and via weekly phone calls. Results: Side effects were generally mild and consistent with known side-effect profiles of each individual drug (i.e., dose-dependent increases in dry mouth with oxybutynin). Heart rate increased by Night 30 in two active drug arms (mean ± standard deviation 8 ± 10 beats/min [P = 0.01] with 80/5 mg and 9 ± 14 beats/min [P = 0.02] with 40/2.5 mg vs. placebo). No clinically relevant changes in blood pressure, International Prostate Symptom Score, and measures of alertness and memory were observed between conditions. Apnea-hypopnea index (AHI) with 4% oxygen desaturation and hypoxic burden decreased by ∼50% with 80/5 mg ato-oxy from baseline but not versus placebo (e.g., AHI with 3% oxygen desaturation and AHI with 4% oxygen desaturation difference at Night 30 was -8.2 [95% confidence interval, -22.5 to 6.2] and -8.5 [95% confidence interval, -18.3 to 1.3] events/h, respectively). Conclusions: One month of nightly noradrenergic and antimuscarinic combination therapy was generally well tolerated, with a side-effect profile consistent with each agent alone, and was associated with an ∼50% reduction from baseline in a key OSA severity metric, the hypoxic burden with the highest dose combination. These findings highlight the potential to target noradrenergic and antimuscarinic mechanisms for OSA pharmacotherapy development. Clinical trial registered with www.anzctr.org.au (ACTRN 12619001153101).

A single dose of noradrenergic/serotonergic reuptake inhibitors combined with an antimuscarinic does not improve obstructive sleep apnoea severity.

Previous trials have demonstrated that the combination of noradrenergic reuptake inhibitors with an antimuscarinic can substantially reduce the apnoea‐hypopnoea index (AHI) and improve airway collapsibility in patients with obstructive sleep apnoea (OSA). However, some studies have shown that when administered individually, neither noradrenergic or serotonergic agents have been effective at alleviating OSA. This raises the possibility that serotonergic agents (like noradrenergic agents) may also need to be delivered in combination to be efficacious. Therefore, we investigated the effect of an antimuscarinic (oxybutynin) on OSA severity when administered with either duloxetine or milnacipran, two dual noradrenergic/serotonergic reuptake inhibiters. A randomized, double‐blind, 4 way cross‐over, placebo‐controlled trial in ten OSA patients was performed. Patients received each drug condition separately across four overnight in‐lab polysomnography (PSG) studies ~1‐week apart. The primary outcome measure was the AHI. In addition, the four key OSA endotypes (collapsibility, muscle compensation, arousal threshold, loop gain) were measured non‐invasively from the PSGs using validated techniques. There was no significant effect of either drug combinations on reducing the total AHI or improving any of the key OSA endotypes. However, duloxetine+oxybutynin did significantly increase the fraction of hypopnoeas to apnoeas (F Hypopnoea) compared to placebo (p = 0.02; d = 0.54). In addition, duloxetine+oxybutynin reduced time in REM sleep (p = 0.009; d = 1.03) which was positively associated with a reduction in the total AHI (R 2 = 0.62; p = 0.02). Neither drug combination significantly improved OSA severity or modified the key OSA endotypes when administered as a single dose to unselected OSA patients.

The influence of drug therapy for obstructive sleep apnoea on couple life. Qualitative study grounded theory

Abstract Background Obstructive sleep apnoea (OSA) is characterised by the collapse of the upper airway during sleep, which determine intermittent hypoxia and sleep fragmentation leading to snoring, impaired cognitive function, excessive daytime sleepiness, and cardiovascular impairments. These disorders have a significant impact on the quality of life and health of both patient and partner, determining stress and frustration also to the couple relationship, and to the workplace. Although the gold standard of treatment for OSA is the use of continuous positive airway pressure (CPAP), many patients find it uncomfortable both for them and for their partners (difficulty in partner intimacy, fear of disturbing their partner's sleep) with consequent low adherence to treatment in about 50% of OSA patients. For these reasons, efforts to develop drug therapies for the treatment of OSA have been ongoing for at least 20 years. Recently, we conducted a randomized controlled trial (RCT) in Italy to test the combination of reboxetine (a noradrenergic agent) and oxybutynin (an antimuscarinic) for OSA treatment with promising results. The aim of this study is to understand how OSA drug therapy has influenced couples' life. Methods The study was conducted from February to March 2020 by the research nurse who participated during the trial. We interviewed 11 patients participating in the pharmacological RCT and 7 partners. The data analysis was conducted in order to collect the subjects' answers in categories, and to identify a core category as the central element for the explanation of the process. Results Interviews permitted to extrapolate 6 main categories and the relative subcategories for patients: 1) OSA: unconscious danger; 2) OSA and couple life (subcategories: sleepiness and nervousness, lack of sleep); 3) transitory situations; 4) drug therapy and couple (subcategories:change in intimacy and sleep quality); 5) motivation to help others (subcategories: therapy recommended for everyone; intention to continue); 6) partner awareness helps in adherence to therapy (subcategories: partner as caregiver, presence and proximity, partner support). While for partners, 7 main categories and the relative subcategories emerged: 1) apprehension and concern for the partner; 2) repercussions on daily life (subcategorie: discomfort); 3) OSA and the couple's lives; 4) drug therapy and couple; 5) support during therapy (subcategorie: before therapy, during therapy); 6) changes during drug therapy; 7) recommended therapy (subcategories: helping others, partner support). “The OSA is our problem” was the core category of the study that linked the categories together. Conclusions Drug therapy is well embraced by both patients and partners as it allows the couple to recover intimacy during sleep and in daily life. The results of this study provide useful information on the need to involve the partner in order to promote adherence to therapy. Funding Acknowledgement Type of funding sources: None.

P001 Safety, tolerability, and efficacy of 1 month of atomoxetine plus oxybutynin in obstructive sleep apnoea

Abstract Introduction Single-night studies with noradrenergic and anti-muscarinics have recently been shown to improve upper-airway function and reduce obstructive sleep apnoea (OSA) severity. This study aimed to determine the safety, tolerability, and efficacy profile of longer-term use of different doses of the noradrenergic agent atomoxetine combined with the anti-muscarinic oxybutynin (ato-oxy) in people with OSA. Methods Thirty-nine people with predominantly severe OSA received either 80/5mg ato-oxy, 40/5mg ato-oxy, 40/2.5mg ato-oxy or placebo nightly for 30 days according to a double-blind, randomised, parallel design. Safety and tolerability were assessed via weekly phone calls for adverse events, vital signs and objective measures of alertness and memory. Participants completed 3 in-laboratory sleep studies (baseline, night 1 and night 30) to assess efficacy. Results Side effects were generally mild and consistent with the known side-effect profile of each drug alone (e.g. dose-dependent increases in dry mouth with oxybutynin). Heart rate increased by night 30 in two of the drug arms versus placebo (e.g. 80/5mg ~9 beats/min, p=0.01). Blood pressure and measures of alertness and memory did not change between conditions. AHI4 and hypoxic burden decreased by ~50% in the 80/5mg arm on night 1 with similar magnitude reductions at night 30. ~50% of participants indicated willingness to continue taking the medication post-study. Discussion 1 month of nightly noradrenergic and anti-muscarinic combination therapy is generally well-tolerated with a side effect profile consistent with each agent alone. These findings also further highlight the potential to target noradrenergic and anti-muscarinic mechanisms for OSA pharmacotherapy development.

The noradrenergic agent reboxetine plus the antimuscarinic hyoscine butylbromide reduces sleep apnoea severity: a double-blind, placebo-controlled, randomised crossover trial.

Recent animal and human physiology studies indicate that noradrenergic and muscarinic processes are key mechanisms that mediate pharyngeal muscle control during sleep. The noradrenergic agent reboxetine combined with the anti-muscarinic hyoscine butylbromide has recently been shown to improve upper airway function during sleep in healthy individuals. However, whether these findings translate to the clinically relevant patient population of people with obstructive sleep apnoea (OSA), and the effects of the agents on OSA severity, are unknown. We found that reboxetine plus hyoscine butylbromide reduced OSA severity, including overnight hypoxaemia, via increases in pharyngeal muscle responsiveness, improvements in respiratory control and airway collapsibility without changing the respiratory arousal threshold. These findings provide mechanistic insight into the role of noradrenergic and anti-muscarinic agents on upper airway stability and breathing during sleep and are important for pharmacotherapy development for OSA. The noradrenergic agent reboxetine combined with the anti-muscarinic hyoscine butylbromide has recently been shown to improve upper airway function during sleep in healthy individuals. However, the effects of this drug combination on obstructive sleep apnoea (OSA) severity are unknown. Accordingly, this study aimed to determine if reboxetine plus hyoscine butylbromide reduces OSA severity. Secondary aims were to investigate the effects on key upper airway physiology and endotypic traits. Twelve people with OSA aged 52±13years, BMI=30±5kg/m2 , completed a double-blind, randomised, placebo-controlled, crossover trial (ACTRN12617001326381). Two in-laboratory sleep studies with nasal mask, pneumotachograph, epiglottic pressure sensor and bipolar fine-wire electrodes into genioglossus and tensor palatini muscles were performed separated by approximately 1week. Each participant received either reboxetine (4mg) plus hyoscine butylbromide (20mg), or placebo immediately prior to sleep. Polysomnography, upper airway physiology and endotypic estimates of OSA were compared between conditions. Reboxetine plus hyoscine butylbromide reduced the apnoea/hypopnoea index by (mean±SD) 17±17events/h from 51±30 to 33±22events/h (P=0.005) and nadir oxygen saturation increased by 6±5% from 82±5 to 88±2% (P=0.002). The drug combination increased tonic genioglossus muscle responsiveness during non-REM sleep (median [25th, 75th centiles]: -0.007 [-0.0004, -0.07] vs. -0.12 [-0.02, -0.40] %maxEMG/cmH2 O, P=0.02), lowered loop gain (0.43±0.06 vs. 0.39±0.07, P=0.01), and improved airway collapsibility (90 [69, 95] vs. 93 [88, 96] %eupnoea, P=0.02), without changing the arousal threshold (P=0.39). These findings highlight the important role that noradrenergic and muscarinic processes have on upper airway function during sleep and the potential for pharmacotherapy to target these mechanisms to treat OSA.

Adaptive aspects of impulsivity and interactions with effects of catecholaminergic agents in the 5-choice serial reaction time task: implications for ADHD

BackgroundWork in humans has shown that impulsivity can be advantageous in certain settings. However, evidence for so-called functional impulsivity is lacking in experimental animals.AimsThis study investigated the contexts in which high impulsive (HI) rats show an advantage in performance compared with mid- (MI) and low impulsive (LI) rats. We also assessed the effects of dopaminergic and noradrenergic agents to investigate underlying neurotransmitter mechanisms.MethodsWe tested rats on a variable inter-trial interval (ITI) version of the 5-choice serial reaction time task (5CSRTT). Rats received systemic injections of methylphenidate (MPH, 1 mg/kg and 3 mg/kg), atomoxetine (ATO, 0.3 mg/kg and 1 mg/kg), amphetamine (AMPH, 0.2 mg/kg), the alpha-2a adrenoceptor antagonist atipamezole (ATI, 0.3 mg/kg) and the alpha-1 adrenoceptor agonist phenylephrine (PHEN, 1 mg/kg) prior to behavioural testing.ResultsUnlike LI rats, HI rats exhibited superior performance, earning more reinforcers, on short ITI trials, when the task required rapid responding. MPH, AMPH and ATI improved performance on short ITI trials and increased impulsivity in long ITI trials, recapitulating the behavioural profile of HI. In contrast, ATO and PHEN impaired performance on short ITI trials and decreased impulsivity, thus mimicking the behavioural profile of LI rats. The effects of ATO were greater on MI rats and LI rats.ConclusionsThese findings indicate that impulsivity can be advantageous when rapid focusing and actions are required, an effect that may depend on increased dopamine neurotransmission. Conversely, activation of the noradrenergic system, with ATO and PHEN, led to a general inhibition of responding.

Pharmacological and Psychoactive Agents for Treatment Resistant Posttraumatic Stress Disorder

The Food and Drug Administration (FDA) approved two selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine for the treatment of posttraumatic stress disorder. Many patients do not respond to them and their side effects commonly occur before noticeable therapeutic effects, leading to their discontinuation. Other patients develop treatment resistance to the two approved SSRIs and are treated with other pharmacological agents. A sizable number of patients also do not respond to pharmacological agents and resort to the use of experimental psychoactive agents. This article reviews the definition of treatment resistant posttraumatic stress disorder, and summarizes the various pharmacological and psychoactive agents that have been used for treatment resistant posttraumatic stress disorder including various antidepressants, antipsychotics ,noradrenergic agents, anticonvulsants, mood stabilizers, anxiolytics, hypnotics ,antihistaminergic agents, naltrexone, buprenorphine, D-Cycloserine, neuropeptides, memantine, cannabinoids, 3,4-methylendioxymethamphetamine and ketamine.

New pharmacological and neuromodulation approaches for impulsive-compulsive behaviors in Parkinson's disease.

A significant proportion of patients with Parkinson's disease (PD) display a set of impulsive-compulsive behaviors at some point during the course of illness. These behaviors range from the so-called behavioral addictions to dopamine dysregulation syndrome, punding and hoarding disorders. These behaviors have been consistently linked to the use of dopaminergic medications used to treat PD motor symptoms (dopamine agonists, levodopa, and other agents) and less consistently to neuromodulation techniques such as deep brain stimulation (DBS). Since there are still no approved treatments for these conditions, their pharmacological management is still a big challenge for clinicians. We conducted an extensive review of current pharmacological and neuromodulation literature for the management of impulsive-compulsive disorders in PD patients. Pharmacological treatment approaches for impulsive-compulsive behaviors and DDS in PD patients include reduction of levodopa (LD), reduction/cessation of dopamine agonist (DA), and initiation of infusion therapies (apomorphine infusion and duodopa). Also, atomoxetine, a noradrenergic agent approved for the treatment of attention deficit hyperactivity disorder, showed some interesting preliminary results but there is still a lack of controlled longitudinal studies. Finally, while DBS effects on impulsive-compulsive disorders are still controversial, non-invasive techniques (such as transcranial magnetic stimulation and transcranial direct current stimulation) could have a potential positive effect but, again, there is still a lack of controlled trials. Managing impulsivity and compulsivity in PD patients is still a non-evidence-based challenge for clinicians. Controlled trials on promising approaches such as atomoxetine and non-invasive neuromodulation techniques are needed.

Individual Differences in Response to Antidepressants

Antidepressants are commonly used to treat major depressive disorder (MDD). Antidepressant outcomes can vary based on individual differences; however, it is unclear whether specific factors determine this variability or whether it is at random. To investigate the assumption of systematic variability in symptomatic response to antidepressants and to assess whether variability is associated with MDD severity, antidepressant class, or study publication year. Data used were updated from a network meta-analysis of treatment with licensed antidepressants in adults with MDD. The Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, and PsycInfo were searched from inception to March 21, 2019. Additional sources were international trial registries and sponsors, drug companies and regulatory agencies' websites, and reference lists of published articles. Data were analyzed between June 8, 2020, and June 13, 2020. Analysis was restricted to double-blind, randomized placebo-controlled trials with depression scores available at the study's end point. Baseline means, number of participants, end point means and SDs of total depression scores, antidepressant type, and publication year were extracted. Log SDs (bln σ̂) were derived for treatment groups (ie, antidepressant and placebo). A random-slope mixed-effects model was conducted to estimate the difference in bln σ̂ between treatment groups while controlling for end point mean. Secondary models determined whether differences in variability between groups were associated with baseline MDD severity; antidepressant class (selective serotonin reuptake inhibitors and other related drugs; serotonin and norepinephrine reuptake inhibitors; norepinephrine-dopamine reuptake inhibitors; noradrenergic agents; or other antidepressants); and publication year. In the 91 eligible trials (18 965 participants), variability in response did not differ significantly between antidepressants and placebo (bln σ̂, 1.02; 95% CI, 0.99-1.05; P = .19). This finding is consistent with a range of treatment effect SDs (up to 16.10), depending on the association between the antidepressant and placebo effects. Variability was not associated with baseline MDD severity or publication year. Responses to noradrenergic agents were 11% more variable than responses to selective serotonin reuptake inhibitors (bln σ̂, 1.11; 95% CI, 1.01-1.21; P = .02). Although this study cannot rule out the possibility of treatment effect heterogeneity, it does not provide empirical support for personalizing antidepressant treatment based solely on total depression scores. Future studies should explore whether individual symptom scores or biomarkers are associated with variability in response to antidepressants.

Individual Differences in Response to Antidepressants

Antidepressants are commonly used worldwide to treat major depressive disorder. Symptomatic response to antidepressants can vary depending on differences between individuals; however, this variability may reflect nonspecific or random factors. To investigate the assumption of systematic variability in symptomatic response to antidepressants and to assess whether this variability is associated with severity of major depressive disorder, antidepressant class, or year of study publication. Data used were from a recent network meta-analysis of acute treatment with licensed antidepressants in adults with major depressive disorder. The following databases were searched from inception to January 8, 2016: the Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, and PsycINFO. Additional sources were international trial registries, drug approval agency websites, and key scientific journals. Analysis was restricted to double-blind, randomized placebo-controlled trials with available data at the study's end point. Baseline and end point means, SDs, number of participants in each group, antidepressant class, and publication year were extracted. The data were analyzed between August 14 and November 18, 2019. With the use of validated methods, coefficients of variation were derived for antidepressants and placebo, and their ratios were calculated to compare outcome variability between antidepressant and placebo. Ratios were entered into a random-effects model, with the expectation that response to antidepressants would be more variable than response to placebo. Analysis was repeated after stratifying by baseline severity of depression, antidepressant class (selective serotonin reuptake inhibitors: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and vilazodone; serotonin and norepinephrine reuptake inhibitors: desvenlafaxine and venlafaxine; norepinephrine-dopamine reuptake inhibitor: bupropion; noradrenergic agents: amitriptyline and reboxetine; and other antidepressants: agomelatine, mirtazapine, and trazodone), and publication year. In the 87 eligible randomized placebo-controlled trials (17 540 unique participants), there was significantly more variability in response to antidepressants than to placebo (coefficients of variation ratio, 1.14; 95% CI, 1.11-1.17; P < .001). Baseline severity of depression did not moderate variability in response to antidepressants. Variability in response to selective serotonin reuptake inhibitors was lower than variability in response to noradrenergic agents (coefficients of variation ratio, 0.88; 95% CI, 0.80-0.97; P = .01), as was the variability in response to other antidepressants compared with noradrenergic agents (coefficients of variation ratio, 0.87; 95% CI, 0.79-0.97; P = .001). Variability also tended to be lower in studies that were published more recently, with coefficients of variation changing by a value of 0.005 (95% CI, 0.002-0.008; P = .003) for every year a study is more recent. Individual differences may be systematically associated with responses to antidepressants in major depressive disorder beyond placebo effects or statistical factors. This study provides empirical support for identifying moderators and personalizing antidepressant treatment.

Attention-Deficit/Hyperactivity Disorder in Children and Adolescents

Attention-deficit/hyperactivity disorder (ADHD) is the most common and thoroughly researched neuropsychiatric disorder affecting children and adolescents. The prevalence of ADHD ranges from 8 to 12% in school-age children, and 70% of these individuals continue to meet DSM-5 criteria for the disorder in adolescence. ADHD is more commonly diagnosed in boys compared with girls. ADHD is chronic, with prominent symptoms and impairment in family, social, and academic functioning. ADHD is often associated with comorbid disorders, including disruptive, mood, and anxiety disorders, and can increase the risk of developing substance use disorders. The diagnosis of ADHD requires a comprehensive clinical assessment, including a detailed history, clinical interview, and collateral information, and is clinically established by review of symptoms and impairment and having established a developmental history of the symptoms. The biological underpinning of the disorder is supported by genetic, neuroimaging, neurochemistry, and neuropsychological data. Treatment should attend to developmental milestones of the child and include family and individual psychosocial interventions. Psychosocial interventions in combination with medication are helpful for ADHD and comorbid problems. Pharmacotherapy, including psychostimulants, noradrenergic agents, alpha agonists, and antidepressants, plays a fundamental role in the treatment and management of ADHD. This review contains 2 figures, 9 tables, and 114 references. Key words: attention, attention-deficit/hyperactivity disorder, comorbidity, hyperactivity, impulsivity, learning, nonstimulants, psychosocial, psychostimulants, treatment

Attention-Deficit/Hyperactivity Disorder in Children and Adolescents

Attention-deficit/hyperactivity disorder (ADHD) is the most common and thoroughly researched neuropsychiatric disorder affecting children and adolescents. The prevalence of ADHD ranges from 8 to 12% in school-age children, and 70% of these individuals continue to meet DSM-5 criteria for the disorder in adolescence. ADHD is more commonly diagnosed in boys compared with girls. ADHD is chronic, with prominent symptoms and impairment in family, social, and academic functioning. ADHD is often associated with comorbid disorders, including disruptive, mood, and anxiety disorders, and can increase the risk of developing substance use disorders. The diagnosis of ADHD requires a comprehensive clinical assessment, including a detailed history, clinical interview, and collateral information, and is clinically established by review of symptoms and impairment and having established a developmental history of the symptoms. The biological underpinning of the disorder is supported by genetic, neuroimaging, neurochemistry, and neuropsychological data. Treatment should attend to developmental milestones of the child and include family and individual psychosocial interventions. Psychosocial interventions in combination with medication are helpful for ADHD and comorbid problems. Pharmacotherapy, including psychostimulants, noradrenergic agents, alpha agonists, and antidepressants, plays a fundamental role in the treatment and management of ADHD. This review contains 2 figures, 9 tables, and 114 references. Key words: attention, attention-deficit/hyperactivity disorder, comorbidity, hyperactivity, impulsivity, learning, nonstimulants, psychosocial, psychostimulants, treatment

Central Noradrenergic Agonists in the Treatment of Ischemic Stroke-an Overview.

Ischemic stroke is the leading cause of morbidity and mortality with a significant health burden worldwide and few treatment options. Among the short- and long-term effects of ischemic stroke is the cardiovascular sympathetic autonomic dysfunction, presented in part as the by-product of the ischemic damage to the noradrenergic centers of the brain. Unlike high levels in the plasma, the brain may face suboptimal levels of norepinephrine (NE), with adverse effects on the clinical and functional outcomes of ischemic stroke. The intravenous administration of NE and other sympathomimetic agents, in an attempt to increase cerebral perfusion pressure, often aggravates the ischemia-induced rise in blood pressure (BP) with life-threatening consequences for stroke patients, the majority of whom present with hypertension at the time of admission. Unlike the systemic administration, the central administration of NE reduces BP while exerting anti-inflammatory and neuroprotective effects. These characteristics of centrally administered NE, combined with the short latency of response, make it an ideal candidate for use in the acute phase of stroke, followed by the use of centrally acting noradrenergic agonists, such as NE reuptake inhibitors and B2-adrenergic receptor agonists for stroke rehabilitation. In addition, a number of nonpharmacological strategies, such as transcutaneous vagus nerve stimulation (tVNS) and trigeminal nerve stimulation (TNS), have the potential to enhance the central noradrenergic functional activities and improve stroke clinical outcomes. Many factors could influence the efficacy of the noradrenergic treatment in stroke patients. These factors include the type of the noradrenergic agent; the dose, frequency, and duration of administration; the timing of administration in relation to the acute event; and the site and characteristics of the ischemic lesions. Having this knowledge, combined with the better understanding of the regulation of noradrenergic receptors in different parts of the brain, would pave the path for the successful use of the centrally acting noradrenergic agents in the management of ischemic stroke.

Neuromodulation-dependent effect of gated high-frequency, LFMS-like electric field stimulation in mouse cortical slices.

Low-field magnetic stimulation (LFMS) is a gated high-frequency non-invasive brain stimulation method (500Hz gated at 2Hz) with a proposed antidepressant effect. However, it has remained unknown how such stimulation paradigms modulate neuronal network activity and how the induced changes depend on network state. Here we examined the immediate and outlasting effects of the gated high-frequency electric field associated with LFMS on the cortical activity as a function of neuromodulatory tone that defines network state. We used a sham-controlled study design to investigate effects of stimulation (20min of 0.5s trains of 500Hz charge-balanced pulse stimulation patterned at 0.5Hz) on neural activity in mouse medial prefrontal cortex in vitro. Bath application of cholinergic and noradrenergic agents enabled us to examine the stimulation effects as afunction of neuromodulatory tone. The stimulation attenuated the increase in firing rate of layer V cortical neurons during thepost-stimulation period in the presence of cholinergic activation. The same stimulation had no significant immediate or outlasting effect in the absence of exogenous neuromodulators or in the presence of noradrenergic activation. These results provide electrophysiological insights into the neuromodulatory-dependent effects of gated high-frequency stimulation. More broadly, our results are the first to provide a mechanistic demonstration of how behavioral states and arousal levels may modify the effects of non-invasive brain stimulation.

Differential Noradrenergic Modulation of Monetary Reward and Visual Erotic Stimulus Processing.

We recently investigated the effects of the noradrenergic antidepressant reboxetine and the antipsychotic amisulpride compared to placebo on neural correlates of primary reinforcers by visual erotic stimulation in healthy subjects. Whereas, amisulpride left subjective sexual functions and corresponding neural activations unimpaired, attenuated neural activations were observed under reboxetine within the nucleus accumbens (Nacc) along with diminished behavioral sexual functioning. However, a global dampening of the reward system under reboxetine seemed not intuitive considering the complementary role of the noradrenergic to the dopamine system in reward-related learning mediated by prediction error processing. We therefore investigated the sample of 17 healthy males in a mean age of 23.8 years again by functional magnetic resonance imaging (fMRI), to explore the noradrenergic effects on neural reward prediction error signaling. Participants took reboxetine (4 mg/d), amisulpride (200 mg/d), and placebo each for 7 days within a randomized, double-blind, within-subject cross-over design. During fMRI, we used an established monetary incentive task to assess neural reward expectation and prediction error signals within the bilateral Nacc using an independent anatomical mask for a region of interest (ROI) analysis. Activations within the same ROI were also assessed for the erotic picture paradigm. We confirmed our previous results from the whole brain analysis for the selected ROI by significant (p < 0.05 FWE-corrected) attenuated activations within the Nacc during visual sexual stimulation under reboxetine compared to placebo. However, activations in the Nacc concerning prediction error processing and monetary reward expectation were unimpaired under reboxetine compared to placebo, along with unimpaired reaction times in the reward task. For both tasks, neural activations and behavioral processing were not altered by amisulpride compared to placebo. The observed attenuated neural activations within the Nacc during visual erotic stimulation along with unimpaired neural prediction error and monetary reward expectation processing provide evidence for a differential modulation of the neural reward system by the noradrenergic agent reboxetine depending on the presence of primary reinforcers such as erotic stimuli in contrast to secondary such as monetary rewards.

F137. Locus Coeruleus Signal Intensity is Decreased in Patients With Late-Life Depression Treated With Noradrenergic Agents

F137. Locus Coeruleus Signal Intensity is Decreased in Patients With Late-Life Depression Treated With Noradrenergic Agents

The effects of noradrenergic and antimuscarinic agents on upper airway dilator muscle activity, breathing and sleep in healthy individuals

The effects of noradrenergic and antimuscarinic agents on upper airway dilator muscle activity, breathing and sleep in healthy individuals

Noradrenergic modulation of neural erotic stimulus perception

We recently investigated neuromodulatory effects of the noradrenergic agent reboxetine and the dopamine receptor affine amisulpride in healthy subjects on dynamic erotic stimulus processing. Whereas amisulpride left sexual functions and neural activations unimpaired, we observed detrimental activations under reboxetine within the caudate nucleus corresponding to motivational components of sexual behavior. However, broadly impaired subjective sexual functioning under reboxetine suggested effects on further neural components. We now investigated the same sample under these two agents with static erotic picture stimulation as alternative stimulus presentation mode to potentially observe further neural treatment effects of reboxetine.19 healthy males were investigated under reboxetine, amisulpride and placebo for 7 days each within a double-blind cross-over design. During fMRI static erotic picture were presented with preceding anticipation periods. Subjective sexual functions were assessed by a self-reported questionnaire.Neural activations were attenuated within the caudate nucleus, putamen, ventral striatum, the pregenual and anterior midcingulate cortex and in the orbitofrontal cortex under reboxetine. Subjective diminished sexual arousal under reboxetine was correlated with attenuated neural reactivity within the posterior insula. Again, amisulpride left neural activations along with subjective sexual functioning unimpaired. Neither reboxetine nor amisulpride altered differential neural activations during anticipation of erotic stimuli.Our results verified detrimental effects of noradrenergic agents on neural motivational but also emotional and autonomic components of sexual behavior. Considering the overlap of neural network alterations with those evoked by serotonergic agents, our results suggest similar neuromodulatory effects of serotonergic and noradrenergic agents on common neural pathways relevant for sexual behavior.