Search

Background Impaired response inhibition in individuals with cocaine use disorder (CUD) is hypothesized to depend on deficient noradrenergic signaling in corticostriatal networks. Remediation of noradrenergic neurotransmission with selective norepinephrine reuptake inhibitors such as atomoxetine may therefore have clinical utility to improve response inhibitory control in CUD. Methods We carried out a randomized, double-blind, placebo-controlled, crossover study with 26 participants with CUD and 28 control volunteers investigating the neural substrates of stop-signal inhibitory control. The effects of a single dose of atomoxetine (40 mg) were compared with placebo on stop-signal reaction time performance and functional network connectivity using dynamic causal modeling. Results We found that atomoxetine speeded Go response times in both control participants and those with CUD. Improvements in stopping efficiency on atomoxetine were conditional on baseline (placebo) stopping performance and were directly associated with increased inferior frontal gyrus activation. Further, stopping performance, task-based brain activation, and effective connectivity were similar in the 2 groups. Dynamic causal modeling of effective connectivity of multiple prefrontal and basal ganglia regions replicated and extended previous models of network function underlying inhibitory control to CUD and control volunteers and showed subtle effects of atomoxetine on prefrontal-basal ganglia interactions. Conclusions These findings demonstrate that atomoxetine improves response inhibition in a baseline-dependent manner in control participants and in those with CUD. Our results emphasize inferior frontal cortex function as a future treatment target owing to its key role in improving response inhibition in CUD.

The association between central nervous (CNS) stimulants used to treat attention deficit hyperactivity disorder (ADHD) and Raynaud's phenomenon (RP) has received little attention to date. Our aim was to map the existing literature on aetiopathogenesis, clinical presentation and management of peripheral vasculopathy, with a focus on RP, secondary to drug therapy for ADHD. We searched the PubMed® database (01/11/1951 to 01/08/2020) and included articles written in English, which focussed on CNS stimulants used to treat ADHD and RP. The search identified 150 articles 9 of which were eligible for inclusion (70 patients). The majority of studies (n = 6) related to children or adolescents; however, adult cases were also identified. Peripheral vascular manifestations included attacks of RP (new and worsening) and cold sensitivity (acrocyanosis and perniosis). Irreversible ischaemic complications including digital autoamputation and lower limb critical digital ischaemia have also been reported. The implicated causative CNS stimulants were Methylphenidate (n = 5), Dextroamphetamine (n = 4), Atomoxetine (n = 2), and Lisdexamphetamine (n = 2). Complete resolution of RP symptoms was observed in half (n = 5) of studies upon drug cessation. Other therapeutic strategies have included dose reduction and switching to an alternative drug therapy. A potential autoimmune association has also been postulated including drug-induced autoimmunity and new cases of systemic sclerosis which have been potentially attributed to treatment. Future research is required to understand the association between CNS stimulant drug therapies for ADHD and peripheral vascular manifestations, including RP.

Background Globally, depression impacts nearly 300 million people, and roughly half do not achieve remission with standard first-line therapies. For such individuals, augmentation strategies are often helpful at reducing the severity of depression. While there are many potential adjunctive medication choices, psychostimulants are among the more controversial options. Objectives The present review sought to clarify the comparative efficacy and safety of different stimulant-like medications to treat depression. Methods We conducted a systematic review and network meta-analysis of randomized, controlled trials (RCTs) using psychostimulant medications to treat adults with depression. Outcomes were pooled using rate ratios (RRs) for dichotomous outcomes (e.g., response, adverse events) and standardized mean differences (SMDs) for continuous outcomes (e.g., change in depression scores). Results We identified 37 eligible studies (ranging from 1958 to 2016). We assessed nine psychostimulants: methylphenidate (n=14), dextroamphetamine (n=9), modafinil (n=6), lisdexamphetamine (n=3), methylamphetamine (n=3), pemoline (n=2), atomoxetine (n=1), desipramine (n=1), and imipramine (n=1). Overall, psychostimulants demonstrated efficacy for depression, reduced fatigue and sleepiness, and appeared well-tolerated. However, there was inconsistent evidence across particular psychostimulants. For example, the only psychostimulant which demonstrated efficacy for depression—in terms of both symptom severity and response rates—was methylphenidate. Conclusions While our review suggests that some psychostimulants—particularly methylphenidate—appear well-tolerated and demonstrate some efficacy for depression, as well as fatigue and sleepiness, the strength of evidence in our estimates was low to very low for most agents given the small sample sizes, few RCTs, and imprecision in most estimates. A lack of consistent evidence precludes a definitive hierarchy of treatments and points to a need for additional, high-quality RCTs.

Methylphenidate (MPD) is used as a first-line treatment for attention-deficit/hyperactivity disorder (ADHD). The number of prescriptions for ADHD patients is increasing, suggesting that the number of fertile women using such medication might be also increasing. The purpose of this study was to clarify the effects of MPD exposure during the fetal period on infant development, behavior, learning, and memory in mice. Expression levels of candidate genes associated with ADHD were also determined in the brain of pups born to MDP-treated dams who were administered MPD orally at a dose of 2.5, 7.5, or 15 mg/kg daily from gestational day 1 to the day before delivery. Offspring aged 6–8 weeks were subjected to the spontaneous locomotor activity, elevated plus-maze, and passive avoidance tests and therapeutic treatments with MPD or atomoxetine. Fetal MPD exposure induced ADHD-like phenotypes, such as hyperactivity and impulsivity, in mouse offspring, which were suppressed by treatment with MPD and atomoxetine. These mice showed decreased Drd2 and Slc6a3 expression levels in the brain, which are often observed in ADHD model animals. Our results suggest that continuous use of MPD during pregnancy induces ADHD phenotypes in the offspring.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders worldwide, and in the majority of patients persists into adulthood. However, it remains unclear how maternal ADHD could affect pregnancy and birth as well as early mother-(father)-child interaction. There are several studies investigating the effect of depressed or anxious parents on parent-child-interactions in early infancy, but data about the influence of parental ADHD is lacking although it is a common mental disorder in parents. Additionally, the prescription of stimulant and other ADHD medication for adult ADHD patients is rising due to improved diagnostic procedures and a greater awareness of this disorder in adulthood among psychiatrists and psychologists. However, this leads to increased numbers of treated ADHD women that wish to have children or experience unplanned pregnancies while taking stimulant medication. In our systematic review we aimed at analysing the current evidence for the association of maternal ADHD with pregnancy and birth outcomes, pregnancy risks and health behaviour in pregnancy, as well as the association of parental ADHD with early parent-child interaction and early child development in the first 3 years. Furthermore, we reviewed recent evidence on the risks of stimulant and non-stimulant treatment for ADHD in pregnancy and lactation.

Objective Resting-state functional magnetic resonance imaging (R-fMRI) studies of the neural correlates of medication treatment in attention-deficit/hyperactivity disorder (ADHD) have not been systematically reviewed. Our objective was to systematically identify, assess and summarize within-subject R-fMRI studies of pharmacological-induced changes in patients with ADHD. We critically appraised strengths and limitations, and provide recommendations for future research. Method Systematic review of published original reports in English meeting criteria in pediatric and adult patients with ADHD up to July 1, 2020. A thorough search preceded selection of studies matching prespecified criteria. Strengths and limitations of selected studies, regarding design and reporting, were identified based on current best practices. Results We identified and reviewed 9 studies (5 pediatric and 4 adult studies). Sample sizes were small-medium (16–38 patients), and included few female participants. Medications were methylphenidate, amphetamines, and atomoxetine. Wide heterogeneity was observed in designs, analyses and results, which could not be combined quantitatively. Qualitatively, the multiplicity of brain regions and networks identified, some of which correlated with clinical improvements, do not support a coherent mechanistic hypothesis of medication effects. Overall, reports did not meet current standards to ensure reproducibility. Conclusion In this emerging field, the few studies using R-fMRI to analyze the neural correlates of medications in patients with ADHD suggest a potential modulatory effect of stimulants and atomoxetine on several intrinsic brain activity metrics. However, methodological heterogeneity and reporting issues need to be addressed in future research to validate findings which may contribute to clinical care. Such a goal is not yet at hand.

Among adolescents suffering from attention-deficit/hyperactivity disorder (ADHD), comorbid anxiety disorders are common, and symptoms need to be recognized early to minimize the potential impact on their quality of life. Anxiety disorders are recognized by using validated screening tools such as the Screen for Child Anxiety Related Emotional Disorders and the Spence Children’s Anxiety Scale. Clinicians should first optimize ADHD therapy to ensure anxiety is not related to uncontrolled ADHD. This population benefits greatest from family-based cognitive behavioral therapy; however, best results are seen with the addition of pharmacotherapy. Pharmacological regimens include switching from stimulants to atomoxetine or the addition of selective serotonin reuptake inhibitors.

Attention-deficit hyperactivity disorder (ADHD) is a common mental disorder with neurodevelopmental origins that typically starts in early childhood and follows a persistent trait-like course. It is characterized by inattention, impulsivity and hyperactivity that are persistent over time and lead to clinical and psychosocial impairments. Emotional instability is a common feature of ADHD that is sometimes the main presenting complaint. Neurodevelopmental and psychiatric co-morbidities are common. ADHD can be diagnosed and treated at all ages and persists into adulthood in around two-thirds of individuals. Many adults with ADHD were not diagnosed as children. In children with moderate impairment, psychological approaches, including parent training and cognitive behavioural therapy, are recommended as first-line treatment. Drug treatment should, however, be offered as a first line to children with ADHD with severe impairment, if psychological interventions have not been effective or if patients prefer medication. In adults, drug treatments are the recommended first-line treatments, with psycho-education and cognitive behavioural therapy as complementary approaches. Drug treatments are similar at all ages. Methylphenidate is the recommended first-line drug, followed by atomoxetine or dexamfetamine/lisdexamfetamine. Atomoxetine may be used as first line when there are concerns with potential drug abuse or diversion, or high levels of co-morbid anxiety.

Attention deficit/hyperactivity disorder (ADHD) is the most prevalent psychiatric childhood disorder, characterized by hyperactivity, impulsivity and impaired attention, treated most frequently with methylphenidate (MPH). For children and adults with ADHD who do not respond satisfactorily or do not tolerate well stimulants such as MPH or D-Amphetamine, for them the alternative is to use Atomoxetine (ATX), a norepinephrine (NE) transporter inhibitor that increase extracellular NE. We examined the effects of ATX on behavior and hippocampal synaptic plasticity in the murine prenatal nicotine exposure (PNE) model of ADHD. ADHD symptoms were measured using behavioral tests, open field for hyperactivity and the Y-maze for spatial working memory. Further, ATX effects on long-term potentiation (LTP) in hippocampal slices at the CA3-CA1 synapse were assessed. PNE mice exhibited the behavioral deficits of ADHD, hyperactivity and spatial memory impairment. Intraperitoneal injection of ATX (2 mg/kg/day) normalized these behaviors significantly after 7 days. In PNE mice LTP was reduced (110.6 ± 4.5% %; n = 7) compared to controls (148.9 ± 5.2%; n = 7; p 0.05). ATX administration (5 µM) reestablished the LTP in PNE mice to levels similar to the controls (157.7 ± 6.3%; n = 7). Paired-pulse ratios (PPR) were not significantly different for any condition. These results indicate that administration of ATX in a PNE model of ADHD reestablishes TBS-dependent LTP in CA3-CA1 synapses. The results suggest postsynaptic changes in synaptic plasticity as part of the mechanisms that underlie improvement of ADHD symptoms induced by ATX.

The first paper indicating that a central nervous system stimulant (amphetamine) could be beneficial for children with attention-deficit/hyperactivity disorder (ADHD)-like behavioral symptoms appeared in 1937.1 Over the subsequent 80 years, a range of additional stimulant (methylphenidate) and nonstimulant (atomoxetine, clonidine, guanfacine, and, most recently, viloxazine) drugs have been approved to treat children and adolescents with ADHD. These drug treatments have been the subject of a large number of randomized controlled trails (RCTs). A network meta-analysis found that using clinician ratings, amphetamine, methylphenidate, and atomoxetine were all significantly superior to a placebo.2 These findings suggest that in the short-term at least, these treatments are effective-data are sparse on the efficacy of longer-term drug treatment. However, there are longstanding worries about the use of such drug treatments with children. In particular there are concerns over possible adverse impact on growth. There are also less tangible, but important, concerns of parents as the whether it is appropriate to subject their children to the modification of behavior by drugs.3 For these reasons, there is an urgent need to develop nonpharmacological treatments for children and adolescents with ADHD. One such nonpharmacological treatment is dietary supplementation with micronutrients. In this issue of the Journal, Johnstone et al.4 present a study of micronutrients showing that, under the stringent conditions of an RCT, micronutrients substantially benefit the well-being of young people with ADHD and irritability (risk ratio [RR] = 2.97; 95% CI = 1.50-5.90).

The contribution of serotonin and noradrenaline to the modulation of pruriceptive processing was evaluated by administrating antidepressants or noradrenaline reuptake inhibitors. The pretreatment with milnacipran, a serotonin and noradrenaline reuptake inhibitor, and mirtazapine, a noradrenergic and specific serotonergic antidepressant, attenuated the induction of scratching behavior by chloroquine, a representative pruritogen, indicating the involvement of serotonin and/or noradrenaline in the modulation of pruriceptive processing. By contrast, the single administration of noradrenaline reuptake inhibitor such as atomoxetine and nisoxetine or serotonin reuptake inhibitor such as fluvoxamine and escitalopram had little effect on chloroquine-induced scratching, whereas the induction of scratching behavior by chloroquine was significantly ameliorated by co-administration of serotonin reuptake inhibitors and noradrenaline reuptake inhibitors. These results indicate that the simultaneous increases of serotonin and noradrenaline elicit the attenuating effect on pruriceptive processing induced by acute itch, and may also play a crucial role in the descending itch inhibitory system.

Aberrant impulsivity is found in a number of psychiatric disorders including attention deficit hyperactivity disorder (ADHD). The 5-choice serial reaction time task (5-CSRTT) is a paradigm commonly used to assess impulsive control. We recently developed a protocol to habituate mice to a variable intertrial interval (vITI) schedule before assessing pharmacological effects on "waiting" impulsivity. This study aimed to develop on that initial investigation by testing the effects of three conventional ADHD medications. Consistent premature response rates were achieved in male C57BL/6 J mice in the first week out of 15 vITI (5-, 10- or 15-s) days (four training days followed by one drug treatment day per week for three weeks) before each drug study commenced. The effects of atomoxetine (1, 3 mg/kg), methylphenidate (1, 2 mg/kg) and guanfacine (0.03, 0.1 mg/kg) were investigated using a Latin-square design. High- and low-impulsive subgroups were determined based on initial training day data before the drug studies initiated. Both 1 and 3 mg/kg atomoxetine reduced premature responding at the 10- (P 0.001, P 0.05) and 15-s (P 0.001) lengths. 2 mg/kg methylphenidate increased impulsive action at the longest 15-s ITI (P 0.05). Guanfacine exerted no effects on premature responding rates at any dose or ITI. Impulsive subgrouping did not reveal any specific drug by subgroup effects. This study indicates that these current ADHD medications have differential effects on impulsive action. In summary, this protocol is a useful preclinical model for testing potential treatments for disorders with dysfunctional impulsive control.

OBJECTIVE: Off-label prescription is a common practice in psychiatry, raising health and economic concerns. Collegial consultation could allow a framed prescription of treatments that are not authorized in specific indications. Attention Deficit Hyperactivity in adult populations (ADHD) is a striking example of a pathology where off-label prescription is frequent. First considered to be a childhood disorder, the awareness of this condition in adults is increasing, leading to the development of new clinical practices and treatments. However, the adult ADHD diagnosis and its management are still emerging in France despite a high prevalence. Treatment of adult ADHD relies on methylphenidate prescription, but the initiation of this drug is not authorized in adult populations. Methylphenidate is a central nervous system stimulant that is structurally close to amphetamine and acts as a norepinephrine and dopamine reuptake inhibitor. Due to these pharmacological properties, neuropsychiatric and cardiovascular side-effects could occur. Furthermore, its addictive potential has led France to classify it as a psychoactive drug, dispensed via secured prescription. The first prescription and the one-year follow-up are restricted to neurologists, paediatrics, psychiatrists and sleep disorders specialists at hospital. The objective of this article is to propose a multidisciplinary framework for the off-label prescription of methylphenidate in adult ADHD. METHODS: The Multidisciplinary Advice Consultation for Exceptional Addiction Treatments (Consultation d'Avis Multidisciplinaire de Traitements d'Exception en Addictologie CAMTEA) was first set up in Lille for the prescription of baclofen in alcohol dependence and was then extended to topiramate in binge eating disorder. This procedure has been adapted to the particularities of ADHD in adult populations, the differential diagnosis (bipolar disorder, depressive disorder, anxious disorder, personality disorder, substance use disorder) and the co-morbidities requiring a full psychiatric and neuropsychological assessment. Moreover, a particular attention has been paid to the monitoring of neuropsychiatric, cardiovascular and misuse risk because of the potential side-effects of methylphenidate. RESULTS: The proposed prescription framework is structured into several specialized consultations. A first psychiatric evaluation aims to diagnose adult ADHD, using the French version of the Diagnostisch Interview Voor ADHD 2.0 questionnaire (DIVA 2.0), and to assess the quality of life impact with the Weiss Functional Inventory Rating Scale (WIFRS). It also searches for the presence of differential diagnosis or co-morbidities. The second appointment consists of a pharmacological evaluation that aims to search for contraindications and potential drug interaction. A neuropsychological evaluation based on standardized tests (Weschler Adulte Intelligence Scale [WAIS IV], Conner's Continuous Performance Test 3 [CPT] and the Minnesota Multiphasic Personnality Inventory [MMPI]) is also required to evaluate neurocognitive disabilities and personality features. Once the parameters of the different assessments have been collected, the synthesis is presented during a multidisciplinary meeting in order to assess the risk-benefit ratio for each patient. Several specialties are involved in this multidisciplinary meeting: psychiatry, addictology, general medicine, addictovigilance, pharmacovigilance and neuropsychology. One strategy among three possibilities can be decided: (1) contraindication to treatment with methylphenidate, (2) attention deficit disorder that does not require medication management, and (3) indication of treatment with methylphenidate with the choice of the pharmacological form (immediate or prolonged release). A biological check-up and an electrocardiogram are carried out systematically before any treatment. If the decision is made to initiate treatment, it is started at the lowest dosage and followed by a titration phase. A weekly follow-up is carried out during the titration phase in order to assess treatment efficacy and safety. After treatment stabilization, the general practitioner can carry out the renewal, and the patient will be reassessed within the framework of the multidisciplinary consultation every 3 months. CONCLUSIONS: When an off-label prescription is being considered, it must comply with the basic rules of good clinical practice, and the benefit/risk ratio should be constantly reassessed. The proposed multidisciplinary framework, adapted to the characteristics of adult ADHD and the pharmacological properties of methylphenidate, appears to be an interesting strategy to meet the requirements of the good clinical practice. The complementary assessments carried out and the collegial framework allow enhancing the patient's follow-up and minimize the drug risk, particularly in the psychiatric, addictive and cardiovascular adverse events. Finally, this framework could also help the monitoring of other off-label treatments for ADHD, such as atomoxetine or guanfacine.

Background Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by deficits in self-controlling attention, behavior, and emotions. In recent years, noninvasive optical techniques, such as near infrared spectroscopy (NIRS), have been used to measure the neural correlates of pharmacological-therapy outcomes in children and adolescents with ADHD. Methods We reviewed a short series of articles that investigated the results of functional NIRS (fNIRS) on developmental-age ADHD. The review was limited to fNIRS studies that investigated the cortical responses that occurred during neuropsychological tasks in ADHD patients who received methylphenidate or atomoxetine. Results The majority of the reviewed studies revealed the presence of increased oxygenated hemoglobin concentrations in the prefrontal cortex following pharmacotherapy in ADHD samples. A higher frequency of right-lateralized results was found. Limitations The considered studies are characterized by substantial methodological heterogeneity in terms of the patients’ medication status and washout period, explored cerebral regions, and neuropsychological tasks. Conclusions fNIRS seems to be a promising tool for the detection of pharmacological-treatment biomarkers in samples of children and adolescents with ADHD.

The nicotinic acetylcholine receptor (nAChR) agonist nicotine and the noradrenaline transporter inhibitor atomoxetine are widely studied substances due to their propensity to alleviate cognitive deficits in psychiatric and neurological patients and their beneficial effects on some aspects of cognitive functions in healthy individuals. However, despite growing evidence of acetylcholine-noradrenaline interactions, there are only very few direct comparisons of the two substances. Here, we investigated the effects of nicotine and atomoxetine on response inhibition in the stop-signal task and we characterised the neural correlates of these effects using blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) at 3T. Nicotine (7 mg dermal patch) and atomoxetine (60 mg per os) were applied to N = 26 young, healthy adults in a double-blind, placebo-controlled, cross-over, within-subjects design. BOLD images were collected during a stop-signal task that controlled for infrequency of stop trials. There were no drug effects on behavioural performance or subjective state measures. However, there was a pronounced upregulation of activation in bilateral prefrontal and left parietal cortex following nicotine during successful compared to unsuccessful stop trials. The effect of nicotine on BOLD during failed stop trials was correlated across individuals with a measure of trait impulsivity. Atomoxetine, however, had no discernible effects on BOLD. We conclude that nicotine effects on brain function during inhibitory control are most pronounced in individuals with higher levels of impulsivity. This finding is compatible with previous evidence of nicotine effects on stop-signal task performance in highly impulsive individuals and implicates the nAChR in the neural basis of impulsivity.

Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental disorder characterized by varying levels of hyperactivity, inattention, and impulsivity. Patients with ADHD are often classified as (1) predominantly hyperactive-impulsive, (2) predominantly inattentive, and (3) combined type. There is a growing interest in developing specific animal models that would recapitulate specific clinical forms of ADHD, with the goal of developing specific therapeutic strategies. In our previous study, we have identified Ataxin-7 (Atxn7) as a hyperactivity-associated gene. Here, we generated Atxn7 overexpressing (Atxn7 OE) mice to investigate whether the increased Atxn7 expression in the brain correlates with ADHD-like behaviors. Quantitative real-time polymerase chain reaction and immunofluorescence confirmed overexpression of the Atxn7 gene and protein in the prefrontal cortex (PFC) and striatum (STR) of the Atxn7 OE mice. The Atxn7 OE mice displayed hyperactivity and impulsivity, but not inattention. Interestingly, treatment with the ADHD drug, atomoxetine (3 mg/kg, intraperitoneal), attenuated ADHD-like behaviors and reduced Atxn7 gene expression in the PFC and STR of these mice. These findings suggest that Atxn7 plays a role in the pathophysiology of ADHD, and that the Atxn7 OE mice can be used as an animal model of the hyperactive-impulsive phenotype of this disorder. Although confirmatory studies are warranted, the present study provides valuable information regarding the potential genetic underpinnings of ADHD.

Attention Deficit Hyperactivity Disorder (ADHD) causes impaired visuospatial working memory (VWM), which primarily maps to the prefrontal cortex. However, little is known about the synaptic processes underlying cognitive loss in ADHD, or those ultimately involved in the preventive effect observed through the clinical use of Atomoxetine (ATX). To investigate the plasticity underlying ADHD related cognitive loss, and that potentially involved in the preventive action of Atomoxetine, allocentric VWM was assessed, as well as the dendritic spine number and proportional density on pyramidal neurons in the prefrontal cerebral cortex layer III of neonatal 6-hydroxydopamine-lesioned rats. The effect of acute ATX treatment was also assessed at 28 days of age. 6-OHDA induced lesions produced increased motor activity and a loss of VWM, concomitant with a reduction in thin spine density. ATX administration reversed cognitive loss, in conjunction with a decrease in thin spines and an increase in mushroom spines. A reduction in the proportion of spines involved in learning in hyperactive animals could account for the loss in cognitive function observed. Considering thin spine density was also reduced after ATX administration, we hypothesized that the restoration in cognitive function recorded could be brought about by an increase in memory related mushroom spines.

Impulsive choice behavior, which can be assessed using the delay discounting task, is a characteristic of various psychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). Guanfacine is a selective α2A-adrenergic receptor agonist that is clinically effective in treating ADHD. However, there is no clear evidence that systemic guanfacine administration reduces impulsive choice behavior in the delay discounting task in rats. In the present study, we examined the effect of systemic guanfacine administration on food-motivated impulsive choice behavior in rats and the neuronal mechanism underlying this effect. Repeated administration of either guanfacine, methylphenidate, or atomoxetine significantly enhanced impulse control, increasing the number of times the rats chose a large but delayed reward in a dose-dependent manner. The effect of guanfacine was significantly blocked by pretreatment with an α2A-adrenergic receptor antagonist. Furthermore, the effect of guanfacine remained unaffected in rats pretreated with a selective noradrenergic neurotoxin, consistent with a post-synaptic action. In contrast, the effect of atomoxetine on impulsive choice behavior was attenuated by pretreatment with the noradrenergic neurotoxin. These results provide the first evidence that systemically administered guanfacine reduces impulsive choice behavior in rats and that direct stimulation of postsynaptic, rather than presynaptic, α2A-adrenergic receptors is involved in this effect.

Introduction The goal of pharmacologic intervention is therapeutic outcome – maximal efficacy with minimal adverse effects. In treating bipolar disorder, this may be complicated by comorbidities and/or adjunctive medications required to address adverse effects. Optimal rational polypharmacy may maximize therapeutic outcome yet could create ethical issues in competitive sports. The World Anti-Doping Code (WADC) and yearly published World Anti-Doping Agency Prohibited List are intended to deter and sanction athletes using performance-enhancing agents while promoting an even playing field for all competitors. This paper presents three hypothetical examples (ADHD/lithium-tremor/pain) wherein unintended Prohibited List contravention would result in doping violation disqualifications without approved Therapeutic Use Exemptions (TUEs). Method Hypothetical case analyses with literature review. Results Comorbid ADHD – the Prohibited List precludes psychostimulants (methylphenidate/amphetamines) in competition (S6) but permits guanfacine/atomoxetine. When psychostimulants effectively treat ADHD in athletes with bipolar disorder but guanfacine/atomoxetine do not, these patient-athletes, with clinician's certification and supportive documentation, should file TUEs. Lithium-tremor – beta-blockers are frequently prescribed to control lithium-tremor but are not permitted for specific sports (P2). If alternatives (primidone) are ineffective, TUEs are indicated. Pain – chronic pain management is difficult in athletes as narcotic analgesics (S7) and cannabinoids (S8) are prohibited in competition. When comorbid pain is not controlled with approved medications, TUEs are required. Conclusion Patient-athletes with bipolar disorder and comorbidities require holistic approaches with appreciation of both the WADC and Prohibited List. Athletes should list all medications with diagnoses/obtain TUEs/verify proposed medication status (banned/restricted/permitted) with appropriate International Federations and/or Olympic organizations. Clinicians should be cognizant of these issues when treating patient-athletes.

We previously identified a novel molecule, SHATI/NAT8L, as having an inhibitory effect on methamphetamine dependence. We generated Shati/Nat8l knockout (KO) mice and found that they showed neurochemical changes and behavioral abnormalities related to attention deficit/hyperactivity disorder (AD/HD). In this study, we assessed validities of the Shati/Nat8l KO mice as a new animal model for AD/HD through a behavioral pharmacology approach. We conducted a locomotor activity test in a novel environment, a cliff avoidance test, and an object-based attention assay using Shati/Nat8l KO mice at the ages of 4 and 8 weeks. We found that at the ages of both 4 and 8 weeks, Shati/Nat8l KO mice showed hyperactivity in locomotor activity test, shortened jumping latency in cliff avoidance test, and lower recognition index in object-based recognition test. Moreover, we evaluated the effects of atomoxetine (ATX) and methylphenidate (MPH) on the behavioral deficits in Shati/Nat8l KO mice. As the result, almost all behavioral deficits were improved by the treatment of both ATX and MPH. Our findings suggest that Shati/Nat8l KO mice have an impaired neural system similar to AD/HD pathophysiology. Shati/Nat8l KO mice might serve as a novel and a useful animal model for the pathophysiology of AD/HD.

Emotional dysregulation (ED) is a dysfunction in modifying an emotional state in an adaptive and goal oriented way, with excitability, ease anger, and mood lability. It is present in up to 70% of adults with ADHD, regardless of other comorbidities, and substantially worsens the psychosocial outcomes of the disorder. Besides fronto-parietal circuits mediating top-down control, brain regions involved in bottom-up processes (e.g., amygdala, orbitofrontal cortex, and ventral striatum) are implicated in ED. We performed a systematic review/meta-analysis of double-blind randomized controlled trials of ADHD medications to assess their effects on ED in adults with ADHD. We searched an extensive set of databases, international trials registries, and contacted study authors/drug companies for unpublished data. We retained 21 trials. We found small-to-moderate effects (methylphenidate: SMD = 0.34, 95% CI = 0.23–0.45; atomoxetine: SMD = 0.24, 95% CI = 0.15–0.34; lisdexamfetamine: SMD = 0.50, 95% CI = 0.21–0.8). We suggest that, whilst ADHD medications are effective on ADHD core symptoms, they may be less effective on bottom-up mechanisms underlying ED. Further research on novel pharmacological and non-pharmacological strategies for ED in adults with ADHD is warranted. PROSPERO: CRD42017068426.

Amphetamine (AMP) and atomoxetine (ATX) represent two of the most widely studied drug treatments used in the investigation of impulsive behaviour. While both drugs have relatively well defined effects in tests designed to investigate impulsive action (e.g. 5-choice task; 5-CSRTT), the effects of both drugs in tests of impulsive choice (e.g. delay discounting) are less consistent. In the present study both AMP and ATX were tested in a rodent gambling task (rGT) and delay discounting in rats separately trained to either an ascending or descending delay schedule. Effects of both drugs were compared to measures of impulsive action (premature (PREM) responses) and perseverative (PSV) responses measured in the 5-choice and rGT tasks. Consistent with previous studies, AMP (0.1–1 mg/kg) increased both PREM and PSV responses, and ATX (0.5–2 mg/kg) reduced both measures in the 5-choice and rGT tasks. At equivalent doses ATX had no reliable effect on choice behaviour in either the rGT or delay discounting suggesting a null effect of this drug on impulsive choice and risky decision making. The effects of AMP were more complex, with a subtle shift in preference to a low risk (P1) choice in the rGT, and an effect on discounting that was unrelated to reinforcer value, but instead dependent on delay sequence and baseline choice preference. One aspect to these outcomes is to highlight the importance of multiple methodological factors when assessing drug effects on complex behaviours such as impulsive choice, and question what are the most appropriate test conditions under which to examine these drugs on discounting.

Data presented are from a sex-differences secondary analysis of a human laboratory investigation of single doses of atomoxetine (40 mg and 80 mg) versus placebo in abstinent individuals with cocaine use disorders (CUD). Subjective drug effects, cognitive performance and cardiovascular measures were assessed. The primary atomoxetine dose analyses (which do not consider sex as a factor) are reported in full elsewhere (DeVito et al., 2017) [1] .

Sudden unexpected death in epilepsy (SUDEP) is a devastating epilepsy complication, and no effective preventive strategies are currently available for this fatal disorder. Clinical and animal studies of SUDEP demonstrate that seizure-induced respiratory arrest (S-IRA) is the primary event leading to death after generalized seizures in many cases. Enhancing brain levels of serotonin reduces S-IRA in animal models relevant to SUDEP, including the DBA/1 mouse. Given that serotonin in the brain plays an important role in modulating respiration and arousal, these findings suggest that deficits in respiration and/or arousal may contribute to S-IRA. It is well known that norepinephrine is an important neurotransmitter that modulates respiration and arousal in the brain as well. Therefore, we hypothesized that enhancing noradrenergic neurotransmission suppresses S-IRA. To test this hypothesis, we examined the effect of atomoxetine, a norepinephrine reuptake inhibitor (NRI), on S-IRA evoked by either acoustic stimulation or pentylenetetrazole in DBA/1 mice. We report the original observation that atomoxetine specifically suppresses S-IRA without altering the susceptibility to seizures evoked by acoustic stimulation, and atomoxetine also reduces S-IRA evoked by pentylenetetrazole in DBA/1 mice. Our data suggest that the noradrenergic signaling is importantly involved in S-IRA, and that atomoxetine, a medication widely used to treat attention deficit hyperactivity disorder (ADHD), is potentially useful to prevent SUDEP.

No pharmacotherapies are approved for the treatment of cocaine use disorders (CUD). Behavioral treatments for CUD are efficacious for some individuals, but recovery rates from CUD remain low. Cognitive impairments in CUD have been linked with poorer clinical outcomes. Cognitive enhancing pharmacotherapies have been proposed as promising treatments for CUD. Atomoxetine, a norepinephrine transporter inhibitor, shows potential as a treatment for CUD based on its efficacy as a cognitive enhancer in other clinical populations and impact on addictive processes in preclinical and human laboratory studies. In this randomized, double-blind, crossover study, abstinent individuals with CUD (N=39) received placebo, 40 and 80mg atomoxetine, over three sessions. Measures of attention, response inhibition and working memory; subjective medication effects and mood; and cardiovascular effects were collected. Analyses assessed acute, dose-dependent effects of atomoxetine. In addition, preliminary analyses investigating the modulation of atomoxetine dose effects by sex were performed. Atomoxetine increased heart rate and blood pressure, was rated as having positive and negative subjective drug effects, and had only modest effects on mood and cognitive enhancement.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a heterogeneous disorder. Current subtypes lack longitudinal stability or prognostic utility. We aimed to identify data-driven biotypes using multiple cognitive measures, then to validate these biotypes using EEG, ECG, and clinical response to atomoxetine as external validators. Study design was a double-blind, randomized, placebo-controlled crossover trial of atomoxetine including 116 subjects ages 6 through 17 with diagnosis of ADHD and 56 typically developing controls. Initial features for unsupervised machine learning included a cognitive battery with 20 measures affected in ADHD. External validators included baseline mechanistic validators (using electroencephalogram/EEG and electrocardiogram/ECG) and clinical response (ADHD Rating Scale and correlation with cognitive change). One biotype, labeled impulsive cognition, was characterized by increased errors of commission and shorter reaction time, had greater EEG slow wave (theta/delta) power and greater resting heart rate. The second biotype, labeled inattentive cognition, was characterized by longer/more variable reaction time and errors of omission, had lower EEG fast wave (beta) power, resting heart rate that did not differ from controls, and a strong correlation (r = −0.447, p < 0.001) between clinical response to atomoxetine and improvement in verbal memory immediate recall. ADHD comprises at least two biotypes that cut across current subtype criteria and that may reflect distinct arousal mechanisms. The findings provide evidence that further investigation of cognitive subtypes may be at least as fruitful as symptom checklist-based subtypes for development of biologically-based diagnostics and interventions for ADHD.

The quenching interaction of atomoxetine (ATX) with bovine serum albumin (BSA) was studied in vitro under optimal physiological condition (pH=7.4) by multi-spectroscopic techniques. The mechanism of ATX-BSA system was a dynamic quenching process and was confirmed by the fluorescence spectra and lifetime measurements. The number of binding sites, binding constants and other binding characteristics were computed. Thermodynamic parameters ∆H° and ∆S° indicated that intermolecular hydrophobic forces predominantly stabilized the drug-protein system. The average binding distance between BSA and ATX was studied by Försters theory. UV-absorption, Fourier transform infrared spectroscopy (FT-IR), circular dichroism (CD), synchronous spectra and three-dimensional (3D) fluorescence spectral results revealed the changes in micro-environment of secondary structure of protein upon the interaction with ATX. Displacement of site probes and the effects of some common metal ions on the binding of ATX with BSA interaction were also studied.

Background Scholastic under achievement, poor decision making and lack of self-regulation are major disadvantages in probands with Attention Deficit Hyperactivity Disorder (ADHD). Since contribution of neurotransmitters, chiefly dopamine (DA)/norepinephrine (NE) have been indicated in the etiology, medications have been developed targeting these neurotransmitters. However, due to variation in response and side effects, treatment is often discontinued. We aimed at understanding the role of DA/NE system gene variants, rs28363170, rs3785143, rs1611115 and rs4680, in medication response. ADHD probands diagnosed after the Diagnostic and Statistical Manual for Mental Disorders-IV were evaluated by the Conners' Parent Rating Scale-revised (CPRS-R). Peripheral blood collected from drug naive probands was used for genomic DNA isolation and analysis of gene variants. Probands were prescribed either Methylphenidate (MPH) or Atomoxetine (ATX) and post-treatment outcome was assessed using the CPRS-R as well as Drug Side Effect Rating Scale. Results While significantly reducing behavioral problems (χ 2 = 8.05, p = 0.005), MPH treatment resulted in more pronounced side effects as compared to ATX. rs28363170 and rs3785143 variants affected MPH and ATX induced improvement in traits differently (Cohen's d > 0.80). Quantitative trait analysis also revealed significant differential role of rs28363170/rs3785143 in medication response (add value > 8.0, 95% CI 1.11–16.11). Conclusion This pioneering study on Indian ADHD probands indicates that rs28363170 and rs3785143 could be major modulators for treatment outcome; while MPH may be more beneficial in the presence of rs28363170 10R and rs3785143 T variants, ATX treatment may provide relief in presence of rs28363170 9R and rs3785143 C variants.

Background: Despite the reduced quality of life in patients with recurrent vasovagal syncope (VVS), pharmacologic treatment options remain limited. Studies indicate that norepinephrine reuptake inhibition reduces tilt-induced syncope/pre-syncope. This study aimed to evaluate the effects of atomoxetine on syncopal/pre-syncopal episodes in patients with recurrent VVS. Methods: In a placebo-controlled trial, we randomized patients with newly diagnosed VVS who experienced ≥3 syncopal episodes in the past three months to receive either atomoxetine (20 mg daily for two weeks followed by 40 mg daily for two weeks) or placebo. The primary endpoint was the combined number of syncopal and pre-syncopal episodes. Results: Among 843 patients initially screened, 46 were randomized (N = 23 in each group) and reevaluated at one and three months. Compared to placebo, atomoxetine significantly reduced the primary endpoint after three months (P

Atomoxetine is used commonly treatment of attention deficit hyperactivity disorder in children, adolescents, and adults. A validated GC–MS assay for the quantitation of atomoxetine in human plasma is presented in the study. The assay method is the first GC–MS-based method reported for the analysis of atomoxetine in plasma for therapeutic drug monitoring. The method has rapid analysis time and simple sample preparation. Atomoxetine and internal standard (IS) pseudoephedrine were extracted from plasma using a liquid-liquid extraction method. The assay method was validated according to the European Medicines Agency (EMA) Guideline on bioanalytical method validation. The lower limit of quantitation of the developed method was 200 ng/mL for atomoxetine. The calibration curve of atomoxetine was between 200 and 2000 ng/mL with showing correlation coefficients >0.99. Also, the method was applied to real patient’s plasma.

We aimed to clarify the prescription trend of ADHD drugs in Japanese pediatric outpatients. From January 2012 to December 2018, we evaluated the trends of prescribing methylphenidate-osmotic-controlled release oral delivery system (OROS), atomoxetine, and guanfacine as monotherapy. In boys, methylphenidate-OROS and atomoxetine prescriptions decreased from 46.5 % to 37.2 % and 18.6 % to 15.6 %, respectively. Prescriptions of guanfacine increased from 0.0 % to 12.3 %. In girls, the methylphenidate-OROS prescriptions was not significantly different (37.0 % to 26.4 %); however, atomoxetine decreased from 23.1 % to 16.3 %, and guanfacine increased from 0.0 % to 12.8 %. Methylphenidate-OROS and atomoxetine prescriptions changed to guanfacine between 2012 and 2018.

Atomoxetine, a non-stimulant, is FDA approved drug used in the management of adult ADHD. Since the presentation of adult ADHD is different from the childhood onset condition, there is an urgent need to study the efficacy of atomoxetine on the different symptom domains of adult ADHD. To study the efficacy of atomoxetine in treating adult ADHD compared to placebo, we performed a Medline search for English language publications of Randomized Controlled Trials (RCTs) comparing atomoxetine to placebo for adult ADHD using the keywords "adult ADHD", "atomoxetine" and "placebo". A total of 41 RCTs were returned of which we included 13 relevant RCTs reporting data on 1824 patients with adult ADHD in the analysis. Standardized mean difference between atomoxetine and placebo for the mean baseline-to-endpoint change in total ADHD scores, impulsivity/hyperactivity and inattention scores was calculated, with a 95% confidence limit. Atomoxetine had superior efficacy than placebo on overall adult ADHD scores [-0.45; 95% CI -0.54, -0.35; overall effect p

Despite several studies suggested that inattention and impulsivity-compulsivity could represent two core dimensions of hoarding disorder (HD), only a small case series study investigated the effectiveness of attention-deficit-hyperactivity-disorder (ADHD) medications in HD. The aim of the present study was to target attentional and inhibitory control networks in HD patients through the ADHD medication atomoxetine, moving from a preclinical investigation on an animal model of compulsive-like behavior (marble burying test) to a clinical investigation on both medicated and unmedicated patients with a primary diagnosis of HD without ADHD. Our preclinical investigation showed that acute administration of atomoxetine significantly reduced the compulsive-like behaviours of mice in the marble burying test without affecting neither locomotor activity and coordination nor exploration behaviours. When compared, atomoxetine and fluoxetine showed similar effects on the marble burying test. However, fluoxetine impaired both locomotor and exploratory activity. In our clinical investigation 12 patients were enrolled and 11 patients completed an open trial with atomoxetine at flexible dose (40–80 mg) for 12 weeks. At the endpoint the mean UCLA Hoarding Severity Scale score decreased by 41.3% for the whole group (p = 0003). Six patients were classified as full responders (mean symptom reduction of 57.2%) and three patients as partial responders (mean symptom reduction of 27.3%). Inattentive and impulsivity symptoms showed a significant mean score reduction of 18.5% from baseline to the endpoint (F (1,9) = 20.9, p = 0.0013). Hoarding symptoms improvement was correlated to reduction of patients’ disability and increased in their global functioning. These preclinical and clinical data suggest that atomoxetine may be effective for HD and therefore should be considered for future controlled trials.

Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent mental disorder of childhood, which often continues into adolescence and adulthood. Stimulants such as methylphenidate (MPH) and non-stimulants such as atomoxetine are effective medications for the treatment of ADHD. However, about 30% of patients do not respond to these medications. Pharmacological treatment for ADHD, although highly effective, is associated with marked variabilities in clinical response, optimal dosage needed and tolerability. This article provides an overview of up-to-date knowledge regarding the clinical and neurobiological factors which contribute to and help predict treatment-refractory ADHD. Pharmacogenetic, pharmacogenomics and neuroimaging studies are still controversial with respect to determining the associations between response to medication and genetic factors, thereby resulting in hypotheses that differences in the genetic factors and neuroimaging findings contribute to treatment outcome. Much research on the potential role of genotype in pharmacological effects has focused on the catecholaminergic gene related to executive functions. Many neuroimaging studies have also reported a relationship between treatment response and common patterns of brain structure or activity according to various genetic polymorphisms. When children, adolescents and adults with ADHD do not respond to MPH, we should consider additional pharmacological options, including other classes of psychostimulants, the nonstimulant atomoxetine, bupropion, tricyclic antidepressant, clonidine, guanfacine and lisdexamphetamine. Prudent choice of an appropriate medication and active engagement of children, parents, and teachers in daily management may help to ensure long-term adherence. Therefore, additional research might help to optimize the treatment of children, adolescents and adults with ADHD and to find new options for the treatment of patients who do not respond to stimulants and the other medications. Because these findings should be interpreted cautiously, further studies are needed to elucidate these issues more clearly.

Two repurposed medications have been proposed to treat cocaine abuse. Progesterone, a gonadal hormone, and atomoxetine, a medication commonly used to treat attention deficit/hyperactivity disorder, have both been separately shown to reduce cocaine self-administration and reinstatement (i.e. relapse). The goal of the present study was to examine sex differences in the individual effects of PRO and ATO as well as the combination PRO+ATO treatment on cocaine (COC), caffeine (CAF), and/or cue-primed reinstatement of cocaine-seeking. Adult male and female Wistar rats lever-pressed under a FR 1 schedule for cocaine infusions (0.4 mg/kg/inf). After 14 sessions of stable responding in daily 2-h sessions, rats underwent a 21-day extinction period when no drug or drug-related stimuli were present. Rats were then separated into four groups that received PRO (0.5 mg/kg) alone (PRO+SAL), ATO (1.5 mg/kg) alone (VEH+ATO), control (VEH+SAL) or combination (PRO+ATO) treatments prior to the reinstatement condition. Reinstatement of cocaine-seeking to cues and/or drug injections of cocaine or caffeine was tested after extinction. During maintenance, females self-administered more cocaine than males, but no sex differences were seen during extinction. Females showed greater cocaine-seeking than males after a CAF priming injection. Individual treatment with ATO did not decrease reinstatement under any priming condition; however, the combination treatment decreased cocaine-seeking under the COC+CUES priming condition in males, and both PRO alone and the combination treatment decreased cocaine-seeking in the CAF+CUES condition in females. Overall, PRO alone was only effective in reducing reinstatement in females, while the combination treatment was consistently effective in reducing reinstatement in both sexes.

Medication is a first-line effective treatment for attention-deficit/hyperactivity disorder (ADHD). Currently, immediate-release methylphenidate (IR-MPH), the osmotic, controlled-release formulation of methylphenidate (OROS-MPH), and atomoxetine (ATX) are the only 3 medications approved in Taiwan for the treatment of ADHD. Short-term discontinuation of ADHD treatment is often seen among patients undergoing drug therapy. The goal of this study was to evaluate potential seasonal patterns in ADHD prescriptions and compare the seasonal changes of IR-MPH, OROS-MPH, and ATX use.Taiwan's National Health Insurance database was used to gather information on patients diagnosed with ADHD (N = 145,269) from January 2000 to December 2011. The monthly data regarding person-days and receipt of treatment with IR-MPH, OROS-MPH, and ATX were analyzed. Time series analyses and autoregressive integrated moving average models were used to examine the seasonal patterns in person-days receiving ADHD pharmacotherapy. A general linear model with a post hoc test was used to determine the differences in monthly consumption of ADHD medications.This study comprised 145,269 patients (mean age: 7.7 years; 78.6% were boys) diagnosed with ADHD. The prescriptions of IR-MPH (seasonal autoregressive: estimate [SE], 0.92 [0.04], t = 22.87, P0.001) and OROS-MPH (estimate [SE], 0.84 [0.09], t = 9.41, P0.001) both showed significant seasonal patterns, but ATX prescriptions did not (estimate [SE], 0.50 [0.55]; t = 0.90; P = 0.373). IR-MPH and OROS-MPH prescriptions shared similar seasonal trends. The mean person-days of consumption in July were lower than in other months, with the exception of February and August. Meanwhile, for ATX, the person-days of consumption in February were the lowest. The mean person-days in February were significantly lower than in March and May but did not differ from those in other months.The seasonal patterns of IR-MPH and OROS-MPH use coincide with school holidays. These findings suggest that discontinuing a drug during the holiday period may be popular for people undergoing ADHD pharmacotherapy, especially with regard to methylphenidate prescriptions. However, additional research is necessary to determine whether temporary discontinuation of drug therapy is related to patient outcomes.

Impulsivity is a trait that is closely linked to addiction, which has been studied in personality, psychiatry and more recently in the neurocognitive arena. Recently, even obesity has been compared to food addiction with the connotation that obese individuals are impulsive in their behavior. This research is a conceptual review of the construct of impulsivity identified inhibitory control and temporal discounting as two key behavioral constructs universal to all key fields of impulsivity research. This research aimed to identify the modifiability of impulsivity through neuronal dopamine pathways through the use of two pharmaceutical agents, modafinil and atomoxetine. A randomized controlled trial design was executed to test the aforementioned neurocognitive enhancement agents (n = 20 participants receiving atomoxetine and n = 20 participants receiving modafinil) against a placebo (n = 40) in normal weight adults. The results showed that modafinil but not atomoxetine was effective in reducing deficits in inhibitory control. These findings highlight the multiconstruct nature of impulsivity and the need for psychometric tests, which capture these constructs better.

Rationale Clinical studies have shown that patients with exaggerated risk-taking tendencies have high baseline levels of norepinephrine. In this work, we systemically manipulated norepinephrine levels in rats and studied their behavioral changes in a probabilistic discounting task, which is a paradigm for gauging risk taking. Methods This study aims to explore the effects of the selective norepinephrine reuptake inhibitor (atomoxetine at doses of 0.6, 1.0 and 1.8 mg/kg), and receptor selective antagonists (propranolol at a single dose of 1.0/kg, and prazosin at a single dose of 0.1 mg/kg), on risk taking using a probabilistic discounting task. In this task, there were two levers available to rats: pressing the ‘small/certain’ lever guaranteed a single food pellet, and pressing the ‘large/risky’ lever yielded either four pellets or none. The probability of receiving four food pellets decreased across the four experimental blocks from 100% to 12.5%. Results Atomoxetine increased the tendency to choose the large/risky lever. It significantly reduced the lose-shift effect (i.e. pressing a different lever after losing a trial), but did not affect the win-stay effect (i.e. pressing the same lever after winning a trial). Furthermore, co-administration of beta-adrenoreceptor antagonist, propranolol, eliminated the effects of atomoxetine on risk taking and the lose-shift effect; but co-administration of alpha 1 -adrenoreceptor antagonist, prazosin, did not. Conclusions Atomoxetine boosted NE levels and increased risk taking. This was because atomoxetine decreased rats' sensitivity to losses. These effects were likely mediated by beta-adrenoreceptor.

Objective The purpose of this study is to determine the risk of developing depressive disorders by evaluating children with attention-deficit/hyperactivity disorder (ADHD) in comparison to controls that do not have ADHD, as well as to analyze whether the medications used to treat ADHD, methylphenidate (MPH) and atomoxetine (ATX), influence the risk of depression. Methods A group of patients newly diagnosed with ADHD ( n =71,080) and age- and gender-matching controls ( n =71,080) were chosen from Taiwan's National Health Insurance database during the period of January 2000 to December 2011. Both the patients and controls were monitored through December 31, 2011. We also explore the potential influence of the length of MPH and ATX treatment on developing depressive disorders. Results The ADHD patients showed a significantly increased probability of developing a depressive disorder when compared to the control group (ADHD: 5.3% vs. controls: 0.7%; aHR, 7.16, 99% CI: 6.28–8.16). Regarding treatment with MPH, a longer MPH use demonstrates significant protective effects against developing a depressive disorder (aOR, 0.91, 99%CI: 0.88–0.94). However, the duration of ATX treatment could not be significantly correlated with the probability of developing a depressive disorder. Limitations The database employed in this study lacks of comprehensive clinical information for the patients with ADHD. Potential moderating factors between ADHD and depression were not considered in-depth in this study. Conclusions The results of this study reveal that youths diagnosed with ADHD have a greater risk of developing depressive disorders. Long-term treatment with MPH correlated to the reduced probability of developing a depressive disorder among youths with ADHD.

In this study, we aimed to evaluate the relationship between attention-deficit/hyperactivity disorder (ADHD) during childhood and subsequent diagnoses of bipolar disorder (BD), as well as to determine whether the pharmacotherapy for ADHD (methylphenidate and atomoxetine) influence the risks of developing BD. A nationwide cohort of patients newly diagnosed with ADHD (n = 144,920) and age- and gender-matching controls (n = 144,920) were found in Taiwan's National Health Insurance database from January 2000 to December 2011. Both patients and controls were observed until December 31, 2011. To determine the effect that the duration of methylphenidate and atomoxetine exposure had on BD, the difference in the risk of developing BD was compared among non-users, short-term users (≤365 days), and long-term users (>365 days). In comparison to the control group, the ADHD group showed a significantly increased risk of developing BD (ADHD: 2.1% vs. controls: 0.4%; aHR: 7.85, 95% CI: 7.09–8.70), and had a younger mean age at the time of first diagnosis (ADHD: 12.0 years vs. controls: 18.8 years). Compared to ADHD patients that had never taken methylphenidate, patients with long-term use of methylphenidate were less likely to be diagnosed with BD (aOR: 0.72, 95% CI: 0.65–0.80). However, the duration of exposure to atomoxetine did not have a significant relationship to a BD diagnosis. The results suggested that a previous diagnosis of ADHD was a powerful indicator of BD, particularly juvenile-onset BD. Nevertheless, the exact mechanisms of the relationships among ADHD, its pharmacotherapy, and BD require further clarification in the future.

Appropriate animal models are necessary to determine the molecular and cellular mechanisms underlying attention-deficit/hyperactivity disorder (ADHD). This study used a battery of behavioral tests to compare Lister hooded rats (LHRs), an old outbred strain frequently used for autistic epilepsy research, with Wistar rats and spontaneously hypertensive rats (SHRs), a commonly used ADHD model. The open field, elevated plus maze, light/dark box, and drop tests demonstrated that LHRs were the most hyperactive animals and displayed the most inattentive- and impulsive-like behaviors, which are characteristics of ADHD. The radial arm maze, social interaction, and Morris water maze tests showed that LHRs did not display deficits characteristic of autism or intellectual disability. Although LHRs did not show different monoamine contents, the mRNA expression levels of various genes linked to ADHD (Cdh13, Drd5, Foxp2, Maoa, Sema6d, Slc9a9, and St3gal3) and tyrosine hydroxylase protein expression levels were lower in the prefrontal cortex of LHRs compared with that of Wistar rats or SHRs. c-Fos, synapsin I, and tau protein expression levels in the prelimbic region of the medial prefrontal cortex were also increased in LHRs compared with Wistar rats. Atomoxetine and guanfacine, commonly used non-stimulant treatments for ADHD, ameliorated ADHD-like behaviors in LHRs. These results suggest that LHRs can serve as a better ADHD model to develop novel pharmacological interventions.

Risk perception is an important factor that may mediate risk-based decision-making processes regulated by noradrenergic (NA) and serotonergic (5-HT) systems. Most risk-based decision-making models involve complex factors, such as risk perception or reward value, such that the final decision is the result of the interactions among these factors. However, the contribution of risk perception per se in risk decisions has remained unclear. Therefore, in the present study, we made some modifications to the classical probabilistic discounting task (PDT) to focus on the impact of risk perception and noradrenergic/serotonergic systems on decision-making behavior. Meanwhile, we conducted an elevated plus-maze (EPM) test to detect the correlation between anxiety and choice behavior. In the current study, rats had to choose between a “certain” lever that delivered a certain number of pellets and a “risky” lever that delivered eight pellets in a probabilistic manner (descending: 50%, 25%, 12.5% or ascending 12.5%, 25%, 50% of the time). The long-term rewarding values of the two levers were always identical in each block within each session. According to their baseline performances in choosing the risky lever, rats were divided into the risk-prefer group and risk-averse group. The results showed that there was a significant correlation between open arm time in EPM and risky choice for both descending order and ascending order, indicating that highly anxious rats more often preferred the safe option under risk. Pharmacological stimulation of α2-adrenergic receptors via dexmedetomidine (0.01 mg/kg) decreased the preference of probabilistic rewards in the risk-prefer group, while blocking α2 receptors by atipamezole (0.3 mg/kg) also reduced risky choices. The NA reuptake inhibitor, atomoxetine, increased the preference for risky choices in the risk-prefer group, the effect of which was attained via multiple superimposed doses. Administration of the 5-HT2A receptor agonist, DOI (0.1 mg/kg), increased risk-taking behavior in the risk-prefer group. Taken together, these results suggest that NA may be more inclined to process negative information such as loss or uncertainty in the regulation of risk-related decision making, whereas 5-HT may function primarily to increase risk-taking behavior. Our findings may help to further elucidate how noradrenergic and serotonergic systems differentially affect individuals with different risk preferences in terms of regulating risk perception in risk-related decision making.

This study aimed to evaluate the baseline sleep habits of children with ADHD and the effects of treatment with methylphenidate (MPH) and atomoxetine (ATX) on sleep parameters. Treatment naive children with clinically normal intelligence diagnosed with ADHD were enrolled in the study. Children were treated naturalistically with MPH and ATX. Treatments were started at 0.5 mg/ kg/ day and titrated weekly to a maximum of 1.2 mg/ kg/ day. The daily equivalent dose was calculated according to clinician toolkits of Utah Academy of Child and Adolescent Psychiatry. DSM-IV Based Screening and Assessment Scale for Disruptive Behavior Disorders- Parent form (DBSASDBD) and Clinical Global Impression Scale were used to assess ADHD symptoms and Children's Sleep Habits Questionnaire (CSHQ)- Short Form was used to assess the sleep habits and problems before and after the treatment. Both MPH and ATX reduced symptom severity of ADHD in all domains and also reduced total CSHQ scores with similar effect sizes. (0.7 for MPH vs. 0.8 for ATX). The rate of clinically significant sleep problems at baseline was 93.5 %. At the end-point, 83.9 % of the sample still displayed clinically significant sleep problems while none of the children were judged to have moderate-severe sleep problems. Our results suggest that both ATX and MPH may selectively improve different sleep domains in children with ADHD. Studies using standardized dosing schemes for longer durations and evaluating sleep with objective measurements may clarify the differential effects of treatments on sleep among children with ADHD. WOS:000573651300010 2-s2.0-85083851580 PubMed: 32361211

Drug repositioning has gained strategic value as a reaction to high attrition rates of new drugs as they pass through the clinical development process. The 5-HT2C receptor agonist lorcaserin (Belviq®), and the selective NA reuptake inhibitor atomoxetine (Strattera®) represent two drugs FDA approved for obesity and ADHD respectively. Although both drugs are of differing pharmacological class, each share a property of regulating impulsive behaviours in preclinical studies, and thus represent candidates for consideration in clinical conditions labelled as ‘impulsive-compulsive disorders’. The present studies investigated both drugs, as well as the highly selective 5-HT2C agonist CP-809101 in two tests of compulsive action: schedule-induced polydipsia (SIP) and increased perseverative [PSV] (and premature [PREM]) responses emitted during an extended ITI 5-choice task. While lorcaserin (0.06–0.6 mg/kg), CP-809101 (0.1–1 mg/kg) and atomoxetine (0.1–1 mg/kg) each reduced both PREM and PSV measures in the 5-choice task, at equivalent doses only lorcaserin and CP-809101 affected excessive water intake in the SIP task, atomoxetine (0.1–2 mg/kg) was essentially ineffective. Further evidence supporting a role of the 5-HT2C receptor as an important regulator of impulsive-compulsive behaviours, the selective antagonist SB-242084 produced the opposing effects to lorcaserin, i.e promoting both impulsive and compulsive behaviours. The profile of atomoxetine may suggest differences in the nature of compulsive action measured either as non-regulatory drinking in the SIP task, and PSV responses made in a 5-choice task. These studies support the consideration of 5-HT2C receptor agonists, typified by lorcaserin, and atomoxetine as potential treatments for clinical conditions categorised as ‘impulsive-compulsive disorders’. This article is part of the special issue entitled ‘Serotonin Research: Crossing Scales and Boundaries’.

Introduction: Approved drugs for attention deficit hyperactivity disorder (ADHD) in Spain are methylphenidate, lisdexamphetamine, atomoxetine and guanfacine. Due to adverse cardiovascular effects, mainly increased blood pressure and heart rate, its use in patients with known or undiagnosed heart disease may be controversial. Objective: To obtain a consensus document from the Spanish Society of Paediatric Cardiology and Congenital Heart Diseases (SECPCC) and experts from other Agencies and Societies as a guide for the paediatric cardiologist and physicians who treat children and adolescents with ADHD. Method: An analysis was performed on the bibliography and Clinical Practice Guidelines, technical data sheets approved by the Spanish Agency of Medicines and Health Devices, and the Spanish Ministry of Health Guidelines. A Working Group was formed, with a Coordinator, as well as members of the Clinical Cardiology Working Group and Arrhythmia Group of the SECPCC. This Group produced a preliminary document that was reviewed by a group of external experts (List 1) and a group of internal experts of the SECPCC (List 2) with a consensus being reached on the final document. Results: The recommendations of the SECPCC and the group of experts are presented on cardiovascular evaluation prior to treatment in children and adolescents with unknown cardiovascular disease and with known cardiovascular disease.The recommendations of the SECPCC and the group of experts are also presented on the use of medications for ADHD in children and adolescents with cardiological symptoms with no evidence of heart disease, congenital heart disease, cardiomyopathy, Marfan syndrome and other aortic diseases, hypertension, and arrhythmias. Resumen: Introducción: Los fármacos aprobados para el trastorno por déficit de atención con hiperactividad (TDAH) en España son: metilfenidato, lisdexanfetamina, atomoxetina y guanfacina. Debido a los efectos adversos cardiovasculares que pueden producir, principalmente aumento de la tensión arterial y la frecuencia cardiaca, su uso en pacientes con cardiopatías conocidas o no diagnosticadas puede ser controvertido. Objetivo: Realización de un documento de consenso de la Sociedad Española de Cardiología Pediátrica y Cardiopatías Congénitas (SECPCC) y expertos de otras Agencias y Sociedades como instrumento para el cardiólogo infantil y los médicos que tratan niños y adolescentes con TDAH. Metodología: Análisis de la bibliografía y Guías de Práctica Clínica, fichas técnicas aprobadas por la Agencia Española del Medicamento y Productos Sanitarios y Guía del Ministerio de Sanidad español. Formación de un Grupo de trabajo con un Coordinador, miembros de los grupos de trabajo de Cardiología Clínica y Arritmias de la SECPCC. Este Grupo realizó un documento que fue revisado por un grupo de expertos externos (Anexo 1) y un grupo de expertos internos de la SECPCC (Anexo 2) llegando a un consenso para la obtención del documento final. Resultados: Se presentan las recomendaciones de la SECPCC y el grupo de expertos sobre la evaluación cardiovascular previa al tratamiento en niños y adolescentes sin enfermedad cardiovascular conocida y con enfermedad cardiovascular conocida. Se presentan las recomendaciones de la SECPCC y el grupo de expertos sobre el uso de medicamentos para el TDAH en niños y adolescentes con síntomas cardiológicos sin evidencia de cardiopatía, cardiopatías congénitas, miocardiopatías, síndrome de Marfan y otras aortopatías, hipertensión arterial y arritmias.