The role of adrenergic neurotransmitter reuptake inhibitors in the ADHD armamentarium.

INTRODUCTION: Adrenergic neurotransmitter reuptake inhibitors are gaining attention in treatment for attention-deficit hyperactivity disorder (ADHD). Due to their effects on norepinephrine, dopamine, and serotonin neurotransmission, they benefit both ADHD and comorbid disorders and have some other advantages including longer duration of action and fewer adverse effects compared to stimulants. There is continued interest in these agents with novel mechanisms of action in treatment of ADHD. AREAS COVERED: The authors conducted a PubMed literature search using the following key words: 'ADHD' AND 'adrenergic reuptake inhibitors' OR 'nonstimulants' OR 'atomoxetine' OR 'Viloxazine' OR 'Dasotraline' OR 'Centanafadine' OR 'PDC-1421' OR 'Reboxetine' OR 'Edivoxetine' OR 'Bupropion' OR 'Venlafaxine' OR 'Duloxetine.' They reviewed FDA fact sheets of available medications for safety/tolerability studies and reviewed published clinical studies of these medications for treatment of ADHD. EXPERT OPINION: Adrenergic neurotransmitter reuptake inhibitors fit the diverse needs of children and adolescents with ADHD with 1) poor tolerability to stimulants (e.g. due to growth suppression, insomnia, rebound irritability, co-morbid depression, anxiety and tic disorders, substance abuse or diversion concerns), 2) cardiac risks, and/or 3) need for extended duration of action. Their differences in receptor affinities and modulating effects support the unique benefits of individual agents.

Systematic Review and Meta-Analysis: Effects of Pharmacological Treatment for Attention-Deficit/Hyperactivity Disorder on Quality of Life.

OBJECTIVE: We conducted a systematic review and meta-analysis to quantify the effect of attention-deficit/hyperactivity disorder (ADHD) medication on quality of life (QoL), and to understand whether this effect differs between stimulants and non-stimulants. METHOD: From the dataset of a published network meta-analysis (Cortese et al., 20181), updated on 27th February 2023 (https://med-adhd.org/), we identified randomized controlled trials (RCTs) of ADHD medications for individuals aged 6 years or more with a diagnosis of ADHD based on the DSM (from third to fifth editions) or the International Classification of Diseases (ICD; ninth or tenth revision), reporting data on QoL (measured with a validated scale). The risk of bias for each RCTs was assessed using the Cochrane Risk of Bias tool 2. Multi-level meta-analytic models were conducted with R 4.3.1. RESULTS: We included 17 RCTs (5,388 participants in total; 56% randomized to active medication) in the meta-analyses. We found that amphetamines (Hedge's g = 0.51, 95% CI = 0.08, 0.94), methylphenidate (0.38; 0.23, 0.54), and atomoxetine (0.30; 0.19, 0.40) were significantly more efficacious than placebo in improving QoL in people with ADHD, with moderate effect size. For atomoxetine, these effects were not moderated by the length of intervention, and did not differ between children/adolescents and adults. CONCLUSION: In addition to being efficacious in reducing ADHD core symptom severity, both stimulant and non-stimulant medications are efficacious in improving QoL in people with ADHD, albeit with lower effect sizes. Future research should explore whether, and to what degree, combining pharmacological and non-pharmacological interventions is likely to further improve QoL in people with ADHD. STUDY PREREGISTRATION INFORMATION: Effects of pharmacological treatment for ADHD on quality of life: a systematic review and meta-analysis; https://osf.io/;qvgps.

The effects of stimulant and non-stimulant medications on the autonomic nervous system (ANS) functioning in people with ADHD: A systematic review and meta-analysis.

We carried out a systematic review and meta-analysis to investigate the effects of stimulant and non-stimulant medications on autonomic functioning in people with ADHD (PROSPERO: CRD42020212439). We searched (9th August 2021) PsycInfo, MEDLINE, EMBASE, Web of Science and The Cochrane Library, for randomised and non-randomised studies reporting indices of autonomic activity, (electrodermal, pupillometry and cardiac), pre- and post-medication exposure in people meeting DSM/ICD criteria for ADHD. In the narrative syntheses, we included 5 electrodermal studies, 1 pupillometry study and 57 studies investigating heart rate and blood pressure. In the meta-analyses, 29 studies were included on blood pressure and 32 on heart rate. Administration of stimulants, and to a lesser degree, non-stimulants increased heart rate and blood pressure in people with ADHD. Similarly, an upregulation of arousal, reflected in increased electrodermal activity and pupil diameter was observed following stimulant use. Yet, the methodological diversity of studies presented in this review reinforces the need for more standardised and rigorous research to fully understand the relationship between arousal, medication, and behaviour in ADHD.

Areas of Interest and Attitudes towards the Pharmacological Treatment of Attention Deficit Hyperactivity Disorder: Thematic and Quantitative Analysis Using Twitter.

We focused on tweets containing hashtags related to ADHD pharmacotherapy between 20 September and 31 October 2019. Tweets were classified as to whether they described medical issues or not. Tweets with medical content were classified according to the topic they referred to: side effects, efficacy, or adherence. Furthermore, we classified any links included within a tweet as either scientific or non-scientific. We created a dataset of 6568 tweets: 4949 (75.4%) related to stimulants, 605 (9.2%) to non-stimulants and 1014 (15.4%) to alpha-2 agonists. Next, we manually analyzed 1810 tweets. In the end, 481 (48%) of the tweets in the stimulant group, 218 (71.9%) in the non-stimulant group and 162 (31.9%) in the alpha agonist group were considered classifiable. Stimulants accumulated the majority of tweets. Notably, the content that generated the highest frequency of tweets was that related to treatment efficacy, with alpha-2 agonist-related tweets accumulating the highest proportion of positive consideration. We found the highest percentages of tweets with scientific links in those posts related to alpha-2 agonists. Stimulant-related tweets obtained the highest proportion of likes and were the most disseminated within the Twitter community. Understanding the public view of these medications is necessary to design promotional strategies aimed at the appropriate population.

Prevalence and determinants of attention deficit/hyperactivity disorder (ADHD) medication use during pregnancy: Results from the Quebec Pregnancy/Children Cohort.

AIMS: The use of attention deficit/hyperactivity disorder (ADHD) medications has grown over the past decade among pregnant women, but these treatments are not without risk. Updated prevalence of ADHD medication use and whether prescribed dosages follow guidelines are needed. The aim of this study is to describe the prevalence of ADHD medication use among pregnant women-dosages and switches-and identify determinants of ADHD medication use. METHOD: A population-based longitudinal cohort study within the Quebec Pregnancy/Children Cohort (QPC). Women aged 15-45 years old covered by the RAMQ prescription drug plan for at least 12 months before and during pregnancy from 1998 to 2015. ADHD medication exposure was assessed before and during pregnancy. We estimated odds ratios (ORs) for determinants of ADHD medication use during pregnancy with generalized estimating equations. RESULTS: Among 428,505 included pregnant women, 1,130 (0.26%) used ADHD medication. A 14-fold increase in the prevalence of ADHD medication use in pregnant women was observed, from 1998 (0.08%) to 2015 (1.2%). Methylphenidate was the most prevalent medication at 70.1%. ADHD medication fillings were at optimal dosage 91.8% of the time based on guidelines and 18.1% of women switched to another ADHD medication class during gestation. Main determinants of ADHD medication use during pregnancy were psychiatric disorders (aOR 2.19; 95% confidence interval [CI] 1.57, 2.96), mood and anxiety disorders (aOR 1.74; 95% CI 1.32, 2.24), and calendar year. CONCLUSIONS: The number of pregnancies exposed to ADHD medications has increased similarly to the increase reported in other countries between 1998 and 2015. In addition to the current literature, the use of ADHD medications during pregnancy is consistent with Canadian guidelines recommendations on dosage.

Lifetime evolution of ADHD treatment.

Attention-deficit hyperactivity disorder (ADHD), has been traditionally considered a neurodevelopmental disorder affecting children and adolescents characterized by inattention, hyperactivity, disruptive behavior, and impulsivity. Although still debated, it is evident that ADHD is also present in adulthood, but this diagnosis is rarely carried out, mainly for the frequent comorbidity with other psychiatric and/or substance abuse disorders. Given the need to shed more light on the pharmacological treatment of ADHD, we performed a naturalistic review to review and comment on the available literature of ADHD treatment across the lifespan. Indeed, stimulants are endowed of a prompt efficacy and safety, whilst non-stimulants, although requiring some weeks to be fully effective, are useful when a substance abuse history is detected. In any case, the pharmacological management of ADHD appears to be still largely influenced by the individual experience of the clinicians. Further longitudinal studies with a careful and detailed characterization of participants across different phases of the lifespan are also required to provide relevant confirmations (or denials) regarding pharmacological treatments amongst the different age groups.

Suicidal ideation and attempts in the United States of America among stimulant-treated, non-stimulant-treated, and untreated patients with a diagnosis of attention-deficit/hyperactivity disorder.

BACKGROUND: Studies of the association between attention-deficit/hyperactivity disorder (ADHD) drug therapy and suicidal ideation and attempts (SIA) have conflicting results. METHODS: Cohorts of patients with ADHD aged 6 years or older with at least one pharmacy claim for a central nervous system (CNS) stimulant or a non-stimulant, or with no claims for ADHD pharmacotherapy, were identified in the US IBM® MarketScan® Research Database from January 2008 to March 2018. Incidence density rates (IDRs) of SIA (i.e., claims for suicide and self-inflicted poisoning, suicide and self-inflicted injuries, or suicidal ideation) were calculated. Cohorts were compared (CNS stimulants vs non-stimulants; CNS stimulants vs no pharmacotherapy) using hazard ratios (HRs) estimated from Cox proportional hazards models. Inverse-probability-of-treatment weighting (IPTW) was used to control for confounding. RESULTS: The study included 797,189 patients (CNS stimulants, 622,536; non-stimulants, 54,615; no pharmacotherapy, 120,038). IDRs of SIA (per 1000 patient-years) were: CNS stimulants, 5.8; non-stimulants, 10.5; and no pharmacotherapy, 10.0. The overall SIA risk was significantly lower with CNS stimulants than with non-stimulants (IPTW-adjusted HR = 0.70, 95% confidence interval = 0.61-0.81, p < 0.001) and no pharmacotherapy (0.62, 0.57-0.67, p < 0.001). LIMITATIONS: SIA assessment was based on diagnostic codes; suicidal ideation may not have been reported; completed suicides were generally not captured; and treatment was not verified. CONCLUSIONS: In this population-based study of patients with ADHD, SIA risk was significantly lower in those receiving CNS stimulants relative to those receiving non-stimulants or no pharmacotherapy, suggesting that CNS stimulants may attenuate SIA risk.

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

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

Attention-deficit/hyperactivity disorder in elite athletes: a narrative review.

Attention-deficit/hyperactivity disorder (ADHD) is a common brain developmental disorder in the general population that may be even more prevalent in elite athletes in certain sports. General population studies of ADHD are extensive and have reported on prevalence, symptoms, therapeutic and adverse effects of treatment and new clinical and research findings. However, few studies have reported on prevalence, symptoms and treatments of ADHD in elite athletes. This narrative review summarises the literature on symptoms, comorbidities, effects of ADHD on performance and management options for elite athletes with ADHD. The prevalence of ADHD in student athletes and elite athletes may be 7%-8%. The symptoms and characteristics of ADHD play a role in athletes' choice of a sport career and further achieving elite status. Proper management of ADHD in elite athletes is important for safety and performance, and options include pharmacologic and psychosocial treatments.

Treatment of Adult ADHD without Stimulants: Effectiveness in A Dually Diagnosed Correctional Population.

Adult ADHD has received increased attention in the past two decades. There is a complex relationship between ADHD and substance use disorders, with ADHD being a risk factor for and a moderator in the treatment of addiction. ADHD is also a risk factor for the development of antisocial personality disorder. As a result, ADHD is prevalent in a correctional dually diagnosed population. This retrospective chart review reports on the effectiveness of the treatment for ADHD in a population with substance use disorders, residing in a correctional community center for treatment and reintegration purposes. Only patients with a primary diagnosis of ADHD were included and only nonstimulants were used. After an average of four visits, or approximately four months, patient showed a moderate response with a pretreatment to posttreatment effect size of 1.4. Sixty-four percent of patients responded and 35% remitted, according to the Clinical Global Index Severity Scale as the primary outcome measure. While stimulants are considered the first-line treatment for ADHD, they clearly present challenges in certain populations, especially in patients with significant antisocial and addiction histories. It does appear that non-stimulants are effective in this population. It is speculated that the response and remission rate could be improved by adding ADHD specific psychosocial interventions.

Evaluation of Two Types of Drug Treatment with QEEG in Children with ADHD.

AIMS: The aim of this study is to evalute the effects of methylphenidate and atomoxetine treatments on electroencephalography (EEG) signals in volunteer children diagnosed with Attention Deficit and Hyperactivity Disorder(ADHD). METHODS: The study contained 40 children all of whom were between the ages of 7 and 17. The participants were classified into two groups as ADHD (n=20), which was in itself divided into two groups as ADHD-MPH (ADHD- Metylphenidate treatment) (n=10) and as ADHD-ATX (ADHD-Atomoxetin treatment) (n=10), and one control group (n=20). Following the first EEG recordings of the ADHD group, long-acting methylphenidate dose was applied to one ADHD group and atomoxetine dose was applied to the other ADHD group. The effect of optimal dosage is about for 4-6 weeks in general. Therefore, the response or lack of response to the treatment was evaluated three months after the beginning of the treatment.After methylphenidate and atomoxetine drug treatment, in order to obtain mean and maximum power values for delta, theta, alpha and beta band, the EEG data were analyzed. RESULTS: The EEG power spectrum densities in all the bands yielded similar findings in both methylphenidate and atomoxetine. Although statistically significant frequency values of the electrodes were amplitude and maximally varied, in general, they appeared mostly at both frontal and temporal regions for methylphenidate and atomoxetine. CONCLUSION: Especially, after atomoxetine treatment, Quantitative Electroencephalography (QEEG) rates at frontal area electrodes were found statistically more significant than methylphenidate QEEG rates. What has been researched in this study is not only whether QEEG is likely to support the diagnosis, but whether changes on QEEG by treatment may be related to the severity of ADHD as well.

A critical appraisal of atomoxetine in the management of ADHD.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder beginning in childhood and often continuing into adulthood. A wealth of data shows that ADHD symptoms respond well to pharmacological treatment. Stimulant medications, including amphetamine and methylphenidate, are most commonly used to treat ADHD. However, with the approval of atomoxetine (Strattera(®), [ATX]) by the US Food and Drug Administration in late 2002, an effective non-stimulant option became available. The US Food and Drug Administration approved ATX for the treatment of ADHD in children, adolescents, and adults. Although the effect size of ATX is generally lower than that of stimulants, the American Academy of Child and Adolescent Psychiatry Practice Parameter for the treatment of ADHD lists ATX as a first-line treatment option. ATX is widely prescribed and accounted for 6% of the prescriptions of ADHD visits in the US in 2010. Numerous trials have found that ATX improves quality of life and emotional lability in addition to core ADHD symptoms. Although some improvement may be seen in a patient as early as one week after the initiation of treatment, ATX generally takes longer to have a full effect. The median time to response using 25% improvement in ADHD symptoms in pooled trials was 3.7 weeks. Data from these trials indicate that the probability of symptom improvement may continue to increase up to 52 weeks after treatment is initiated. ATX has been shown to be safe and effective in combination with stimulants. It has also been studied systematically in subjects with ADHD and comorbid oppositional defiant disorder, anxiety, depression, and substance use disorders. The mechanism of action of ATX, its efficacy, and adverse events reported in trials is reviewed.

Pharmacological treatment of attention deficit hyperactivity disorder in children and adolescents: clinical strategies.

Attention deficit hyperactivity disorder (ADHD) is a common neurobehavioral disorder of childhood that can result in significant functional impairment, and if not adequately treated can lead to impaired quality of life. Pharmacotherapy is considered the first-line treatment for ADHD in children and adolescents. We review both recent literature and seminal studies regarding the pharmacological treatment of ADHD in children and adolescents. There is ample evidence for the efficacy and safety of both stimulants and non-stimulants in the treatment of ADHD. We review important aspects of evaluation and assessment and discuss first-line pharmacological treatments and as well as when to consider using alternative pharmacological agents. Treatment approaches to manage frequently seen comorbid disorders with ADHD are also covered.

Drug therapy of attention deficit hyperactivity disorder: current trends.

Attention deficit hyperactivity disorder is a developmental disorder with an age onset prior to 7 years. Children with ADHD have significantly lower ability to focus and sustain attention and also score higher on impulsivity and hyperactivity. Stimulants, such as methylphenidate, have remained the mainstay of ADHD treatment for decades with evidence supporting their use. However, recent years have seen emergence of newer drugs and drug delivery systems, like osmotic release oral systems and transdermal patches, to mention a few. The use of nonstimulant drugs like atomoxetine and various other drugs, such as α-agonists, and a few antidepressants, being used in an off-label manner, have added to the pharmacotherapy of ADHD. This review discusses current trends in drug therapy of ADHD and highlights the promise pharmacogenomics may hold in the future.

Effectiveness of pharmaceutical therapy of ADHD (Attention-Deficit/Hyperactivity Disorder) in adults - health technology assessment.

BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) is a mental disorder. Symptoms include hyperactivity, lack of attentiveness, and frivolousness. This disorder always begins in childhood, but can remain through adulthood. ADHD affects all areas of life and limits the quality of life due to its symptoms and the high rate of associated disorders that can develop. An established form of therapy is using stimulant medications, most commonly, containing Methylphenidate as the active ingredient. However, in Germany this ingredient is not approved for adults suffering from ADHD. Therefore, many adults cannot obtain appropriate medication to treat this disorder. OBJECTIVE: The following report (Health Technology Assessment [HTA]) examines the effectiveness and cost-effectiveness of the medical treatment of ADHD in adults as well as the ethical, social and legal aspects thereof. METHODS: In August 2009, a systematic literature search is performed in all relevant scientific databases. The selected citations fulfill predetermined inclusion criteria. The data in the publications is then systematically extracted, reviewed and assessed. A manual search of citations is conducted as well. RESULTS: NINETEEN STUDIES FULFILL THE INCLUSION CRITERIA: nine randomised controlled studies (RCT), five meta-analyses, three economic studies and two studies relevant to the legal aspects of the HTA. All RCT reveal that adult patients who receive medication containing a stimulant (Methylphenidate and Amphetamine) and Atomoxetine, see a reduction of ADHD symptoms compared to the placebo-treated patients. The drug response rate among the control group ranges from 7 to 42%; in the treatment group from 17 to 59.6%. The meta-analyses confirm the findings of the RCT. In light of the control group, it can be ascertained that there are higher annual costs (both direct and indirect) for patients with ADHD. The average annual medical expenses for an adult with ADHD were 1,262 $ in 1998 and 1,673 $ in 2001 (the converted and inflation-adjusted rate for 2009: between 1,270 and 1,619 Euro). The use of stimulants use may impair the patient's ability to drive, travel or do sports. No relevant studies can be identified concerning the ethical, social and/or legal aspects of stimulant medication for ADHD patients. DISCUSSION/CONCLUSION: Medical treatment, particularly including Methylphenidate and Atomoxetine, proves to have a positive effect. In order to attain an optimal drug response, dosing must be determined on an individual basis. There is a need of high-quality studies that directly compare various agents - an aspect which is relevant to medical effectiveness of a therapy. No definite statement can be made about the cost-effectiveness of the medical treatment of ADHD in adults. More health economic studies are therefore required. Apart from the unquestionable mental indication, it is already recommended by health economic reasons to establish the conditions for an adequate treatment with these medicaments also for adults.