Attention-deficit/hyperactivity Disorder Pharmacotherapy Research Articles

Pharmacotherapy of ADHD in Adults

There is a complex overlap between major depressive disorder (MDD) and attention-deficit/hyperactivity disorder (ADHD). The different therapeutic options for adult ADHD mirror those used for children with ADHD. Both stimulant and nonstimulant medications are used to treat the disorder.

ADHD and the Rise in Stimulant Use Among Children

Attention-deficit/hyperactivity disorder (ADHD) holds the distinction of being the most extensively studied pediatric mental disorder and one of the most controversial, in part because it is also the most commonly diagnosed mental disorder among minors. Currently, almost 8% of youth aged 4 to 17 years have a diagnosis of ADHD, and approximately 4.5% both have the diagnosis and are using a stimulant (methylphenidate or amphetamine) as treatment for the disorder. Yet a diagnosis of ADHD is not simply a private medical finding; it carries with it a host of policy ramifications. The enduring controversy over ADHD in the public arena therefore reflects the discomfort over what happens when science is translated into policies and rules that govern how children will be treated medically, educationally, and legally. This article (1) summarizes the existing knowledge of ADHD, (2) provides the relevant history and trends, (3) explains the controversy, (4) discusses what is and is not unique about ADHD and stimulant pharmacotherapy, (5) outlines future directions of research, and (6) concludes with a brief analysis of how two North Carolina counties have established community protocols that have improved the screening, treatment, and societal consensus over ADHD and stimulants.

Adverse Effects of Pharmacotherapies for Attention-Deficit Hyperactivity Disorder

Medication for the treatment of attention-deficit hyperactivity disorder (ADHD) is in widespread use globally. There is considerable data suggesting that overall, the adverse effect burden from this use is dose dependent and is in the mild to moderate category, but few comprehensive reviews exist of the epidemiology of adverse effects alone. This review provides a general and systems-specific summary of the scientific literature regarding adverse effect data for the drugs in general use for the treatment of ADHD. Although several areas lack definitive data, current evidence suggests that, for the majority of those treated for ADHD, the medications currently available pose little in the way of risk of significant harm. Epidemiological data suggest a low incidence of serious adverse effects, whilst the less serious adverse effects, such as insomnia and anorexia, are relatively common. Also, some specific areas of study suggest lower risks of harm than previously thought, e.g. tic disorders and seizures. However, pre-existing conditions and other interindividual differences may raise the risk of harmful adverse effects, which adds emphasis to the need for careful pretreatment assessment and monitoring. Potential but unlikely long-term treatment effects need to be investigated as carefully as possible, particularly with regard to cardiac sequelae and carcinogenesis. There are both overlaps and differences between the adverse effects of stimulants and nonstimulants, such as atomoxetine. For example, the latter shares the stimulant group's potential for changing cardiovascular parameters, but may not cause insomnia.

Long-term Efficacy of ADHD Pharmacotherapy in Children

<h4>EXCERPT</h4> <p>Attention-deficit/hyperactivity disorder (ADHD) is a chronic neurobehavioral disorder with core symptoms of inattention, overactivity, and impulsivity that adversely affect many domains of function across the lifespan. Numerous short-term studies confirm decrease in core symptoms from pharmacotherapy, primarily stimulants, and more recently atomoxetine. Despite ADHD being a chronic disorder and ADHD pharmacotherapy being one of the most researched topics in child psychiatry, long-term efficacy has been examined only recently. Efficacy for core symptoms through 15 months appears well established, and there is reasonable evidence through 2 years for continued efficacy in some patients. However, evidence beyond 2 years is scant and confounded with self-selection for continuation. In general, evidence for benefit in associated domains (social skills, achievement, family function, internalizing symptoms) is not as impressive as for core symptoms, but there appears to be some benefit through 14 months and possibly 2 years of treatment. The long-term examination of efficacy is complicated by the presence/development of co-morbidities, poor follow-up, poor adherence to prescribed regimens, and the healthcare system’s inability to provide prolonged, careful medication management. Future studies are needed to examine the longer-term (beyond 2 years) effects of medication management when provided at optimal, carefully monitored levels.</p> <h4>ABOUT THE AUTHORS</h4> <p>Richard H. Gilchrist, MD, is Child Psychiatrist, Nationwide Children’s Hospital, and Clinical Assistant Professor, Department of Psychiatry, The Ohio State University. L. Eugene Arnold, MD, is Professor Emeritus, Department of Psychiatry, The Ohio State University.</p> <p>Address correspondence to: Richard H. Gilchrist, MD, Nationwide Children’s Hospital, 700 Children’s Drive, Timken Hall H 206, Columbus OH 43054; <a href="mailto:Richard.Gilchrist@osumc.edu">Richard.Gilchrist@osumc.edu</a>.</p> <p>Dr. Gilchrist has disclosed no relevant financial relationships. Dr. Arnold has disclosed the following relevant financial relationships: Organon, Novartis, and Shire: Consultant; Bristol-Myers Squibb, Eli Lilly, and Shire: Research funding recipient; and McNeil, Novartis, and Shire: Member of Speakers’ Bureau.</p> <H4>EDUCATIONAL OBJECTIVES</H4><OL> <LI>Review the core symptoms of ADHD and discuss prevalence estimates in children and adolescents.</LI><LI>Discuss the findings of the Multi-Modal Treatment Study of ADHD (MTA) Cooperative Group and how they relate to the long-term efficacy of stimulant medications in children and adolescents.</LI><LI>Determine the current evidence for the effect of long-term stimulant medication on substance abuse, accidents, risk taking behavior, and quality of life scores in children and adolescents with ADHD.</LI></OL>

Collicular dysfunction in attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder characterised by (inter alia) an increase in distractibility. The current front-line pharmacotherapies for the treatment of ADHD, namely the psychostimulants methylphenidate and amphetamines, have clear abuse potential, hence there is a strong need to develop new drug treatments for this disorder. Central to this process is the identification of the pathophysiological changes which underlie ADHD. Given the heterogeneity of the disorder, multiple loci are probably involved, providing multiple potential therapeutic targets. Here, we hypothesise (Hypothesis 1) that one such locus is the superior colliculus (SC), a sensory structure intimately linked with distractibility and the production of eye and head movements. It is proposed that in ADHD, the colliculus is hyper-responsive, leading to the core symptom of increased distractibility. Hypothesis 1 is supported by: 1. ADHD patients show increased distractibility in tasks which are sensitive to collicular function; 2. ADHD patients have a general problem inhibiting saccades, the generation of which involves the SC; 3. Saccadic deficits in ADHD include defects in the production of saccadic types (anti-saccades and express saccades) which are particularly associated with the colliculus; 4. Covert shifts in attention (which also have been argued to involve the SC) are also impaired in ADHD; 5. Reading disorders are frequently co-morbid with ADHD; dyslexia (which is associated with eye movement problems) is linked to a specific visual perceptual deficit in the M pathway, a major recipient of which is the colliculus. Whether or not the SC is indeed hyper-responsive in ADHD as Hypothesis 1 suggests, the SC may well represent an important therapeutic target for drugs. In fact current psychostimulant therapies, which reduce distractibility, may already work at that level (Hypothesis 2), a contention which is supported by: 1. The colliculus and structures immediately afferent to it contain the neurochemical machinery necessary to respond to these drugs; 2. d-Amphetamine depresses visually evoked activity in the rat colliculus in a dose-dependent manner. Fortunately, again, even if psychostimulants do not achieve their therapeutic effects on distractibility in ADHD by acting on the SC, then the development of drugs which dampen stimulus-related activity in the colliculus could still represent an important novel path for drug development to take. Pharmacological manipulations of this structure are able to decrease distractibility. As a consequence, sensory responsiveness in the SC may represent a new model system for use in the development of non-addictive pharmacotherapies for ADHD.

Long-Term Safety of Stimulant Medications Used to Treat Children with ADHD

Attention-deficit/hyperactivity disorder (ADHD) is a common mental health condition that affects children, adolescents, and adults. Because it is a chronic condition and typically requires effective treatment for several years or more, information on the benefits and risks of long-term pharmacotherapy for ADHD is vital to clinicians. This article reviews the emerging literature on the safety of long-term stimulant medications in ADHD-the most commonly prescribed medications for this condition. Common side effects, including cardiovascular effects, growth effects, and tics, are discussed, as well as treatment of children younger than age 6 and evidence of carcinogenic and reproductive effects.

Impact of Attention-Deficit/Hyperactivity Disorder (ADHD) on prescription dug spending for children and adolescents: increasing relevance of health economic evidence

BackgroundDuring the last decade, pharmaceutical spending for patients with attention-deficit-hyperactivity disorder (ADHD) has been escalating internationally.ObjectivesFirst, to estimate future trends of ADHD-related drug expenditures from the perspectives of the statutory health insurance (SHI; Gesetzliche Krankenversicherung, GKV) in Germany and the National Health Service (NHS) in England, respectively, for children and adolescents age 6 to 18 years. Second, to evaluate the budgetary impact on individual prescribers (child and adolescent psychiatrists and pediatricians treating patients with ADHD) in Germany.MethodsA model was developed to predict plausible scenarios of future pharmaceutical expenditures for treatment of ADHD. Model inputs were derived from demographic and epidemiological data, a literature review of past spending trends, and an analysis of new pharmaceutical products in development for ADHD. Only products in clinical development phase III or later were considered. Uncertainty was addressed by way of scenario analysis. For each jurisdiction, five scenarios used different assumptions of future diagnosis prevalence, treatment prevalence, rates of adoption and unit costs of novel drugs, and treatment intensity.ResultsAnnual ADHD pharmacotherapy expenditures for children and adolescents will further increase and may exceed €310 m (D; E: ₤78 m) in 2012 (2002: ~€21.8 m; ~₤7.0 m). During this period, overall drug spending by individual physicians may increase 2.3- to 9.5-fold, resulting from the multiplicative effects of four variables: increased number of diagnosed cases, growing acceptance and intensity of pharmacotherapy, and higher unit costs of novel medications.DiscussionEven for an extreme low case scenario, a more than six-fold increase of pharmaceutical spending for children and adolescents is predicted over the decade from 2002 to 2012, from the perspectives of both the NHS in England and the GKV in Germany. This budgetary impact projection represents a partial analysis only because other expenditures are likely to rise as well, for instance those associated with physician services, including diagnosis and psychosocial treatment. Further to this, by definition budgetary impact analyses have little to nothing to say about clinical appropriateness and about value of money.ConclusionProviders of care for children and adolescents with ADHD should anticipate serious challenges related to the cost-effectiveness of interventions.

Changes and challenges: managing ADHD in a fast-paced world.

Attention-deficit/hyperactivity disorder (ADHD) impairs the lives of both children and adults. Undiagnosed and untreated, ADHD may have serious lifelong consequences. Research has identified diagnostic clues, neurotransmitter pathways, and psychiatric comorbidities related to ADHD, as well as effective pharmacologic, behavioral, and psychosocial interventions. Stimulant agents have been the foundation of ADHD therapy for more than 50 years. Availability of new extended-release (XR or ER) and longer-acting (LA) formulations and novel agents allows for wider and more individualized treatment choices. Side effects of stimulants are generally mild, short lived, and responsive to adjustments in dosage or timing. Outcomes in ADHD treatment can be improved with the use of clear treatment guidelines and tools to aid clinicians in implementing them efficiently and effectively. The Texas Children's Medication Algorithm Project (CMAP) provides a system of algorithm-driven treatment decisions that is evidence based and easy to implement. To (1) review the psychological components of attention, the neurotransmitter pathways associated with ADHD, and the array of therapeutic options for ADHD, with an emphasis on the most recent introductions to the therapeutic armamentarium; (2) discuss the rare psychiatric and cardiovascular side effects associated with stimulants; (3) review abuse liability, comorbidities, and suggested approaches to these issues; and (4) review the development and use of CMAP and offer resources for its implementation in clinical practice. The pathophysiology of ADHD is linked to dysfunction of fronto-subcortical networks and dysregulation of dopaminergic, noradrenergic, and nicotinic neurotransmitter systems. An additive effect of multiple genes as well as environmental influences contributes to the clinical picture. Treatment with stimulants and nonstimulants has proven effective in different subgroups, with the effectiveness of specific agents most likely related to the primary neurotransmitter involved. Availability of XR, ER, LA, and transdermal stimulant formulations, as well as alternative nonstimulant agents, offers new options for the pharmacotherapy of ADHD. Major concerns associated with abuse liability of stimulants have been allayed by the availability of ER formulations, which have reduced reinforcing effects associated with short-acting preparations. Medication outcomes in ADHD can be enhanced by the use of evidence-based algorithms such as CMAP. Keys to success are adequate initial assessment and diagnosis, the use of sustained-release products, sufficient dose titration, and the use of clinical rating scales with feedback from caregivers and teachers. Optimal treatment outcomes can be achieved by appropriate pharmacotherapy combined with psychosocial interventions.

Current status of cognitive-behavioral therapy as a psychosocial treatment for adult attention-deficit/hyperactivity disorder

A convergence of research has established that attention-deficit/hyperactivity disorder (ADHD) is a valid clinical syndrome affecting individuals of all ages. ADHD is associated with significant impairment in many important life domains that often requires clinical intervention. Although medications are a well-researched and effective first-line treatment option, many adult patients with ADHD continue to experience significant functional impairment despite the symptom improvement afforded by pharmacotherapy. Consequently, adjunctive psychosocial treatments often are indicated for adults with ADHD. The aim of this paper is to review the status of cognitive-behavioral therapy (CBT) as an effective psychosocial treatment (when combined with pharmacotherapy) for adult ADHD. This review includes a brief discussion of the CBT conceptualization of ADHD, a summary of clinical outcome studies of psychosocial treatments for adult ADHD, directions for future research, and a discussion of the various possible mechanisms of change involved in CBT for adult ADHD.

Pharmakotherapie der ADHS im Erwachsenenalter bei komorbider Depression

Attention-deficit/hyperactivity disorder (ADHD) is a common disorder with a high prevalence of 2-6% in adults. The often distinctive clinical symptomatology has a great practical relevance and the diagnostic demarcation of other psychiatric illnesses can be difficult which underlines the necessity of a differential and careful diagnosis. ADHD is a risk factor for comorbid disorders like anxiety, personality disorders and addiction. Comorbid depression is also frequent and has an important meaning in the differential diagnostic process. A review was made about diagnostics and pharmacotherapy of ADHD with comorbid depression. For the combination treatment of ADHD with comorbid depression there are good pharmacological procedures of treatment. Here in particular modern antidepressants with noradrenergic or noradrenergic-serotonergic active principles play an important role. Very important is an exact diagnosis and differentiated treatment of ADHD, i.e. a "multimodal therapy" using pharmacological and psychotherapeutic concepts.

Emerging drugs for attention-deficit/hyperactivity disorder

Symptoms of attention-deficit/hyperactivity disorder (ADHD) are heterogeneous and often accompanied by comorbid psychiatric disorders. Although symptoms tend to lessen with age, many patients continue to be affected by the disorder into adulthood. Although many medications are available to treat ADHD, it is unlikely that a single medication will ever be developed to work for all patients. Recent advances, such as long-acting, extended-release formulations and transdermal delivery systems, have lengthened the duration of effectiveness, which has increased compliance and eliminated the need for additional medication dosing during the school or work day. Additional safe, well-tolerated, long-acting medications with further reduced potential for diversion and abuse are needed. Catecholamine pathways and their effect on executive functions and ADHD symptom control have been productive areas of research. Potential therapies such as adrenergic receptor agonists, glutamatergic agents, GABA receptor antagonists and nicotine receptor agonists are being explored as future pharmacotherapies for ADHD.

A naturalistic study of the effects of pharmacotherapy on substance use disorders among ADHD adults

Studies of adults with attention deficit hyperactivity disorder (ADHD) show an elevated prevalence of substance use disorders (SUDs) and the substance abuse literature shows that ADHD is elevated in substance users. Some researchers postulate that stimulant treatment of ADHD increases the risk for SUD in ADHD patients but follow-up studies suggest treatment protects patients from subsequent SUDs. This report uses retrospective data to assess the impact of prior ADHD pharmacotherapy on SUDs in 206 ADHD adults (n=79 late-onset ADHD, n=127 full ADHD) grouped by lifetime history of ADHD treatment (no treatment, past treatment, current and past treatment). Structured Clinical Interview for DSM-IV (SCID) data were used to establish abuse and dependence, and Drug Use Screening Inventory (DUSI) responses were used to establish prevalence of use, preference for cigarettes, alcohol and drugs of abuse, complications from use, and motivation for use (get high, change mood, sleep better). No differences were found in the prevalence of cigarette smoking, alcohol or drug abuse or dependence, as well as no significant differences in 1-month prevalence of any use or use more than 20 times. No differences were found in complications of drug or alcohol use across groups. Subjects with current treatment rated getting high as a motivating factor significantly more frequently than subjects in the past treatment group; this result lost significance when we included ADHD diagnostic category. Our results are consistent across substances and ADHD diagnoses, and support the hypothesis that pharmacotherapy does not cause subsequent SUDs.

Patients receiving pharmacotherapies for attention-deficit hyperactivity disorder (ADHD) must be informed of potential cardiovascular and psychiatric adverse events

Patients receiving pharmacotherapies for attention-deficit hyperactivity disorder (ADHD) must be informed of potential cardiovascular and psychiatric adverse events

Patients receiving pharmacotherapies for attention-deficit hyperactivity disorder (ADHD) must be informed of potential cardiovascular and psychiatric adverse events

Patients receiving pharmacotherapies for attention-deficit hyperactivity disorder (ADHD) must be informed of potential cardiovascular and psychiatric adverse events

Measurement of the Subjective Effects of Methylphenidate in 11- to 15-Year-Old Children with Attention-Deficit/Hyperactivity Disorder

This study examined subjective and other behavioral effects of methylphenidate (MPH) among adolescents. Standard abuse liability assessment methods that have been used in adult populations were modified for attention-deficit/hyperactivity disorder (ADHD) adolescents. MPH effects (0, 0.25 mg/kg) were evaluated under randomized, double-blind conditions in two 5-hour laboratory sessions in 24 (13 female) 11-15 year olds diagnosed with ADHD. Repeated measures analysis of covariance indicated significant dose and dose by time interactions on subjective ratings on the modified amphetamine (A) [F (1, 20) = 5.98; p < 0.05; eta2 = 0.36], morphine-benzedrine group (MBG) [F (1, 21) = 8.93 p < 0.01; eta2 = 0.38] and benzedrine group scale (BG) [F (1, 21) + 13.10 p < 0.01; eta2 = 0.37] scales of the Addiction Research Center Inventory; "Hungry" and "How sure are you that you got the medication today?" from the Visual Analogue Scale, the Profile of Mood States Depression scale, performance on the Continuous Performance Task, heart rate and blood pressure, and level of activity. This is the first study to document subjective effects of stimulants in adolescents with ADHD that have been associated with drug abuse potential in adults. There are increasing concerns about nontherapeutic stimulant use in adolescents and young adults. Assessing subjective effects of pharmacotherapies for ADHD along with other measures of abuse potential such as drug self-administration may aid in assessing the therapeutic effects and/or risk of medications used in the treatment of ADHD.

Combination pharmacotherapy for adult ADHD

Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent neuropsychiatric disorders of adulthood. Although clinical guidelines recommend monotherapy with stimulants or atomoxetine, combination pharmacotherapy is a common practice among clinicians. There are four main situations in which combination medications may be necessary: partial response, dose-limiting side effects, associated disorders, and comorbid diagnoses. We present data from two chart reviews that support existing research on combination pharmacotherapy. Adjunct treatment of d-methylphenidate to stimulant medications extended the duration of therapeutic effect. Adjunct treatment of mirtazapine to stimulant medications reduced associated insomnia. These data support previous research that validates the use of combination pharmacotherapy for adults with ADHD.

Dopamine Transporter Ligands: Recent Developments and Therapeutic Potential

The dopamine transporter (DAT) is a target for the development of pharmacotherapies for a number of central disorders including Parkinson's disease, Alzheimer's disease, schizophrenia, Tourette's syndrome, Lesch-Nyhan disease, attention deficit hyperactivity disorder (ADHD), obesity, depression, and stimulant abuse as well as normal aging. Considerable effort continues to be devoted to the development of new ligands for the DAT. In this review, we present some of the more interesting ligands developed during the last few years from the 3-phenytropane, 1,4-dialkylpiperazine, phenylpiperidine, and benztropine classes of DAT uptake inhibitors as well as a few less studied miscellaneous DAT uptake inhibitors. Studies related to the therapeutic potential of some of the more studied compounds are presented. A few of the compounds have been studied as pharmacotherapies for Parkinson's disease, ADHD, and obesity. However, most of the drug discovery studies have been directed toward pharmacotherapies for stimulant abuse (mainly cocaine). A number of the compounds showed decreased cocaine maintained responding in rhesus monkeys trained to self-administer cocaine. One compound, GBR 12,909, was evaluated in a Phase 1 clinical trial.

Innovations and recent trends in the treatment of ADHD

Initiatives to develop better-tolerated, more efficacious pharmacological agents with improved drug delivery systems have driven recent research in attention-deficit hyperactivity disorder (ADHD). While stimulants are the primary pharmacotherapy for ADHD, these drugs have a limited duration of action and a subset of patients will either fail to respond to these medications or have side effects that preclude their use. The development of atomoxetine, the first nonstimulant approved for ADHD, has been followed by additional innovative research, such as the methylphenidate transdermal system, modafinil, NRP-104 and cholinergic agents. This review highlights some of the recent trends in ADHD treatment and the current status of promising treatment options that may help to shape the future of ADHD treatment.

The α2C-adrenergic receptor mediates hyperactivity of coloboma mice, a model of attention deficit hyperactivity disorder

Drugs that modify noradrenergic transmission such as atomoxetine and clonidine are increasingly prescribed for the treatment of attention deficit hyperactivity disorder (ADHD). However, the therapeutic targets of these compounds are unknown. Norepinephrine is also implicated in the hyperactivity exhibited by coloboma mice. To identify the receptor subtypes that regulate the hyperactivity, coloboma mice were systematically challenged with adrenergic drugs. The beta-adrenergic receptor antagonist propranolol and the alpha(1)-adrenergic receptor antagonist prazosin each had little effect on the hyperactivity. Conversely, the alpha(2)-adrenergic receptor antagonist yohimbine reduced the activity of coloboma mice but not control mice. Subtype-selective blockade of alpha(2C)-, but not alpha(2A)- or alpha(2B)-adrenergic receptors, ameliorated hyperactivity of coloboma mice without affecting activity of control mice, suggesting that alpha(2C)-adrenergic receptors mediate the hyperactivity. Localized in the basal ganglia, alpha(2C)-adrenergic receptors are in a prime position to impact locomotor activity and are, therefore, potential targets of pharmacotherapy for ADHD.

The Texas Children's Medication Algorithm Project: Revision of the Algorithm for Pharmacotherapy of Attention-Deficit/Hyperactivity Disorder

In 1998, the Texas Department of Mental Health and Mental Retardation developed algorithms for medication treatment of attention-deficit/hyperactivity disorder (ADHD). Advances in the psychopharmacology of ADHD and results of a feasibility study of algorithm use in community mental health centers caused the algorithm to be modified and updated. We convened a consensus conference of academic clinicians and researchers, practicing clinicians, administrators, consumers, and families to revise the algorithms for the pharmacotherapy of ADHD itself as well as ADHD with specific comorbid disorders. New research was reviewed by national experts, and rationales were provided for proposed changes and additions to the algorithms. The changes to the algorithms were discussed and approved both by the national experts and experienced clinicians from the Texas public mental health system. The panel developed consensually agreed-upon algorithms for ADHD with and without comorbid disorders. The major changes included elimination of pemoline as a treatment option, adding atomoxetine to the algorithm, and refining guidelines for treating ADHD with comorbid depression, aggressive behaviors, and tic disorders. Medication algorithms for ADHD can be modified to keep abreast of developments in the field. Although these evidence- and consensus-based treatment recommendations may be a useful approach to guide the treatment of ADHD in children, additional research is needed to determine how these algorithms can be used to maximally benefit child outcomes.