New drugs for treatment of attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is one of the longest recognised and most common neuropsychiatric disorders of childhood. Recent research indicates that ADHD is most often a lifelong condition associated with significant impairment in multiple domains of functioning. ADHD is a clinical diagnosis made on the basis of history and clinical examination. Current molecular, neuroimaging and neuropsychological studies have greatly elucidated our understanding of the basic science of ADHD. The underlying pathophysiology of ADHD has been theorised to be dysregulation of inhibitory noradrenergic frontocortical activity on dopaminergic striatal structures. Pharmacotherapy is recognised as the most effective component of ADHD treatment, although some role exists for proper educational placement, parent management training and social skills development. Methylphenidate and amphetamine are the current standards in ADHD medication treatment. Other medication classes such as tricyclic antidepressants and certain antihypertensives are also used in off-label therapy. Anticipated improvements in new ADHD medications include the development of extended release delivery systems, improved tolerability, alternative mechanisms of action and enhanced efficacy in treatment refractory cases.     

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.     

New methylphenidate formulations for the treatment of attention-deficit/hyperactivity disorder

dl-Methylphenidate (MPH) remains the most widely used pharmacological agent in the treatment of attention-deficit/hyperactivity disorder (ADHD). The predominantly dopaminergic mechanism of the psychostimulant actions has become more clearly defined. Neuroimaging and genetic studies are revealing the underlying neuropathology in ADHD. Novel extended-release (ER) MPH formulations now offer drug delivery options to overcome both the short-term actions of immediate-release (IR) MPH and the acute tolerance associated with the first-generation ER-MPH products. These novel MPH products apply proprietary technologies such as OROS (Alza), Diffucaps (Eurand) and SODAS (Elan) to offer both the convenience of once-a-day administration and absorption profiles resembling, to varying degrees, the standard multiple dose schedules of IR-MPH. The pharmacodynamics of the separate MPH enantiomers is in the process of further neuropharmacological characterisation. It is well established that dl-MPH undergoes marked stereoselective metabolism. Although l-MPH exhibits only minimal oral absorption, it may preferentially penetrate the brain, and interacts with ethanol to form the metabolite ethylphenidate. The newly approved resolved enantiomer product d-MPH is now available in an IR formulation, and when administered at one-half the dose to that of the racemate, is purported to produce a longer duration of clinical effect, despite essentially identical pharmacokinetics. A long-acting formulation of d-MPH, which employs the SODAS technology, is in the advanced stages of clinical development.     

New methylphenidate formulations for the treatment of attention-deficit/hyperactivity disorder

dl-Methylphenidate (MPH) remains the most widely used pharmacological agent in the treatment of attention-deficit/hyperactivity disorder (ADHD). The predominantly dopaminergic mechanism of the psychostimulant actions has become more clearly defined. Neuroimaging and genetic studies are revealing the underlying neuropathology in ADHD. Novel extended-release (ER) MPH formulations now offer drug delivery options to overcome both the short-term actions of immediate-release (IR) MPH and the acute tolerance associated with the first-generation ER-MPH products. These novel MPH products apply proprietary technologies such as OROS® (Alza), Diffucaps® (Eurand) and SODAS? (Elan) to offer both the convenience of once-a-day administration and absorption profiles resembling, to varying degrees, the standard multiple dose schedules of IR-MPH. The pharmacodynamics of the separate MPH enantiomers is in the process of further neuropharmacological characterisation. It is well established that dl-MPH undergoes marked stereoselective metabolism. Although l-MPH exhibits only minimal oral absorption, it may preferentially penetrate the brain, and interacts with ethanol to form the metabolite ethylphenidate. The newly approved resolved enantiomer product d-MPH is now available in an IR formulation, and when administered at one-half the dose to that of the racemate, is purported to produce a longer duration of clinical effect, despite essentially identical pharmacokinetics. A long-acting formulation of d-MPH, which employs the SODAS technology, is in the advanced stages of clinical development.     

Pozanicline for the treatment of attention-deficit/hyperactivity disorder

Introduction: Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder occurring in childhood and often continues into adolescence and adulthood. The pathophysiology of ADHD is complex and likely involves multiple neurotransmitter systems. Medications currently used for the treatment of ADHD enhance dopaminergic and/or noradrenergic transmission. However, none of these drugs target the cholinergic system, which is also thought to play a significant role in cognitive disturbances such as those found in ADHD.

Areas covered: In this review, the authors briefly discuss the cholinergic system, including multiple neuronal nicotinic receptor (NNR) subtypes that mediate the positive and negative effects of nicotine, in the context of animal models of ADHD. They also discuss the pharmacology of the NNR pozanicline, a partial agonist with high in vitro binding affinity and selectivity for the α₄β₂ NNR subtype. Finally, the authors examine pozanicline’s clinical developments.

Expert opinion: Pozanicline was shown to be effective in a pilot study in humans with ADHD, but larger trials were negative. Developing an efficacious therapy is difficult. ADHD is a complex disorder with an unknown cause, and it is unclear, at this time, which qualities from NNR agonists are needed to treat it. It is therefore necessary to develop a more enhanced understanding of the nicotinic cholinergic system and its role in ADHD. Furthermore, new research paradigms may need to be employed to find drugs that are effective in patients with ADHD.     

Guanfacine ER for the treatment of adolescent attention-deficit/hyperactivity disorder

Introduction: Guanfacine extended release (GXR) is an alpha 1A noradrenergic agonist that has been approved by the FDA for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) as a monotherapy, and as an adjunctive therapy to stimulants for the treatment of ADHD in children and adolescents age 6 – 17.

Areas covered: PubMed, the Ovid Medline database, and the PsycInfo database were searched using the term ‘guanfacine'. Results were then limited to criteria such as English and human, from 1990 through December 2011. The resulting yield from the comprehensive literature search was 4391 articles. The titles and abstracts of all articles were reviewed. Studies were selected for full-text review based upon their place in the hierarchy of evidence (e.g., randomized controlled trials), relevance and quality of individual studies, and generalizability to clinical practice. The search was augmented by further search of article reference lists. A total of 15 articles were selected for full-text examination.

Expert opinion: Due to the absence of positive evidence for the efficacy of GXR for monotherapy in adolescents, clinicians should be guarded in the use of GXR for monotherapy in adolescents with ADHD. The use of GXR has considerable promise as an adjunct to stimulants for other behavioral conditions associated with ADHD.     

Pharmacological treatment of attention-deficit/hyperactivity disorder in adults

With increased awareness that attention-deficit/hyperactivity disorder (ADHD) can persist beyond childhood, pharmacological treatment options for adults have expanded. Short-acting stimulants continue to be the first-line approach, demonstrating clinical efficacy and few adverse events in well-controlled trials, with long-acting stimulants also showing promise. Atomoxetine has also been reported to improve ADHD symptoms and associated dysfunction, although longer-term, head-to-head studies with stimulants are needed. Several antidepressants (e.g., desipramine and buproprion) appear to be effective in the treatment of adult ADHD, but to a lesser extent than stimulants. Data are limited in evaluating the impact of combining pharmacological treatments for ADHD and comorbid conditions. This paper describes the safety and efficacy of medications for treating the core symptoms, psychosocial features and cognitive dysfunctions associated with adult ADHD.     

Pharmacological treatment of attention-deficit/hyperactivity disorder in adults

With increased awareness that attention-deficit/hyperactivity disorder (ADHD) can persist beyond childhood, pharmacological treatment options for adults have expanded. Short-acting stimulants continue to be the first-line approach, demonstrating clinical efficacy and few adverse events in well-controlled trials, with long-acting stimulants also showing promise. Atomoxetine has also been reported to improve ADHD symptoms and associated dysfunction, although longer-term, head-to-head studies with stimulants are needed. Several antidepressants (e.g., desipramine and buproprion) appear to be effective in the treatment of adult ADHD, but to a lesser extent than stimulants. Data are limited in evaluating the impact of combining pharmacological treatments for ADHD and comorbid conditions. This paper describes the safety and efficacy of medications for treating the core symptoms, psychosocial features and cognitive dysfunctions associated with adult ADHD.     

Bupropion treatment for cocaine abuse and adult attention-deficit/hyperactivity disorder

There are few published studies assessing the efficacy of pharmacologic treatments for attention-deficit hyperactivity disorder (ADHD) among substance abusers seeking treatment. Eleven patients who met DSM-IV diagnostic criteria for cocaine dependence and adult ADHD were entered into a 12-week single-blind trial of divided daily doses of bupropion (BPR). All patients received weekly individual standardized relapse prevention therapy. Treatment compliance and retention were good. Patients reported significant reductions in attention difficulties, hyperactivity and impulsivity. Self-reported cocaine use, cocaine craving, and cocaine positive toxicologies, also decreased significantly. In a previously published trial, 12 patients who met similar diagnostic criteria for adult ADHD and cocaine dependence were entered into a 12-week trial of divided daily doses of sustained-release methylphenidate (MPH). Improvements observed on BPR were similar to, and did not differ from those previously observed with MPH. These preliminary data suggest that BPR may be as effective as sustained-release MPH, when combined with relapse prevention therapy, for cocaine abusers with adult ADHD. However, a future study directly comparing BPR to MPH in a double-blind placebo-controlled trial is needed.     

Pharmacological treatment of attention-deficit/hyperactivity disorder: assessing outcomes

A substantial body of evidence has supported the efficacy and safety of pharmacological treatment available for attention deficit/hyperactivity disorder (ADHD). There is increasing agreement that the important treatment outcomes for ADHD extend beyond improvement in core symptoms and that a more generic (or global) concept of remission is the overarching goal of treatment. However, there is no consensus on the best definition of remission or on how best to conceptualize and measure broader treatment outcomes. In this article, we provide an overview of the various methods and approaches to measuring treatment outcomes for ADHD with respect to symptoms, impairment, quality of life, adverse events and safety as well as cognition. We will describe the ways that they may be used within routine clinical practice and think ahead about the kinds of studies that are required to move the field forward.     

Update on atomoxetine in the treatment of attention-deficit/hyperactivity disorder

Background: Atomoxetine, an inhibitor of, the presynaptic transporter of norepinephrine, was approved for the treatment of attention-deficit/ hyperactivity disorder (ADHD) in children aged 6 years and older, adolescents and adults in the USA in 2002, and in Europe, first in the UK and then by mutual recognition in several countries during 2003 and 2004. Since that time, the use of atomoxetine has spread globally and extensive additional research has been conducted evaluating its efficacy and safety. Objective: The objective of this review is to provide a summary of the available data on atomoxetine, with an emphasis on postmarketing clinical research, which is helping to clarify the role of this agent in ADHD pharmacotherapy. Methods: Recent as well as long-term safety and efficacy data are reviewed, with an emphasis on comparison with long-acting psychostimulants, ADHD in special populations and in patients with psychiatric comorbidities. Results/conclusion: Atomoxetine is an effective acute and long-term pharmacotherapy for ADHD, and may play a particular role in the treatment of patients with comorbid disorders and those who have failed or are unable to tolerate stimulants.     

Comparing guanfacine and dextroamphetamine for the treatment of adult attention-deficit/hyperactivity disorder

The objective of this study was to compare the efficacy of the alpha-2a agonist guanfacine with that of dextroamphetamine for the treatment of adult attention-deficit/hyperactivity disorder (ADHD). Seventeen adult outpatients who met DSM-IV criteria for ADHD participated in a double-blind, placebo-controlled, crossover study comparing drug effects on ADHD symptoms. Measures of change included the DSM-IV ADHD Behavior Checklist for Adults and the Copeland Symptom Checklist for Adult Attention Deficit Disorders. Cognitive measures of attention included the Stroop and Controlled Oral Word Association Test using the letters "C," "F," and "L" (COWAT, CFL version). For each trial, the drug was administered daily and titered up to optimal doses of maximum efficacy but with a minimum of side effects, and then data were collected. Both drugs significantly reduced ADHD symptoms on the DSM-IV Adult Behavior Checklist for Adults over placebo (p < 0.05). The Stroop Color subscale showed significant improvement for both drugs (p < 0.05), but the Color-Word measures showed significant improvement for guanfacine only (p < 0.01). The average dose of guanfacine was 1.10 (SD = 0.60), and the most common side effect of guanfacine was fatigue. No subjects discontinued drug trials. This preliminary study indicates that guanfacine may be a well-tolerated treatment option for adult ADHD.     

Animal models of attention-deficit/hyperactivity disorder

Attention-deficit hyperactivity disorder (AD/HD) is a clinically heterogenous disorder including hyperactivity, impulsivity, and inattention. Both psychostimulant and non-psychostimulant drugs such as methylphenidate and atomoxetine, respectively, to modulate catecholeamine neurotransmission are used as current pharmacotherapies for AD/HD. Multiple lines of evidence suggest that genetic factors play major roles in the etiology of AD/HD. meta-Analyses and pooled data analyses have suggested associations between AD/HD and polymorphisms in genes encoding monoamine neurotransmission molecules. There has been considerable research on this disorder using genetic, pharmacological, and neuroimaging approaches, and several animal models of AD/HD such as spontaneously hypertensive rat (SHR), dopamine transporter (DAT) knockout mice, coloboma mutant mouse, and Grin1 mutant mouse have been reported. These animal models are valuable tools for investigating molecular, cellular, and behavioral mechanisms as well as the neural development and circuit mechanisms of AD/HD. Here, we review the recent literature on animal models of AD/HD and discuss their advantages and limitations.     

Evidence-based pharmacotherapy for attention-deficit hyperactivity disorder

There is a substantial body of literature documenting the efficacy of multiple unrelated pharmacological agents in attention-deficit hyperactivity disorder (ADHD) individuals throughout the life-cycle. The available literature indicates the important role of psychopharmacological agents in the reduction of the core symptoms of ADHD and associated impairments. The literature documents that stimulants not only improve abnormal behaviours of ADHD, but also improves self-esteem, cognition, and social and family function. However, response varied in different age groups and with certain comorbidities. In addition there is a large body of literature documenting the efficacy of atomoxetine which shows improvement in these same domains. More research is needed on alternative pharmacological treatments and to further evaluate established therapeutics beyond school-aged Caucasian boys. Further, more research is needed on the efficacy of treatment for comorbid ADHD, use of combined medications, and the combination of medication and psychosocial treatment.     

An update on the safety of psychostimulants for the treatment of attention-deficit/hyperactivity disorder

Introduction: Methylphenidate is the first-line pharmacological treatment of attention-deficit/hyperactivity disorder (ADHD). Although methylphenidate has a well-established evidence base for treating ADHD, its long-term benefits are unclear.

Areas covered: Physical adverse effects, psychiatric adverse events and brain development

Expert opinion: Some physical adverse events have been described (e.g. sleep disturbances, growth reduction, loss of appetite), although most are of transient nature. Psychiatric adverse events seem more related to the diagnosis ADHD itself, and not stimulant treatment. Concluding, short-to-mid-term use (i.e., up to 2 years) stimulants are relatively safe, but much less is known about longer-term efficacy and safety of these drugs.     

Hepatic events associated with atomoxetine treatment for attention-deficit hyperactivity disorder

OBJECTIVE: This study describes and assesses potential hepatobiliary events related to atomoxetine therapy, as reported in clinical trials and as spontaneous adverse event reports post-launch in 2002. METHODS: Case reports that contained potential hepatobiliary events were identified by a computerized search of the Eli Lilly and Company atomoxetine spontaneous adverse events and clinical trials databases. All cases were reviewed by at least two company physicians, one with expertise in hepatology, to determine the relevance of the information in respect of potential liver toxicity. RESULTS: Of 7961 paediatric and adult patients treated with atomoxetine in clinical trials, 41 were identified as having hepatobiliary events requiring additional analysis. Most of these events were mild increases in ALT and AST levels. None of these cases met Hy's rule criteria or progressed to liver failure. During the 4 years after market launch, 351 spontaneous reports of adverse events were related to the liver, of which 69 had other explanations unrelated to atomoxetine. Of the remaining 282 cases, 133 contained possible confounding factors (and were deemed to be possibly related), 146 presented too little information to assess, and three suggested atomoxetine as a probable cause of liver injuries. One of the three had a positive rechallenge. All three patients recovered after discontinuation of the drug. CONCLUSIONS: Since the launch of atomoxetine therapy, three spontaneously reported cases of reversible drug-induced liver injury were deemed probably related to it. Atomoxetine should be discontinued in patients with jaundice or laboratory evidence of liver injury and should not be restarted.     

Atomoxetine: a selective noradrenaline reuptake inhibitor for the treatment of attention-deficit/hyperactivity disorder

Atomoxetine (Strattera^?, Eli Lilly & Co.) is a selective noradrenaline reuptake inhibitor that has been studied for use in the treatment of attention-deficit/hyperactivity disorder (ADHD). So far, two open-label and seven randomised, double-blind, placebo-controlled, clinical trials have been published, six in youths and three in adults. Each of these trials has shown a positive response as measured by the primary efficacy measures, the ADHD-IV Rating Scale (ADHD RS) or the Conners Adult ADHD Rating Scale (CAARS). Atomoxetine has generally been well tolerated. In November of 2002 the FDA approved atomoxetine for use in the US for the treatment of ADHD in children, adolescents and adults. Atomoxetine is the first nonstimulant approved by the FDA for the treatment of ADHD and the first medication approved for the treatment of adult ADHD.