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.     

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.     

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.     

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.     

Neurocognitive effects of methylphenidate in adult attention-deficit/hyperactivity disorder

Rationale Features of childhood attention-deficit/hyperactivity disorder (ADHD) often persist into adulthood. It has been shown that adult ADHD is associated with various neurocognitive deficits, including impairments in spatial working memory (SWM) and attention. It is not known whether these deficits are ameliorated by methylphenidate in adult ADHD.Objectives The aim of this study was to evaluate the neurocognitive effects of a single dose of methylphenidate on SWM, visual memory, spatial span and sustained attention in adult ADHD.Methods Twenty-four adult patients, recruited from a specialised clinic for the assessment of adult ADHD, were entered into a double-blind, randomised, placebo-controlled crossover study using a single 30 mg dose of methylphenidate.Results Eighteen patients met DSM-IV criteria for adult ADHD. Methylphenidate resulted in an improvement in SWM performance and sustained attention, together with a speeding in response time, in these patients. Six patients with attentional difficulties, who did not meet a DSM-IV diagnosis of ADHD, showed a different pattern of response to methylphenidate compared to the ADHD group. For the combined group, moderate correlations were shown between childhood ratings of ADHD (both self-reported and informant ratings) and response to methylphenidate on the SWM task.Conclusions Adults with ADHD had a similar neurocognitive response to methylphenidate to that previously reported for childhood ADHD. Our results provide further support for the validity of the ADHD syndrome as defined by DSM-IV and indicate possible neurocognitive substrates for clinical improvement with chronic methylphenidate.     

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.     

Limits of meta-analysis: methylphenidate in the treatment of adult attention-deficit hyperactivity disorder

Guidelines for the treatment of attention-deficit hyperactivity disorder (ADHD) in adults advocate methylphenidate as first-line treatment. The aim of this study was to review the effectiveness of methylphenidate treatment of adult ADHD and to examine the influence of methods on meta-analytic results. Electronic databases were searched to identify clinical trials comparing methylphenidate with placebo in the treatment of adult ADHD. Studies were summarised with meta-analytic methods. Subgroup analyses were conducted with respect to parallel group versus cross-over trials and self versus observer ratings. The relationship between dosage and effect size was explored by weighted regression analysis. The results were tested for publication bias, and several sensitivity analyses were performed. Findings and methods were compared with a previous meta-analysis. Eighteen studies met the inclusion criteria of which 16 were included in the meta-analysis. The overall effect size (d = 0.42) was significantly different from zero, but was only half the size expected on the basis of a previous meta-analysis. No significant differences could be observed in the subgroup analyses. The regression analysis showed no significant influence of mean daily dose on effect size. These results contradict findings of a previous meta-analysis and challenge guideline recommendations. Methodological issues in meta-analyses are discussed.     

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.     

New drugs for the treatment of attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is the most common neuropsychiatric disorder of childhood. Recent research indicates that ADHD most often persists into adolescence and adulthood, and is associated with impairments in academic, social and occupational functioning. The ADHD diagnosis is based on history and clinical examination. There are no objective laboratory measures for diagnosis. ADHD is largely heritable. Its underlying pathophysiology has been theorised to include dysregulation of inhibitory noradrenergic frontocortical activity on dopaminergic striatal structures. Evidence shows that ADHD is highly responsive to pharmacological treatments resulting in global functional improvements. Although pharmacotherapy is recognised as the most effective treatment, additional components to optimise ADHD management include proper educational placement, parent management training and social skills development. Central nervous system stimulants, specifically methylphenidate and amphetamine, remain first-line pharmacological treatments. Atomoxetine, a selective noradrenergic re-uptake inhibitor, is the first non-stimulant compound to receive FDA approval for paediatric and adult ADHD. Other medication classes, including alpha-agonist antihypertensives, tricyclic antidepressants, other antidepressants such as buproprion, and the wake-promoting agent modafinil, are prescribed in off-label therapy. Ongoing development of new ADHD medications is expected to emphasise alternative and extended-release delivery systems and non-stimulant compounds.     

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.     

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.     

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.     

Meta-analysis of the efficacy of methylphenidate for treating adult attention-deficit/hyperactivity disorder

This article reviews the efficacy of methylphenidate (MPH) for adult attention-deficit/hyperactivity disorder (ADHD). A literature search identified double-blind placebo-controlled MPH treatment studies of ADHD adults. Meta-analysis estimated the pooled effect size for MPH treatment and tested for publication bias. Meta-analysis regression assessed the influence of study design features on medication effects. Six trials met criteria and were included in this meta-analysis. These studies included a total of 140 MPH-treated ADHD adults and 113 placebo-treated ADHD adults. The mean effect size of 0.9 was statistically significant and there was no evidence of publication bias. Larger MPH effect sizes were associated with physician ratings of outcome and use of higher doses. When treatment is optimized to high doses, the effect size for MPH in adults was 1.3. We found strong support for the assertion that MPH is efficacious for treating adult ADHD. Because the degree of efficacy of MPH in treating ADHD adults is similar to what has been reported from meta-analyses of the child and adolescent literature, our work provides further assurance to clinicians that the diagnosis of ADHD can be validly applied in adulthood.     

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.     

Alcohol, drugs, and attention-deficit/ hyperactivity disorder: a model for the study of addictions in youth

There has been increasing interest in the developmental origins of substance use disorders (SUDs) in children and adolescents. Because of its early onset, high prevalence and known risk for SUD, attention deficit hyperactivity disorder (ADHD) is a model developmental disorder to evaluate in context to SUDs. A selected review of the literature was undertaken examining ADHD as an antecedent disorder to subsequent SUD. ADHD and its co-occurring comorbid psychopathology increase the risk for cigarette smoking and SUD and is associated with greater SUD severity and chronicity. The treatment of ADHD appears to decrease the risk for cigarette smoking and SUD. ADHD is an important antecedent disorder in children and adolescents worthy of further targeted preventive efforts to diminish the risk for cigarette smoking and SUD.