Attention deficit-hyperactivity disorder (ADHD) is an increasingly recognized and heterogeneous disorder of unclear etiology 1 characterized by core symptoms of hyperactivity, inattentiveness, and impulsivity. The prevalence of ADHD in school-age children is estimated at 6–8% worldwide 2, with symptoms persisting into adulthood in approximately 50% of individuals with childhood onset ADHD 3. Recent epidemiological data suggest that ADHD occurs in 4.4% of adults in the US 4. ADHD in adults is associated with academic, employment, and marital difficulties, as well as comorbid psychiatric disorders such as substance abuse, depression, anxiety, and personality disorders 567. Moreover, cost-of-illness data in untreated adults without ADHD show significantly higher cost than in matched adults with ADHD both for medical and societal expenses 8.

The aggregate data also support the concept that ADHD in adults shares many phenotypic and genotypic similarities with the childhood form of the disorder 9. Due to the phenotypic, genotypic, and pharmacological response similarities between adults and children with ADHD 9 the ethical considerations of exposing children to novel compounds with potential adverse events have led to adults with ADHD being used increasingly for early phase II trials.

Currently, the treatment of ADHD in adults is largely predicated upon use of both stimulant and non-stimulant medications, as well as adjunctive structured psychotherapies 10. Despite the availability of both FDA-approved and other agents for ADHD, a number of individuals either cannot tolerate, or do not respond to existing compounds necessitating the development of alternative agents.

While the precise etiology of ADHD is unknown continued interest has been focused on the role of the catecholaminergic and nicotinic/cholinergic systems in ADHD. Evidence that dopamine dysfunction plays a role in ADHD comes from findings from studies describing excessive motor activity and cognitive dysfunction and neuroanatomical studies. For instance, compared to controls, differences have been identified in the binding potential of the dopamine transporter protein in adults with ADHD 111213. Similarly, candidate genes and functional imaging abnormalities in ADHD point to alterations in areas of the brain rich in dopaminergic/noradrenergic innervations. Along with longstanding associations of cigarette smoking in ADHD 1415, recent work has shown the efficacy of nicotine and nicotinic analogs in the treatment of ADHD 1617. Along those lines, predominately dopaminergic, noradrenergic, and mixed dopaminergic/noradrenergic agents have been shown to have efficacy in treating ADHD 1819.

One such mixed monoamine reuptake blocker is the novel agent NS2359, which acts by equipotent reuptake blockade across the noradrenalin, dopamine and serotonin transporters. NS2359 has also been shown to enhance the release of acetylcholine in the frontal cortex and hippocampus an effect considered relevant for attentional performance 2021. In a previous study NS2359 was found to have positive effects on attention and memory in healthy volunteers 22 and given the high degrees of cognitive dysfunction in ADHD 23, these effects taken together with the mode of action of NS2359 makes it a suitable candidate for treating ADHD. Moreover, the slow entrance of NS2359 into the human brain makes it a candidate for the treatment of ADHD with minimal potential for abuse.

In this paper we report the results of a randomized, double blind, placebo-controlled study of NS2359 in the treatment of adults with ADHD. The primary aim of the study was to investigate the efficacy and safety of NS2359 in DSM IV diagnosed adults with ADHD. The secondary aim was to evaluate the effects of NS2359 on cognitive function, particularly attention, working memory and episodic memory. This study was designed as an exploratory, signal-detection, Phase IIa study to provide proof-of-concept for this novel compound prior to embarking on a larger scale Phase IIb program.

The results of this 8 week controlled study indicate that for both primary and secondary clinical outcomes, there were no clinically or statistically significant effects of NS2359 in ADHD symptoms compared to placebo for the overall study population. However, NS2359 was found to favorably affect cognitive function (the ability to focus attention and also the ability to store and retrieve episodic information) in the overall study population. A trend for improvement was also seen to working memory. These improvements are in major domains of cognitive function and have the potential for clinical relevance in ADHD patients.

Although there was little improvement compared to placebo in overall summary scores of ADHD on any of the primary or secondary outcomes, there was evidence of improvements in the inattentive subgroup with NS2359 treatment. These were seen in the patient rated ADHD-RS, the CAARS and the Brown adult scale as well as a greater reduction in the CGI-Severity of illness, a greater proportion of responders (>30% change) and a greater improvement on the CGI Improvement scale.

The NS2359 compound improved all three of the domains of cognitive function assessed with the CDR. Power of Attention reflects the ability to focus attention and to rapidly process information, and the positive effects with NS2359 indicate that subjects were better able to direct their attention to ongoing tasks and to sustain concentration. The trend for improvement in working memory indicated that the subjects were better able to hold information temporarily 'on line', potentially facilitating the performance of everyday tasks and activities. Finally the improvement to Quality of Episodic Secondary Memory with the active medication indicated that subjects were better able to encode, store and retrieve verbal and pictorial information of an episodic nature.

These cognitive data derived from the CDR testing showed that NS2359 improved attention, episodic memory, and working memory in these adults with ADHD – areas previously identified as problematic in separate studies of adults with ADHD 31. Our combined findings of an overall lack of response coupled with evidence of improvement in the inattentive subtype and CDR suggest an overall pro-cognitive effect of the medication in ADHD. It may be that higher doses of NS2359 are required to improve the more overt behavioral symptoms of the ADHD. In support of the latter, a relationship between doses of stimulants necessary to improve cognition (lower) relative to hyperactivity/impulsivity (higher) has been speculated 32. The lack of effect on the combined group may indicate that NS2359 has little effect on hyperactive/impulsive symptoms. An additional confounding effect could be that patients of the inattentive subtype typically have fewer ADHD symptoms and hence less severe ADHD and therefore benefit more by treatment. Given the limited previous human exposure of NS2359, a conservative low dose of the medication was chosen for safety considerations that may have under treated the entire spectrum of ADHD.

The findings of improvement in measures of cognitive functioning (CDR) and in the inattentive subtype of ADHD add to a growing literature on the usefulness of mixed catecholaminergic reuptake inhibitors 33 on ADHD. For example, studies with mixed dopaminergic and noradrenergic reuptake inhibitors such as the tricyclic antidepressants, bupropion, and noradrenergic reuptake inhibitors (atomoxetine) have yielded generally positive results, albeit with lower overall response rates and effect sizes relative to the psychostimulants. Similarly, NS2359 has been shown to enhance the release of acetylcholine in the frontal cortex and hippocampus, an effect that may be relevant for attentional performance 2021. For example, studies with procholinergic (nicotinic) agents have demonstrated improvement in attentional/cognitive functioning and symptoms in ADHD 161734. Hence, the combined monoaminergic reuptake inhibition plus pro-cholinergic effects of NS2359 may be related to the aggregate evidence of improved cognitive functioning in the current study.

There are a number of limitations in the current study. Because of the nature of the study, a homogenous study population was selected that may not generalize to typical adults with ADHD. For example, subjects with significant medical histories and psychiatric co-morbidities were excluded. In addition, the sample size was relatively small, limiting the power to detect differences. Furthermore, only one relatively low dose of NS2359 was studied that mostly likely underestimated the effect of the medication.

One of the dilemmas of early phase studies is the determination of the optimal dose(s) for a disorder. The dose evaluated for this study was selected on the basis of a dose-escalating study using SPECT, as well as tolerability data from pharmacokinetic studies. A dose of 0.5 mg/day NS2359 was shown to give DA occupancy of 35%, which is in the range of other clinically efficacious compounds used for treatment of ADHD patients 35. Given only one low dose of NS2359 was tested, this dose may have been insufficient to treat ADHD.

In the current study, there were no serious side effects or reports of withdrawal symptomatology and no clinically meaningful cardiovascular or other laboratory abnormalities were detected. However the ability to detect infrequent and idiosyncratic reactions is limited by the small number of subjects and the relatively low dose and short duration of study treatment.

Despite the limitations presented above, these data show that the current dose of NS2359 is well tolerated but insufficient to treat ADHD adequately in the general population of adults with ADHD. A signal emerged in the inattentive subtype and on specific measures of neuropsychological functioning suggesting the potential utility of the agent. Given the mixed findings in this group of subjects, larger, parallel design dose ranging studies with NS2359 using higher doses are warranted.

Dr. Timothy Wilens receives grant support from, is a speaker for, or is a consultant for the following sources: Abbott, McNeil, Lilly, NIH (NIDA), Merck, Novartis, Cephalon and Shire.

Thorsten Klint, is a former employee of Neurosearch.

Dr. Lenard Adler receives grant support from, is a speaker for, or is a consultant for the following sources: Abbott Laboratories, Cortex Pharmaceuticals, Bristol-Myers Squibb, Merck & Co, Novartis Pharmaceuticals, Pfizer, Shire, Eli Lilly, Ortho McNeil/Jannsen/Johnson and Johnson, New River Pharmaceuticals, Cephalon, National Institute of Drug Abuse, Organon, Sanofi-Aventis Pharmaceuticals.

Dr. Scott West receives Industry Research Funding from: Abbott, Addrenex, Allergan, Allon, AstraZeneca, Avera, Bristol-Myers Squibb, Cephalon, Cortex, DOV, Eli Lilly, Epix, Forest Laboratories, GlaxoSmithKline, Jazz, Labopharm, McNeil, Merck, Myriad, Novartis, Ono, Organon, Pfizer, Saegis, Sanofi, Sepracor, Shire, Solvay, Somaxon, Transtech, Wyeth and has a consulting relationship with Abbott and Novartis.

Dr. Keith Wesnes is sole shareholder of CDR Ltd, which received financial support to supply the cognitive tests in the study. His company is employed by dozens of pharmaceutical companies and he is a consultant to a number of companies also.

Ole Graff, is an employee of GSK and former employee at Neurosearch.

Birgit Ohrt Mikkelsen is an employee of NeuroSearch and owns NeuroSearch shares.

TW, TK, LA, OG, and BM assisted in the design of the study, TW, LA, and SW executed the study, KW was involved in the neuropsychological assessments, and all authors were involved in the development and editing of the final manuscript.