Attention deficit hyperactivity disorder (ADHD) is a prevalent disorder estimated to affect at least 5% of schoolchildren
(1). While its prevalence in adults is less well-known
(2), longitudinal follow-up studies have documented a persistent course in a substantial number of affected youth
(3–
6). Characterized by high degrees of symptoms of inattentiveness
(7), adults with ADHD have been documented in controlled studies to have more psychopathology, substance abuse, occupational, academic, and relationship difficulties than adults without ADHD
(3,
4,
8,
9).
Although central noradrenergic and dopaminergic neurotransmission dysregulation has been hypothesized as the underlying pathophysiology of this disorder
(10), in recent years, evidence has suggested that nicotinic dysregulation may also play a role in the pathophysiology of ADHD. Independent lines of investigation have documented that subjects with ADHD have a greater risk, and earlier age at onset, of cigarette smoking than comparison subjects without ADHD
(11,
12). In addition, maternal smoking during pregnancy appears to increase the risk for ADHD in the offspring
(13), and in utero exposure to nicotine in animals confers a heightened risk for an ADHD-like syndrome in the newborn
(14,
15). That nicotine dysregulation could play an important role in the pathophysiology of ADHD is not surprising, considering that nicotinic activation enhances dopaminergic neurotransmission
(16,
17).
One such promising agent is ABT-418. ABT-418 is a prototype of a new class of compounds referred to as selective cholinergic channel activators. ABT-418 is a potent and selective agonist for α-4 β-2 subtype central nervous system (CNS) neuronal nicotinic receptors
(19,
20). In addition to sharing some structural similarities to nicotine
(21), ABT-418 is equipotent to (‐)‐nicotine in enhancing cognitive performance in animal models (20). However, because of its selectivity for CNS neuronal nicotinic receptor subtypes, ABT-418 is less potent than (-)-nicotine in eliciting EEG activation, hypothermia, seizures, and locomotor reduction
(22). ABT-418 also had markedly lower effects on mean arterial pressure and heart rate than (-)-nicotine
(22). For example, in animal (canine) testing, intravenous (‐)‐nicotine (500 nmol/kg) resulted in a rapid, dose-related biphasic response characterized as a short-lived depressor response followed by a 2–5-minute pressor increase of 50 mm Hg. In contrast, ABT-418 at the same dose had no pressor effects and only a modest depressor response in dogs and had no effect on either systolic or diastolic blood pressure or heart rate in primates
(22). Moreover, in a study of 251 normal volunteers and elderly subjects with Alzheimer’s disease, at presumed therapeutic doses (75 mg/day or less), ABT-418 had no clinically meaningful cardiovascular abnormalities (Abbott Laboratories, unpublished data).
RESULTS
Of 130 subjects screened, 32 subjects met inclusion and exclusion criteria and were enrolled in the study. Ninety-eight subjects were screened out: 28 had a history of bipolar disorder, 27 were women of child-bearing potential, 22 did not meet criteria for ADHD, nine had major depression, eight were receiving concurrent exclusionary medications, and four had a substance use disorder. The final group consisted of four women and 28 men who ranged in age from 25 to 60 years (mean age=40.3 years, SD=9.4). Twenty-nine subjects (91%) completed the protocol; of the three subjects who dropped out, one did so because of adverse effects, and two because of noncompliance.
Subjects were most frequently diagnosed with the combined subtype of ADHD (N=24, 75%), followed by the inattentive (N=5, 16%) and hyperactive/impulsive (N=3, 9%) subtypes. As depicted in
table 1, 91% of subjects with ADHD had at least one past comorbid psychiatric disorder, and for 44% the comorbid disorder was also present within the past month. The two groups did not differ on these variables (placebo to ABT-418 versus ABT-418 to placebo: χ
2=0.4, df=1, p=0.5 for past disorders, χ
2=0.0, df=1, p=1.0 for current disorders). Baseline ratings of depression (mean Hamilton depression score=4.3, SD=2.3; mean Beck depression score=7.6, SD=4.6) and anxiety (mean Hamilton anxiety score=7.3, SD=4.6) were relatively low and did not differ between groups. Only two subjects had scores above standard cutoff points for depression (Hamilton depression score greater than 16, Beck depression score greater than 19), and only one subject had scores indicative of meaningful anxiety (Hamilton anxiety score greater than 21). Before entering this study, only two subjects had received medications for ADHD, and 12 others had received medications for non-ADHD psychiatric disturbance. This group of adults with ADHD had average to above average intelligence (mean IQ=108.9, SD=11.1).
Average daily doses of ABT-418 at the end of each weekly assessment period were 70 mg/day for week 1, 69 mg/day for week 2, and 67 mg/day for week 3. Of the 32 patients enrolled in the study, 31 were exposed to ABT-418; of these, 25 received the full daily dose of 75 mg (two patches), and six received 37.5 mg/day (one patch).
Outcome Assessment
On the basis of categorical definitions of improvement in ADHD with the last observation carried forward, ABT-418 was found to be clinically and statistically superior to placebo (
figure 1). On the basis of a predefined criterion of a CGI improvement of 1 or 2 (much to very much improved) for ADHD
(37,
41), a significantly higher proportion of subjects were considered improved while receiving ABT-418 than while receiving placebo (40% versus 13%; p=0.03) (
figure 1). A similar trend was found by using a preestablished definition of improvement of a 30% or more reduction in the DSM-IV ADHD symptom checklist scores
(37,
41); more subjects improved during the ABT-418 phase than during the placebo phase (47% versus 22%) (χ
2=3.5, df=1, p=0.06; McNemar test).
To test for the presence of a medication carryover effect, an order effects analysis was performed on the ADHD symptom checklist by random regression. This analysis failed to reveal a significant order effect (ABT-418 first versus placebo first). Results from the random regression model indicated a significant effect of time (z=–2.7, p=0.006), no significant main effect of drug (ABT-418 or placebo), and a trend toward a drug-by-time interaction for ADHD symptoms (z=–1.9, p=0.06). Endpoint analysis (weeks 3 and 7, last observation carried forward) revealed that the ADHD symptom checklist scores were reduced by 28% with ABT-418, compared to 15% with placebo (by linear regression, t=–2.2, df=31, p=0.04).
To evaluate what ADHD characteristics might have accounted for our findings on the ADHD symptom checklist, we stratified our group both by ADHD DSM-IV subtype and ADHD severity. Response to treatment was not significantly related to ADHD subtype (inattentive versus combined). However, when we stratified the group by severity of ADHD symptoms (using the median value on the ADHD symptom checklist), we found a significant drug effect for the less severe subgroup (by random regression, z=–2.25, p=0.03).
We also evaluated the effect of ABT-418 on DSM-IV ADHD symptoms at the end of each treatment phase (last observation carried forward). Subjects treated with ABT-418 had significantly greater overall improvement than placebo-treated subjects in ADHD symptoms (McNemar χ2=8.1, df=1, p=0.004). The improvement was particularly notable in the inattentive subgroup (McNemar χ2=5.2, df=1, p=0.02), compared to the hyperactivity/impulsivity subgroup (McNemar χ2=1.3, df=1, p=0.25). These analyses also showed that compared to baseline, 15 of 18 DSM-IV ADHD symptoms improved significantly during the ABT-418 phase (all nine DSM-IV symptoms of inattention and six of nine symptoms of hyperactivity/impulsivity), whereas only five of 18 DSM-IV ADHD symptoms improved during the placebo phase.
ABT-418 resulted in neither improvement nor deterioration in symptoms of depression and anxiety. There was no effect of gender, socioeconomic status, or current or lifetime history of smoking, anxiety, or depressive disorders on response to ABT-418.
Adverse Effects
No serious adverse drug effects were observed during the trial. With the exception of one subject who dropped out during the ABT-418 phase of treatment because of nausea, ABT-418 was well tolerated. The rate of individuals with at least one adverse effect was high in both groups, but there were no statistically significant differences observed between ABT-418 and placebo arms (73% versus 61%) (McNemar χ
2=2.3, df=1, p=0.13). As depicted in
table 2, the most common adverse effects during ABT-418 treatment were dizziness, skin irritation, nausea, and headaches. Six subjects taking ABT-418 and one subject taking placebo had the dose lowered because of adverse effects. No clinically meaningful heart rate, blood pressure, or ECG findings were observed in either phase. There were no significant changes in laboratory studies, including liver, renal, and thyroid function tests and electrolytes, during this short-term study. Similarly, according to detailed medical and neurological examinations, there were no clinically significant changes in neurological or general medical status at the end of the study.
DISCUSSION
Results of this randomized, placebo-controlled pilot investigation of ABT-418 showed clinical efficacy of a cholinergic-nicotinic analog for treatment of ADHD in adults. A preferential improvement with this treatment was found in adults with the inattentive symptom cluster of ADHD, as well as in those adults with less severe ADHD symptoms. ABT-418 was relatively well tolerated, with predictable cholinergic adverse events. Further controlled trials of ABT-418, with higher dosing and a longer duration of treatment, are warranted.
Our results with this nicotinic analog are consistent with those obtained by Levin et al.
(18) with the nicotine patch. In that brief controlled trial, nicotine patch administration to 17 adults with ADHD resulted in a modest reduction in ADHD symptoms, with concomitant reduction in reaction time on the Continuous Performance Test
(18). Other work has also demonstrated an improvement in attention associated with nicotine administration in subjects without ADHD (for review, see reference 44). For example, improvement in cognition has been reported in studies of adults receiving nicotine by gum (2 and 4 mg)
(27), cigarette consumption
(26), and subcutaneous injection
(25). Nicotine has also been shown to improve rapid visual information processing
(26), reaction time
(25), and vigilance
(45). Consistent with cholinergic activating agents’ broad effects on attention
(44), ABT-418 resulted in significantly larger improvement in the inattentive cluster of symptoms than in the hyperactive/impulsive symptoms.
Although the 47% response rate for ABT-418 (30% or greater reduction in DSM-IV ADHD symptoms) is quite consistent with our findings in a controlled investigation of pemoline
(37) and tomoxetine
(41) in adults with ADHD that used identical methodology, the response was lower than that observed in our prior trials of methylphenidate
(30) and desipramine
(31). Moreover, whereas methylphenidate had a more rapid onset of action, ABT-418 was similar to pemoline, tomoxetine, and desipramine in the time course of effect
(30,
31,
37,
41). Unlike the stimulants and antidepressants that result in comparable reductions in hyperactive, impulsive, and attentional symptom clusters of ADHD, ABT-418 appears to more selectively affect the attentional symptoms. While the apparent difference in the magnitude of effect could suggest that ABT-418 may have a weaker anti-ADHD effect than some stimulants or tricyclic antidepressants, it could also be due to nonspecific cognitive-enhancing properties of this cholinergic agent
(44) or insufficient dosing and duration of the trial. In support of the latter notion is the observation that there was continued improvement in both the ADHD symptom checklist and the CGI at the completion of each active phase, and the effect of higher dosing of ABT-418 on ADHD symptoms remains unknown. Although nicotine has a rapid habituation period
(44,
46,
47), ABT-418 may not have a similar pharmacodynamic time course. Moreover, studies of other compounds with presumably rapid onset of action, such as pemoline
(48), suggest the need for at least 3 weeks to obtain maximal response in adults with ADHD
(37). Clearly, more information, based on a longer study using variable doses fixed over time, is needed to establish a dose-response and time-course profile of ABT-418 in the treatment of ADHD in adults.
Consistent with our previous controlled pharmacological studies of ADHD, response to ABT-418 was not affected by gender, socioeconomic class, or psychiatric comorbidity. Moreover, past or current smoking status did not influence outcome; however, there were only a small number of current smokers. We also found that adults with less severe ADHD symptoms manifested more robust improvement with ABT-418 than did subjects with more severe symptoms. Our finding of a preferential improvement in attentional symptoms, coupled with reports suggesting less overall severity in the inattentive subtype of ADHD
(7,
49), led us to speculate that this compound may have more efficacy in the inattentive subtype of ADHD. Contrary to our expectation, our analysis found that response was independent of ADHD subtype. It may be that ABT-418, by nature of its cholinergic agonistic properties, may nonspecifically improve attention independent of ADHD status. Clearly, more work needs to be completed to elaborate the specific neuropsychological and behavioral outcomes of cholinergic agents on ADHD.
ABT-418 was relatively well tolerated, and most subjects achieved the targeted dose. Adverse effects of ABT-418 reported in the current study were similar to those described with other cholinergic agents, namely, dizziness, nausea, headaches, and dysphoria
(44,
50). Our observations of the generally transient nature of adverse effects of ABT-418 are consistent with findings that repeated exposure to nicotine results in habituation to its acute effects
(50). In the current study, there were no reports of withdrawal symptoms or cravings for cigarettes or other forms of nicotine or drugs of abuse, consistent with the low abuse liability of transdermal application of nicotine
(51). No cardiovascular or other laboratory abnormalities occurred during the study; yet, our ability to detect infrequent and idiosyncratic reactions was limited by the relatively small number of subjects and short-term duration of the study. Given that cardiovascular changes have been associated with chronic nicotine administration
(21), longer-term studies of ABT-418 are necessary.
The combined positive findings of a nicotinic agent for reduction of ADHD symptoms provide further support for the hypothesis linking cholinergic influence on catecholaminergic neurotransmission in ADHD
(18,
44). Data from laboratory studies showed that nicotine stimulates dopaminergic neurotransmission
(16,
17). For example, administration of nicotine resulted in a concentration-dependent release of dopamine from superfused slices of rat striatum
(17). Moreover, specificity in dopamine release appears dependent on specific subtypes of cholinergic agents administered
(17,
52). Whereas muscarinic antagonism has no apparent effect on dopamine release, nicotinic receptor antagonism results in diminished dopamine release
(17) and a blunted effect of the indirect-acting sympathomimetic amine methylphenidate on reticular formation firing in rat brain
(52).
The results of this study should be viewed in light of methodological limitations. The majority of subjects were from relatively higher socioeconomic strata; hence, the results of the current study may not generalize to subjects from lower socioeconomic strata. Other limitations include the use of a crossover design, a relatively short exposure to medication, and dosing restrictions. Further controlled dose-response trials, employing a parallel design, longer treatment duration, and higher dosing, are needed.
While our results are based on self-reports from affected individuals, it has been suggested that subjects with ADHD may not be ideal reporters of their disorder
(33). Although this places some limits on the interpretation of our results, the highly significant effects on ADHD symptoms observed in this and previous studies
(30,
37,
41,
53) suggest that adults with ADHD are acceptable reporters of their own condition. In addition, self-report of ADHD symptoms has been shown to be a reliable and valid method of assessing ADHD in adults
(54,
55).
Despite these limitations, the results of this pilot study show that ABT-418 was well tolerated and improved ADHD symptoms in adults. This nicotinic analog appeared to have preferential efficacy for the attentional symptom cluster of the disorder. These pilot findings add to a growing clinical and basic science literature linking nicotinic-cholinergic agents to catecholamine function and improvement in ADHD. Given the continuity of pharmacological responsivity across the life cycle in subjects with ADHD
(56), further study that evaluates the efficacy and tolerability of novel agents in the treatment of ADHD in adults, before use of these agents in youth with ADHD, appears to be a promising concept.