This pilot study supports the importance of exploring efficacy of atomoxetine for PD-related ED in future studies, using controlled designs. In 75% of subjects, we observed clinically significant improvement that corresponded to a decline in behavioral symptoms of ED. The majority tolerated atomoxetine and motor function was unaffected, but gastrointestinal effects and hypomania were notable AEs.
Two other studies describe treatment of PD-related ED in non-demented patients. A cognitive training program focusing on working memory showed improved performance on executive tasks, but did not assess ED in daily functioning.21
Consistent with our results, a 16-week open-label study (n=10) of donepezil, an acetylcholinesterase inhibitor, showed improved CGI ratings in the absence of changes in cognitive measures of ED.22
The focus on behavioral aspects of ED is a unique aspect of this study that ensured its clinical relevance. Given the diverse processes involved in ED and heterogeneous neuropsychological deficits of PD, there is no current basis for a single primary cognitive outcome measure.23
Thus, cognitive complaints and behavioral evidence for acquired ED provided a standardized approach for defining appropriate study candidates, a potentially useful strategy for future trials. The CAARS-L Inattention/Memory Problems subscale captures many behaviors described by our subjects, but has not been studied in PD. We also used the FrSBe, a validated measure of behavioral changes associated with frontal systems damage.12
Whereas the CAARS-L, FrSBE, and CGI-C were sensitive tools for evaluating ED severity and treatment response in this study, our subjects were generally unimpaired on psychometric tests. This is not uncommon when evaluating individuals with ED in structured test settings.12
High pre-morbid function in our sample may also limit detection of deficits relative to published norms. Nonetheless, evidence for changes from pre-PD FrSBE ratings () reflected previously intact executive abilities. The utility of the FrSBe for identifying PD subgroups with ED or predicting cognitive decline needs further investigation; in the future, behavioral changes might serve as a basis for interventions, instead of delaying treatments until declines in cognitive performance are evident.4
The mechanism by which atomoxetine may improve ED is unknown; previous studies emphasize effects on inhibitory control. Atomoxetine acts primarily via presynaptic norepinephrine transporter blockade. It also elevates dopamine in selective cortical regions and has procholinergic effects.24,25
In rats, atomoxetine improved performance on learning, memory consolidation, retrieval, and inhibitory control tasks.25,26
In adult control and ADHD subjects, single atomoxetine doses produced selective effects on response inhibition in the absence of effects on attention or working memory.27,28
Longer-term atomoxetine trials in adults with ADHD also showed improved measures of inhibitory control.29,30
An advantage of atomoxetine is that its long duration of action sustains elevations of prefrontal norepinephrine and dopamine, which may also account for its lack of abuse potential when compared to transient changes seen with psychostimulants.24
In other studies of PD patients, manipulation of the noradrenergic system influences executive functions that rely on attentional resources and subcortical dopaminergic effects.31,32,33
Methylphenidate, a psychostimulant, benefited attention, but only in non-demented patients taking l-dopa, supporting its primary dopaminergic effects.34,35
Furthermore, dopaminergic drugs mainly improve motor function and only minimally benefit or possibly aggravate cognitive deficits, including ED.34,36
Atomoxetine was generally well-tolerated. AEs, especially gastrointestinal symptoms, were consistent with other reports14
and there were no clinically significant motor effects. While pre-existing psychiatric conditions were controlled at baseline, one patient developed hypomania. A previous report describes onset of mania in an adult treated with atomoxetine for depression.37
This study has several limitations. As an open-labeled study, placebo effects cannot be excluded; a blinded, placebo-controlled study with a larger sample is necessary to assess effectiveness and tolerability of atomoxetine for PD-related ED. The small sample size, inter-subject variability, possible inclusion bias, ceiling, and practice effects limit interpretations of neuropsychological data. We did not correct for multiple comparisons and the sample size precludes evaluation of differential effects of atomoxetine relative to baseline cognitive performance. Finally, our sample was restricted to subjects younger than age 65 years.
In this study, atomoxetine was generally tolerable and reduced severity of behavioral symptoms associated with ED. Diagnosis of ED based on clinical symptoms may allow inclusion of patients in trials with disease-related behavioral changes before progression to the point of cognitive deficits on formal testing. Future trials should take into account heterogeneity of ED and cognitive impairment in PD, with deficits and variable progression across multiple domains and involvement of multiple neurotransmitter systems. The noradrenergic system may be an important target, with a favorable role for atomoxetine suggested by the present results, but requiring further study.