Use of lisdexamfetamine dimesylate in treatment of executive functioning deficits and chronic fatigue syndrome: A double blind, placebo-controlled study
Introduction
Chronic fatigue syndrome (CFS) affects millions of people each year (Centers for Disease Control and Prevention, 2009a, Centers for Disease Control and Prevention, 2009b). Although it is often perceived to be a disorder characterized by only long-term, persistent fatigue that cannot be explained by another medical condition or by ongoing exertion, a variety of other symptoms are also typically present for at least 6 months. These include post-exertion malaise, muscle and joint pain, headaches, unrefreshing sleep, tender cervical or axillary lymph nodes, and a frequent or recurring sore throat (see Fukuda et al., 1994). For some patients, the most distressing symptoms of CFS are executive functioning deficits that include impaired short-term memory, delayed reaction time, and a subjective sensation of “mental fogginess”. Combined with fatigue and pain, these executive function deficits can be debilitating, and it is estimated that they affect as many as 80% of all individuals who suffer from CFS (Afari and Buchwald, 2003, Short et al., 2002).
A variety of treatment options are available to patients with CFS, but none have proved to be universally effective. Among these options are cognitive-behavioral therapy, exercise therapy, dietary interventions, homeopathic treatments, and pharmacological interventions (see, e.g., Luyten et al., 2008). After reviewing the many available interventions, Van Houdenhove et al. (2010) called for investigations that examine intervention techniques that could be used to treat specific patient populations. Their hope was to begin answering the question of “what works for whom?” (p. 219). The present study was designed to contribute to the literature in this way.
Specifically, the present study was designed primarily to determine whether a common psychostimulant medication lisdexamfetamine dimesylate (LDX) could be used to reduce executive functioning deficits in CFS patients who also present with clinically significant executive functioning deficits. LDX is a long-acting amphetamine-based pro-drug currently approved for the treatment of children, adolescents, and adults with attention deficit/hyperactivity disorder (ADHD) (Shire, 2010), but its efficacy for other conditions has not been widely studied. Psychostimulant medications have been used for many years to successfully treat executive functioning impairments among patients with conditions like ADHD (see, e.g., Young, 2007), and case-study evidence has suggested that they may hold promise for improving executive functioning in patients with CFS as well (Young and Redmond, 2007). However, no empirical studies to date have specifically examined whether the executive functioning deficits reported among the subgroup of patients with both CFS and clinically significant executive functioning deficits can be ameliorated with currently available pharmacological interventions.
A number of studies have demonstrated that some common pharmacological interventions (e.g., anti-depressant medications) have a degree of promise for treating a variety of the symptoms associated with CFS, including pain, fatigue, depressed mood, and sleep disturbances (Pae et al., 2009), but the extent to which these medications treat executive functioning deficits in patients with CFS remains unknown. Similarly, although the effect of psychostimulants on CFS patients has been explored to some extent, these studies have not fully explored the role of these drugs in improving executive functioning. For example, one study of 60 CFS patients compared twice daily methylphenidate treatment to placebo and found that nearly 20% of participants who took the psychostimulant experienced a clinically significant reduction in fatigue and inattention (Blockmans et al., 2006), but a similar study showed that low dose dexamphetamine reduced only fatigue in 90% of participants receiving active treatment compared to a reduction in 40% of those receiving placebo (Olson et al., 2003).
The present study builds on these clinical observations and existing CFS research studies to explore the role of LDX in treating CFS. The primary objective of the present study was to examine whether LDX could be used to improve executive functioning among patients with both CFS and clinically significant executive functioning deficits. It was hypothesized that treatment with a daily dose of LDX would improve executive functioning deficits (vs. placebo) in adult patients with both CFS and clinically significant executive functioning impairments, as assessed by scores on the Behavioral Rating Inventory of Executive Function-Adult version (BRIEF-A). A secondary objective of the present study was to examine whether LDX could be used to improve fatigue, pain, and overall functioning among patients with both CFS and clinically significant executive functioning deficits. A secondary hypothesis was that a daily dose of LDX would improve fatigue, pain, and overall functioning (vs. placebo) in adult patients with both CFS and clinically significant executive functioning impairments. A tertiary aim of the study was to examine the safety and tolerability of LDX throughout the course of treatment. It was hypothesized that LDX would not differ in safety and tolerability relative to placebo.
Section snippets
Methods
The study was conducted at the Rochester Center for Behavioral Medicine (RCBM), a research and treatment center in suburban Detroit. RCBM actively participates in clinical care and new medication investigations. Clinical trials include multi-centered national trials and single site, investigator-initiated studies. The research unit is led by a board-certified psychiatrist and supported by an experienced team of clinical coordinators. Study medications were obtained from Shire's Investigator
Primary outcome measure: Executive function impairment
The primary outcome measure was participants' level of change on the Global Executive Composite (GEC) of the BRIEF—A. These scores were calculated by subtracting participants' endpoint GEC scores from their initial baseline GEC scores. These change scores show the total change in executive functioning over the course of the trial. Higher values indicate improved executive functioning at the end of the trial compared to the beginning. These data were initially analyzed with a one-way, two-tailed
Discussion
Chronic fatigue syndrome is a poorly understood condition that afflicts millions and has no clear treatment (Pae et al., 2009). As a result, researchers have recently called for new approaches to treatment (and treatment investigations) that are targeted toward specific subsets of the larger population of CFS patients (Van Houdenhove et al., 2010). The subset of interest in the present study was those CFS patients who also have clinically significant deficits in executive functioning, and the
Study sponsorship: Shire
Employees of Shire did not design or conduct the study nor were they involved in the interpretation of data.
Disclosures statements for author
Speaker's Bureau: AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly and Company, Forest Pharmaceuticals, GlaxoSmithKline, Novartis, Schering-Plough, Sunovion, and Shire; Grants/Research Support: Cyberonics, Eli Lilly and Company, Novartis, Otsuka, and Shire; Advisory Boards: Eli Lilly and Company, Novartis, Shire, and Shionogi Inc.
Acknowledgments
The author wishes to acknowledge the valuable contributions of Max Butterfield for statistical support and guidance. Jaime Saal contributed significantly in the preparation of this manuscript.
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