http://informahealthcare.com/bij ISSN: 0269-9052 (print), 1362-301X (electronic) Brain Inj, 2014; 28(12): 1514–1522 ! 2014 Informa UK Ltd. DOI: 10.3109/02699052.2014.919530
ORIGINAL ARTICLE
Atomoxetine for attention deficits following traumatic brain injury: Results from a randomized controlled trial David L. Ripley1, Clare E. Morey2, Don Gerber2, Cynthia Harrison-Felix2, Lisa A. Brenner2,3, Christopher R. Pretz2, Chris Cusick2, & Keith Wesnes4,5
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1
Department of Physical Medicine and Rehabilitation, Northwestern University Feinberg School of Medicine, Rehabilitation Institute of Chicago, Chicago, IL, USA, 2Department of Physical Medicine and Rehabilitation, University of Colorado School of Medicine, Aurora, CO, USA, 3Departments of Psychiatry, Neurology, and Physical Medicine and Rehabilitation, University of Colorado, School of Medicine, Aurora, CO, USA, 4Bracket Global, Goring-on-Thames, UK, and 5Centre for Human Psychopharmacology, Swinburne University of Technology, Melbourne, Australia Abstract
Keywords
Objective: To determine if atomoxetine would improve attention impairment following traumatic brain injury (TBI). Setting: Outpatients from a free-standing, private, not-for-profit rehabilitation hospital. Population: Fifty-five adult participants with a history of a single moderate-to-severe TBI, who were at least 1 year from injury and with self-reported complaints of attention difficulties. Intervention: Atomoxetine, a selective norepinephrine re-uptake inhibitor with a primary indication for attention dosed at 40 mg twice a day for 2 weeks, compared to placebo. Design: Randomized double-blind placebo controlled trial, with placebo run-in. Measures: Cognitive Drug Research (CDR), Computerized Cognitive Assessment System, Stroop Color and Word Test, Adult ADHD Self-Report Scale (ASRS-v1.1), Neurobehavioural Functioning Inventory (NFI). Results: Atomoxetine was well-tolerated by the subject sample. The use of atomoxetine by individuals with reported attention difficulty following TBI did not significantly improve scores on measures of attention, the CDR Power of Attention domain or the Stroop Interference score. In addition, no significant relationship was found between atomoxetine use and self-reported symptoms of attention or depression. Conclusion: Atomoxetine did not significantly improve performance on measures of attention among individuals post-TBI with difficulties with attention. This study follows a trend of other pharmacological studies not demonstrating significant results among those with a history of TBI. Various possibilities are discussed, including the need for a more sophisticated system of classification of TBI.
Attention, atomoxetine, cognitive drug research, controlled trial, norepinephrine, traumatic brain injury
Introduction Attention deficits after TBI William James, in his Principles of Psychology, stated that attention is ‘the taking possession of the mind, in clear and vivid form, of one out of what seem several possible objects or trains of thought’ [1]. Deficits in attention following traumatic brain injury (TBI) have long been recognized as a frequent and significant problem. In one study of individuals hospitalized for TBI, 27% of participants reported difficulty with attentiveness at 1-year post-injury [2]. Disorders of attention may result from a number of pathophysiological mechanisms, but most theories subscribe to deficits in frontal lobe functioning. Deficits in attention remain a challenge to the successful rehabilitation of individuals following TBI, primarily due to their importance in neurocognitive processes. Correspondence: David L. Ripley, MD, Medical Director, Brain Injury Medicine and Rehabilitation, Rehabilitation Institute of Chicago, Chicago, IL 60611, USA. Tel: 312-238-1125. E-mail: [email protected]
History Received 5 November 2013 Revised 14 March 2014 Accepted 26 April 2014 Published online 29 August 2014
Attention disorders following TBI have significant functional implications and have been correlated with poorer returnto-work rates [3] and below-average school performance [4]. A number of treatments ranging from cognitive rehabilitation to pharmacological interventions have been utilized for attention deficits following TBI with limited success. Pharmacological studies have tended to focus on traditional neurostimulant medications. Despite extensive anecdotal reports of efficacy of these medications, most of these studies have failed to demonstrate efficacy in controlled trials. Some of these failures are due to the significant limitations of performing pharmacological research on individuals who have sustained a TBI. Problems with research with this population include the effect of natural neurological recovery, variations in the neuroanatomy of injury, memory problems limiting the recall of symptoms over time, cognitive and neurological impairments limiting the ability to perform outcomes testing and limitations with the current systems for classifying TBI. In clinical use, a number of problems are potentially associated with use of the traditional neurostimulant drugs,
Atomoxetine for attention deficits following TBI
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DOI: 10.3109/02699052.2014.919530
not the least of which is the potential for abuse. An alternative treatment with less abuse potential would be valued by clinicians. Moreover, up to 30% of individuals with disorders of attention do not tolerate or do not respond to treatment with traditional stimulant medications [5]. Therefore, an alternative medication that is effective in treating attention problems is clearly of interest. Atomoxetine is a non-stimulant medication currently indicated for attention deficit hyperactivity disorder (ADHD). Atomoxetine was originally investigated as a potential anti-depressant medication [6]. Studies investigating its use for depression did not reveal significant efficacy. However, it was later found to demonstrate improvement in symptoms of impaired attention. A large multi-centre study of the efficacy of atomoxetine demonstrated a significant decline in symptoms of ADHD using the ADHD rating scale [7]. Although several other non-stimulant medications have demonstrated efficacy in treating ADHD [8], none are approved for such use. Atomoxetine is almost a pure norepinephrine re-uptake inhibitor. It does not bind with great affinity to receptors for acetylcholine, histamine, alpha-2 adrenergic or dopamine [9]. The primary area in the brain with noradrenergic activity is the locus coeruleus, located at the base of the fourth ventricle. This area is responsible for regulating the state of arousal in the individual and also has function in facilitating neural activity related to processing environmental stimuli [10]. It is theorized that atomoxetine exerts its affect by increasing noradrenergic activity in the pathways from the locus coeruleus to the prefrontal cortex [5, 10]. Currently, it is the only medicine the US Food and Drug Administration (FDA) has approved for treatment of attention-deficit disorder (ADD) in adults [5, 11]. Unlike most medications used to treat attention impairments, atomoxetine is not a US Drug Enforcement Agency Schedule II medication and, therefore, is more convenient for physicians and patients, as unique prescriptions are not needed for each month’s dosage. In theory, the abuse potential of atomoxetine is much lower than traditional neurostimulant medications, as it lacks the significant arousal properties of these medications [12] which leads to their being frequently drugs of abuse. It is felt that these properties of the traditional neurostimulant medications, like methylphenidate, are primarily due to their action on dopamine receptors in pleasure centres of the brain. Atomoxetine lacks this effect. Safety profile studies of atomoxetine indicated that it is a well-tolerated medication in controlled trials [13, 14]. Particular side-effects noted with atomoxetine that occur with significantly greater frequency than placebo are nausea, vomiting and constipation [5], small reversible increases in blood pressure, small dose-dependent increases in heart rate, palpitations [15], urinary retention [5], decreased appetite and weight loss [13], mood swings and sexual dysfunction [5, 11]. Atomoxetine has gained considerable interest as an alternative for treating TBI-related attention problems, hypo-arousal, initiation disorders and fatigue. Hypothesis Subjects with attention impairment after moderate-to-severe TBI will demonstrate improved performance on measures of
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attention while on atomoxetine as compared to performance while on placebo.
Methods This trial was registered on ClinicalTrials.gov, trial registry number NCT00702364. Participants The primary method of recruitment involved mailing recruitment flyers to 1010 individuals with TBI who had received care at an inpatient rehabilitation programme and who lived in the surrounding metropolitan area. In addition, flyers were distributed to physicians and neuropsychologists who treat individuals with TBI in the community, the state brain injury association and other community TBI organizations. Phone screening and, when possible, chart review, were used to determine study eligibility. Eligible participants were between the ages of 18–65 (inclusive); and had a history of moderate-to-severe TBI (defined as initial Glasgow Coma Scale (GCS) score of 12 or less, post-traumatic amnesia (PTA) of greater than 24 hours or radiographic evidence of intracranial injury). All who participated were at least 1 year post-injury. A telephone screening call was performed during which all potential subjects were administered the Adult ADHD Self-Report Scale (ASRS-v1.1) screener [16, 17] and the Cognitive Failures Questionnaire (CFQ) [18]. When available, the potential subjects’ primary caregiver/significant other was administered the ‘Other CFQ’. Individuals who scored a 4 or higher on the ASRS; or a 0.35 or higher on the CFQ or a 0.42 or higher on the Other CFQ were considered to meet the inclusion criteria for symptoms consistent with attention dysfunction. These inclusion criteria for the CFQ were determined by taking the mean score plus 1 SD for uninjured controls as reported by Hart et al. [19]. Individuals were excluded for the following reasons: (1) non-English speaking (study measures were all normalized and administered in English only); (2) current history of seizures; (3) cardiovascular disease including dysrhythmias, angina, history of myocardial infarction, uncontrolled hypertension and valvular heart disease; (4) history of significant psychiatric illness requiring hospitalization; (5) use of monoamine oxidase inhibitors; (6) severe renal or hepatic impairment; or (7) pregnant or lactating. Figure 1 shows the screening and enrolment process. Setting This clinical trial was performed at a free-standing notfor-profit rehabilitation hospital in the US. Data collection took place in a private research office and was scheduled 2 hours after prescribed medication administration and held constant for each participant throughout the study. Intervention Atomoxetine 40 mg taken twice a day at 7 am and 12 noon was the intervention during the active arm of the study, vs placebo capsules identical to the atomoxetine capsules. Capsules of active drug and placebo were provided for this
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Figure 1. CONSORT Patient Enrollment Diagram.
study by Lilly Pharmaceuticals, Indianapolis, Indiana. There were no identifying markings on either placebo or active drug capsules. Capsules were provided in blister packs to facilitate tracking adherence to study protocol by the participants. Design This study received approval by the hospital’s institutional review board. The design of this study was a randomized, double-blind, placebo-controlled, cross-over design. As explained fully in the results section, due to an inability to detect medication effect during medication washout, the final analysis was treated as a two-arm study [20]. Eligible participants met with the research physician to obtain informed consent. After obtaining informed consent, the research physician completed a history and physical exam to ensure participants had no medical conditions that would make them ineligible. Participants then met with the study coordinator to complete training on study assessments. Each participant completed the primary outcome assessment battery twice, which served to control for practice effects. Participants returned within a week of the training visit to
complete baseline assessment. Following baseline assessment, all participants underwent a 2-week placebo run in, then returned for a repeat baseline assessment, after which they were randomized to either the DRUG FIRST or PLACEBO FIRST group. Investigators, data collectors, data analysts and participants were blinded to which protocol (drug first or placebo first) was received. For a diagram of the study design, see Figure 2. Randomization was performed utilizing a computer generated randomization sequence. This randomization sequence was given to the pharmacy and no study staff had access to it. The study physician and study co-ordinator enrolled participants and assigned study numbers sequentially as participants enrolled. After enrolment, the study coordinator contacted the hospital pharmacy and provided them with the participant’s name and study number in order for the pharmacy to administer the randomization protocol. Participants randomized to DRUG FIRST began taking 40 milligrams of atomoxetine twice a day at 7 am and 12 noon. This dosage was maintained for 14 days, at which time participants returned for testing and then began taking the placebo for a 14-day wash-out period. Following the wash-out
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Figure 2. Study Protocol Diagram.
period, DRUG FIRST participants returned for testing and then began taking placebo for 14 days on the same time schedule as the active drug phase of the trial. Participants randomized to PLACEBO FIRST began taking placebo twice a day at 7 am and noon for 14 days, at which time participants returned for testing and then continued taking placebo for 14 more days. Following this, PLACEBO FIRST participants returned for testing and then began taking atomoxetine for 14 days, twice a day at 7 am and noon. Throughout the study, the study co-ordinator, who was blind to treatment condition (drug first or placebo first), telephoned each participant every other week (weeks when participant was not scheduled for in-person re-assessment) to check for adherence to study protocol, side-effects and adverse events. During all testing conditions, compliance with medication was monitored by reviewing each subject’s pill supply when they returned for testing, as well as telephone calls to remind them to adhere to the study protocol. Outcome measures The study co-ordinator or data collector, both of whom were blind to treatment condition (drug first or placebo first), administered and collected all outcome measures (Primary and Secondary) described below at the following time points: baseline, 2 weeks (repeat baseline, Day 14), 4 weeks (Day 28), 6 weeks (Day 42) and 8 weeks (Day 56). Primary outcome measure The Cognitive Drug Research (CDR) Computerized Cognitive Assessment System [21] is comprised of a battery of computer-controlled tasks administered on a laptop computer, with parallel forms of the tests being presented on each testing session. This allows for repeated testing by presenting different, but equivalent, stimuli at each administration. The test battery takes about 25 minutes to perform. The following tests of the CDR were administered at each assessment in this order: immediate word recall, picture presentation, simple reaction time, digit vigilance task, choice reaction time, spatial working memory, numeric working memory, delayed word recall, word recognition and picture recognition.
All tasks were computer-controlled, the information being presented on the screen of a laptop computer. Responses were recorded via a response module containing two buttons, one marked ‘NO’ and the other ‘YES’. Subjects were required to use the same hand for all study sessions. In most cases, this was the participant’s dominant hand unless limited by neurologic or orthopaedic conditions. In the Word Recall tasks the responses were recorded by the staff person administering the assessment, scored and entered into the CDR database. The CDR system has been utilized in over 500 clinical trials worldwide. It has been validated and used with a variety of patient groups including Alzheimer’s disease [22] and TBI [23]. Assessment of attention is a particular strength of the CDR system and has been used in clinical trials in conditions characterized by attention deficits such as Parkinson’s disease [24] and Dementia with Lewy bodies [25], in addition to studies with healthy subjects [26]. The CDR test results are combined into factor scores: Power of Attention (POA), Continuity of Attention (COA), Quality of Working Memory (QWM), Quality of Episodic Memory (QEM) and Speed of Memory (SOM). All of the factors’ scores have been evaluated and validated in a number of different populations including TBI [23]. The Power of Attention factor was selected as the primary outcome measure because of its strong psychometric properties in other drug studies with cognitively compromised populations [22]. To control for multiplicity, statistical inference was based solely on the primary outcome (Power of Attention) and secondary analyses were treated as exploratory. If significant results were found in the secondary analyses, additional studies would need to be done to confirm these findings. Secondary outcome measures The CDR Continuity of Attention (COA), Quality of Episodic Memory (QEM) and Speed of Memory (SOM) factors were analysed as secondary outcomes. In addition, a new CDR factor score, Efficiency of Attention (EOA), derived from Continuity of Attention *1000/Power of Attention was calculated to provide an index of the relationship of accuracy to speed (throughput).
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The Stroop Color and Word Test [27] is frequently used to study deficits of attention and executive function in individuals with TBI [28–31] and has adequate test–re-test reliability [31]. At each administration, the following scores were obtained, Word Reading, Colour Naming and Interference. Raw scores were converted to demographically-adjusted T-scores using Golden and Freshwater [31] norms. The Adult ADHD Self-Report Scale (ASRS-v1.1) [16, 32] is a self-report questionnaire that consists of questions involving the 18-items of the DSM-IV-TR criteria for ADHD that rate symptoms on a Likert scale ranging from 0–4 based on the frequency of symptoms (‘never’, ‘rarely’, ‘sometimes’, ‘often’ and ‘very often’). A previous study of the ASRS found the self-report to be both valid (Cronbach’s alpha ¼ 0.88) and reliable (ICC ¼ 0.84) [16]. Scores on the 18 items were summed for a total ASRS score. The Neurobehavioral Functioning Inventory (NFI) [33] was developed as a clinical and research tool to quantify a variety of post-injury behaviours and symptoms characteristic of neurologic disability and encountered in daily life. The inventory is comprised of 76 items organized into six analytically derived factor scales: Depression, Somatic, Memory/Attention, Communication, Aggression and Motor; with a separate patient and family form. The inventory was standardized on individuals with TBI aged 16 and older and validity has been established with Cronbach’s alpha analysis indicating high internal reliability for all scales ranging from 0.86–0.95. Respondents are asked to rate items as occurring ‘never’, ‘rarely’, ‘sometimes’, ‘often’ or ‘always’. Given the early investigations using atomoxetine as an antidepressant, this measure was used to determine if there was a subjective effect on mood attributable to atomoxetine, as well as to control for any effects that co-morbid depression may have had on the participants’ performance on attention measures. Sample size The sample size for this study was chosen based on data from prior pharmacological studies utilizing the CDR as the primary outcome measure. The Power of Attention score in TBI patients has been estimated to have a mean of 1394 milliseconds with a standard deviation of 337 milliseconds. The age-matched norm is 1107 milliseconds, which implies a TBI deficit of 287 milliseconds [23]. Table I summarizes the power of a paired t-test (with 2-sided alpha ¼ 0.05) for various sample sizes, effect sizes (detectable differences) and for various values of the correlation between repeated measurements on an individual. In Table I, mT mP denotes the true treatment effect (i.e. ‘detectable difference’), which is expressed as either a difference in the improvement in speed (milliseconds; negative values denote faster speed with atomoxetine treatment), a percentage reduction in the deficit of 287 milliseconds or as a proportion of the standard deviation (‘effect size’). Based on the reliability/repeatability data for the CDR power of attention test, the within-individual correlation is likely to be 0.5 or higher, resulting in 80% power for detecting improvements larger than 215 milliseconds (more than a 75% reduction in the TBI deficit). This study called for enrolling 60 subjects, which gave power of 86–89% for 45–50 subjects,
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Table I. Power of a paired t-test for various sample sizes. mT mP
Study power
n
ms
% Deficit reduction
Effect size
R ¼ 0.0
R ¼ 0.5
R ¼ 0.7
40
287 215 168
100 75 59
0.85 0.64 0.50
0.77 0.52 0.35
0.97 0.81 0.61
40.99 0.96 0.82
45
287 215 168
100 75 59
0.85 0.64 0.50
0.81 0.57 0.39
0.98 0.86 0.66
40.99 0.97 0.86
50
287 215 168
100 75 59
0.85 0.64 0.50
0.85 0.64 0.50
0.99 0.89 0.70
40.99 0.98 0.90
after allowing for dropout. Ultimately 60 subjects were recruited and 55 completed the entire protocol. Statistical methods All analyses were conducted using SAS 9.3 [34]. Although the original analytic approach called for comparing treatment and control groups by use of a cross-over design, an alternative strategy was ultimately utilized as pre-analysis of the mean profiles for each group across time was unable to confirm the presence of medication wash out. Specifically, in both groups, no difference was seen in test results at the end of the first arm of the study compared to test results after the medication wash out. In situations where medication wash out cannot be confirmed, it is typical to examine only the first sequence of a cross-over design, effectively transforming the design into a two-arm study [20]. This tact was employed for the current study. However, instead of utilizing a t-test to compare treatment and control groups, treatment and control groups for both primary and secondary outcomes were compared utilizing an analysis of covariance (ANCOVA) model in which repeat baseline measures taken on each respective outcome served as a covariate. This method controls for any differences that may exist between the groups at baseline. Model assumptions for conducting an ANCOVA were investigated for all primary and secondary analyses, where no violations of model assumptions were detected. Additionally, when present, outliers were investigated and none were found to be the result of recording errors. To assess the influence of outliers, analyses were conducted with and without outliers present. In each instance, conclusions regarding treatment effect remained the same.
Results Demographic characteristics of the participant population are outlined in Table II. Overall, the sample was predominately Caucasian, well-educated and severely injured, with a mean GCS of 6.8 and a mean of 52.7 days in PTA. The sample was fairly evenly split between married and unmarried individuals. Time since injury ranged from 1–22 years, with a mean of 7.8 years since injury. The mean baseline scores for all outcome measures are presented in Table III. Analysis of the primary and secondary outcomes yielded no statistically significant results. Patients in both groups did demonstrate improving trends on
Atomoxetine for attention deficits following TBI
DOI: 10.3109/02699052.2014.919530
Table II. Demographic characteristics of study participants. Period 1 treatment
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All subjects
Placebo
Strattera
p
Age, n 55 29 26 0.832 Mean (SD) 40.6 (11.78) 40.3 (12.5) 41.0 (11.1) Min/Max 20/64 20/63 21/64 Glasgow Coma Scale, n 38 22 16 0.658 Mean (SD) 6.8 (4.3) 6.5 (4.0) 7.2 (4.9) Min/Max 3/15 3/15 3/15 Days in PTA, n 49 26 23 0.462 Mean (SD) 52.7 (57.9) 58.5 (70.8) 46.2 (39.3) Min/Max 1/365 1/365 1/105 Years post-injury, n 55 29 26 0.321 Mean (SD) 7.8 (5.8) 6.6 (5.5) 8.2 (6.1) Min/Max 1/22 0/21 1/19 Gender, n 55 29 26 0.392 Female 14 (25.4%) 6 (20.7%) 8 (30.8%) Male 41 (74.6%) 23 (79.3%) 18 (69.2%) Race, n 55 29 26 0.942 Caucasian 48 (87.3%) 25 (86.2%) 23 (88.5%) Hispanic Origin 5 (9.1%) 3 (10.3%) 2 (7.7%) African American 2 (3.6%) 1 (3.4%) 1 (3.8%) Education, n 55 29 26 0.473 5High School 4 (7.3%) 4 (13.8%) 0 (0.0%) High School 9 (16.4%) 4 (13.8%) 5 (19.2%) 54 Years College 17 (30.9%) 8 (27.6%) 9 (34.6%) Bachelor’s Degree 20 (36.4%) 11 (37.9%) 9 (34.6%) Master’s Degree 3 (5.5%) 1 (3.4%) 2 (7.7%) Doctoral Degree 2 (3.6%) 1 (3.4%) 1 (3.8%) Employment status, n 55 29 26 0.527 Full/part-time Student 4 (7.3%) 3 (10.3%) 1 (3.8%) Employed 20 (36.4%) 9 (31.0%) 11 (42.3%) Unemployed 7 (12.7%) 4 (13.8%) 3 (11.5%) Retired (Disability) 22 (40.0%) 11 (37.9%) 11 (42.3%) Volunteer 2 (3.6%) 2 (6.9%) 0 (0.0%) Marital status, n 55 29 26 0.989 Single 23 (41.8%) 12 (41.4%) 11 (42.3%) Married/Common Law 25 (45.5%) 13 (44.8%) 12 (46.2%) Divorced 5 (9.1%) 3 (10.3%) 2 (7.7%) Widowed 2 (3.6%) 1 (3.4%) 1 (3.8%)
Table III. Baseline performance on outcome measures. Measure
n
CDR Power of Attention POA CDR Continuity of Attention COA CDR Efficiency COA/POA Stroop Interference Trial 4 ASRS NFI Depression Scale
55 55 55 54 51 54
Mean (SD) 1270.50 (189.45) ms 91.24 (3.33) % accuracy 73.27 56.96 32.33 29.98
(10.54) % accuracy/ms (9.71) (10.43) (8.47)
performance in all measures in the same way, indicating a successful placebo run-in; however, trends towards significance; p Values 50.15 were absent. Table IV displays the treatment and control group comparisons for both primary and secondary outcomes. In addition, no significant differences were seen between groups, suggesting there was no drug effect on the measures evaluated. Due to lack of significant results in this sample, post-hoc analysis was performed to review the neuropathology of the subject sample. Thirty-three subjects (60%) had MRI scans available for review. These images were reviewed by a board-certified neuroradiologist and a physiatrist with subspecialization in brain injury rehabilitation, both of whom
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were blinded to treatment group. Post-hoc analysis showed that 26 (79%) had multifocal injuries, suggesting heterogeneous neuropathology. Additionally, it is notable that 27 (82%) had frontal grey matter pathology, 19 (58%) had frontal white matter pathology, 14 (42%) had subcortical grey pathology and six (18%) had brainstem pathology. Further sub-analysis of the population to correlate response to medication with location of pathology proved to be impossible with this sample size and the preponderance of individuals in the sample with multifocal injury. Medication adherence Compliance to treatment was determined by having the subjects bring all unused medication to each follow-up visit. By counting the returned pills, it was determined how many missed dosages there were. Overall, subjects demonstrated good compliance to study protocols, See Table V for Drug Compliance information. In the situation where one subject missed an inordinate amount of medication, analysis conducted with and without this individual revealed no difference in the study outcome. In many studies of subjects with TBI, variability in test performance is a significant challenge, as subjects can show intra-day and inter-day performance variations for multiple reasons such as attention impairments, cognitive fatigue, level of motivation, etc. To examine this potential confounder, Pearson’s r was calculated for the CDR factors from baseline and day 14 placebo run-in time points. The CDR POA, EOA and SOM all had strong reliability coefficients (therefore, little variability). The COA and QEM factors were less stable with significant variability (Table VI). Side effects Atomoxetine at the dosage utilized for this study was welltolerated. Only two side-effects were reported with greater frequency in the treatment arm than the placebo arm. Two patients (7.41%) respectively reported insomnia and dry mouth on treatment, compared to none on placebo. Other side-effects reported included sore throat, hypertension, irritable bowel, loss of appetite, nasal congestion, shoulder pain and urinary retention. No participants who dropped from the study reported dropping out of the study due to medication side-effects. Pulse and blood pressure were not measured objectively during the study. Self-reported sideeffects were monitored weekly; in person on weeks where testing occurred and via telephone on alternate weeks. These telephone ‘check-ins’ were also used to monitor compliance with study medication.
Discussion In this study of individuals with TBI and self-reported attention problems, the use of atomoxetine did not demonstrate a significant positive treatment effect over a placebo effect on either objective attention impairments as measured by objective neurocognitive tests. Additionally, no significant effect was noted on subjective attention and mood symptoms as measured by self-report inventories. In this study, atomoxetine was well-tolerated, with no participant dropping
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Table IV. Results of ANCOVA analysis.
Variable/outcome CDR Power of Attention (POA) (Primary Outcome) CDR Continuity of Attention (COA) (Secondary Outcome) CDR Efficiency (COA/POA) (Secondary Outcome) STROOP (Secondary outcome) ASRS (Secondary Outcome) NFI Depression (Secondary Outcome)
Adjusted means
Difference between adjusted means (C T)
Lower 95% CL
Upper 95% CL
p Value
T ¼ 1262.17 C ¼ 1252.95 T ¼ 91.65 C ¼ 90.77 T ¼ 74.14 C ¼ 73.57 T ¼ 56.50 C ¼ 55.44 T ¼ 28.98 C ¼ 31.00 T ¼ 27.53 C ¼ 29.47
9.220
81.74
63.29
0.80
0.882
2.51
0.745
0.28
0.56
4.43
3.31
0.77
1.062
3.58
1.46
0.40
2.11
2.23
6.45
0.33
1.95
1.74
5.63
0.29
T, Treatment; C, Control.
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Table V. Drug compliance information.
Table VI. Test–re-test reliability, baseline to day 14 (repeat baseline).
# participants/# doses missed Time point/CONDITION Day 14 PLACEBO RUN-IN
Placebo 1st Group 1 participant/1 dose
Day 28 1 participant/7 doses TREATMENT Day 42 1 participant/1 dose PLACEBO WASH OUT 1 participant/5 doses Day 56 2 participants/2doses TREATMENT 1 participant/13 doses
Drug 1st Group 9 2 1 3 1 7 1 1 5 2
participants/1 dose participants/3 doses participant/13 doses participants/1 dose participant/2 doses participants/2 doses participant/3 doses participant/1 dose participants/2 doses participants/5 doses
from the study due to side-effects. The only side-effects occurring with greater frequency than placebo were dry mouth and insomnia. These results follow a trend of negative results studies for pharmacological interventions following TBI. Many medications that are felt anecdotally to be effective for individuals with TBI have not been found to demonstrate efficacy in clinical trials. There are a number of potential issues contributing to this phenomenon. Primary among these is variations in the neuropathology of injury among subjects with TBI, resulting in variance in response to pharmacological interventions. In this sample, post-hoc analysis revealed multifocal pathology in 79%, and 82% had frontal pathology. These anatomical findings are suggestive of disruption of the proposed physiological pathway of atomoxetine, which is the noradrenergic pathway from the locus coeruleus to the prefrontal cortex. This may explain in part the lack of effect in this population. Further sub-analysis of the population to correlate response to medication with location of pathology proved to be impossible with this sample size and the preponderance of individuals in the sample with multifocal injury. Although the authors attempted to control for the issue of variation in neuropathology by attempting to evaluate treatment, a specific problem (disorder of attention), variation in the underlying neuropathology may have ultimately affected the efficacy of the intervention in some subjects, washing out the effect of the medication. This speaks to the need for a more sophisticated way to classify individuals with TBI, so that research studies can be designed to target individuals
Factor Attention Factor Power of Attention Continuity of Attention Quality of Working Memory Quality of Episodic Memory Speed of Memory
Pearson’s r 0.88 0.87 0.53 0.72 0.43 0.9
with specific underlying neuroanatomical changes and ultimately find appropriate treatments targeted at these deficits. A comprehensive discussion of classification systems is beyond the scope of this manuscript. However, the primary method of classification of TBI used in most studies relies on the Glasgow Coma Scale (GCS) to divide subjects into subgroups of ‘mild, moderate and severe’. This classification method ignores the variations in neuropathology that can occur between different individuals. For instance, excluding patients based on presence or absence of pathology in a certain region may have ultimately led to different findings. Of course, the problem with this approach is that it is difficult enough to recruit subjects to participate in research studies, so that finding enough subjects with specific types of neuropathology would be even more challenging. One other problem is that, by its very nature, many patients have diffuse injury or multiple areas of injury. If a standardized system for classification of subjects into neuropathological categories were available and universally utilized, this may facilitate collaboration between institutions to ‘share’ subjects with specific underlying neuropathology and, in turn, allow clinical studies to be designed to target deficits related to specific types of pathology and ultimately lead to more efficacious treatments. Limitations While it is the belief of the authors that this study was wellcontrolled with good drug compliance and the results are valid, several limitations must be acknowledged. The primary outcome measure may not have adequately measured the pharmacological effects of atomoxetine. The mechanism of action of atomoxetine suggests that it would be best utilized in situations to help specifically with visual attention. The
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DOI: 10.3109/02699052.2014.919530
primary outcome measure, the CDR Power of Attention factor, an index of reaction time, may not have adequately measured the pharmacological effect of atomoxetine; however, none of the other attention measures, including the selfreport measure, were significant either. This is an example of complexity of attention and difficulty with measuring attention constructs. Another limitation acknowledged is the use of a self-report measure, the ASRS, as it requires recall of symptomatic experience over a long period of time, which is sometimes difficult for individuals with cognitive impairments from TBI. Many subjects with TBI have significant memory impairment, which may limit their recollection of symptoms. This may have been true in this sample, which may have limited accurate reporting of symptoms and, therefore, affected the study outcome. The sample in this study also exhibited a wide variation in time since injury. Although subjects who were less than 1 year from the date of the injury were excluded to limit the effects of natural recovery, the population ranged from 1–22 years post-injury. Time since injury may be a factor that impacts the efficacy of pharmaceutical interventions and this must be acknowledged as a limitation. Variability in performance is often a challenge for pharmacological studies on populations of individuals after TBI. However, this analysis indicates significant variability on only two of the outcome measures and these were both secondary outcome measures. The primary outcome measure ‘Power of Attention’ demonstrated surprisingly little variability, with a Pearson’s r of 0.87. It is felt that this does not explain the lack of significant findings in the study. Lastly, the design of the study called for 2 weeks in each arm of the study. It has been suggested that patients may need longer time on medication for a more robust treatment effect. Summary Atomoxetine is a non-stimulant medication for attention deficit hyperactivity disorder. Unlike most medications commonly utilized for ADHD, atomoxetine specifically acts on noradrenergic systems by decreasing the pre-synaptic reuptake of norepinephrine. Despite anecdotal evidence that it may have a role in treating specific attention problems following TBI, this randomized clinical trial did not demonstrate clinical efficacy. This follows a trend of studies failing to demonstrate clinical efficacy in a population of participants with TBI. A major limitation is in the current way individuals with TBI are classified by injury severity. The authors strongly endorse the development of a new, more sophisticated classification system for individuals with TBI. It is felt that atomoxetine still may have a role in the treatment and recovery following TBI. Further investigation is recommended.
Acknowledgements The authors wish to thank Gale Whiteneck, PhD, for his wisdom and advice.
Declaration of interest This research was supported by the Rocky Mountain Regional Brain Injury System (Grant number H133A070022) which
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was funded by an award from the US Department of Education’s National Institute on Disability and Rehabilitation Research. The contents of this publication are the opinions of the authors and do not necessarily reflect the views of the Department of Education. Additionally, this research received investigator-initiated support from Lilly Research Laboratories, who provided active drug and placebo for this project.
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ORIGINAL ARTICLE
Atomoxetine for attention deficits following traumatic brain injury: Results from a randomized controlled trial David L. Ripley1, Clare E. Morey2, Don Gerber2, Cynthia Harrison-Felix2, Lisa A. Brenner2,3, Christopher R. Pretz2, Chris Cusick2, & Keith Wesnes4,5
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1
Department of Physical Medicine and Rehabilitation, Northwestern University Feinberg School of Medicine, Rehabilitation Institute of Chicago, Chicago, IL, USA, 2Department of Physical Medicine and Rehabilitation, University of Colorado School of Medicine, Aurora, CO, USA, 3Departments of Psychiatry, Neurology, and Physical Medicine and Rehabilitation, University of Colorado, School of Medicine, Aurora, CO, USA, 4Bracket Global, Goring-on-Thames, UK, and 5Centre for Human Psychopharmacology, Swinburne University of Technology, Melbourne, Australia Abstract
Keywords
Objective: To determine if atomoxetine would improve attention impairment following traumatic brain injury (TBI). Setting: Outpatients from a free-standing, private, not-for-profit rehabilitation hospital. Population: Fifty-five adult participants with a history of a single moderate-to-severe TBI, who were at least 1 year from injury and with self-reported complaints of attention difficulties. Intervention: Atomoxetine, a selective norepinephrine re-uptake inhibitor with a primary indication for attention dosed at 40 mg twice a day for 2 weeks, compared to placebo. Design: Randomized double-blind placebo controlled trial, with placebo run-in. Measures: Cognitive Drug Research (CDR), Computerized Cognitive Assessment System, Stroop Color and Word Test, Adult ADHD Self-Report Scale (ASRS-v1.1), Neurobehavioural Functioning Inventory (NFI). Results: Atomoxetine was well-tolerated by the subject sample. The use of atomoxetine by individuals with reported attention difficulty following TBI did not significantly improve scores on measures of attention, the CDR Power of Attention domain or the Stroop Interference score. In addition, no significant relationship was found between atomoxetine use and self-reported symptoms of attention or depression. Conclusion: Atomoxetine did not significantly improve performance on measures of attention among individuals post-TBI with difficulties with attention. This study follows a trend of other pharmacological studies not demonstrating significant results among those with a history of TBI. Various possibilities are discussed, including the need for a more sophisticated system of classification of TBI.
Attention, atomoxetine, cognitive drug research, controlled trial, norepinephrine, traumatic brain injury
Introduction Attention deficits after TBI William James, in his Principles of Psychology, stated that attention is ‘the taking possession of the mind, in clear and vivid form, of one out of what seem several possible objects or trains of thought’ [1]. Deficits in attention following traumatic brain injury (TBI) have long been recognized as a frequent and significant problem. In one study of individuals hospitalized for TBI, 27% of participants reported difficulty with attentiveness at 1-year post-injury [2]. Disorders of attention may result from a number of pathophysiological mechanisms, but most theories subscribe to deficits in frontal lobe functioning. Deficits in attention remain a challenge to the successful rehabilitation of individuals following TBI, primarily due to their importance in neurocognitive processes. Correspondence: David L. Ripley, MD, Medical Director, Brain Injury Medicine and Rehabilitation, Rehabilitation Institute of Chicago, Chicago, IL 60611, USA. Tel: 312-238-1125. E-mail: [email protected]
History Received 5 November 2013 Revised 14 March 2014 Accepted 26 April 2014 Published online 29 August 2014
Attention disorders following TBI have significant functional implications and have been correlated with poorer returnto-work rates [3] and below-average school performance [4]. A number of treatments ranging from cognitive rehabilitation to pharmacological interventions have been utilized for attention deficits following TBI with limited success. Pharmacological studies have tended to focus on traditional neurostimulant medications. Despite extensive anecdotal reports of efficacy of these medications, most of these studies have failed to demonstrate efficacy in controlled trials. Some of these failures are due to the significant limitations of performing pharmacological research on individuals who have sustained a TBI. Problems with research with this population include the effect of natural neurological recovery, variations in the neuroanatomy of injury, memory problems limiting the recall of symptoms over time, cognitive and neurological impairments limiting the ability to perform outcomes testing and limitations with the current systems for classifying TBI. In clinical use, a number of problems are potentially associated with use of the traditional neurostimulant drugs,
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not the least of which is the potential for abuse. An alternative treatment with less abuse potential would be valued by clinicians. Moreover, up to 30% of individuals with disorders of attention do not tolerate or do not respond to treatment with traditional stimulant medications [5]. Therefore, an alternative medication that is effective in treating attention problems is clearly of interest. Atomoxetine is a non-stimulant medication currently indicated for attention deficit hyperactivity disorder (ADHD). Atomoxetine was originally investigated as a potential anti-depressant medication [6]. Studies investigating its use for depression did not reveal significant efficacy. However, it was later found to demonstrate improvement in symptoms of impaired attention. A large multi-centre study of the efficacy of atomoxetine demonstrated a significant decline in symptoms of ADHD using the ADHD rating scale [7]. Although several other non-stimulant medications have demonstrated efficacy in treating ADHD [8], none are approved for such use. Atomoxetine is almost a pure norepinephrine re-uptake inhibitor. It does not bind with great affinity to receptors for acetylcholine, histamine, alpha-2 adrenergic or dopamine [9]. The primary area in the brain with noradrenergic activity is the locus coeruleus, located at the base of the fourth ventricle. This area is responsible for regulating the state of arousal in the individual and also has function in facilitating neural activity related to processing environmental stimuli [10]. It is theorized that atomoxetine exerts its affect by increasing noradrenergic activity in the pathways from the locus coeruleus to the prefrontal cortex [5, 10]. Currently, it is the only medicine the US Food and Drug Administration (FDA) has approved for treatment of attention-deficit disorder (ADD) in adults [5, 11]. Unlike most medications used to treat attention impairments, atomoxetine is not a US Drug Enforcement Agency Schedule II medication and, therefore, is more convenient for physicians and patients, as unique prescriptions are not needed for each month’s dosage. In theory, the abuse potential of atomoxetine is much lower than traditional neurostimulant medications, as it lacks the significant arousal properties of these medications [12] which leads to their being frequently drugs of abuse. It is felt that these properties of the traditional neurostimulant medications, like methylphenidate, are primarily due to their action on dopamine receptors in pleasure centres of the brain. Atomoxetine lacks this effect. Safety profile studies of atomoxetine indicated that it is a well-tolerated medication in controlled trials [13, 14]. Particular side-effects noted with atomoxetine that occur with significantly greater frequency than placebo are nausea, vomiting and constipation [5], small reversible increases in blood pressure, small dose-dependent increases in heart rate, palpitations [15], urinary retention [5], decreased appetite and weight loss [13], mood swings and sexual dysfunction [5, 11]. Atomoxetine has gained considerable interest as an alternative for treating TBI-related attention problems, hypo-arousal, initiation disorders and fatigue. Hypothesis Subjects with attention impairment after moderate-to-severe TBI will demonstrate improved performance on measures of
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attention while on atomoxetine as compared to performance while on placebo.
Methods This trial was registered on ClinicalTrials.gov, trial registry number NCT00702364. Participants The primary method of recruitment involved mailing recruitment flyers to 1010 individuals with TBI who had received care at an inpatient rehabilitation programme and who lived in the surrounding metropolitan area. In addition, flyers were distributed to physicians and neuropsychologists who treat individuals with TBI in the community, the state brain injury association and other community TBI organizations. Phone screening and, when possible, chart review, were used to determine study eligibility. Eligible participants were between the ages of 18–65 (inclusive); and had a history of moderate-to-severe TBI (defined as initial Glasgow Coma Scale (GCS) score of 12 or less, post-traumatic amnesia (PTA) of greater than 24 hours or radiographic evidence of intracranial injury). All who participated were at least 1 year post-injury. A telephone screening call was performed during which all potential subjects were administered the Adult ADHD Self-Report Scale (ASRS-v1.1) screener [16, 17] and the Cognitive Failures Questionnaire (CFQ) [18]. When available, the potential subjects’ primary caregiver/significant other was administered the ‘Other CFQ’. Individuals who scored a 4 or higher on the ASRS; or a 0.35 or higher on the CFQ or a 0.42 or higher on the Other CFQ were considered to meet the inclusion criteria for symptoms consistent with attention dysfunction. These inclusion criteria for the CFQ were determined by taking the mean score plus 1 SD for uninjured controls as reported by Hart et al. [19]. Individuals were excluded for the following reasons: (1) non-English speaking (study measures were all normalized and administered in English only); (2) current history of seizures; (3) cardiovascular disease including dysrhythmias, angina, history of myocardial infarction, uncontrolled hypertension and valvular heart disease; (4) history of significant psychiatric illness requiring hospitalization; (5) use of monoamine oxidase inhibitors; (6) severe renal or hepatic impairment; or (7) pregnant or lactating. Figure 1 shows the screening and enrolment process. Setting This clinical trial was performed at a free-standing notfor-profit rehabilitation hospital in the US. Data collection took place in a private research office and was scheduled 2 hours after prescribed medication administration and held constant for each participant throughout the study. Intervention Atomoxetine 40 mg taken twice a day at 7 am and 12 noon was the intervention during the active arm of the study, vs placebo capsules identical to the atomoxetine capsules. Capsules of active drug and placebo were provided for this
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Figure 1. CONSORT Patient Enrollment Diagram.
study by Lilly Pharmaceuticals, Indianapolis, Indiana. There were no identifying markings on either placebo or active drug capsules. Capsules were provided in blister packs to facilitate tracking adherence to study protocol by the participants. Design This study received approval by the hospital’s institutional review board. The design of this study was a randomized, double-blind, placebo-controlled, cross-over design. As explained fully in the results section, due to an inability to detect medication effect during medication washout, the final analysis was treated as a two-arm study [20]. Eligible participants met with the research physician to obtain informed consent. After obtaining informed consent, the research physician completed a history and physical exam to ensure participants had no medical conditions that would make them ineligible. Participants then met with the study coordinator to complete training on study assessments. Each participant completed the primary outcome assessment battery twice, which served to control for practice effects. Participants returned within a week of the training visit to
complete baseline assessment. Following baseline assessment, all participants underwent a 2-week placebo run in, then returned for a repeat baseline assessment, after which they were randomized to either the DRUG FIRST or PLACEBO FIRST group. Investigators, data collectors, data analysts and participants were blinded to which protocol (drug first or placebo first) was received. For a diagram of the study design, see Figure 2. Randomization was performed utilizing a computer generated randomization sequence. This randomization sequence was given to the pharmacy and no study staff had access to it. The study physician and study co-ordinator enrolled participants and assigned study numbers sequentially as participants enrolled. After enrolment, the study coordinator contacted the hospital pharmacy and provided them with the participant’s name and study number in order for the pharmacy to administer the randomization protocol. Participants randomized to DRUG FIRST began taking 40 milligrams of atomoxetine twice a day at 7 am and 12 noon. This dosage was maintained for 14 days, at which time participants returned for testing and then began taking the placebo for a 14-day wash-out period. Following the wash-out
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Figure 2. Study Protocol Diagram.
period, DRUG FIRST participants returned for testing and then began taking placebo for 14 days on the same time schedule as the active drug phase of the trial. Participants randomized to PLACEBO FIRST began taking placebo twice a day at 7 am and noon for 14 days, at which time participants returned for testing and then continued taking placebo for 14 more days. Following this, PLACEBO FIRST participants returned for testing and then began taking atomoxetine for 14 days, twice a day at 7 am and noon. Throughout the study, the study co-ordinator, who was blind to treatment condition (drug first or placebo first), telephoned each participant every other week (weeks when participant was not scheduled for in-person re-assessment) to check for adherence to study protocol, side-effects and adverse events. During all testing conditions, compliance with medication was monitored by reviewing each subject’s pill supply when they returned for testing, as well as telephone calls to remind them to adhere to the study protocol. Outcome measures The study co-ordinator or data collector, both of whom were blind to treatment condition (drug first or placebo first), administered and collected all outcome measures (Primary and Secondary) described below at the following time points: baseline, 2 weeks (repeat baseline, Day 14), 4 weeks (Day 28), 6 weeks (Day 42) and 8 weeks (Day 56). Primary outcome measure The Cognitive Drug Research (CDR) Computerized Cognitive Assessment System [21] is comprised of a battery of computer-controlled tasks administered on a laptop computer, with parallel forms of the tests being presented on each testing session. This allows for repeated testing by presenting different, but equivalent, stimuli at each administration. The test battery takes about 25 minutes to perform. The following tests of the CDR were administered at each assessment in this order: immediate word recall, picture presentation, simple reaction time, digit vigilance task, choice reaction time, spatial working memory, numeric working memory, delayed word recall, word recognition and picture recognition.
All tasks were computer-controlled, the information being presented on the screen of a laptop computer. Responses were recorded via a response module containing two buttons, one marked ‘NO’ and the other ‘YES’. Subjects were required to use the same hand for all study sessions. In most cases, this was the participant’s dominant hand unless limited by neurologic or orthopaedic conditions. In the Word Recall tasks the responses were recorded by the staff person administering the assessment, scored and entered into the CDR database. The CDR system has been utilized in over 500 clinical trials worldwide. It has been validated and used with a variety of patient groups including Alzheimer’s disease [22] and TBI [23]. Assessment of attention is a particular strength of the CDR system and has been used in clinical trials in conditions characterized by attention deficits such as Parkinson’s disease [24] and Dementia with Lewy bodies [25], in addition to studies with healthy subjects [26]. The CDR test results are combined into factor scores: Power of Attention (POA), Continuity of Attention (COA), Quality of Working Memory (QWM), Quality of Episodic Memory (QEM) and Speed of Memory (SOM). All of the factors’ scores have been evaluated and validated in a number of different populations including TBI [23]. The Power of Attention factor was selected as the primary outcome measure because of its strong psychometric properties in other drug studies with cognitively compromised populations [22]. To control for multiplicity, statistical inference was based solely on the primary outcome (Power of Attention) and secondary analyses were treated as exploratory. If significant results were found in the secondary analyses, additional studies would need to be done to confirm these findings. Secondary outcome measures The CDR Continuity of Attention (COA), Quality of Episodic Memory (QEM) and Speed of Memory (SOM) factors were analysed as secondary outcomes. In addition, a new CDR factor score, Efficiency of Attention (EOA), derived from Continuity of Attention *1000/Power of Attention was calculated to provide an index of the relationship of accuracy to speed (throughput).
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The Stroop Color and Word Test [27] is frequently used to study deficits of attention and executive function in individuals with TBI [28–31] and has adequate test–re-test reliability [31]. At each administration, the following scores were obtained, Word Reading, Colour Naming and Interference. Raw scores were converted to demographically-adjusted T-scores using Golden and Freshwater [31] norms. The Adult ADHD Self-Report Scale (ASRS-v1.1) [16, 32] is a self-report questionnaire that consists of questions involving the 18-items of the DSM-IV-TR criteria for ADHD that rate symptoms on a Likert scale ranging from 0–4 based on the frequency of symptoms (‘never’, ‘rarely’, ‘sometimes’, ‘often’ and ‘very often’). A previous study of the ASRS found the self-report to be both valid (Cronbach’s alpha ¼ 0.88) and reliable (ICC ¼ 0.84) [16]. Scores on the 18 items were summed for a total ASRS score. The Neurobehavioral Functioning Inventory (NFI) [33] was developed as a clinical and research tool to quantify a variety of post-injury behaviours and symptoms characteristic of neurologic disability and encountered in daily life. The inventory is comprised of 76 items organized into six analytically derived factor scales: Depression, Somatic, Memory/Attention, Communication, Aggression and Motor; with a separate patient and family form. The inventory was standardized on individuals with TBI aged 16 and older and validity has been established with Cronbach’s alpha analysis indicating high internal reliability for all scales ranging from 0.86–0.95. Respondents are asked to rate items as occurring ‘never’, ‘rarely’, ‘sometimes’, ‘often’ or ‘always’. Given the early investigations using atomoxetine as an antidepressant, this measure was used to determine if there was a subjective effect on mood attributable to atomoxetine, as well as to control for any effects that co-morbid depression may have had on the participants’ performance on attention measures. Sample size The sample size for this study was chosen based on data from prior pharmacological studies utilizing the CDR as the primary outcome measure. The Power of Attention score in TBI patients has been estimated to have a mean of 1394 milliseconds with a standard deviation of 337 milliseconds. The age-matched norm is 1107 milliseconds, which implies a TBI deficit of 287 milliseconds [23]. Table I summarizes the power of a paired t-test (with 2-sided alpha ¼ 0.05) for various sample sizes, effect sizes (detectable differences) and for various values of the correlation between repeated measurements on an individual. In Table I, mT mP denotes the true treatment effect (i.e. ‘detectable difference’), which is expressed as either a difference in the improvement in speed (milliseconds; negative values denote faster speed with atomoxetine treatment), a percentage reduction in the deficit of 287 milliseconds or as a proportion of the standard deviation (‘effect size’). Based on the reliability/repeatability data for the CDR power of attention test, the within-individual correlation is likely to be 0.5 or higher, resulting in 80% power for detecting improvements larger than 215 milliseconds (more than a 75% reduction in the TBI deficit). This study called for enrolling 60 subjects, which gave power of 86–89% for 45–50 subjects,
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Table I. Power of a paired t-test for various sample sizes. mT mP
Study power
n
ms
% Deficit reduction
Effect size
R ¼ 0.0
R ¼ 0.5
R ¼ 0.7
40
287 215 168
100 75 59
0.85 0.64 0.50
0.77 0.52 0.35
0.97 0.81 0.61
40.99 0.96 0.82
45
287 215 168
100 75 59
0.85 0.64 0.50
0.81 0.57 0.39
0.98 0.86 0.66
40.99 0.97 0.86
50
287 215 168
100 75 59
0.85 0.64 0.50
0.85 0.64 0.50
0.99 0.89 0.70
40.99 0.98 0.90
after allowing for dropout. Ultimately 60 subjects were recruited and 55 completed the entire protocol. Statistical methods All analyses were conducted using SAS 9.3 [34]. Although the original analytic approach called for comparing treatment and control groups by use of a cross-over design, an alternative strategy was ultimately utilized as pre-analysis of the mean profiles for each group across time was unable to confirm the presence of medication wash out. Specifically, in both groups, no difference was seen in test results at the end of the first arm of the study compared to test results after the medication wash out. In situations where medication wash out cannot be confirmed, it is typical to examine only the first sequence of a cross-over design, effectively transforming the design into a two-arm study [20]. This tact was employed for the current study. However, instead of utilizing a t-test to compare treatment and control groups, treatment and control groups for both primary and secondary outcomes were compared utilizing an analysis of covariance (ANCOVA) model in which repeat baseline measures taken on each respective outcome served as a covariate. This method controls for any differences that may exist between the groups at baseline. Model assumptions for conducting an ANCOVA were investigated for all primary and secondary analyses, where no violations of model assumptions were detected. Additionally, when present, outliers were investigated and none were found to be the result of recording errors. To assess the influence of outliers, analyses were conducted with and without outliers present. In each instance, conclusions regarding treatment effect remained the same.
Results Demographic characteristics of the participant population are outlined in Table II. Overall, the sample was predominately Caucasian, well-educated and severely injured, with a mean GCS of 6.8 and a mean of 52.7 days in PTA. The sample was fairly evenly split between married and unmarried individuals. Time since injury ranged from 1–22 years, with a mean of 7.8 years since injury. The mean baseline scores for all outcome measures are presented in Table III. Analysis of the primary and secondary outcomes yielded no statistically significant results. Patients in both groups did demonstrate improving trends on
Atomoxetine for attention deficits following TBI
DOI: 10.3109/02699052.2014.919530
Table II. Demographic characteristics of study participants. Period 1 treatment
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All subjects
Placebo
Strattera
p
Age, n 55 29 26 0.832 Mean (SD) 40.6 (11.78) 40.3 (12.5) 41.0 (11.1) Min/Max 20/64 20/63 21/64 Glasgow Coma Scale, n 38 22 16 0.658 Mean (SD) 6.8 (4.3) 6.5 (4.0) 7.2 (4.9) Min/Max 3/15 3/15 3/15 Days in PTA, n 49 26 23 0.462 Mean (SD) 52.7 (57.9) 58.5 (70.8) 46.2 (39.3) Min/Max 1/365 1/365 1/105 Years post-injury, n 55 29 26 0.321 Mean (SD) 7.8 (5.8) 6.6 (5.5) 8.2 (6.1) Min/Max 1/22 0/21 1/19 Gender, n 55 29 26 0.392 Female 14 (25.4%) 6 (20.7%) 8 (30.8%) Male 41 (74.6%) 23 (79.3%) 18 (69.2%) Race, n 55 29 26 0.942 Caucasian 48 (87.3%) 25 (86.2%) 23 (88.5%) Hispanic Origin 5 (9.1%) 3 (10.3%) 2 (7.7%) African American 2 (3.6%) 1 (3.4%) 1 (3.8%) Education, n 55 29 26 0.473 5High School 4 (7.3%) 4 (13.8%) 0 (0.0%) High School 9 (16.4%) 4 (13.8%) 5 (19.2%) 54 Years College 17 (30.9%) 8 (27.6%) 9 (34.6%) Bachelor’s Degree 20 (36.4%) 11 (37.9%) 9 (34.6%) Master’s Degree 3 (5.5%) 1 (3.4%) 2 (7.7%) Doctoral Degree 2 (3.6%) 1 (3.4%) 1 (3.8%) Employment status, n 55 29 26 0.527 Full/part-time Student 4 (7.3%) 3 (10.3%) 1 (3.8%) Employed 20 (36.4%) 9 (31.0%) 11 (42.3%) Unemployed 7 (12.7%) 4 (13.8%) 3 (11.5%) Retired (Disability) 22 (40.0%) 11 (37.9%) 11 (42.3%) Volunteer 2 (3.6%) 2 (6.9%) 0 (0.0%) Marital status, n 55 29 26 0.989 Single 23 (41.8%) 12 (41.4%) 11 (42.3%) Married/Common Law 25 (45.5%) 13 (44.8%) 12 (46.2%) Divorced 5 (9.1%) 3 (10.3%) 2 (7.7%) Widowed 2 (3.6%) 1 (3.4%) 1 (3.8%)
Table III. Baseline performance on outcome measures. Measure
n
CDR Power of Attention POA CDR Continuity of Attention COA CDR Efficiency COA/POA Stroop Interference Trial 4 ASRS NFI Depression Scale
55 55 55 54 51 54
Mean (SD) 1270.50 (189.45) ms 91.24 (3.33) % accuracy 73.27 56.96 32.33 29.98
(10.54) % accuracy/ms (9.71) (10.43) (8.47)
performance in all measures in the same way, indicating a successful placebo run-in; however, trends towards significance; p Values 50.15 were absent. Table IV displays the treatment and control group comparisons for both primary and secondary outcomes. In addition, no significant differences were seen between groups, suggesting there was no drug effect on the measures evaluated. Due to lack of significant results in this sample, post-hoc analysis was performed to review the neuropathology of the subject sample. Thirty-three subjects (60%) had MRI scans available for review. These images were reviewed by a board-certified neuroradiologist and a physiatrist with subspecialization in brain injury rehabilitation, both of whom
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were blinded to treatment group. Post-hoc analysis showed that 26 (79%) had multifocal injuries, suggesting heterogeneous neuropathology. Additionally, it is notable that 27 (82%) had frontal grey matter pathology, 19 (58%) had frontal white matter pathology, 14 (42%) had subcortical grey pathology and six (18%) had brainstem pathology. Further sub-analysis of the population to correlate response to medication with location of pathology proved to be impossible with this sample size and the preponderance of individuals in the sample with multifocal injury. Medication adherence Compliance to treatment was determined by having the subjects bring all unused medication to each follow-up visit. By counting the returned pills, it was determined how many missed dosages there were. Overall, subjects demonstrated good compliance to study protocols, See Table V for Drug Compliance information. In the situation where one subject missed an inordinate amount of medication, analysis conducted with and without this individual revealed no difference in the study outcome. In many studies of subjects with TBI, variability in test performance is a significant challenge, as subjects can show intra-day and inter-day performance variations for multiple reasons such as attention impairments, cognitive fatigue, level of motivation, etc. To examine this potential confounder, Pearson’s r was calculated for the CDR factors from baseline and day 14 placebo run-in time points. The CDR POA, EOA and SOM all had strong reliability coefficients (therefore, little variability). The COA and QEM factors were less stable with significant variability (Table VI). Side effects Atomoxetine at the dosage utilized for this study was welltolerated. Only two side-effects were reported with greater frequency in the treatment arm than the placebo arm. Two patients (7.41%) respectively reported insomnia and dry mouth on treatment, compared to none on placebo. Other side-effects reported included sore throat, hypertension, irritable bowel, loss of appetite, nasal congestion, shoulder pain and urinary retention. No participants who dropped from the study reported dropping out of the study due to medication side-effects. Pulse and blood pressure were not measured objectively during the study. Self-reported sideeffects were monitored weekly; in person on weeks where testing occurred and via telephone on alternate weeks. These telephone ‘check-ins’ were also used to monitor compliance with study medication.
Discussion In this study of individuals with TBI and self-reported attention problems, the use of atomoxetine did not demonstrate a significant positive treatment effect over a placebo effect on either objective attention impairments as measured by objective neurocognitive tests. Additionally, no significant effect was noted on subjective attention and mood symptoms as measured by self-report inventories. In this study, atomoxetine was well-tolerated, with no participant dropping
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Table IV. Results of ANCOVA analysis.
Variable/outcome CDR Power of Attention (POA) (Primary Outcome) CDR Continuity of Attention (COA) (Secondary Outcome) CDR Efficiency (COA/POA) (Secondary Outcome) STROOP (Secondary outcome) ASRS (Secondary Outcome) NFI Depression (Secondary Outcome)
Adjusted means
Difference between adjusted means (C T)
Lower 95% CL
Upper 95% CL
p Value
T ¼ 1262.17 C ¼ 1252.95 T ¼ 91.65 C ¼ 90.77 T ¼ 74.14 C ¼ 73.57 T ¼ 56.50 C ¼ 55.44 T ¼ 28.98 C ¼ 31.00 T ¼ 27.53 C ¼ 29.47
9.220
81.74
63.29
0.80
0.882
2.51
0.745
0.28
0.56
4.43
3.31
0.77
1.062
3.58
1.46
0.40
2.11
2.23
6.45
0.33
1.95
1.74
5.63
0.29
T, Treatment; C, Control.
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Table V. Drug compliance information.
Table VI. Test–re-test reliability, baseline to day 14 (repeat baseline).
# participants/# doses missed Time point/CONDITION Day 14 PLACEBO RUN-IN
Placebo 1st Group 1 participant/1 dose
Day 28 1 participant/7 doses TREATMENT Day 42 1 participant/1 dose PLACEBO WASH OUT 1 participant/5 doses Day 56 2 participants/2doses TREATMENT 1 participant/13 doses
Drug 1st Group 9 2 1 3 1 7 1 1 5 2
participants/1 dose participants/3 doses participant/13 doses participants/1 dose participant/2 doses participants/2 doses participant/3 doses participant/1 dose participants/2 doses participants/5 doses
from the study due to side-effects. The only side-effects occurring with greater frequency than placebo were dry mouth and insomnia. These results follow a trend of negative results studies for pharmacological interventions following TBI. Many medications that are felt anecdotally to be effective for individuals with TBI have not been found to demonstrate efficacy in clinical trials. There are a number of potential issues contributing to this phenomenon. Primary among these is variations in the neuropathology of injury among subjects with TBI, resulting in variance in response to pharmacological interventions. In this sample, post-hoc analysis revealed multifocal pathology in 79%, and 82% had frontal pathology. These anatomical findings are suggestive of disruption of the proposed physiological pathway of atomoxetine, which is the noradrenergic pathway from the locus coeruleus to the prefrontal cortex. This may explain in part the lack of effect in this population. Further sub-analysis of the population to correlate response to medication with location of pathology proved to be impossible with this sample size and the preponderance of individuals in the sample with multifocal injury. Although the authors attempted to control for the issue of variation in neuropathology by attempting to evaluate treatment, a specific problem (disorder of attention), variation in the underlying neuropathology may have ultimately affected the efficacy of the intervention in some subjects, washing out the effect of the medication. This speaks to the need for a more sophisticated way to classify individuals with TBI, so that research studies can be designed to target individuals
Factor Attention Factor Power of Attention Continuity of Attention Quality of Working Memory Quality of Episodic Memory Speed of Memory
Pearson’s r 0.88 0.87 0.53 0.72 0.43 0.9
with specific underlying neuroanatomical changes and ultimately find appropriate treatments targeted at these deficits. A comprehensive discussion of classification systems is beyond the scope of this manuscript. However, the primary method of classification of TBI used in most studies relies on the Glasgow Coma Scale (GCS) to divide subjects into subgroups of ‘mild, moderate and severe’. This classification method ignores the variations in neuropathology that can occur between different individuals. For instance, excluding patients based on presence or absence of pathology in a certain region may have ultimately led to different findings. Of course, the problem with this approach is that it is difficult enough to recruit subjects to participate in research studies, so that finding enough subjects with specific types of neuropathology would be even more challenging. One other problem is that, by its very nature, many patients have diffuse injury or multiple areas of injury. If a standardized system for classification of subjects into neuropathological categories were available and universally utilized, this may facilitate collaboration between institutions to ‘share’ subjects with specific underlying neuropathology and, in turn, allow clinical studies to be designed to target deficits related to specific types of pathology and ultimately lead to more efficacious treatments. Limitations While it is the belief of the authors that this study was wellcontrolled with good drug compliance and the results are valid, several limitations must be acknowledged. The primary outcome measure may not have adequately measured the pharmacological effects of atomoxetine. The mechanism of action of atomoxetine suggests that it would be best utilized in situations to help specifically with visual attention. The
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DOI: 10.3109/02699052.2014.919530
primary outcome measure, the CDR Power of Attention factor, an index of reaction time, may not have adequately measured the pharmacological effect of atomoxetine; however, none of the other attention measures, including the selfreport measure, were significant either. This is an example of complexity of attention and difficulty with measuring attention constructs. Another limitation acknowledged is the use of a self-report measure, the ASRS, as it requires recall of symptomatic experience over a long period of time, which is sometimes difficult for individuals with cognitive impairments from TBI. Many subjects with TBI have significant memory impairment, which may limit their recollection of symptoms. This may have been true in this sample, which may have limited accurate reporting of symptoms and, therefore, affected the study outcome. The sample in this study also exhibited a wide variation in time since injury. Although subjects who were less than 1 year from the date of the injury were excluded to limit the effects of natural recovery, the population ranged from 1–22 years post-injury. Time since injury may be a factor that impacts the efficacy of pharmaceutical interventions and this must be acknowledged as a limitation. Variability in performance is often a challenge for pharmacological studies on populations of individuals after TBI. However, this analysis indicates significant variability on only two of the outcome measures and these were both secondary outcome measures. The primary outcome measure ‘Power of Attention’ demonstrated surprisingly little variability, with a Pearson’s r of 0.87. It is felt that this does not explain the lack of significant findings in the study. Lastly, the design of the study called for 2 weeks in each arm of the study. It has been suggested that patients may need longer time on medication for a more robust treatment effect. Summary Atomoxetine is a non-stimulant medication for attention deficit hyperactivity disorder. Unlike most medications commonly utilized for ADHD, atomoxetine specifically acts on noradrenergic systems by decreasing the pre-synaptic reuptake of norepinephrine. Despite anecdotal evidence that it may have a role in treating specific attention problems following TBI, this randomized clinical trial did not demonstrate clinical efficacy. This follows a trend of studies failing to demonstrate clinical efficacy in a population of participants with TBI. A major limitation is in the current way individuals with TBI are classified by injury severity. The authors strongly endorse the development of a new, more sophisticated classification system for individuals with TBI. It is felt that atomoxetine still may have a role in the treatment and recovery following TBI. Further investigation is recommended.
Acknowledgements The authors wish to thank Gale Whiteneck, PhD, for his wisdom and advice.
Declaration of interest This research was supported by the Rocky Mountain Regional Brain Injury System (Grant number H133A070022) which
Atomoxetine for attention deficits following TBI
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was funded by an award from the US Department of Education’s National Institute on Disability and Rehabilitation Research. The contents of this publication are the opinions of the authors and do not necessarily reflect the views of the Department of Education. Additionally, this research received investigator-initiated support from Lilly Research Laboratories, who provided active drug and placebo for this project.
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