Psychosomatics 42:48-54, February 2001
© 2001 The Academy of Psychosomatic Medicine
Cognitive Improvement With Treatment of Depression Following Mild Traumatic Brain Injury
Jesse R. Fann, M.D., M.P.H.,
Jay M. Uomoto, Ph.D., and
Wayne J. Katon, M.D.
Received March 21, 2000; revised July 11, 2000; accepted September 14, 2000. From Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington; Department of Graduate Psychology, Seattle Pacific University, Seattle, Washington.. Address correspondence and reprint requests to Dr. Fann, M.D., M.P.H., Department of Psychiatry and Behavioral Sciences, Box 356560, University of Washington, Seattle, WA 98195; e-mail: fann{at}u.washington.edu
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ABSTRACT
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The authors examined the effect of antidepressant treatment on cognitive performances in people with mild traumatic brain injury. An 8-week nonrandomized, single-blind, placebo run-in trial of sertraline was completed and neuropsychological testing measures were compared before and after the treatment trial. Results showed improvements in psychomotor speed, recent verbal memory, recent visual memory, and general cognitive efficiency. Improvements were also seen in self-perception of cognitive symptomatology. It appears that successful depression treatment resulted in significant alleviation of cognitive impairments, which may not have been accounted for by natural recovery alone.
Key Words: Depression • Cognition • Brain Injury
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INTRODUCTION
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Clinical depression occurs with a significant degree of frequency in people who have sustained traumatic brain injury (TBI) and leads to significant psychosocial and functional impairment.1–3 Studies have found that up to 77% of those with TBI suffer from a major depressive disorder.4,5 Up to 35% of those with mild TBI, who make up the vast majority of TBI cases, suffer from depression.6 The etiological factors that underlie the common comorbidity of depression in brain injury remain unclear,7 although some have suggested that neurochemical changes and psychosocial reactions to the neurological insult are contributory.8
Cognitive impairment is prevalent following TBI, including mild TBI.9 The diagnostic criteria for a major depressive episode also include problems with diminished ability for thinking and concentration.10 The impact of comorbid depression and TBI on cognition is less clear, however. For example, Satz et al.11 found those patients who sustained TBI with depression, while showing more evidence of disability as an outcome, did not have more impaired neuropsychological test scores than those patients without depression. Clinically, patients who sustain a TBI and suffer symptoms of depression typically attribute their cognitive impairments to their TBI, although these impairments may, in fact, be a result of both TBI and depression. Although there are few means to improve TBI-related cognitive functioning beyond that which occurs with natural recovery, patients may experience improvements upon treatment for depression.12 This latter conceptualization is the focus of our current study.
Cognitive problems have been identified in those with depression, and these problems may be associated with abnormalities in regional brain function.13 For example, Kopelman14 found that in comparison to normal control subjects, patients with depression perform more poorly on recent memory tasks, although they do not perform as poorly as those patients with brain dysfunction. Others have found similar patterns of distinctly impaired cognitive functions in those patients with major depression.15,16 Austin et al.17 found memory, selective attention, and set-shifting problems in depressed patients with melancholia compared with patients without melancholia. In Austin et al.'s study, frontal system impairment, particularly anterior cingulate dysfunction, was suggested by their findings. Frontal system impairments have also been found in other such neuropsychological studies of depression.18,19 More recently, Veiel20 conducted a meta-analysis of 13 studies published since 1975 that examined neuropsychological findings in subjects with major depressive disorder. These studies examined several different realms of neuropsychological functioning. Results were mixed, with studies that showed no significant differences in patients with and without major depression and studies that demonstrated clear and sometimes marked differences between the two groupings. Although there was variability in results among the studies, those studies that found cognitive differences implicated global-diffuse and frontal lobe pathology, as indicated by decrements in cognitive efficiency, mental flexibility, and adaptive reasoning.
The treatment of depression clearly has implications for the alleviation of psychosocial and functional sequelae of brain injury. Studies in other medical and neurological populations, such as stroke patients,21 have shown that treating depression can be effective and can decrease functional impairment, somatic symptoms, and self-perception of their impairment. Some researchers have demonstrated the benefit of tricyclic and selective serotonin reuptake inhibitor (SSRI) antidepressants in the treatment of depression following TBI.22 However, no study has examined changes in cognitive functioning resulting from pharmacological intervention in depressed patients with mild TBI.
The purpose of our current study is to determine if there are cognitive improvements in a group of patients with mild TBI and depression who were treated with the SSRI, sertraline. We also want to examine if there are specific neuropsychological functions that show differential change with such pharmacological treatment.
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METHODS
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Subjects
We recruited subjects through advertisements in local newspapers and health magazines. The advertisements requested inquiries from those who had sustained a TBI within the past 3–24 months. By use of a telephone interview, we selected those subjects who met the criteria for mild TBI as defined by the American Congress of Rehabilitation Medicine—Head Injury Interdisciplinary Special Interest Group.23 Mild TBI is defined by at least one of the following: 1) any period of loss of consciousness of 30 minutes or less; 2) any posttraumatic amnesia for not more than 24 hours; 3) any alteration of mental status at the time of the accident (e.g., feeling dazed, disoriented, or confused); and 4) any focal neurologic deficits, which may or may not be transient, but result in loss of consciousness or posttraumatic amnesia no more severe than described in 1) and 2), and after 30 minutes, an initial Glasgow Coma Scale24 score of 13–15. At this time, the Beck Depression Inventory—Short Form25 was given, and possible inclusion was based on subjects scoring of 5 or greater. Individuals meeting these criteria were asked to undergo a structured interview using the Diagnostic Interview Schedule (DIS).26
Inclusion criteria included the following: 1) DSM-III-R criteria fulfilled for major depression on the DIS; 2) a minimum score of 18 on the 17-item Hamilton Depression Rating Scale (HAM-D);27 3) between the ages of 18 to 60; 4) absence of severe language or cognitive deficits that would compromise the ability to comprehend or answer verbal or written questions; 5) no current serious or progressive medical illness; 6) not currently pregnant or breast-feeding; 7) no known mass brain lesions; 8) no history of more than one TBI; 9) no current or past history of psychosis or mania; 10) no current alcohol or recreational drug use; 11) not currently on any psychoactive medication (including beta blockers and steroids); 12) no prior or current use of sertraline; and 13) no current suicidal ideation requiring hospitalization.
By use of these criteria, 32 of the respondents were excluded from participation. The four most common reasons for exclusion were history of more than one TBI (n=8), more than 24 months since TBI (n=7), prior use of sertraline (n=5), and severity of TBI (n=4). The final study sample consisted of 15 ambulatory participants who consecutively entered the study and met the above-mentioned inclusion criteria. Informed consent was obtained from all subjects.
Characteristics of the study sample are presented in Table 1. Seven participants (46.7%) had a major depressive episode at some time before their TBI. Three subjects met criteria for current dysthymia, and three met criteria for current generalized anxiety disorder. More detailed characteristics of the study sample are described elsewhere.28
Neuropsychological Measures
The neuropsychological measures administered in our study included those that were more likely to be sensitive to change in cognition across time and one test that is robust to change due to the sequelae of brain injury or depression.
Digit Span. This subtest of the Wechsler Adult Intelligence Scale—Revised (WAIS-R)29 measures auditory registration of information and immediate attentional skill. The digits-forward (repetition of digit strings) score is added to the digits-backward (repetition of digit strings in reverse order) score and then translated to a scale score (ranging from 1 to 18, mean±SD=10±3).
Digit Symbol. This subtest of the WAIS-R involves copying symbols that are associated with numbers within a grid under timed constraints. It measures visual-motor coordination, speed, and general cognitive efficiency.
Vocabulary. Word knowledge is ascertained on this subtest of the WAIS-R by having the subjects define words of increasing difficulty. Vocabulary is strongly correlated with verbal intelligence and tends to be robust to the impact of brain injury or depression.
Finger Tapping Test. This subtest is a part of the Halstead-Reitan Neuropsychological Test Battery (HRNB).30 It measures bilateral motor speed and also measures psychomotor retardation that is often associated with major depression.
Trailmaking Test, Parts A and B. These tests are included in the expanded HRNB. Part A measures simple psychomotor speed and Part B measures cognitive flexibility and alternating attentional capacity.
Controlled Oral Word Association Test (COWAT). The COWAT31 measures oral word fluency and assesses expressive language skills. It requires the rapid production of words that begin with specific letters ("F," "A," "S") and taps into higher-level executive functioning abilities.
Logical Memory I and II. These subtests of the Wechsler Memory Scale—Revised (WMS-R)32 involve the auditory recall of two paragraph stories immediately (I) and after a 30-minute delay (II). This test measures recent verbal memory and, specifically, retrieval of verbal information.
Visual Reproduction I and II. Recent visual memory for simple geometric designs is assessed with this subtest of the WMS-R. Designs are shown to the subject for 10 seconds, the design is then removed, and then the subjects are asked to draw the design. After 30 minutes, the subjects are asked to draw the design again from memory.
Buschke Selective Reminding Test (SRT). The SRT33 is a word-list learning task where 10 words are read to the subjects, the subjects are then asked to recall as many words as possible. The examiner then selectively reminds the subjects of only those words that the subjects were unable to recall. After these reminders, the subjects are asked to recall as many of the whole list as possible. This process is repeated until the subjects are able to recall all 10 words twice in a row (i.e., reaching criterion) or until 10 trials are attempted. The version of the SRT used in this study has been employed in earlier studies on neuropsychological outcomes in TBI patients.34 Total Recall (the total number of words recalled across all trials; out of a possible of 100 words) and consistent long-term recall (words that were consistently recalled during each trial until the end of the test) were indices utilized in this study.
Benton Visual Retention Test (BVRT). The BVRT35 is a test of visual recent memory in which geometric designs are presented and the subjects are asked to draw the design after the design is removed. The two scores used in this study were the total number correct and the total number of errors.
Self-Perception of TBI Severity. Subjects are asked to rate their perception of the severity of their TBI. One item presents a five-category rating with the following labels: Very Mild Injury, Mild Injury, Moderate Level of Injury, Severe Injury, and Very Severe Injury. A second item is an 11-point rating scale that asks the subject to circle a number ranging from 0 to 10 (0=Not a Problem At All to 10=Very Severe Problem) that best represents the subjects' perception of severity of their injury. A third item requires the subjects to rate the percentage of which they feel they have recovered from cognitive impairments secondary to TBI.
Procedures
Our study was a nonrandomized, single-blind, placebo run-in trial of sertraline after mild TBI. At the beginning of their participation in the study, subjects were informed that they would receive a placebo for 1 week at sometime during the treatment trial. They were also informed that they would receive 8 weeks of treatment with sertraline. All subjects were administered one capsule of an inert placebo every morning during Week 1 of the trial. Subjects were then given an 8-week single-blind course of sertraline, which started at 25 mg every morning. After Week 1, the dose was adjusted to 25–50 mg/day. Further adjustment was made in Week 3 to 25–100 mg/day, and during Weeks 4–8, the dose was adjusted to 25–200 mg/day, depending on clinical response and tolerability.
Subjects were seen by the principal investigator (JF) to make these dose determinations. Medication side effects were noted at each assessment point. The HAM-D was administered at baseline, after placebo run-in, and at Weeks 1, 2, 4, 6, and 8 of sertraline. At Week 8, all baseline questionnaires and neuropsychological testing measures were readministered. During the placebo run-in, subjects whose initial HAM-D decreased by 50% of their initial score or dropped below a score of 10 were judged to be placebo responders. A treatment responder was determined by 50% drop from the HAM-D score from the baseline measurement to that obtained at Week 8 of sertraline. A remission in depression was judged to occur if the final HAM-D score was less than 7.
A master's degree trained psychometrist administered all neuropsychological tests. The psychometrist was given training by one of the authors (JU) to assure standardized administration and scoring of all neuropsychological protocols. Neuropsychological test scores were scored and entered into the database once subjects completed the study.
Statistical Analysis
Paired t-test comparisons were made between initial neuropsychological testing scores and those obtained at Week 8 of sertraline treatment. Composite scores were also constructed for some of the test scores to allow for analyses of global performances on these tests. For the Finger Tapping Test, the composite score consisted of the sum of dominant and nondominant hand performances in which a higher score indicated slower or more impaired performance. On the Trailmaking Test, each of the times of Parts A and B were summed with higher scores denoting a poorer performance. On the SRT, the Total Recall (out of a possible 100) and Consistent Long-Term Recall (out of 100) were each summed, with a higher score indicating a better performance.
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RESULTS
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Depression scores changed significantly with sertraline, from the baseline mean±SD HAM-D score of 25.0±4.36 to a mean of 7.2±5.30 at Week 8 (t=10.44; df=14, P< 0.001). Further, according to the scoring criteria above, there were no placebo responders, two nonresponders, and 13 sertraline treatment responders. Ten patients (66.7%) had a complete remission of their depression. A full description of treatment results can be found elsewhere.28 Table 2 presents comparisons between baseline and Week 8 neuropsychological test scores.
As expected, scores on Vocabulary were unchanged between baseline and Week 8. This suggests there was relative stability in verbal intelligence across time and that verbal intelligence was unaffected by changes in depression levels. Simple auditory attention did not significantly change as shown by the Digit Span score findings. Scores on Digit Symbol changed significantly suggesting improvement in general cognitive efficiency ability.
There appears to have been some mildly improved psychomotor speed for the dominant hand on Finger Tapping. The nondominant hand performance remained the same, with a trend toward improvement. The composite score indicated this trend toward an improved generalized psychomotor effect. Psychomotor efficiency and attention improved on the Trailmaking Test Part A, as did subjects' speed and flexible thinking skills on Part B. The composite score also reflects improvements in these areas. There was no significant effect for oral word fluency.
There were improvements in recent memory ability at Week 8. Findings appear more robust for verbal recent memory tests, with improved performances on both immediate recall and delayed retrieval of verbal material. This was also seen on the WMS-R Logical Memory tests where the amount of details recalled increased after treatment. Some improvements on the Consistent Long-Term Recall portion of the SRT suggested that there was an impact on more subtle recall ability where organized retention is required. Simple visual retention appeared to be unaffected and this may be due to a ceiling effect on these scores at baseline. There was a significant improvement in more complex visual retention on the BVRT number correct score. All three indices of self-perceived cognitive improvements and judgments about injury severity also improved.
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DISCUSSION
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Our present study adds to the findings in our previous study that found two-thirds of mild TBI patients with major depression met remission criterion after an 8-week treatment trial of sertraline.28 Fann et. al also found that measures of psychological distress, functional status, and endorsements of postconcussion symptoms improved significantly.
In our current study, we found that there were significant changes in neuropsychological functioning after the 8-week treatment trial. The improvement in cognitive functions found in the present study were primarily in the realms of psychomotor speed, cognitive efficiency, flexible thinking, and recent memory ability. In connection with the latter, measures of verbal retention that require immediate and delayed retrieval of information were improved. Simple visual percept recall did not change, though a more rigorous measure of complex visual retrieval (e.g., Benton Visual Retention Test) was found to also improve. Verbal intellectual skills remain unchanged by the impact of reduced depression levels. Those areas that have been shown to be a part of clinical depression, namely psychomotor retardation, attention, and memory deficits, appear to have been significantly impacted by the treatment regimen in this study. Our findings support a strong impact on memory by a relatively brief treatment trial of sertraline. Self-perception of cognitive improvement and decrease in the overall impact of their injury was also found and was commensurate with many of the neuropsychological test findings.
There may have been a practice effect that entered into the findings. Repeated exposure to neuropsychological tests can sometimes inflate scores. However, this effect may have been minimized by the 9-week period of time between test administrations. Psychomotor tests and motor speed tests may be more highly influenced by practice. The retesting effect has been examined across the range of TBI severity, including mild TBI, where the recovery effect on measures of attention exceeded the retesting effect in patient populations in comparison to control subjects.36 Thus, the retesting effect may actually be minimal in patients with TBI. Natural recovery after brain injury is also not likely to have significantly influenced the results given the short amount of time that passed during the study. However, because this study was a nonrandomized, single-blind trial, some of the improvement in cognitive function may have been a result of natural improvement or regression to the mean that was independent of the intervention. The results cannot be generalized to all mild TBI populations because of the small sample size. The current neuropsychological test findings may also be limited by the narrow range of test scores in these subjects with mild TBI. Because some individual neuropsychological scores fell within the normal range at the initial assessment, this may have led to a ceiling effect on treatment-associated improvements. Given this potential ceiling effect, the findings of significant neuropsychological improvements in this study are particularly noteworthy. Because we do not have follow-up data beyond 8 weeks of sertraline, it is not possible to determine if the cognitive improvements were sustained.
Dopamine has been postulated to be a key neurotransmitter regulating left-hemispheric and frontal lobe cognitive skills critical to human language and thought.37 Among the SSRIs, sertraline has the most dopaminergic activity.38 The relationship between the level of dopaminergic activity of an antidepressant agent and cognitive improvement following TBI needs further study. Although there is some evidence for serotonin-mediated cognitive difficulties,39 most studies report cognitive improvement with SSRIs.40 Thus, it is highly unlikely that serotonergic effects accounted for the lack of improvement on some neuropsychological tests.
Regardless of the objective neuropsychological test findings, the patients in this study rated the severity of their TBI and their cognitive functioning as significantly improved from baseline. This suggests that treating depression may improve patients' subjective perceptions of their health and cognitive status, thus potentially decreasing illness behaviors and unnecessary health care utilization.
Future research using a double-blind, placebo-controlled study of a serotonin reuptake inhibitor needs to be completed in order to examine differential neuropsychological outcomes. Further testing that uses measures of working memory and executive functioning may be more sensitive to the breadth of cognitive changes that may occur with depression treatment. Our current study underscores the relative importance of treating concurrent conditions in those with brain injury. Depression results in an additive disability in those with neurological disorders41 and this appears to apply to those with TBI. Results of our study suggest that treatment may lead to an alleviation of cognitive impairments, particularly with recent memory skills, cognitive efficiency, and attention. Finally, our study's results suggest that rehabilitation for individuals with brain injury is best delivered from a biopsychosocial perspective, including pharmacological treatments that can lead to the reduction of depression and disability in this population.
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ACKNOWLEDGMENTS
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The authors thank Robley Yee, Ph.D. for assistance with neuropsychological testing
Presented in part at the annual meeting of the American Psychiatric Association, Washington, DC, May 15– 20, 1999 and was supported by an unrestricted educational grant from Pfizer Pharmaceuticals.
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ABSTRACT
INTRODUCTION
