human psychopharmacology Hum Psychopharmacol Clin Exp 2005; 20: 97–104. Published online 7 January 2005 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hup.668

Comparing effects of methylphenidate, sertraline and placebo on neuropsychiatric sequelae in patients with traumatic brain injury Hoon Lee, Sung-Wan Kim, Jae-Min Kim, Il-Seon Shin, Su-Jin Yang and Jin-Sang Yoon* Department of Psychiatry and Research Institute of Medical Science, Chonnam National University Medical School, Kwangju, Republic of Korea

Background This study aimed to investigate the effects of methylphenidate and sertraline compared with placebo on various neuropsychiatric sequelae associated with traumatic brain injury (TBI). Methods This was a 4 week, double-blind, parallel-group trial. Thirty patients with mild to moderate degrees of TBI were randomly allocated to one of three treatment groups (n ¼ 10 in each group) with matching age, gender and education, i.e. methylphenidate (starting at 5 mg/day and increasing to 20 mg/day in a week), sertraline (starting at 25 mg/day and increasing to 100 mg/day in a week) or placebo. At the baseline and at the 4 week endpoint, the following assessments were administered: subjective (Beck Depression Inventory) and objective (Hamilton Depression Rating Scale) measures of depression; Rivermead Postconcussion Symptoms Questionnaire for postconcussional symptoms; SmithKline Beecham Quality of Life Scale for quality of life; seven performance tests (Critical Flicker Fusion, Choice Reaction Time, Continuous Tracking, Mental Arithmetic, Short-Term memory, Digit Symbol Substitution and Mini-Mental State Examination); subjective measures of sleep (Leeds Sleep Evaluation Questionnaire) and daytime sleepiness (Epworth Sleepiness Scale). All adverse events during the study period were recorded and their relationships to the drugs were assessed. Results Neuropsychiatric sequelae seemed to take a natural recovery course in patients with traumatic brain injury. Methylphenidate had significant effects on depressive symptoms compared with the placebo, without hindering the natural recovery process of cognitive function. Although sertraline also had significant effects on depressive symptoms compared with the placebo, it did not improve many tests on cognitive performances. Daytime sleepiness was reduced by methylphenidate, while it was not by sertraline. Conclusions Methylphenidate and sertraline had similar effects on depressive symptoms. However, methylphenidate seemed to be more beneficial in improving cognitive function and maintaining daytime alertness. Methylphenidate also offered a better tolerability than sertraline. Copyright # 2005 John Wiley & Sons, Ltd. key words — methylphenidate; sertraline; depression; cognitive function; traumatic brain injury

INTRODUCTION The number of patients with traumatic brain injury (TBI) has been steadily increasing from traffic and other accidents (Bruns and Hauser, 2003). TBI brings various neuropsychiatric sequelae such as depressive symptoms (Seel et al., 2003), cognitive impairments * Correspondence to: Professor J.-S. Yoon, Department of Psychiatry, Chonnam National University Medical School, 5 Hak-dong, Dong-ku, Kwangju, 501-746, Republic of Korea. Tel: þ82-62-2206142. Fax: þ82-62-225-2351. E-mail: [email protected]

Copyright # 2005 John Wiley & Sons, Ltd.

(Millis et al., 2001), sleep disturbances (Castriotta and Lai, 2001) and other postconcussional symptoms (King, 1996). Many psychopharmacological trials have been developed for treating these conditions. The common use of antidepressants for the patients with depression following TBI, has been supported theoretically by the findings that the levels of dopamine and serotonin were reduced in the cerebrospinal fluid of patients with TBI (Vecht et al., 1975). However, the effect of traditional tricyclic antidepressants on the depression following TBI has been controversial; i.e. these proved to be effective in some studies Received 28 September 2004 Accepted 15 November 2004

98

h. lee

(Wroblewski et al., 1996) and failed to show significant effects in other studies (Dinan and Mobayed, 1992; Saran, 1985). Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, citalopram or sertraline have seemed to be effective on depressive symptoms following TBI (Cassidy, 1989; Fann et al., 2000; Perino et al., 2001). Methylphenidate (MPD) might be a candidate drug for treating depression following TBI, considering its effectiveness on depression in patients with organic brain lesions such as stroke (Grade et al., 1998; Lazarus et al., 1994). For treating cognitive impairments following TBI, dopaminergic agonists or psychostimulants have been recommended as the first line drugs (Kraus, 1995; Whyte et al., 2002). Of them, methylphenidate has been the most widely studied, and its effectiveness has been proved in some studies (Kaelin et al., 1996; Whyte et al., 1997) and contested in others (Speech et al., 1993; Williams et al., 1998). SSRIs have also shown conflicting results. Sertraline (SER) had beneficial effects on cognitive function in a study (Fann et al., 2001), while it failed to show improvement in another study (Meythaler et al., 2001). With respect to sleep problems following TBI, there was a case report presenting the effectiveness of methylphenidate in the treatment of posttraumatic narcolepsy (Francisco and Ivanhoe, 1996). However, there have been few systematized clinical trials for sleep problems in patients with TBI. Overall, the treatment effectiveness of psychopharmacological drugs on neuropsychiatric sequelae after TBI has shown inconsistent results. This may be due to selection bias in that study samples consisted of patients with differing degrees of TBI, and whose treatment effects might therefore be different. Other limitations were that many previous studies did not have a control group, which would make it difficult to discriminate whether the improvement was caused by the effects of the medication or had occurred naturally with time (Rutherford et al., 1979); in addition, the researchers have focused on limited symptom domains, although TBI yielded to various neuropsychiatric sequelae. In addition, to our knowledge, there has been no comparison trial between methylphenidate and antidepressants in these respects. To clarify these issues, a placebo controlled comparative drug study (MPD vs SER) was conducted with standardized assessment scales in patients with mild to moderate degrees of TBI. The principal objective of the present study was to compare the effects of methylphenidate, sertraline and the placebo on the various neuropsychiatric sequelae of TBI. Copyright # 2005 John Wiley & Sons, Ltd.

ET AL.

METHODS Subjects Study subjects were recruited from patients with TBI in Mokpo Hankook Hospital Trauma Center (Chonnam, Republic of Korea). At screening, all eligible subjects were evaluated by clinical interview, physical and neurological examinations, laboratory tests, brain computed tomography (CT), and psychiatric assessment including the Beck Depression Inventory (BDI) (Beck et al., 1961), Mini-Mental State Examination (MMSE) (Folstein et al., 1975) and the Korean translation of Composite Scale (KtCS) (Yoon et al., 1997). The KtCS, originally developed by Smith et al. in 1989, was employed as a tool for identifying subjects’ circardian rhythm types as morning, evening or intermediate. To ascertain the homogeneity of the study sample, all subjects were required (i) to have a mild to moderate degree of TBI, defined by the criteria that the duration of unconsciousness was less than 20 min, memory loss was less than 24 h after head trauma (McAllister, 1994); (ii) to have been injured over 2 weeks ago but no longer than 1 year ago; (iii) to be aged 18–55; (iv) and to meet the diagnostic criteria for major depressive episode by DSMIV (American Psychiatric Association, 1994); (v) to have with a score of 18 or higher on the BDI; (vi) to have a score of 20 or higher on the MMSE; (vii) to be in the intermediate type of circardian rhythm evaluated by the KtCS. Subjects were excluded from the study if they were known or suspected (i) to have multiple trauma making examinations impossible; (ii) to have current serious or progressive medical illnesses, serious allergy to any drug, current schizophrenia, or epilepsy; (iii) to have significantly abnormal findings in laboratory examinations; (iv) to have been treated with neuroleptics within 2 weeks, monoamine oxidase inhibitors within 3 weeks, SSRIs within 4 weeks, and lithium or electroconvulsive therapy within 8 weeks before baseline, and finally; (v) to be involved in other experimental drug trials within 3 months from baseline. This study was approved by Chonnam National University Hospital Review Board. Prior to investigation, the nature and purpose of the study was explained to all eligible patients, and written informed consent was obtained from all participants. Study design and procedure This was a 4-week prospective, double-blind, placebo-controlled, comparative drug trial with methylphenidate or sertraline. The three patient groups were matched by age, gender and education, but Hum Psychopharmacol Clin Exp 2005; 20: 97–104.

methylphenidate and sertraline in tbi otherwise were randomly allocated. Methylphenidate was started at 5 mg/day and was gradually increased by 2.5 mg every day until it reached 20 mg/day. Sertraline was started at 25 mg and was increased by 25 mg every 2 days until it reached 100 mg/day. The administered doses of MPD and SER were selected based on previous studies (Leonard et al., 2004; Meythaler et al., 2001; Williams et al., 1998). MPD and SER were given in equally divided doses at 8 am and 12 pm. The MPD and SER of different doses and placebo were supplied in identical capsules to ensure the double-blind nature of the study. Baseline demographic and clinical characteristics were ascertained. The outcome of efficacy was measured at baseline and at the 4-week endpoint in the domains of depressive symptoms, postconcussional symptoms, quality of life, sleep and daytime sleepiness, as well as cognitive function. A questionnaire on sleep was completed immediately after awaking in the morning. Tests on cognitive function were performed approximately 90 min after the morning medication. Scales for depressive and postconcussional symptoms, and daytime sleepiness were adminstered at 5 pm. Prior to the investigation, all subjects were thoroughly trained on all psychometric tests. They were asked to avoid staying up all night and taking medicine that could affect sleep or cognitive performance for 24 h before the test. Smoking was not permitted during the morning of the test day. No drinks or food containing caffeine were allowed during the test day. Adverse events were monitored at the time of development by hospital staff for inpatients and were investigated (both patient and caregiver were interviewed) at each visit to the outpatient clinic. The authors adopted conventional methods for calculating the sample size, which is used to detect one standard difference with a statistical power of 80% and a significance level of 0.05. At least 15 patients were needed in each group to satisfy the condition. A total of 76 patients with TBI were enrolled within the time frame of the present study. Unfortunately, only 30 subjects fulfilled the required inclusion and exclusion criteria, and completed all the questionnaires and tests (described below in detail) of the study. Therefore, each group (MDP, SER and placebo) was composed of ten patients with TBI. With this sample size, 1.25 standard differences in the tests are needed for detecting the differences between the study groups with a statistical power of 80%. Assessments and measures Baseline characteristics. Data on age, gender, education, elapsed time from the head trauma and the preCopyright # 2005 John Wiley & Sons, Ltd.

99

sence of abnormal findings in the brain CT were obtained. Depressive symptoms. The Hamilton Rating Scale for Depression (HAM-D) (Hamilton, 1960) and the BDI were used. The HAM-D was administered by the examiner, while the BDI was self reported. The HAM-D consists of 17 items and the BDI consists of 21 items, each of which ranges from 0 point to 3 points. A higher score indicates a greater degree of depression. Postconcussional symptoms. The Rivermead PostConcussion Symptoms Questionnaire (RPQ) (King et al., 1995) was administered to measure the degree of common symptoms of head trauma. It consists of 16 items with Likert formation (0–4). A higher score indicates greater pathology. Quality of life. The SmithKline Beecham ‘Quality of Life’ Scale (SBQoL) was used (Stoker et al., 1992). It consists of 23 items, which ranges from 1–10 points. A higher score indicates a better quality of life. Its Korean version was proven to be reliable and valid (Yoon et al., 1998). Cognitive function. 1.Critical Flicker Fusion Threshold (CFFT). This is a means of measuring the ability to distinguish units of sensory data and is taken as an index of overall CNS activity (Hindmarch, 1982). Patients were required to discriminate flicker from fusion and vice versa, in a set of four light emitting diodes held in foveal fixation at 1 m. Individual thresholds were determined by the psychophysical method of limits on three ascending and three descending scales (Woodworth and Schlosberg, 1958). 2. Choice Reaction Time (CRT). This task assesses the overall sensori-motor performance by measuring the ability to attend and respond to a stimulus (Hindmarch and Parrot, 1977). From a central starting position, patients were required to extinguish one of six equidistant red lights illuminated at random by touching the appropriate response button next to the light. The test provides three measures: Recognition Reaction Time (RRT) (time to notice the stimulus), Motor Reaction Time (MRT) (time to respond by pressing the appropriate button) and Total Reaction Time (TRT). The mean reaction time for 20 stimulus presentations was recorded. 3. Compensatory Tracking Task (CTT). The CTT assesses skilled and exact motor ability, reacting to complex visual information such as driving (Hindmarch et al., 1983). Patients were required to keep Hum Psychopharmacol Clin Exp 2005; 20: 97–104.

100

h. lee

a computer mouse controlled cursor (an equilateral triangle with 1 cm sides) in line with a computer controlled target (a smaller triangle inverted) moving along a horizontal axis in the centre of the screen in random fashion while simultaneously responding to visual stimuli (filled white circles, with 1 cm diameter) presented briefly and randomly in the four corners of the screen. The root mean square (RMS) of the tracking error and the reaction times to the ten peripheral stimuli were recorded at each presentation. The duration of the task was approximately 2 min. 4. Mental Arithmetic Test (MAT). The MAT assesses ability for problem solving in information processing (Hindmarch, 1980). Patients were required to push the ‘yes’ or ‘no’ button as rapidly as possible, responding to whether the one digit addition or subtraction equations presented in the monitor were correct. Half of the examples of equation presented were correct. The average time taken to push the ‘yes’ button to a right answer and the ‘no’ button to a wrong answer was measured. 5. Sternberg Memory Scanning Task (STM). The STM measures high speed scanning ability and retrieval from short term memory using a reaction time technique (Sternberg, 1975). Patients were required to memorize a series of one, three or five digits, which were randomly displayed on the computer screen. They were then presented with a series of individual probe digits and were required to respond to the probes by pushing the ‘yes’ or ‘no’ button. The average time required for a correct answer was measured. 6. Digit-Symbol Substitution Test (DSST). The DSST (Wechsler, 1981) measures general cognitive efficiency and visuo-motor coordination. In the present study, the subtest of the Korean-Wechsler Adult Intelligence Scale (Yum et al., 1992) was applied for the DSST. The number of correct substitutions in a 90 s period was the response measure taken. 7. Mini-mental state examination (MMSE). The MMSE is a screening test widely used in general clinical practice for cognitive impairment, which consists of 30 items. A lower score indicates a greater degree of cognitive impairment (Folstein et al., 1975). Sleep and daytime sleepiness. The Leeds Sleep Evaluation Questionnaire (LSEQ) (Parrot and Hindmarch, 1980) was administered for assessing sleep. It measures aspects of subjective assessment on factors of sleep, i.e. ease of getting to sleep (GTS), quality of sleep (QOS), ease of awakening in the morning from sleep (AFS) and integrity of behaviour following wakefulness (BFS) using 100 mm line analogue rating Copyright # 2005 John Wiley & Sons, Ltd.

ET AL.

scales. A lower score indicates better sleep condition. Patients were required to rate how they perceived these four factors at the time of rating. Using the Chonnam Epworth Sleepiness Scale (CESS), patients were asked to rate the likelihood of their falling asleep in a number of everyday situations. The CESS is an adaptation of the Epworth Sleepiness Scale (Johns, 1991) using a set of 100 mm visual analogue rating scales. The overall mean score represents the level of daytime sleepiness. Adverse events All adverse events which occurred during the course of the study were recorded on the case report form. Their relationships to the treatment drugs were assessed. Statistical analyses The baseline characteristics of the three drug groups (MPD, SER and placebo) were compared by ANOVA or Fisher’s exact test, as appropriate. In the efficacy analyses, a repeated measures of ANOVA was fitted with factors for treatment group and time points. If the analysis showed a significant group
time interaction, a post hoc analysis was further carried out using the Tukey test. Statistical analyses were conducted with SPSS 10.0. RESULTS A total of 76 patients with TBI were enrolled within the timeline of the present study. Of them, only 30 subjects fulfilled the required inclusion and exclusion criteria, and completed all the questionnaires and tests of the study. Each group (MDP, SER and the placebo) was composed of ten patients with TBI. Baseline demographic and clinical characteristics are summarized in Table 1. There were no significant differences in these regards among the three groups. Data on depressive and postconcussional symptoms, and quality of life are displayed in Table 2. Depressive symptoms measured by the BDI and HAM-D improved significantly in all three groups. However, the post hoc analyses for the interaction between group
time showed that methylphenidate and sertraline were significantly superior to the placebo in HAM-D. Postconcussional symptoms were significantly improved in the MPD and placebo groups, while no significant improvement was observed in the SER group. Quality of life was significantly improved in all three groups. Hum Psychopharmacol Clin Exp 2005; 20: 97–104.

101

methylphenidate and sertraline in tbi Table 1. General description of the study groups Methylphenidate (n ¼ 10) Age, mean (SD) years Gender, M : F Education, mean (SD) years Interval from head trauma, mean (SD) days Abnormal brain computed tomography finding, no : yes

35.3 (8.0) 8:2 11.4 (1.9) 34.8 (3.9) 8:2

Sertraline (n ¼ 10)

Placebo (n ¼ 10)

33.6 (12.3) 8:2 10.1 (3.5) 31.9 (5.8) 9:1

35.5 (7.2) 8:2 11.0 (2.3) 30.0 (6.5) 7:3

All p-values for comparing independent variables among the study groups were over 0.1.

Table 2. Data on depressive and postconcussion symptoms, and quality of life Test

BDI (score)

Time

Baseline 4 week HAM-D (score) Baseline 4 week RPQ (score) Baseline 4 week KvSBQoL (score) Baseline 4 week

Methylphenidate (M) (n ¼ 10)

Sertraline (S) (n ¼ 10)

24.5 (9.0) 17.6 (11.1)c 25.2 (4.1) 15.7 (5.6)c 38.0 (7.8) 24.8 (10.0)c 101.1 (15.6) 119.4 (11.9)b

30.0 (8.6) 21.6 (6.5)b 27.6 (6.2) 20.0 (4.6)b 32.0 (10.2) 30.3 (9.4) 91.4 (33.9) 112.9 (10.9)a

Placebo (P) Group effect Group
time effect Post hoc (n ¼ 10) p F p Comparison p 25.9 (4.0) 20.8 (7.8)a 25.7 (4.7) 22.3 (4.2)b 39.4 (8.8) 30.4 (10.7)a 95.3 (25.6) 109.8 (31.9)a

0.407

1.196

0.318

0.167

6.365

0.005

0.496

2.859

0.075

0.642

0.333

0.719

M>P S>P

0.005 0.050

BDI, Beck Depression Inventory; HAM-D, Hamilton Rating Scale for Depression; RPQ, Rivermead Postconcussion Symptoms Questionnaire; KvSBQoL, Korean version of SmithKline-Beecham Quality of Life Scale. a p < 0.05; bp < 0.01; cp < 0.001 compared with baseline.

Data on cognitive function are displayed in Table 3. Overall, significant time effects were found in most cognitive tests in the MPD and placebo groups, while was not in the SER group. In particular, there were significantly better improvements on the RRT in the MPD and placebo groups compared with the SER group in the post hoc tests. Data on sleep and daytime sleepiness are displayed in Table 4. All three groups showed significant improvement in QOS and BFS in the LSEQ. GTS was significantly improved only in the SER group. However, AFS was significantly improved in MPD and placebo groups, and MPD group showed a significant superior effect to the SER group in the post hoc analyses. Daytime sleepiness was significantly improved in MPD and the placebo groups as well. During the 4 week trial, the nature and numbers of adverse events related to treatment drugs were noted. The total number of adverse events was significantly higher in the SER group than in the MPD group (13 vs 6; p ¼ 0.010). This difference mainly arose from the ‘autonomic’ aspects of adverse events such as nausea/vomiting, diarrhoea, constipation, palpitation, sweating, and so on (7 vs Copyright # 2005 John Wiley & Sons, Ltd.

3; p ¼ 0.045). There were no differences in other aspects of adverse events. DISCUSSION Considerable efforts have been made to investigate the psychopharmacological treatment of neuropsychiatric sequelae after TBI. However, there have been few well-controlled systematized studies for pharmacological treatment of cognitive impairment as well as behavioural disturbances following TBI. The subjects in most previous studies were not homogenous in terms of age (Kaelin et al., 1996; Whyte et al., 1997) which is closely related with cognitive decline, intensity of trauma (Kaelin et al., 1996; Plengeretal., 1996; Speech et al., 1993; Whyte et al., 1997) and post-injury periods (Plenger et al., 1996; Speech et al., 1993; Whyte et al., 1997; Williams et al., 1998) which are important factors for clinical outcome from TBI. Furthermore, there has been no drug comparison study in these respects, which made it difficult to determine guidelines for the choice of drug in clinical practice. To our knowledge, this study is the first to compare a drug’s effectiveness on Hum Psychopharmacol Clin Exp 2005; 20: 97–104.

102

h. lee

ET AL.

Table 3. Data on cognitive function Test

Time

CFFT (Hz)

Baseline 4 week RRT (ms) Baseline 4 week MRT (ms) Baseline 4 week TRT (ms) Baseline 4 week CTT (pixel) Baseline Tracking task 4 week CTT (ms) Baseline Peripheral 4 week MAT (ms) Baseline 4 week STM (ms) Baseline 4 week DSST (score) Baseline 4 week MMSE (score) Baseline 4 week

Methylphenidate (M) (n ¼ 10) 31.4 (3.3) 32.8 (2.6)a 399.2 (51.2) 340.2 (34.5)b 217.4 (38.6) 178.7 (26.7)b 616.6 (76.4) 518.9 (51.9)c 51.5 (36.2) 27.0 (9.1)a 673.2 (213.6) 575.0 (187.5)c 4519.9 (1779.0) 4433.9 (2074.5) 1147.7 (304.5) 937.7 (317.5)b 40.1 (14.9) 54.2 (14.4)c 26.7 (3.8) 29.4 (1.3)a

Sertraline (S) (n ¼ 10)

Placebo (P) Group effect Group
time effect Post hoc (n ¼ 10) p F p Comparison p

31.3 (2.9) 30.0 (2.1) 31.5 (2.8) 31.0 (1.6)a 405.8 (56.7) 443.8 (60.7) 389.5 (61.3) 377.3 (37.1)b 242.2 (60.5) 245.5 (22.1) 208.0 (43.2) 221.8 (14.8)b 648.1 (108.2) 689.3 (71.3) 597.5 (89.2)a 599.0 (41.1)b 56.2 (19.4) 44.8 (18.4) 41.5 (13.6) 36.0 (11.3)a 679.7 (176.2) 779.0 (365.6) 656.1 (161.7) 701.5 (202.5) 5419.3 (1401.2) 6140.6 (4671.4) 6369.8 (2958.4) 6093.3 (3720.4) 1320.6 (260.3) 1156.5 (373.9) 1292.8 (474.9) 929.2 (207.8)a 31.5 (8.2) 31.6 (14.2) 40.8 (10.7)a 38.5 (16.0)b 27.0 (2.6) 26.9 (2.2) 28.1 (2.0) 27.9 (1.7)

0.356

1.840

0.178

0.161

4.486

0.021

0.055

0.443

0.647

0.061

1.929

0.165

0.399

1.418

0.260

0.479

0.561

0.577

0.392

1.060

0.361

0.086

1.208

0.314

0.085

2.637

0.090

0.760

1.507

0.240

M>S P>S

0.045 0.026

CFFT, Critical Flicker Fusion Threshold; RRT, Recognition Reaction Time; MRT, Motor Reaction Time; TRT, Total Reaction Time; CTT, Compensatory Tracking Task; MAT, Mental Arithmetic Test; STM, Sternberg Memory Scanning Task; DSST, Digit Symbol Substitution Test; MMSE, Mini-Mental State Examination. a p < 0.05; bp < 0.01; cp < 0.001 compared with baseline. Table 4. Data on sleep and daytime sleepiness Test

LSEQ (mm) GTS LSEQ (mm) QOS LSEQ (mm) AFS LSEQ (mm) BFS CESS (mm)

Time

Baseline 4 week Baseline 4 week Baseline 4 week Baseline 4 week Baseline 4 week

Methylphenidate (M) (n ¼ 10) 63.2 (17.7) 50.2 (3.5) 67.8 (11.3) 51.7 (5.0)b 74.6 (12.7) 52.1 (6.1)b 72.1 (17.3) 50.9 (2.6)b 61.2 (8.5) 53.5 (4.2)b

Sertraline (S) (n ¼ 10) 62.2 (15.8) 51.6 (12.2)a 63.3 (21.5) 50.0 (14.7)b 65.2 (17.7) 61.0 (11.5) 72.1 (14.4) 58.7 (11.5)b 55.3 (13.9) 52.2 (7.2)

Placebo Group effect Group
time effect (P) (n ¼ 10) p F p 62.9 (22.6) 54.8 (11.2) 68.5 (11.9) 62.2 (12.3)a 71.2 (14.8) 56.2 (10.0)c 73.4 (12.4) 61.4 (15.1)a 64.4 (8.6) 58.4 (6.7)a

0.912

0.206

0.815

0.308

2.140

0.137

0.991

5.320

0.011

0.474

1.135

0.336

0.099

0.766

0.475

Post hoc Comparison

p

M>S

0.009

LSEQ, Leeds Sleep Evaluation Questionnaire; GTS, Ease of Getting to Sleep; QOS, Quality of Sleep; AFS, ease of waking in the morning from sleep; BFS, integrity of behaviour following wakefulness; CESS, Chonnam Epworth Sleepiness Scale. a p < 0.05; bp < 0.01; cp < 0.001 compared with baseline.

various neuropsychiatric symptoms following mild to moderate TBI with standardized assessment scales. Because methylphenidate and sertraline have different pharmacological mechanisms, it is worthwhile comparing their effects. Another strength of the present study was that the homogeneity of the study sample was kept in terms of demographic and clinical characteristics. Both methylphenidate and sertraline significantly improved the patients’ depressive symptoms, and no Copyright # 2005 John Wiley & Sons, Ltd.

significant differences were found in the treatment effectiveness between the two drugs. These findings supported the theory that at the neurotransmitter level, depressive symptoms following TBI were associated with both dopaminergic and serotonergic systems (Vecht et al., 1975). When compared with the placebo, methylphenidate and sertraline had significantly better effects on depressive symptoms measured by HAM-D, while no significant differences were found in the BDI scale. It could be suggested that an Hum Psychopharmacol Clin Exp 2005; 20: 97–104.

methylphenidate and sertraline in tbi objective instrument as well as a subjective one might be needed to evaluate the changes of depressive symptoms following TBI. In terms of cognitive function, methylphenidate and the placebo significantly improved nine and seven of ten cognitive tests assessed in the study, respectively. On the other hand, sertraline had significant beneficial effects only on two tests. From these results, methylphenidate seemed to facilitate the recovery process but sertraline did not and possibly hindered the natural recovery process in patients in a subacute stage of TBI. Methylphenidate increases the synaptic concentration of dopamine and noradrenaline by blocking their reuptake, resulting in an increase in extracellular levels of these neurotransmitters in various brain regions (Whyte et al., 2002). These mechanisms contribute to improving cognitive functions such as attention, memory and mental processing (Kaelin et al., 1996; Plenger et al., 1996; Whyte et al., 1997) as well as depression. Sertraline has shown controversial effects on cognitive function (Fann et al., 2001; Meythaler et al., 2001). Depression is associated with executive function (Jorge et al., 2004), therefore it is important to consider depressive symptoms when evaluating cognitive function. In the present study, sertraline had significant effects on depressive symptoms but not on most of the cognitive domains. Regarding the ease of waking in the morning, methylphenidate showed a significantly superior effect to sertraline. In addition, methylphenidate and the placebo significantly reduced daytime sleepiness assessed by the CESS, while sertraline did not. So, it would be reasonable to conclude that the relatively inferior effects of sertraline on daytime alertness might be one of the contributing factors for its lesser effect on cognitive performances compared with methylphenidate and the placebo. Postconcussional symptoms measured by the RPQ were significantly improved by methylphenidate and the placebo, but were not by sertraline. These results might be related to the side effect profiles of the drugs, which scored higher in sertraline than methylphenidate or the placebo. However, the quality of life was improved in all three drug-treatment results, which meant all drugs were generally effective. Summing up our results, various neuropsychiatric sequelae following mild to moderate TBI seemed to take a natural recovery course, in the subacute stage of TBI. Methylphenidate had significant effects on depressive symptoms compared with the placebo, without hindering the natural recovery process of cognitive functioning. Sertraline also had significant effects on depressive symptoms compared with the Copyright # 2005 John Wiley & Sons, Ltd.

103

placebo. However, sertraline did not improve most cognitive performances, and even significantly hindered the natural recovery process, particularly in recognition reaction time tasks. However, several points should be considered before drawing conclusions on the comparative results of methylphenidate and sertraline. First, to maintain the double-blind study design, all drugs were given during the daytime. This regime might be more favourable for methylphenidate. Second, this was a 4 week study, which may be a sufficient period for treatment response of methylphenidate but not of sertraline. Third, there was a report that the effect waned and tolerance developed after a period of time with methylphenidate administration (Gaultiere and Evans, 1988). Fourth, other factors affecting the outcome of TBI treatments such as existing cognitive difficulties, past psychiatric history, and the area of brain injury were not investigated. And finally, the sample size was not adequate for proper investigation. Future research will be required with larger sample sizes and longer follow-up periods. At the present stage, it is concluded that in patients with mild to moderate TBI, both methylphenidate and sertraline had significant effects on the depressive symptoms compared with the placebo, while methylphenidate seemed to have more beneficial effects on cognitive function and daytime alertness than sertraline, at least in the 4 week treatment of patients with TBI. REFERENCES American Psychiatric Association. 1994. Diagnositc and Statistical Manual of Mental Disorders, 4th edn. American Psychiatric Press Inc: Washington, DC. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. 1961. An inventory for measuring depression. Arch Gen Psychiatry 5: 561–571. Bruns J Jr, Hauser WA. 2003. The epidemiology of traumatic brain injury: a review. Epilepsia 44(Suppl): 2–10. Cassidy JW. 1989. Fluoxetine: a new serotonergically active antidepressant. J Head Trauma Rehabil 4: 67–69. Castriotta RJ, Lai JM. 2001. Sleep disorders associated with traumatic brain injury. Arch Phys Med Rehabil 82: 1403–1406. Dinan TG, Mobayed M. 1992. Treatment resistance of depression after head injury: a preliminary study of amitriptyline response. Acta Psychiatr Scand 85: 292–294. Fann JR, Uomoto JM, Katon WJ. 2000. Sertraline in the treatment of major depression following mild traumatic brain injury. J Neuropsychiatry Clin Neurosci 12: 226–232. Fann JR, Uomoto JM, Katon WJ. 2001. Cognitive improvement with treatment of depression following mild traumatic brain injury. Psychosomatics 42: 48–54. Folstein MF, Folstein SE, McHugh PR. 1975. Mini-mental state: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12: 189–198.

Hum Psychopharmacol Clin Exp 2005; 20: 97–104.

104

h. lee

Francisco G, Ivanhoe C. 1996. Successful treatment of posttraumatic narcolepsy with methylphenidate: a case report. Am J Phys Med Rehabil 75: 63–65. Gaultiere CT, Evans RW. 1988. Stimulant treatment for the neurobehavioural sequelae of traumatic brain injury. Brain Inj 2: 273–290. Grade C, Redford B, Chrostowski J, Toussaint L, Blackwell B. 1988. Methylphenidate in early poststroke recovery: a doubleblind, placebo-controlled study. Arch Phys Med Rehabil 79: 1047–1050. Hamilton M. 1960. A rating scale for depression. J Neurol Neurosurg Psychiatry 23: 56–62. Hindmarch I. 1980. Psychomotor function and psychoactive drugs. Br J Clin Pharmacol 10: 189–209. Hindmarch I. 1982. Critical Flicker Fusion Frequency (CFF): the effects of psychotropic compounds. Pharmacopsychiatrica 15(S1): 44–48. Hindmarch I, Subhan Z, Stoker MJ. 1983. The effects of zimelidine and amitriptyline on car driving and psychomotor performance. Acta Psychiatr Scand 68: 141–146. Hindmarch I, Parrott AC. 1977. Repeated dose comparisons of nomifensine, imipramine and placebo on subjective assessments of sleep and objective measures of psychomotor performance. Br J Clin Pharmacol 4(S2): 167–173. Johns MW. 1991. A new method for measuring daytime sleepiness: The Epworth Sleepiness Scale. Sleep 14: 540–545. Jorge RE, Robinson RG, Moser D, Tateno A, Crespo-Facoro B, Arndt S. 2004. Major depression following traumatic brain injury. Arch Gen Psychiatry 61: 42–50. Kaelin KL, Cifu DX, Matthies B. 1996. Methylphenidate effect on attention deficit in the acutely brain-injured adult. Arch Phys Med Rehabil 77: 6–9. King NS. 1996. Emotional, neuropsychological, and organic factors: their use in the prediction of persisting postconcussion symptoms after moderate and mild head injuries. J Neurol Neurosurg Psychiatry 61: 75–81. King NS, Crawford S, Wenden FJ, Moss NE, Wade DT. 1995. The Rivermead Postconcussion Symptoms Questionnaire: a measure of symptoms commonly experienced after head injury and its reliability. J Neurol 242: 587–592. Kraus MF. 1995. Neuropsychiatric sequelae of stroke and traumatic brain injury: the role of psychostimulants. Int J Psychiatry Med 25: 39–51. Lazarus LW, Moberg PJ, Langsley PR, Lingam VR. 1994. Methylphenidate and nortriptyline in the treatment of poststroke depression: a retrospective comparison. Arch Phys Med Rehabil 75: 403–406. Leonard BE, McCartan D, White J, King DJ. 2004. Methylphenidate: a review of its neuropharmacological, neuropsychological and adverse clinical effects. Hum Psychopharmacol 19: 151–180. McAllister TW. 1994. Mild traumatic brain injury and the postconcussive syndrome. In Neuropsychiatry of Traumatic Brain Injury, Silver JM, Yudofsky SC, Hales RE (eds). American Psychiatric Press Inc: Washington, DC; 357–392. Meythaler JM, Depalma L, Devivo MJ, Guin-Renfroe S, Novack TA. 2001. Sertraline to improve arousal and alertness in severe traumatic brain injury secondary to motor vehicle crashes. Brain Inj 15: 321–331. Millis SR, Rosenthal M, Novack TA, et al. 2001. Long-term neuropsychological outcome after traumatic brain injury. J Head Trauma Rehabil 16: 343–355. Parrot AC, Hindmarch I. 1980. The Leeds Sleep Evaluation Questionnaire in psychopharmacological investigation—a review. Psychopharmacology 71: 173–179.

Copyright # 2005 John Wiley & Sons, Ltd.

ET AL.

Perino C, Rago R, Cicolini A, Torta R, Monaco F. 2001. Mood and behavioural disorders following traumatic brain injury: clinical evaluation and pharmacological management. Brain Inj 15: 139–148. Plenger PM, Dixon CE, Castilo RM, Frankowski RF, Yablon SA, Levin HS. 1996. Subacute methylphenidate treatment for moderate to moderately severe traumatic brain injury: a preliminary double-blind placebo-controlled study. Arch Phys Med Rehabil 77: 536–540. Rutherford WH, Merrett JD, McDonald JR. 1979. Symptoms at one year following concussion from minor head injuries. Injury 10: 225–230. Saran AS. 1985. Depression after minor closed head injury: role of dexamethasone suppression test and antidepressants. J Clin Psychiatry 46: 335–338. Seel RT, Kreutzer JS, Rosenthal M, Hammond FM, Corrigan JD, Black K. 2003. Depression after traumatic brain injury: a National Institute on Disability and Rehabilitation Research Model Systems multicenter investigation. Arch Phys Med Rehabil 84: 177–184. Smith CS, Reilly C, Midkiff K. 1989. Evaluation of three circadian rhythm questionnaires with suggestions for an improved measure of morningness. J Appl Psychol 74: 728–738. Speech TJ, Rao SM, Osmon DC, Sperry LT. 1993. A double-blind controlled study of methylphenidate treatment in closed head injury. Brain Inj 7: 333–338. Sternberg S. 1996. High speed scanning in human memory. Science 153: 652–654. Stoker MJ, Dunbar GC, Beaumont G. 1992. The SmithKline Beecham ‘Quality of Life’ Scale: a validation and reliability study in patients with affective disorder. Qual Life Res 1: 385–395. Vecht CJ, van Woerkom CA, Teelken AW, Minderhoud JM. 1975. Homovanillic acid and 5-hydroxyindoleacetic acid cerebrospinal fluid levels: a study with and without probenecid administration of their relationship to the state of consciousness after head injury. Arch Neurol 32: 792–797. Wechsler D. 1981. Wechsler Adult Intelligence Scale-Revised. The Psychological Corporation: New York. Whyte J, Hart T, Schuster K, Fleming M, Polansky M, Coslett HB. 1997. Effects of methylphenidate on attentional function after traumatic brain injury. Am J Phys Med Rehabil 76: 440–450. Whyte J, Vaccaro M, Grieb-Neff P, Hart T. 2002. Psychostimulant use in the rehabilitation of individuals with traumatic brain injury. J Head Trauma Rehabil 17: 284–299. Williams SE, Douglas Ris M, Ayyangar R, Schefft BK, Berch D. 1998. Recovery in pediatric brain injury: is psychostimulant medication beneficial? J Head Trauma Rehabil 13: 73–81. Woodworth RS, Schlosberg H. 1958. Experimental Psychology. London. Wroblewski BA, Joseph AB, Cornblatt RR. 1996. Antidepressant pharmacotherapy and the treatment of depression in patients with severe traumatic brain injury: a controlled, prospective study. J Clin Psychiatry 57: 582–587. Yoon JS, Kook SH, Lee MS. 1998. A preliminary study on Korean Version of the SmithKline Beecham ‘Quality of Life’ (KvSBQoL). J Korean Neuropsychiatr Assoc 37: 280–294. Yoon JS, Shin SM, Kook SH, Lee HY. 1997. A preliminary study on the Korean Translation of Composite Scale (KtCS) to measure morningness-eveningness. J Korean Neuropsychiatr Assoc 36: 122–134. Yum TH, Park YS, Oh KJ, Kim JG, Lee YH. 1992. Manual for the Korean Wechsler Adult Intelligence Scale. Korea Guidance: Seoul.

Hum Psychopharmacol Clin Exp 2005; 20: 97–104.