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Name /oak/jn 122_5y4356/M _226 05/01/2000 07:52AM Plate # 0 Sertraline in the
Treatment of Major
Depression Following
Mild Traumatic
Brain Injury
Jesse R. Fann, M.D., M.P.H.
Jay M. Uomoto, Ph.D.
Wayne J. Katon, M.D.

An 8-week, nonrandomized, single-blind, placebo run-in trial of sertraline was conducted on 15 pa- oftraumatic brain injury (TBI) in both inpatient tients diagnosed with major depression between 3 and outpatient populations.1 Although most studieshave included a majority ofpatients with moderate to and 24 months after a mild traumatic brain in- severe injuries, patients with mild injuries also appear jury. On the Hamilton Rating Scale for Depres- to have an increased risk for depression after TBI.2 Pa- sion, 13 (87%) had a decrease in score of 50% tients with TBI and subsequent depression have greater ("response"), and 10 (67%) achieved a score of functional disability and postconcussive symptoms and ⱕ7 ("remission") byweek 8 of sertraline. There perceive their injury as more severe than do those with- was statisticallysignificant improvement in psy- chological distress, anger and aggression, func- Studies in other medical and neurological populations tioning, and postconcussive symptoms with treat- have shown that treating depression can be effective andcan decrease functional impairment, somatic symptoms, and perception ofimpairment. A few studies have ex- (The Journal ofNeuropsychiatry and Clinical amined the efficacy of antidepressants in the treatment Neurosciences 2000; 12:226–232) ofdepression following TBI.4–8 However, few have fo-cused on those with mild TBI or have examined whethertreatment decreases functional disability and postcon-cussive symptoms.
The goals ofthis study were to determine iftreating major depression following mild TBI with sertraline, aselective serotonin reuptake inhibitor, is associated withdecreases in 1) symptoms ofdepression, 2) psychologi-cal distress, 3) functional disability, and 4) postconcus-sive symptoms.
Received June 22, 1999; revised July 30, 1999; accepted September 1,1999. From the Department ofPsychiatry and Behavioral Sciences,University ofWashington, and the Department ofGraduate Psychol-ogy, Seattle Pacific University, Seattle, Washington. Address corre-spondence to Dr. Fann, Department ofPsychiatry and Behavioral Sci-ences, Box 356560, University ofWashington, Seattle, WA 98195.
Copyright 䉷 2000 American Psychiatric Press, Inc.
J Neuropsychiatry Clin Neurosci 12:2, Spring 2000 Name /oak/jn 122_5y4356/M _227 05/01/2000 07:52AM Plate # 0 FANN et al.
(HISC),17 and the Sheehan Disability Scale18 modifiedfor patients with head injuries.
Subjects were informed that they would receive pla- Subjects were 16 consecutive ambulatory respondents to cebo for a week at some time during the trial as well as advertisements in local newspapers, health magazines, 8 weeks oftreatment with sertraline. All subjects re- and head injury support groups who had sustained a ceived one capsule ofan inert placebo every morning mild closed TBI within the past 3 to 24 months. Mild during the first week ofthe trial. Ifthe Ham-D decreased TBI was determined by using the criteria set forth by the by 50% or dropped below 10, the patient would be Head Injury Interdisciplinary Special Interest Group of judged a placebo responder but would complete the ac- the American Congress ofRehabilitation Medicine9 and tive treatment portion ofthe study. Patients were then is defined as manifested by at least one of the following: given an 8-week single-blind course ofsertraline, which a) any period ofloss ofconsciousness of30 minutes or started at 25 mg every morning. After 1 week, the dose less, b) any posttraumatic amnesia lasting not more than was adjusted in the range of25–50 mg per day, depend- 24 hours, c) any alteration ofmental status at the time ing on tolerability. Further adjustment was made in ofthe accident (e.g., feeling dazed, disoriented, or con- week 3 in the range of25–100 mg/day, and during fused), and d) any focal neurologic deficits, which may weeks 4 through 8 the dose was adjusted in the range or may not be transient, resulting in loss ofconscious- of25–200 mg/day, depending on clinical response and ness or posttraumatic amnesia no more severe than de- tolerability. Medication side effects were noted at each scribed in a) and b) and, after 30 minutes, an initial Glas- assessment point. The Ham-D and Clinical Global Im- gow Coma Scale10 score of13 to 15. Potential subjects pression scale (CGI)19 were administered at baseline and were asked to undergo an in-person diagnostic inter- weeks 1, 2, 4, 6, and 8. At week 8, all baseline question- view using the Diagnostic Interview Schedule (DIS).11 naires were readministered.
Patients were between 18 and 60 years old, met Treatment response was determined by a 50% drop DSM-III-R criteria for major depression on the DIS, and on the 17-item Ham-D from baseline to week 8. A re- had a minimum score of18 on the 17-item Hamilton mission was determined by a final Ham-D of7 or less.
Rating Scale for Depression (Ham-D).12 Repeated-measures analysis ofvariance (ANOVA) was Exclusion criteria included severe language or cog- used to compare Ham-D scores over time. Baseline and nitive deficits that would compromise their ability to endpoint psychological and disability measures were comprehend or answer verbal or written questions; cur- compared by use ofpaired t-tests. Two-sample t-tests for rent serious medical illness; pregnancy or breast- continuous variables and chi-square tests for categorical feeding; mass brain lesions; history of more than one variables were used to compare remitters to nonremit- TBI; current or past psychosis or mania; current alcohol ters on baseline data. All t-tests were two-tailed.
or drug abuse; current psychoactive medication use; McNemar's test was used to compare categorical data prior use ofsertraline; or current suicidal ideation re- on postconcussive symptom status on the HISC. For this quiring hospitalization. On the basis ofthese criteria, 32 analysis, the categories ofsymptoms that were wors- advertisement respondents were excluded from parti- ening or staying the same were combined and compared cipation. The four most common reasons for exclusion with the category ofsymptoms that were improving in were history ofmore than one TBI (n⳱8), more than 24 a 2⳯2 table ofconcordant and discordant pairs. Means months since TBI (n⳱7), prior use ofsertraline (n⳱5), are reported with standard deviations throughout.
and severity ofTBI (n⳱4).
All study participants gave written informed con- sent, as determined by the University ofWashington's institutional review board. All subjects were adminis-tered the depression, dysthymia, panic, generalized Sixteen patients began the study and 15 completed the anxiety, and alcohol and substance abuse and depen- protocol. The demographics ofthe patients who com- dence sections ofthe DIS. DSM-III-R symptoms ofpost- pleted the study are shown in Table 1. The mean age of traumatic stress disorder were also assessed during the the patients who completed the study was 41.9 years interview. All patients completed baseline question- (range 24–54). Thirteen (86.7%) were Caucasian. The naires, which included the Symptom Checklist-90– mean time from TBI to initial interview was 10.6 months Revised (SCL-90-R),13 the BriefAnger and Aggression (range 5–24). Six (40%) were currently in some form of Questionnaire,14 the Medical Outcomes Study Health litigation. The patient who dropped out ofthe study Status Questionnaire–Short Form (SF-36),15 the Sickness complained ofheadache, dizziness, nausea, tinnitus, Impact Profile,16 the Head Injury Symptom Checklist and lethargy after 1 day of sertraline 25 mg. Table 2 J Neuropsychiatry Clin Neurosci 12:2, Spring 2000 Name /oak/jn 122_5y4356/M _228 05/01/2000 07:52AM Plate # 0 SERTRALINE FOR DEPRESSION AFTER MILD TBI
shows the rates ofcurrent and lifetime psychiatric di- measures ANOVA (F⳱73.2; df⳱1,14; P⬍0.001). There agnoses among the 15 patients who completed the was no confounding by age, gender, or education. Sig- nificant drops were seen in the CGI severity, efficacy, The mean Ham-D score at baseline assessment was and improvement subscales from the end of placebo 25Ⳳ4.4 (range 18–32) among those who completed the run-in to the end oftreatment, with respective scores of study; the score was 24 for the patient who dropped out.
4.6 , 4.3, and 3.9 after placebo run-in and 1.9, 1.9, and None ofthe patients had a 50% drop in Ham-D after the 1.7 post-treatment (P⬍0.001 for all pairs). Thirteen 1-week, single-blind, placebo run-in period, and base- (86.7%) had a CGI improvement score of1 (very much line scores were not significantly different from scores improved) or 2 (much improved) at week 8. Standard- after 1 week of placebo. The mean Ham-D score at the ized T-scores on all SCL-90-R scales were reduced sig- end ofthe 8-week treatment phase was 7.2Ⳳ5.3 (range nificantly from baseline to week 8 (Figure 2).
1–22;), representing a mean drop of71.2%. Thirteen pa- The final dose ofsertraline ranged from 25 mg to 150 tients (86.7%) had a 50% drop in Ham-D ("response"), mg (mean⳱75Ⳳ39.0 mg). Remitters had a mean final and 10 (66.7%) had a final Ham-D score of7 or less ("re-mission"). Mean scores are displayed in Figure 1. No FIGURE 1.
Mean scores on the 17-item Hamilton Rating Scale
significant differences emerged between remitters and for Depression (Ham-D) among the 15 subjects who
nonremitters on any ofthe demographic or diagnostic completed the study. The 8-week mean was
variables listed in Tables 1 and 2. The post-treatment significantly lower than the baseline mean (P0.001)
and the post-placebo run-in mean (P

mean was significantly less than both the baseline mean (t⳱10.44, df⳱14, P⬍0.001), and the post-placebo run-in mean (t⳱11.14, df⳱14, P⬍0.001). A significant time ef- fect on Ham-D scores was found in the repeated- Characteristics of the 15 subjects who completed the
Female gender, n (%) Caucasian, n (%) baseline run-in week 1 week 2 week 4 week 6 week 8 Not married, n (%) Years ofeducation, meanⳲSD Months from injury to initial interview, meanⳲSD Involved in litigation, n (%) Family psychiatric history, n (%) FIGURE 2.
Standardized T-scores on the Symptom Checklist-90–
R (SCL-90-R) at baseline and after 8 weeks of
sertraline. Som
somatization; ocobsessive-
Current and lifetime psychiatric diagnoses of the 15
subjects who completed the study
positive symptom total; psdipositive symptom
distress index. *P
Prior to traumatic brain injury Generalized anxiety disorder Posttraumatic stress disorder Current and lifetime Note: Two patients had current comorbid generalized anxiety disorder and posttraumatic stress disorder. One patient had current Subscale of SCL-90-R comorbid generalized anxiety disorder and dysthymia.
J Neuropsychiatry Clin Neurosci 12:2, Spring 2000 Name /oak/jn 122_5y4356/M _229 05/01/2000 07:52AM Plate # 0 FANN et al.
dose of57.5Ⳳ23.7 mg, and nonremitters had a final dose were rated as being the same, worsening, or improving.
of110Ⳳ41.8 mg. Adverse effects that occurred in 3 or The number ofpatients who reported improving symp- more patients were nausea (n⳱4), abdominal cramps toms increased from baseline to week 8 for all 12 post- (n⳱4), headache (n⳱3), and diarrhea (n⳱3).
concussive symptoms (Table 3). There were significantly Scores on the BriefAnger and Aggression Question- more patients reporting improvement from baseline to naire dropped significantly (t⳱2.33, df⳱14, P⬍0.05) post-treatment in the symptoms ofheadache, fatigue, from a mean of 9.3Ⳳ4.1 at baseline to 6.5Ⳳ5.1 post- irritability, memory difficulties, and sleep disturbance.
Patients also rated the severity oftheir injury before Significant improvement was seen in the SF-36 sub- treatment, on average, as 4.7Ⳳ2.1 on a 0 to 10 Likert scales ofphysical role f unctioning (t⳱2.3, df⳱14, scale, which is significantly more severe than their post- P⬍0.05), emotional role functioning (t⳱4.4, df⳱14, treatment mean rating of3.4Ⳳ2.5 (t⳱3.0, df⳱14, P⬍0.005), social functioning (t⳱2.7, df⳱14, P⬍0.05), mental health (t⳱3.3, df⳱14, P⬍0.01), and vitality(t⳱5.9, df⳱14, P⬍0.001). Results are displayed in Fig-ure 3. Comparison scores in general, medical, depressed, and TBI populations have been reported elsewhere.3,20,21 Patients showed significant improvements on the This pilot study suggests that sertraline may be effica- Sickness Impact Profile subscales ofsleep and rest cious in treating major depression in patients who have (t⳱2.9, df⳱14, P⬍0.05), emotional behavior (t⳱3.8, sustained a mild traumatic brain injury within the past df⳱14, P⬍0.005), social interaction (t⳱2.4, df⳱14, 2 years. Two-thirds ofpatients had remission oftheir P⬍0.05), and work (t⳱2.3, df⳱11, P⬍0.05). Results are depression. Our findings are consistent with Cassidy's displayed in Figure 4. The subscales ofambulation, case series,4 in which 5 of9 patients with severe TBI and body care and movement, and mobility were excluded major depression were found to be "moderately" or because baseline scores were less than 10. Comparison "markedly" improved with the serotonergic antidepres- scores in general, medical, and TBI populations have sant fluoxetine. Reports ofthe efficacy oftricyclic anti- been reported elsewhere.16,17,22,23 depressants have been inconsistent.5–8 The inconsistent Scores on the Sheehan Disability Scale also improved results found in these latter studies may be due to the significantly from baseline to post-treatment in all 3 sub- small sample sizes, the wide range ofcase definitions scales of family functioning (5.5Ⳳ3.1 to 3.2Ⳳ3.7; t⳱3.0, for both TBI and depression, the inconsistent diagnostic df⳱14, P⬍0.05), social functioning (5.3Ⳳ2.8 to 3.5Ⳳ3.5; methods used, and the lack of controlling for confound- t⳱2.6, df⳱14, P⬍0.05), and work functioning (5.6Ⳳ2.8 ing variables. No large-scale, double-blind, placebo- to 3.8Ⳳ3.5; t⳱2.5, df⳱14, P⬍0.05).
controlled studies ofantidepressants f Patients rated postconcussive symptoms that were have been performed in the TBI population.
present after their TBI on the Head Injury Symptom The doses required in this study are similar to those Checklist at baseline and post-treatment. Symptoms needed in the general population for the treatment ofmajor depression without psychotic features. In general,side effects were minimal.
Scores on the SF-36 Health Status Questionnaire at
baseline and after 8 weeks of sertraline. *P
All subscales on the SCL-90-R decreased significantly, FIGURE 4.
Scores on the Sickness Impact Profile (SIP) at
baseline and after 8 weeks of sertraline. *P0.05;
*sleep **emotional home *social alertness *work recreation total J Neuropsychiatry Clin Neurosci 12:2, Spring 2000 Name /oak/jn 122_5y4356/M _230 05/01/2000 07:52AM Plate # 0 SERTRALINE FOR DEPRESSION AFTER MILD TBI
suggesting that treating depression decreases overall suggesting altered serotonin function in these patients psychological distress across many domains. Because compared with patients not depressed after mild TBI.27 patients with TBI typically do not present with symp- Behavioral problems, particularly agitation and ag- toms that fall into strict DSM diagnostic categories, but gression, are often comorbid with depression28 and can rather with an array ofsymptoms that may include de- occur in up to 70% ofpatients with TBI.29 Although it is pression, anxiety, irritability, anger, and even psychotic well known that anger and aggression are common symptoms, this finding is encouraging.
problems among patients with TBI, they are typically Our finding that sertraline is associated with de- associated with and recognized in patients with more creased depressive symptoms after TBI is consistent severe injuries. Our finding that patients reported their with evidence about the neuropathological mechanism levels ofanger and aggression as significantly improved that may contribute to the development ofmajor de- after treatment for depression may show that anger and pression following TBI. Human postmortem patho- aggression are more ofa problem, and more treatable, logic,24 cerebrospinal fluid,25 and imaging26 evidence among patients with mild TBI than previously recog- supports a role for serotonin in the depressions of neu- nized. Sertraline has been shown to improve aggression rologic patients. Patients who are depressed following significantly in neuropsychiatric patients.30,31 Even mild TBI have blunted prolactin response to buspirone, among medically and psychiatrically healthy volun-teers, the magnitudes ofpsychometric assaultiveness, ir-ritability, negative affect, and behavioral affiliation were Frequency and course of postconcussive symptoms as
recorded on the Head Injury Symptom Checklist that

correlated to plasma levels ofthe SSRI paroxetine.32 were present after traumatic brain injury at baseline
The present study shows that treating major depres- and after 8 weeks of sertraline
sion following TBI may significantly improve function- ing in a variety ofareas, including emotional function- ing and mental health; physical functioning, sleep, and vitality; and social, work, and family functioning. Given the myriad stressors that can affect a patient's physical, social, work, and family functioning, the finding that pharmacological treatment ofdepression can improve functioning in these areas is especially salient.
This study also suggests that treating depression in Bothered by noise patients with mild TBI may significantly decrease the burden ofpostconcussive symptoms. Postconcussive Bothered by light symptoms are a significant problem in many patients with mild TBI.33 Most patients see improvement in these symptoms within the first month, but many experience continuing symptoms for months or years after their in- jury. While some educational and behavioral treatments for postconcussive symptoms have been developed,34 no pharmacological trials have been performed and no Trouble concentrating treatments for postconcussive symptoms have been widely studied.
Although many postconcussive symptoms overlap with symptoms ofdepression, our current study shows a decrease in postconcussive symptoms that do not over- Memory difficulties lap with depression, such as headache, dizziness, and blurred vision, and a change in perception ofhead in- jury severity with treatment ofdepression. Studies in other medical populations have also shown decreased Sleep disturbance subjective severity ofphysical symptoms and level of illness and distress with antidepressants.35,36 Screening for and treating depression in patients with persisting aMcNemar's test. Binomial distribution was used. Symptoms that postconcussive symptoms may be an effective way to were worsening or staying the same at each time point were decrease unnecessary suffering and reduce excess dis- combined into one category for the analysis.
ability. Treating depression in mild TBI patients may J Neuropsychiatry Clin Neurosci 12:2, Spring 2000 Name /oak/jn 122_5y4356/M _231 05/01/2000 07:52AM Plate # 0 FANN et al.
also minimize health services utilization and costs by whether or not the positive effects of sertraline were decreasing unexplained somatic symptoms, perception maintained. However, all patients who had remission of ofillness severity and disability, and subsequent illness their depression elected to continue sertraline.
Future research will require controlled, double-blind Methodological limitations ofthis study must lead to studies with larger sample sizes and longer follow-up caution in interpreting the results. This was a nonran- periods to determine the efficacy and effectiveness of domized, single-blind study; therefore, some improve- different antidepressants in treating depressive symp- ments over time may have been a result ofnatural im- toms, in decreasing associated psychological, behav- provement or regression to the mean in distressed ioral, cognitive, and somatic symptoms, and in decreas- patients that was independent ofthe intervention. The ing functional disability.
results cannot be generalized to all TBI populations be-cause ofthe small sample size and the large proportion The authors thank Joan Russo, Ph.D., for statistical assis- ofCaucasian, female, and highly educated patients com- tance. This studywas supported byan unrestricted educa- pared with the general TBI population in the United tional grant from Pfizer Pharmaceuticals. The work was pre- States. Because we do not have follow-up data beyond sented in part at the 152nd annual meeting of the American 8 weeks oftreatment, it is not possible to conclude Psychiatric Association, Washington, DC, May 15–20, 1999. 1. Rosenthal M, Christensen BK, Ross TP: Depression following 15. Ware JE, Sherbourne CD: The MOS 36-Item Short-Form Health traumatic brain injury. Arch Phys Med Rehabil 1998; 79:90–103 Survey (SF-36). Med Care 1992; 30:473–483 2. Busch CR, Alpern HP: Depression after mild traumatic brain 16. Bergner M, Bobbitt RA, Carter WB, et al: The Sickness Impact injury: a review ofthe current research. Neuropsychology Re- Profile: development and final revision ofa health status mea- view 1998; 8:95–108 sure. Med Care 1981; 19:787–805 3. Fann JR, Katon WJ, Uomoto JM, et al: Psychiatric disorders and 17. McLean A, Dikmen S, Temkin N, et al: Psychosocial functioning functional disability in outpatients with traumatic brain injuries.
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