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A Randomized Controlled Trial of Sertraline for the Treatment of Depression in Persons With Traumatic Brain Injury

      Abstract

      Ashman TA, Cantor JB, Gordon WA, Spielman L, Flanagan S, Ginsberg A, Engmann C, Egan M, Ambrose F, Greenwald B. A randomized controlled trial of sertraline for the treatment of depression in persons with traumatic brain injury.

      Objective

      To examine the efficacy of sertraline in the treatment of depression after traumatic brain injury (TBI).

      Design

      Double-blind, randomized controlled trial.

      Setting

      Research center at a major urban medical center.

      Participants

      Subjects were a referred and volunteer sample of 52 participants with TBI, a diagnosis of major depression disorder (MDD), and a score on the Hamilton Rating Scale for Depression (HAM-D) of 18 or greater. The majority of the sample was male (58%), had less than 14 years of education (73%), had incomes below $20,000 (82%), and were from minority backgrounds (75%). Approximately one third of the sample had mild brain injuries, and two thirds had moderate to severe brain injuries. The mean age was 47±11, and the mean time since injury was 17±14 years. One participant withdrew from the study because of side effects.

      Intervention

      Daily oral sertraline in doses starting at 25mg and increasing to therapeutic levels (up to 200mg) or placebo for 10 weeks.

      Main Outcome Measures

      The HAM-D, the Beck Anxiety Inventory, and the Life-3 quality of life (QOL).

      Results

      No statistically significant differences were found at baseline between drug and placebo groups on baseline measures of depression (24.8±7.3 vs 27.7±7.0), anxiety (16.4±12.3 vs 24.0±14.9), or QOL (2.96±1.0 vs 2.9±0.9). The income level of those receiving placebo was significantly lower than those participants receiving medication. Analyses of covariance revealed significant changes from preintervention to posttreatment for all 3 outcome measures (P<.001) but no group effects. Random-effects modeling did not find any significant difference in patterns of scores of the outcome measures between the placebo and medication groups.

      Conclusions

      Both groups showed improvements in mood, anxiety, and QOL, with 59% of the experimental group and 32% of the placebo group responding to the treatment, defined as a reduction of a person's HAM-D score by 50%.

      Key Words

      List of Abbreviations:

      BAI (Beck Anxiety Inventory), DSM-IV (Diagnostic and Statistical Manual of Mental Disorders-IV), HAM-D (Hamilton Rating Scale for Depression), MDD (major depressive disorder), NS (not significant), QOL (quality of life), SCID (Structured Clinical Interview for DSM-IV Axis I Disorders), TBI (traumatic brain injury)
      DEPRESSION AFTER TBI is well documented in the literature. The frequency of depressive disorders has been reported to range between 16% and 60%,
      • Ashman T.A.
      • Spielman L.A.
      • Hibbard M.R.
      • Silver J.M.
      • Chandna T.
      • Gordon W.A.
      Psychiatric challenges in the first 6 years after traumatic brain injury: cross-sequential analyses of Axis I disorders.
      • Kim E.
      • Lauterbach E.C.
      • Reeve A.
      • et al.
      Neuropsychiatric complications of traumatic brain injury: a critical review of the literature (a report by the ANPA committee on research).
      • Rapoport M.J.
      • McCullagh S.
      • Shammi P.
      • Feinstein A.
      Cognitive impairment associated with major depression following mild and moderate traumatic brain injury.
      • Hibbard M.R.
      • Uysal S.
      • Kepler K.
      • Bogdany J.
      • Silver J.
      Axis I psychopathology in individuals with traumatic brain injury.
      • Jorge R.E.
      • Robinson R.G.
      • Starkstein S.E.
      • Arndt S.V.
      Depression and anxiety following traumatic brain injury.
      • Jorge R.E.
      • Robinson R.G.
      • Arndt S.V.
      • Starkstein S.E.
      • Forrester A.W.
      • Geisler F.
      Depression following traumatic brain injury: a 1 year longitudinal study.
      • Jorge R.E.
      • Robinson R.G.
      • Arndt S.
      Are there symptoms that are specific for depressed mood in patients with traumatic brain injury?.
      • Jorge R.E.
      • Robinson R.G.
      • Moser D.
      • Tateno A.
      • Crespo-Facorro B.
      • Arndt S.
      Major depression following traumatic brain injury.
      • Fann J.R.
      • Katon W.J.
      • Uomoto J.M.
      • Esselman P.C.
      Psychiatric disorders and functional disability in outpatients with traumatic brain injuries.
      • Bowen A.
      • Neumann V.
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      • Tennant A.
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      Mood disorders following traumatic brain injury: identifying the extent of the problem and the people at risk.
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      • et al.
      Head injury in early adulthood and the lifetime risk of depression.
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      The prevalence and symptom rates of depression after traumatic brain injury: a comprehensive examination.
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      Depression amongst outpatients with traumatic brain injury.
      and MDD is the most commonly reported mood disorder after TBI, ranging from 24% to 35%.
      • Ashman T.A.
      • Spielman L.A.
      • Hibbard M.R.
      • Silver J.M.
      • Chandna T.
      • Gordon W.A.
      Psychiatric challenges in the first 6 years after traumatic brain injury: cross-sequential analyses of Axis I disorders.
      • Kim E.
      • Lauterbach E.C.
      • Reeve A.
      • et al.
      Neuropsychiatric complications of traumatic brain injury: a critical review of the literature (a report by the ANPA committee on research).
      • Seel R.T.
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      Depression after traumatic brain injury: a national institute on disability and rehabilitation research model systems multicenter investigation.
      • Koponen S.
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      • Portin R.
      • et al.
      Axis I and II psychiatric disorders after traumatic brain injury: a 30-year follow-up study.
      The frequency of MDD is particularly noteworthy when contrasted with base rates of 6% to 7% in community-based samples.
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      Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the national comorbidity survey replication.
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      Estimating the prevalence of mental disorders in U.S. adults from the epidemiologic catchment area survey.
      Although some persons who experience post-TBI depression have a history of MDD or other depressive disorders before their TBI, the frequency of depression after TBI far exceeds premorbid rates.
      • Rapoport M.J.
      • McCullagh S.
      • Shammi P.
      • Feinstein A.
      Cognitive impairment associated with major depression following mild and moderate traumatic brain injury.
      • Jorge R.E.
      • Robinson R.G.
      • Moser D.
      • Tateno A.
      • Crespo-Facorro B.
      • Arndt S.
      Major depression following traumatic brain injury.
      • Fann J.R.
      • Katon W.J.
      • Uomoto J.M.
      • Esselman P.C.
      Psychiatric disorders and functional disability in outpatients with traumatic brain injuries.
      The large variation in rates of post-TBI depression reported in the literature can be attributed to inconsistencies in diagnostic and/or sampling methods used to categorize a person as depressed. Although the majority of studies since the mid-1990s have used more rigorous diagnostic criteria as defined by the DSM-IV,
      American Psychiatric Association
      Diagnostic and Statistical Manual of Mental Disorders.
      there continue to be significant methodologic differences between studies investigating prevalence (eg, whether the sample assesses only a current diagnosis of depression or includes lifetime rates of depression, both before and after injury). Even when confining the literature review to studies that diagnose MDD based on DSM-IV criteria determined through clinical interview, the research
      • Ashman T.A.
      • Spielman L.A.
      • Hibbard M.R.
      • Silver J.M.
      • Chandna T.
      • Gordon W.A.
      Psychiatric challenges in the first 6 years after traumatic brain injury: cross-sequential analyses of Axis I disorders.
      • Kim E.
      • Lauterbach E.C.
      • Reeve A.
      • et al.
      Neuropsychiatric complications of traumatic brain injury: a critical review of the literature (a report by the ANPA committee on research).
      • Seel R.T.
      • Kreutzer J.S.
      • Rosenthal M.
      • Hammond F.M.
      • Corrigan J.D.
      • Black K.
      Depression after traumatic brain injury: a national institute on disability and rehabilitation research model systems multicenter investigation.
      • Koponen S.
      • Taiminen T.
      • Portin R.
      • et al.
      Axis I and II psychiatric disorders after traumatic brain injury: a 30-year follow-up study.
      indicates that depression rates after TBI are extremely high (24%–35%). This research
      • Ashman T.A.
      • Spielman L.A.
      • Hibbard M.R.
      • Silver J.M.
      • Chandna T.
      • Gordon W.A.
      Psychiatric challenges in the first 6 years after traumatic brain injury: cross-sequential analyses of Axis I disorders.
      • Hibbard M.R.
      • Uysal S.
      • Kepler K.
      • Bogdany J.
      • Silver J.
      Axis I psychopathology in individuals with traumatic brain injury.
      • Jorge R.E.
      • Robinson R.G.
      • Starkstein S.E.
      • Arndt S.V.
      Depression and anxiety following traumatic brain injury.
      • Jorge R.E.
      • Robinson R.G.
      • Arndt S.V.
      • Starkstein S.E.
      • Forrester A.W.
      • Geisler F.
      Depression following traumatic brain injury: a 1 year longitudinal study.
      • Jorge R.E.
      • Robinson R.G.
      • Arndt S.
      Are there symptoms that are specific for depressed mood in patients with traumatic brain injury?.
      • Fann J.R.
      • Katon W.J.
      • Uomoto J.M.
      • Esselman P.C.
      Psychiatric disorders and functional disability in outpatients with traumatic brain injuries.
      • Bowen A.
      • Neumann V.
      • Conner M.
      • Tennant A.
      • Chamberlain M.A.
      Mood disorders following traumatic brain injury: identifying the extent of the problem and the people at risk.
      • Holsinger T.
      • Steffens D.C.
      • Phillips C.
      • et al.
      Head injury in early adulthood and the lifetime risk of depression.
      • Seel R.T.
      • Kreutzer J.S.
      • Rosenthal M.
      • Hammond F.M.
      • Corrigan J.D.
      • Black K.
      Depression after traumatic brain injury: a national institute on disability and rehabilitation research model systems multicenter investigation.
      • Koponen S.
      • Taiminen T.
      • Portin R.
      • et al.
      Axis I and II psychiatric disorders after traumatic brain injury: a 30-year follow-up study.
      • Chamelian L.
      • Feinstein A.
      The effect of major depression on subjective and objective cognitive deficits in mild to moderate traumatic brain injury.
      • Rapoport M.J.
      • McCullagh S.
      • Streiner D.
      • Feinstein A.
      The clinical significance of major depression following mild traumatic brain injury.
      • Levin H.S.
      • McCauley S.R.
      • Josic C.P.
      • et al.
      Predicting depression following mild traumatic brain injury.
      • Hibbard M.R.
      • Ashman T.A.
      • Spielman L.A.
      • Chun D.
      • Charatz H.J.
      • Melvin S.
      Relationship between depression and psychosocial functioning after traumatic brain injury.
      • Fedoroff J.P.
      • Starkstein S.E.
      • Forrester A.W.
      • et al.
      Depression in patients with acute traumatic brain injury.
      has reported that persons can experience an MDD at any time after the TBI, ranging from 1 month to 30 years postinjury.
      In addition, the presence of a coexisting anxiety disorder can further compromise a person's ability to cope with depression and worsen prognosis after TBI.
      • Jorge R.E.
      • Robinson R.G.
      • Moser D.
      • Tateno A.
      • Crespo-Facorro B.
      • Arndt S.
      Major depression following traumatic brain injury.
      Several researchers
      • Jorge R.E.
      • Robinson R.G.
      • Starkstein S.E.
      • Arndt S.V.
      Depression and anxiety following traumatic brain injury.
      • Holsinger T.
      • Steffens D.C.
      • Phillips C.
      • et al.
      Head injury in early adulthood and the lifetime risk of depression.
      • Fedoroff J.P.
      • Starkstein S.E.
      • Forrester A.W.
      • et al.
      Depression in patients with acute traumatic brain injury.
      • Deb S.
      • Lyons I.
      • Koutzoukis C.
      • Ali I.
      • McCarthy G.
      Rate of psychiatric illness 1 year after traumatic brain injury.
      • Bryant R.A.
      • Marosszeky J.E.
      • Crooks J.
      • Baguley I.
      • Gurka J.
      Coping style and post-traumatic stress disorder following severe traumatic brain injury.
      have reported anxiety disorders after TBI as common, with prevalence rates ranging between 3% and 28%. Estimates of comorbidity of depression and anxiety disorders have ranged from 11% to 77%.
      • Ashman T.A.
      • Spielman L.A.
      • Hibbard M.R.
      • Silver J.M.
      • Chandna T.
      • Gordon W.A.
      Psychiatric challenges in the first 6 years after traumatic brain injury: cross-sequential analyses of Axis I disorders.
      • Hibbard M.R.
      • Uysal S.
      • Kepler K.
      • Bogdany J.
      • Silver J.
      Axis I psychopathology in individuals with traumatic brain injury.
      • Jorge R.E.
      • Robinson R.G.
      • Moser D.
      • Tateno A.
      • Crespo-Facorro B.
      • Arndt S.
      Major depression following traumatic brain injury.
      • Jorge R.E.
      • Robinson R.G.
      • Starkstein S.E.
      • Arndt S.V.
      Influence of major depression on 1-year outcome in patients with traumatic brain injury.
      • van Reekum R.
      • Bolago I.
      • Finlayson M.A.
      • Garner S.
      • Links P.S.
      Psychiatric disorders after traumatic brain injury.
      Post-TBI depression has been associated with numerous negative outcomes including greater functional disability, reduced participation in activities of daily living, less social and recreational activity, less employment potential, increased caregiver burden, greater sexual dysfunction, lower ratings of health, poor subjective well-being, poorer QOL, and increased rates of suicidal ideation.
      • Kim E.
      • Lauterbach E.C.
      • Reeve A.
      • et al.
      Neuropsychiatric complications of traumatic brain injury: a critical review of the literature (a report by the ANPA committee on research).
      • Rapoport M.J.
      • McCullagh S.
      • Shammi P.
      • Feinstein A.
      Cognitive impairment associated with major depression following mild and moderate traumatic brain injury.
      • Jorge R.E.
      • Robinson R.G.
      • Moser D.
      • Tateno A.
      • Crespo-Facorro B.
      • Arndt S.
      Major depression following traumatic brain injury.
      • Bowen A.
      • Neumann V.
      • Conner M.
      • Tennant A.
      • Chamberlain M.A.
      Mood disorders following traumatic brain injury: identifying the extent of the problem and the people at risk.
      • Hibbard M.R.
      • Ashman T.A.
      • Spielman L.A.
      • Chun D.
      • Charatz H.J.
      • Melvin S.
      Relationship between depression and psychosocial functioning after traumatic brain injury.
      • Malec J.F.
      • Testa J.A.
      • Rush B.K.
      • Brown A.W.
      • Moessner A.M.
      Self-assessment of impairment, impaired self-awareness, and depression after traumatic brain injury.
      • Rosenthal M.
      • Christensen B.K.
      • Ross T.P.
      Depression following traumatic brain injury.
      These negative consequences can hamper the person's reintegration into the community, adjustment after injury, and overall QOL.
      Despite the high frequency of post-TBI depression and the mounting evidence of its negative impact on functioning and QOL, research
      National Institute of Health
      Rehabilitation of persons with traumatic brain injury.
      on psychopharmacologic approaches to treating depression remains limited. Although several reviews have outlined options for treatment of post-TBI depression with antidepressants
      • Tenovuo O.
      Pharmacological enhancement of cognitive and behavioral deficits after traumatic brain injury.
      • O'Shanick G.J.
      Update on antidepressants.
      • Zafonte R.D.
      • Cullen N.
      • Lexell J.
      Serotonin agents in the treatment of acquired brain injury.
      • Alderfer B.S.
      • Arciniegas D.B.
      • Silver J.M.
      Treatment of depression following traumatic brain injury.
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      • Starkstein S.E.
      Pathophysiologic aspects of major depression following traumatic brain injury.
      • Glenn M.B.
      • Wroblewski B.
      Twenty years of pharmacology.
      and some have even attempted to establish treatment guidelines,
      • Silver J.M.
      • Sandberg D.P.
      • Hales R.E.
      New approaches in the pharmacotherapy of posttraumatic stress disorder.
      • Turner-Stokes L.
      • MacWalter R.
      Guideline Development Group of the British Society of Rehabilitation Medicine, British Geriatrics Society, Royal College of Physicians London
      Use of antidepressant medication following acquired brain injury: concise guidance.
      there has been little empirical support on which to base these guidelines for people with TBI.
      • Tenovuo O.
      Pharmacological enhancement of cognitive and behavioral deficits after traumatic brain injury.
      Indeed in a recent review, the Neurobehavioral Guidelines Working Group
      • Warden D.L.
      • Gordon B.
      • et al.
      Neurobehavioral Guidelines Working Group
      Guidelines for the pharmacologic treatment of neurobehavioral sequelae of traumatic brain injury.
      concluded that the limited number of studies and the conflicting results provided insufficient evidence to establish guidelines for pharmacologic treatment of affective disorders after TBI.
      The review by the Neurobehavioral Guidelines Working Group
      • Warden D.L.
      • Gordon B.
      • et al.
      Neurobehavioral Guidelines Working Group
      Guidelines for the pharmacologic treatment of neurobehavioral sequelae of traumatic brain injury.
      found only 2 class II studies and 5 class III studies on the utility of medications in the treatment of depression after TBI, consisting largely of case studies or open trial studies. Sertraline has been the most frequently studied medication for the treatment of depression in persons with TBI and stroke.
      • Almeida O.P.
      • Waterreus A.
      • Hankey G.J.
      Preventing depression after stroke: results from a randomized placebo-controlled trial.
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      • Bria P.
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      • Robinson R.G.
      Response of emotional unawareness after stroke to antidepressant treatment.
      • Murray V.
      • von Arbin M.
      • Bartfai A.
      • et al.
      Double-blind comparison of sertraline and placebo in stroke patients with minor depression and less severe major depression.
      • Spalletta G.
      • Caltagirone C.
      Sertraline treatment of post-stroke major depression: an open study in patients with moderate to severe symptoms.
      • Rasmussen A.
      • Lunde M.
      • Poulsen D.L.
      • Sorensen K.
      • Qvitzau S.
      • Bech P.
      A double-blind, placebo-controlled study of sertraline in the prevention of depression in stroke patients.
      • Spalletta G.
      • Guida G.
      • Caltagirone C.
      Is left stroke a risk-factor for selective serotonin reuptake inhibitor antidepressant treatment resistance?.
      • Turner-Stokes L.
      • Hassan N.
      • Pierce K.
      • Clegg F.
      Managing depression in brain injury rehabilitation: the use of an integrated care pathway and preliminary report of response to sertraline.
      • Turner-Stokes L.
      • Hassan N.
      Depression after stroke: a review of the evidence base to inform the development of an integrated care pathway Part 2: treatment alternatives.
      • Goodnick P.J.
      • Hernandez M.
      Treatment of depression in comorbid medical illness.
      • Burns A.
      • Russell E.
      • Stratton-Powell H.
      • Tyrell P.
      • O'Neill P.
      • Baldwin R.
      Sertraline in stroke-associated lability of mood.
      There has been no published research on the effectiveness of pharmacologic treatments of anxiety after TBI, especially when anxiety is comorbid with MDD. However, selective serotonin reuptake inhibitors have been approved by the Food and Drug Administration for the treatment of the 3 most common post-TBI anxiety disorders, posttraumatic stress disorder, obsessive-compulsive disorder, and panic disorder,
      • Ashman T.A.
      • Spielman L.A.
      • Hibbard M.R.
      • Silver J.M.
      • Chandna T.
      • Gordon W.A.
      Psychiatric challenges in the first 6 years after traumatic brain injury: cross-sequential analyses of Axis I disorders.
      • Hibbard M.R.
      • Uysal S.
      • Kepler K.
      • Bogdany J.
      • Silver J.
      Axis I psychopathology in individuals with traumatic brain injury.
      • Piccinelli M.
      • Patterson M.
      • Braithwaite I.
      • Boot D.
      • Wilkinson G.
      Anxiety and depression disorders 5 years after severe injuries: a prospective follow-up study.
      and sertraline has been found to be particularly effective in the treatment of depression and anxiety in many patient groups.
      • Kamijima K.
      • Aoki M.
      Effectiveness of paroxetine in the treatment of obsessive-compulsive disorders.
      • Davidson J.R.
      Pharmacologic treatment of acute and chronic stress following trauma: 2006.
      • Cipriani A.
      • Brambilla P.
      • Furukawa T.
      • et al.
      Fluoxetine versus other types of pharmacotherapy for depression.
      The purpose of the present study was to test the hypothesis that, compared with placebo, sertraline would be significantly more effective in reducing post-TBI depression and anxiety symptoms and that these changes would be associated with significantly improved QOL. Hypothesized outcomes were measured by using the HAM-D,
      • Hamilton M.
      A rating scale for depression.
      the BAI,
      • Beck A.T.
      • Steer R.
      • Brown G.
      Beck Depression Inventory-II.
      and the Life-3.
      • Andrews F.M.
      • Withey S.B.
      Social indicators of well-being: Americans' perceptions of life quality.

      Methods

       Research Design

      This 10-week controlled, double-blind randomized controlled trial of sertraline (Zoloft) versus placebo was designed to determine the efficacy of sertraline in the treatment of post-TBI depression and examine the impact of sertraline on any comorbid anxiety disorders. The severity of depressive and anxiety symptoms was assessed at baseline, biweekly throughout the treatment, and immediately at the end of treatment. Participants were accessed into the study on a rolling admission basis and random assignment to treatment conditions (sertraline or placebo) was balanced by using a block design (blocks of 8) with computer-generated random number sequences in individual presealed envelopes.

       Participants

      Participants were recruited through physician referrals and flyers posted in outpatient rehabilitation treatment areas and distributed at TBI-survivor support groups. In addition, participants from past research projects who had agreed to be contacted for future studies were contacted. The study was approved by the Institutional Review Board of the Mount Sinai School of Medicine, and the conduct of the investigation conformed to the protocol and ethical principles governing research with human beings. When a potential participant arrived at the research center for a screening evaluation, the nature and purpose of the study was explained. After written informed consent was obtained, all potential subjects were evaluated for eligibility. To be included in the study, participants had to be 18 years or older, have a history of TBI with a documented loss of consciousness or other evidence of a TBI (ie, pathology on neuroimaging), be at least 6 months postinjury, meet diagnostic criteria for a major depressive episode using DSM-IV criteria, have a score 18 or greater on the HAM-D, and be able to comprehend or answer verbal or written questionnaires. All participants also had to abstain from seeking new psychosocial or pharmacologic treatments during the course of the intervention, use daily reminders to take the medication, document daily medication compliance and side effects in a written diary; and come to the study facility every other week for the duration of the study for physician visits and a brief evaluation of mood and anxiety.
      Participants were excluded from the study if they were known or suspected (1) to be using antidepressant medication, (2) to be in psychotherapy currently, (3) to have active suicidal plans or depression severe enough to require hospitalization, (4) to have a serious medical illness, (5) to be pregnant or breast-feeding, (6) to have mass brain lesions or other neurologic diagnoses other than TBI, (7) to have a history of current or past psychosis or mania using DSM-IV criteria, (8) to have a current substance abuse disorder using DSM-IV criteria, or (9) to have a history of clinically significant liver or renal disease.
      Participants who met eligibility criteria were then administered the BAI
      • Jorge R.E.
      • Robinson R.G.
      • Arndt S.V.
      • Starkstein S.E.
      • Forrester A.W.
      • Geisler F.
      Depression following traumatic brain injury: a 1 year longitudinal study.
      • Beck A.T.
      Beck Anxiety Inventory.
      and a measure of QOL.
      • Andrews F.M.
      • Withey S.B.
      Social indicators of well-being: Americans' perceptions of life quality.
      Additional demographic data and TBI-related history (ie, date of injury, duration of altered mental state, time since injury) were also obtained. Medical eligibility was assessed by one of the study physicians (SF, BG, AA) who determined if the person's medical history or current medical conditions and medication regimen contraindicated the use of sertraline. Once medically cleared, all participants were randomized into the medication or placebo arm of the study by the pharmacy. Thus, both study staff and participants were blinded to the type of intervention received (ie, whether the participant was prescribed sertraline or placebo).

       Procedure

      Participants were randomly assigned to placebo or drug (sertraline) condition for a 10-week trial. Following the protocol used by Fann et al,
      • Fann J.R.
      • Uomoto J.M.
      • Katon W.J.
      Sertaline in the treatment of major depression following mild traumatic brain injury.
      participants started at doses of 25mg daily of either sertraline or placebo for weeks 1 and 2, with dosages adjusted during the physician visit at the end of week 2. Further adjustments of dosage were determined by the physician during subsequent office visits occurring every 2 weeks for the duration of the intervention. During the week 2 visit, physicians increased the dosage to between 25 and 100mg/d depending on the participant's self-report of symptoms of depression as reported on the HAM-D and the physician's clinical assessment of the severity of these symptoms. During weeks 4, 6, and 8, dosage of medications continued to be adjusted as clinically indicated, with dosages falling in the range of 25 to 200mg/d depending on clinical response and tolerance by the end of the clinical trial.

       Dispensing medications

      The pharmacy implemented masking and random assignment of participants to sertraline or placebo conditions and was responsible for dispensing medications with identical markings to the project physicians for distribution. All medications were packaged in 25-mg quantities and had the same markings so that increases in the number of pills taken in both drug conditions were identical. Medication side effects were noted at each assessment point. All adverse events during the intervention period were recorded, and their relationship to the medication was assessed.

       Assessments

      After the initial screening and baseline assessment, all participants were seen by a study physician every 2 weeks for the duration of the clinical trial to monitor drug dosage, reaction to medications, and mood. In addition, a postdoctoral fellow or licensed psychologist rated the clinical severity of the participant's depressive (HAM-D) and anxiety (BAI) symptoms independently from the physician at each biweekly visit. In an attempt to control for psychologic support, research staff followed a standard protocol, and the duration of each contact was kept constant. In addition, participants were not necessarily seen by the same staff member (ie, physician or psychologist) at each visit. At the end of the intervention, all participants completed a posttreatment assessment. These assessments were administered by a different staff member than the person who administered the initial assessment. Participants underwent clinical interviews by using the SCID and the HAM-D. Additionally, the BAI and Life-3 were administered.

       Measures

       Structured Clinical Interview for DSM-IV Axis I Disorders

      The SCID modules
      • First M.
      • Spitzer R.
      • Gibbon M.
      • Williams J.
      User's guide for the structured clinical interview for DSM-IV Axis I Disorders - SCID.
      • Spitzer R.L.
      • Williams J.B.
      • Gibbon M.
      • First M.B.
      The structured clinical interview for DSM-III-R (SCID) I: history, rationale, and description.
      were used to establish psychiatric diagnoses at the baseline and posttreatment assessments. This interview resulted in a dichotomous score indicating the presence or absence of current and lifetime depressive disorders, lifetime psychotic disorders, and current anxiety disorders and substance abuse disorders in accordance with DSM-IV criteria. Reliability scores for the SCID are high, with the kappa value between .70 and 1.00,
      • First M.
      • Spitzer R.
      • Gibbon M.
      • Williams J.
      User's guide for the structured clinical interview for DSM-IV Axis I Disorders - SCID.
      and the interview is considered a criterion standard in research studies evaluating most clinical populations.
      • Bowman E.S.
      • Coons P.M.
      The differential diagnosis of epilepsy, pseudoseizures, dissociative identity disorder, and dissociative disorder not otherwise specified.
      • Segal D.L.
      • Hersen M.
      • Van Hasselt V.B.
      Reliability of the structured clinical interview for DSM-III-R: an evaluative review.
      • Fach M.
      • Bischof G.
      • Schmidt C.
      • Rumpf H.J.
      Prevalence of dependence on prescription drugs and associated mental disorders in a representative sample of general hospital patients.
      • Jones J.E.
      • Hermann B.P.
      • Woodard J.L.
      • et al.
      Screening for major depression in epilepsy with common self-report depression inventories.
      • Booth B.M.
      • Kirchner J.E.
      • Hamilton G.
      • Harrell R.
      • Smith G.R.
      Diagnosing depression in the medically ill: validity of a lay-administered structured diagnostic interview.

       Hamilton Rating Scale for Depression

      The 17-item HAM-D54 is a widely used clinician-rated measurement of depression severity.
      • Williams J.B.
      A structured interview guide for the Hamilton Depression Rating Scale.
      • Faries D.
      • Herrera J.
      • Rayamajhi J.
      • DeBrota D.
      • Demitrack M.
      • Potter W.Z.
      The responsiveness of the Hamilton Depression Rating Scale.
      The scale has high reliability
      • Williams J.B.
      A structured interview guide for the Hamilton Depression Rating Scale.
      • Williams J.B.
      • Gibbon M.
      • First M.B.
      • et al.
      The structured clinical interview for DSM-III-R (SCID) II. Multisite test-retest reliability.
      and validity.
      • Maier W.
      The Hamilton Depression Scale and its alternatives: a comparison of their reliability and validity.
      • Maier W.
      • Heuser I.
      • Philipp M.
      • Frommberger U.
      • Demuth W.
      Improving depression severity assessment–II Content, concurrent and external validity of three observer depression scales.
      • Maier W.
      • Philipp M.
      • Heuser I.
      • Schlegel S.
      • Buller R.
      • Wetzel H.
      Improving depression severity assessment–I Reliability, internal validity and sensitivity to change of three observer depression scales.
      • Rehm L.P.
      • O'Hara M.W.
      Item characteristics of the Hamilton Rating Scale for Depression.
      Four different subscales have been suggested by researchers
      • Faries D.
      • Herrera J.
      • Rayamajhi J.
      • DeBrota D.
      • Demitrack M.
      • Potter W.Z.
      The responsiveness of the Hamilton Depression Rating Scale.
      • Maier W.
      • Philipp M.
      • Heuser I.
      • Schlegel S.
      • Buller R.
      • Wetzel H.
      Improving depression severity assessment–I Reliability, internal validity and sensitivity to change of three observer depression scales.
      • Bech P.
      • Allerup P.
      • Reisby N.
      • Gram L.F.
      Assessment of symptom change from improvement curves on the Hamilton Depression Scale in trials with antidepressants.
      • Gibbons R.D.
      • Clark D.C.
      • Kupfer D.J.
      Exactly what does the Hamilton Depression Rating Scale measure?.
      to address unidimensional aspects of the measure, with effect sizes ranging from .40 to .45. The total score and these 4 subscales were tested to detect changes in depression between the treatment arms.

       Beck Anxiety Inventory

      The BAI
      • Beck A.T.
      Beck Anxiety Inventory.
      is a 21-item self-report measure that assesses subjective, somatic, or panic-related symptoms associated with anxiety. The instrument has good internal consistency (.92), good test-retest reliability (.75), and acceptable validity.
      • Beck A.T.
      • Epstein N.
      • Brown G.
      • Steer R.A.
      An inventory for measuring clinical anxiety: psychometric properties.
      The BAI also has been widely used with participants with TBI.
      • Trahan D.E.
      • Ross C.E.
      • Trahan S.L.
      Relationships among postconcussional-type symptoms, depression, and anxiety in neurologically normal young adults and victims of mild brain injury.
      • Fleming J.M.
      • Strong J.
      • Ashton R.
      Cluster analysis of self-awareness levels in adults with traumatic brain injury and relationship to outcome.
      • Wallace C.A.
      • Bogner J.
      Awareness of deficits: emotional implications for persons with brain injury and their significant others.

       Life-3

      Life-3 is a single-item QOL measure that uses a 7-point Likert-type scale to assess satisfaction with life during the past month.
      • Andrews F.M.
      • Withey S.B.
      Social indicators of well-being: Americans' perceptions of life quality.
      It is typically administered twice during an evaluation, and the mean of the 2 obtained scores is used. Higher scores on this measure indicate higher levels of subjective QOL. The Life-3 has correlated well with other measures of global or domain-specific life satisfaction. Prior research
      • Dijkers M.
      • Layman D.
      • Ashman T.
      • Brown M.
      Self-report of quality of life by persons with traumatic brain injury: a reliability study.
      with persons with TBI found a test-retest value of 0.84 (intraclass correlation coefficient) for a 1-week interval.

       Statistical Power and Analysis

      In a previous uncontrolled, single-blind study of sertraline in patients with mild TBI, Fann et al
      • Fann J.R.
      • Uomoto J.M.
      • Katon W.J.
      Sertaline in the treatment of major depression following mild traumatic brain injury.
      reported that an 8-week treatment, with medication individually adjusted up to 200mg, resulted in a response to medication for 87% of study participants (as measured by a reduction of the HAM-D score by at least 50%). In estimating study power, the following assumptions were made, which are more conservative than those reported in the Fann study
      • Fann J.R.
      • Uomoto J.M.
      • Katon W.J.
      Sertaline in the treatment of major depression following mild traumatic brain injury.
      : (1) in the treatment group, 75% would respond to sertraline (defined as a reduction of HAM-D score by more than 50%), and (2) in the placebo group, 35% would experience a similar response (the placebo response in general population clinical trials of antidepressant medication is typically 30%–35%).
      Sample-size estimates were based on the ability to test these proportions (75% vs 35% response rate). Setting power requirements at .80, a significance level of .05, and a 1-sided test of difference of proportions indicated that 38 cases were needed to complete the study.
      A second power analysis was conducted with regard to the repeated administrations of the HAM-D as a continuous outcome measure. These sample-size estimates were based on the formula outlined by Diggle et al
      • Diggle P.J.
      • Heagerty P.
      • Liang K.Y.
      • Zeger S.L.
      Analysis of longitudinal data.
      for longitudinal studies. Thus, in addition to estimating the size of the effect that would be clinically interesting and establishing desired significance level and power, rho, the within-subject correlation over time also was estimated. Assuming a baseline HAM-D score ± SD of 25±10, a 5-point drop (ie, half of a SD) would be the smallest effect that would still indicate a clinically viable treatment. The calculations were based on the assumption of a moderate correlation within subjects for the 6 assessments over time, ρ equal to .30 and α equal to .05. A sample size of 21 per group was found to be sufficient at 80% power to detect the effect.
      Thus, the primary outcome measure in this study was the HAM-D, and it was the basis of the power analysis. Additional analyses of other measures (eg, BDI-II, Life-3) informed interpretation of the effects of the intervention on additional symptoms but were not the main goal of the study, and, therefore, they were not included in the power calculations.
      Between-group comparisons of demographic and other data at baseline were computed by using chi-square analyses and t tests. An intent-to-treat analysis compared the outcomes of all study participants, including participants who received minimal treatment (eg, ≤6wks), to determine if noncompletion was based on treatment failure or some other variable. A last-observation-carried-forward procedure combined the 2 participants who completed 8 weeks with those who completed all 10 weeks of treatment. Random-effects models for repeated measures with 6 time points were conducted to assess within- and between-group differences over time between the medication and placebo groups. The dependent variable in both the intent-to-treat and last-observation-carried-forward subsamples came from the last assessment of each participant. Random-effects models are preferred over traditional repeated-measures analysis of variance because these approaches more appropriately model the within-subject correlation of observations over time and for their ability to tolerate different numbers of observations (eg, a few subjects were missing 1 of the 6 assessments).

      Results

      Of the 91 respondents screened, 52 were eligible and agreed to participate in the study. Reasons for ineligibility included no diagnosis of depression (n=16), current substance abuse diagnosis (n=9), other exclusionary psychiatric diagnosis (ie, bipolar disorder or psychosis) (n=10), history of stroke (n=2), and current antidepressant use (n=2). Out of the 52 participants who qualified for the study, 41 completed the clinical trial. Of the 11 who did not complete the study, 3 were removed for clinical reasons: 1 participant because of increased anxiety after the baseline assessment, a second because of increased depression after a death in the family 4 weeks into the treatment, and a third because of a mild allergic reaction 4 weeks into the treatment (the latter 2 were receiving placebo). The 8 other noncompleters were noncompliant with the protocol by missing multiple follow-up appointments, not picking up medications, or failing to respond to follow-up contacts.
      As shown in table 1, the sample represented a middle-aged, urban, lower socioeconomic status group with a wide range of times since injury. Compared with national estimates,
      • Robins L.N.
      • Regier D.A.
      Psychiatric disorders in America: the epidemiologic catchment area study.
      there was underrepresentation of mild TBI, nonminorities, youths, and older adults. No significant differences were found between drug and placebo groups on sex; age; education; race; income; etiology of injury; time since injury; injury severity; or baseline measures of depression, anxiety, or QOL.
      Table 1Sample Demographics
      CharacteristicsSertraline GroupPlacebo GroupSample
      (n=22)(n=19)(n=41)
      Age (mean ± SD)46.8±12.851.5±8.249.1±10.9
      Time since injury (mean ± SD)18.6±13.816.6±13.917.7±13.7
      Sex
       Male45.563.258.5
       Female54.536.841.5
      Ethnicity
       White22.731.626.8
       Black63.636.851.2
       Hispanic/Latino/other13.631.621.9
      Education
       High school/GED or less45.053.348.6
       Trade school/some college45.026.737.1
       Bachelors degree or more10.020.114.3
      Income
       ≤$10,00050.042.946.9
       $10,000–$20,00016.750.031.3
       ≥$20,00033.47.121.8
      Injury severity
       Mild20.050.035.5
       Moderate46.631.338.7
       Severe33.418.825.8
      Etiology of injury
       Assault46.3
       Fall14.6
       GSW to head2.4
       Hit by falling object2.4
       MVC or pedestrian hit by MV34.2
      NOTE. Values are percentages unless otherwise noted.
      Abbreviations: GSW, gun shot wound; MV, motor vehicle; MVC, motor vehicle collision.
      Eleven participants dropped out of the study before completing 8 weeks of treatment, 5 dropped out after the initial assessment, 3 after 4 weeks, and 3 after 6 weeks. The intent-to-treat analyses found differences between the last assessment HAM-D score for those who dropped out of treatment as compared with the assessment HAM-D score of those participants who remained in treatment (F=4.0, P=.052), with the dropouts tending to have higher HAM-D scores.
      Of the 11 participants who continued to have a depressive disorder diagnosis at the end of the intervention according to the SCID, 7 were in the placebo condition (reflecting a nonresponse rate of 37% for this group) and 4 were in the medication condition (reflecting a nonresponse rate of 18% for this group). The difference in nonresponse rates between the groups was not statistically significant (χ2=1.81, NS). Those who continued to have a depressive diagnosis had significantly lower scores on the initial Life-3 than did participants who no longer had a depression diagnosis at the end of treatment (t39=2.2, P=.03; Mnonresp=2.3±1.1, Mresp=3.0±0.8) and a trend toward higher scores on the initial BAI score (t39=2.0, P=.06; Mnonresp=29.3±17.5, Mresp=19.3±13.2). They also had significantly higher postintervention scores on the HAM-D (t39=2.3, P=.03; Mnonresp=20.3±10.0, Mresp=12.9±8.8) and BAI (t39=2.2, P=.03; Mnonresp=18.2±12.7, Mresp=9.6±10.5) than those without a posttreatment diagnosis. All means and SDs for all measures can be found in table 2.
      Table 2Outcome Variables and Diagnosis by Time and Group
      VariableBaselineEnd of Treatment
      Sertraline GroupPlacebo GroupSertraline GroupPlacebo Group
      (n=22)(n=19)(n=22)(n=19)
      HAM-D score27.5±7.125.2±8.013.7±9.716.2±9.6
      Alternate HAM-D Score
       Beck Melancholia12.4±3.012.3±2.85.2±4.17.4±4.7
       Maier & Philipp12.4±2.912.4±3.15.0±4.27.5±4.5
       Gibbons14.6±4.015.1±4.46.1±5.58.7±5.5
       5 most sensitive10.4±2.611.4±2.73.9±3.56.2±4.1
       BAI23.2±15.220.5±14.911.1±11.913.1±11.6
       Life 32.8±1.02.8±0.96.3±8.04.9±3.5
       SCID dx MDD, n (%)22 (100)19 (100)4 (18)7 (37)
      NOTE. Values are mean ± SD or as otherwise noted.
      Participants were considered treatment responders if their initial HAM-D decreased by 50% or dropped below a score of 10 at the end of the intervention. Fifty-nine percent of the participants in the medication condition (13 out of 22) and 32% of those in the placebo condition (6 out of 19) were treatment responders (χ2=3.1, P=.08; with continuity correction P=.15).
      Random-effects models for repeated measures, calculated for the 6 assessments, were performed on the HAM-D scores, with group as the fixed effect. The group effect was NS (FHAM-D(1 222.93)=.481, NS). A similar model was examined for the Life-3 and BAI measures; as with the HAM-D, the group effects were not statistically significant, although the results for the Life-3 showed a trend toward significance (FLife1,227.44=2.94, P=.09; FBAI1,215.17=.008, NS). Repeated-measures analysis of variances was also performed on the baseline and endpoint HAM-D, BAI, and Life-3 scores. Findings indicated significant time effects for depression (F1,39=66.3, P<.001; Mpre=26.4±7.5, Mpost=14.9±9.6), anxiety (F1,39=25.1, P<.001; Mpre=21.9±14.9, Mpost=11.9±11.6), and QOL (F1,39=8.1, P<.01; Mpre=2.8±0.9, Mpost=5.7±6.7) but no group effects (Fig 1, Fig 2, Fig 3).
      Because the HAM-D is a multidimensional measure of depressive symptoms, some researchers
      • Faries D.
      • Herrera J.
      • Rayamajhi J.
      • DeBrota D.
      • Demitrack M.
      • Potter W.Z.
      The responsiveness of the Hamilton Depression Rating Scale.
      • Maier W.
      • Philipp M.
      • Heuser I.
      • Schlegel S.
      • Buller R.
      • Wetzel H.
      Improving depression severity assessment–I Reliability, internal validity and sensitivity to change of three observer depression scales.
      • Bech P.
      • Allerup P.
      • Reisby N.
      • Gram L.F.
      Assessment of symptom change from improvement curves on the Hamilton Depression Scale in trials with antidepressants.
      • Gibbons R.D.
      • Clark D.C.
      • Kupfer D.J.
      Exactly what does the Hamilton Depression Rating Scale measure?.
      have indicated that unidimensional subscales may be more effective in detecting differences on core depressive symptoms, particularly in medication trials. Therefore, the analyses described previously were conducted by using these unidimensional subscales. Results were the same as with the HAM-D total score, indicating significant time effects but no group effects.
      Finally, the biweekly unidimensional subscales of the HAM-D were used in a random-effects model to determine whether the pattern of changes in depression and anxiety symptoms was different between the medication and placebo group. Two of the subscales, HamG and HamFive, did show a significant fixed effect for group (FHamG[1,226.71]=4.26, P=.04; FHamFive[1,225.74]=3.79, P=.05). In both cases, the placebo group scored significantly higher than the medication group (HamG: meanpla ± SE, 9.62±0.52, meanmed ± SE, 8.16±0.48; HamFive: meanpla ± SE, 6.64±0.37, meanmed, 5.65±0.35), suggesting that 2 scales were more sensitive to changes in depression symptoms related to medication use.

      Discussion

      In this sample, both groups showed significant improvements in depressive symptoms, as measured by the HAM-D. Even those participants (37% in the placebo group and 18% in the medication group) who continued to meet diagnostic criteria for a depressive disorder (eg, MDD, depression not otherwise specified, or dysthymia) had significantly lower HAM-D scores at the end of treatment than they did at the beginning of treatment. Additionally, all participants reported significantly lower anxiety symptoms as measured by the BAI with no differences between drug and placebo group.
      It is interesting that the findings of this study do not support those of Fann et al.
      • Fann J.R.
      • Uomoto J.M.
      • Katon W.J.
      Sertaline in the treatment of major depression following mild traumatic brain injury.
      It is possible that this different set of findings could be related to the fact that the participants in their study were restricted to those with mild TBI and those included herein were more heterogeneous with regard to injury severity. In addition, all participants in Fann's study received placebo for the first week of the trial followed by 8 weeks of treatment with sertraline, so the long-term effects of placebo were not examined.
      It is important to review the sample characteristics when considering the findings of the current study. For example, their average time since injury was longer than is often found in the literature; however, this ruled out the recovery of emotional function as playing a role in the findings. In addition, although the participants who entered this study were representative of people with TBI, there was a high proportion of participants with low incomes and from minority backgrounds who are often underrepresented in TBI research. Although the literature indicates that post-TBI depression is not associated with either ethnicity or income, epidemiologic surveys have found that the relationship between race and MDD is complex.
      • Robins L.N.
      • Regier D.A.
      Psychiatric disorders in America: the epidemiologic catchment area study.
      • Demyttenaere K.
      • Bruffaerts R.
      • Posada-Villa J.
      • et al.
      Prevalence, severity, and unmet need for treatment of mental disorders in the World Health Organization world mental health surveys.
      • Kessler R.C.
      • Berglund P.
      • Demler O.
      • et al.
      The epidemiology of major depressive disorder: results from the national comorbidity survey replication (NCS-R).
      • Greenberg P.E.
      • Kessler R.C.
      • Birnbaum H.G.
      • et al.
      The economic burden of depression in the United States: how did it change between 1990 and 2000?.
      • Blazer D.G.
      • Kessler R.C.
      • McGonagle K.A.
      • Swartz M.S.
      The prevalence and distribution of major depression in a national community sample: the national comorbidity survey.
      Although blacks often have lower lifetime rates of MDD than whites, they often receive poorer quality care.
      US Department of Health and Human Services
      Mental health: culture, race, and ethnicity: a supplement to mental health: a report of the surgeon general-executive summary.
      Therefore, it is possible that the lower socioeconomic status of the participants in this study may have resulted in poorer prestudy access to regular medical care, including treatment for depression than in other samples of persons with TBI.
      The remission of depression in the majority of participants, regardless of whether they were receiving active or inactive medication, suggests that engagement with the research treatment team by this largely underserved group could have been an important component in the study outcomes. The therapeutic effect of connecting with a medical center and receiving regularly scheduled assessments and treatment by a caring research team may have played a role in reducing depressive symptoms in both groups of participants.
      • Givens J.L.
      • Houston T.K.
      • Van Voorhees B.W.
      • Ford D.E.
      • Cooper L.A.
      Ethnicity and preferences for depression treatment.
      • Wang J.
      • White-Means S.I.
      • Hufstader M.A.
      • Walker G.D.
      The economic implications of the racial and ethnic disparities in the use of selective serotonin reuptake inhibitors.
      However, this sample may have unique needs and barriers to health care that are not representative of the larger population of persons with TBI, including the etiology of injury, and may therefore underestimate the efficacy of sertraline on other samples of persons with TBI. Although this is a potential limitation of this study, it is also a strength because persons from minority groups are infrequently included in randomized controlled trials.
      • Wang J.
      • White-Means S.I.
      • Hufstader M.A.
      • Walker G.D.
      The economic implications of the racial and ethnic disparities in the use of selective serotonin reuptake inhibitors.

       Study Limitations

      Because the sample size was small, the participants who dropped out of the study could have reduced the differential effect between the medication and placebo groups. There was a difference between those who dropped out of treatment and those who remained in treatment, with the dropouts having higher depression scores at the time they left treatment; however, the number of dropouts was similar for both conditions. Additionally, among those who completed the study, there were more responders in the treatment group as compared with the placebo group (59% and 32%) and fewer nonresponders (17% and 37%), although these percentages were not statistically significant.
      There are other limitations to the study. First, the sample was heterogeneous in terms of the severity of injury and the time since injury. Thus, the medication may indeed be helpful for persons with mild TBI and not helpful for those with moderate or severe TBI. Second, the high representation of persons from minority backgrounds of lower socioeconomic status limits the generalizability of the findings to the larger TBI population. Future research on more homogeneous samples may better define which persons with TBI are most likely to experience an improvement in their mood after treatment with sertraline.

      Conclusions

      The findings of this study highlight the importance of identifying high-risk subgroups in the TBI population and the continuing need to target effective interventions to them. Finally, although the sample size is small, even without the intent-to-treat analysis, the remaining participants provide sufficient power (70%) to detect a medium effect. Of the 11 who did not complete the study, 5 dropped out immediately; however, the remaining 6 had some treatment, and half of the 6 had 6 weeks of treatment. This would suggest that the findings are robust despite the small sample.
      Given the high prevalence of post-TBI depression (and anxiety), more randomized controlled studies are needed to examine the efficacy of various types of both pharmaceutical and behavioral treatments. This study is just one of many that need to be completed to develop an empirical basis for treatment.

      Acknowledgments

      The authors gratefully acknowledge all of the conscientious clinicians who conducted the structured interviews (Joshua Masino, PhD, Giselle Braganza, PhD, Charles Filanosky, PhD, Theodore Tsaousides, PhD, Adam Warshowsky, PhD, Amanda Sacks, PhD, Guido Mascialino, PhD). The authors also thank Jonathan Silver, MD, for his advice on study design.

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