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Study concept and design: Bombardier, Fann, Temkin, Esselman, Dikmen
Acquisition of data: Bombardier, Fann, Temkin
Analysis and interpretation of data: Temkin, Bombardier, Fann, Barber
Drafting of the manuscript: Bombardier, Fann, Temkin, Barber
Critical revision of the manuscript for important intellectual content: Dikmen, Esselman
Statistical analysis: Temkin, Barber
Obtained funding: Bombardier, Fann
Administrative, technical, or material support: Bombardier, Fann
Study supervision: Bombardier, Fann
Uncertainties exist about the rates, predictors and outcomes of major depressive disorder (MDD) among people with traumatic brain injury (TBI).
To describe MDD related rates, predictors, outcomes and treatment during the first year after TBI
Cohort from 6/2001–3/2005 followed by structured telephone interviews at months 1–6, 8, 10, and 12 (data collection ending 2/2006).
Harborview Medical Center, a Level I trauma center in Seattle, WA
559 consecutively hospitalized adults with complicated mild to severe TBI
The Patient Health Questionnaire (PHQ) depression and anxiety modules were administered at each assessment and the European Quality of Life measure (EQ-5D) was given at 12 months.
53% met criteria for MDD at least once in the follow-up period. Point prevalences ranged between 31% at one month and 21% at six months. In a multivariate model, increased risk of MDD after TBI was associated with MDD at the time of injury (risk ratio [RR], 1.62; 95% confidence interval [CI], 1.37–1.91), history of MDD prior to injury (but not at the time of injury) (RR, 1.54; 95% CI, 1.31–1.82), age (RR, 0.61; 95% CI, 0.44–0.83 for 60+ years vs. 18–29 years) and lifetime alcohol dependence (RR, 1.34; 95% CI, 1.14–1.57). Those with MDD were more likely to report co-morbid anxiety disorders after TBI than those without MDD (60% versus 7%; RR, 8.77; 95% CI, 5.56–13.83). Only 44% of those with MDD received antidepressants or counseling. After adjusting for predictors of MDD, persons with MDD reported lower quality of life at one year, compared to the nondepressed group.
Among a cohort of patients hospitalized for TBI, 53% met criteria for MDD during the first year after TBI. MDD was associated with prior history of MDD and was an independent predictor of poorer health-related quality of life.
Traumatic brain injury (TBI) is a major cause of disability in the United States1 and a signature injury among wounded soldiers.2 Assessment and treatment of TBI typically focus on physical and cognitive impairments, yet psychological impairments represent significant causes of disability.3 Major depressive disorder (MDD) may be the most common and disabling psychiatric condition in people with TBI.4 Poorer cognitive functioning,5 aggression and anxiety,6, 7 greater functional disability,6, 8 poorer recovery,9 higher rates of suicide attempts,10 and greater health care costs11 are thought to be associated with MDD after TBI.
Despite considerable research, the rates, predictors and outcomes of MDD after TBI remain uncertain. Depression prevalence rates have ranged from 10–77%.12 Small sample size, selection bias, retrospective reporting, use of measures without diagnostic validity and failure to exclude cases that were depressed at the time of injury have limited studies of rates and correlates of TBI related MDD.13 More definitive studies could galvanize efforts to improve recognition and treatment of this important secondary condition. Therefore, we sought to describe the rate of MDD during the first year after TBI, multivariate predictors of MDD, MDD related comorbidities, and the relationship of MDD to one year quality of life outcomes in a large prospectively studied sample of consecutive patients hospitalized for complicated mild to severe TBI.
This study was the recruitment phase of a clinical trial investigating the efficacy of sertraline for MDD after TBI. The trial is completed and the outcome analysis is in progress. Eligibility criteria for the cohort study were: admitted to Harborview Medical Center (a Level I trauma center in Seattle, WA) with TBI; radiological evidence of acute traumatically induced brain abnormality or Glasgow Coma Scale (GCS) less than 13 (based on the lowest score within 24 hours after admission or the first after paralytic agents were withdrawn). Participants were residents of King, Pierce, Kitsap, Jefferson, Mason, Thurston or Snohomish counties, at least 18 years old and English speaking. We excluded those with uncomplicated mild TBI (GCS 13–15 and no radiological abnormality) due to diagnostic unreliability in this population.14 Other exclusion criteria were: homelessness, no contact information, incarceration and schizophrenia (See Figure 1). Participants with GCS < 13 and no radiological evidence of TBI were excluded if their blood alcohol level (BAL) exceeded 199 mg/dL because alcohol intoxication can decrease GCS scores.15 Enrollment occurred from 6/2001 through 3/2005 and follow up assessments ended in 2/2006. We obtained a waiver of consent to determine eligibility and retain selected demographic information on non-recruited patients. Otherwise, participation required written consent. Study procedures were approved by the University of Washington Institutional Review Board and followed HIPAA guidelines.
Consecutively eligible inpatients with TBI were identified via daily automatic electronic medical records queries and TBI consultation lists. Research staff consented eligible patients who were fully oriented prior to discharge. For patients disoriented at discharge we obtained assent from legal next of kin to conduct follow-up. We recruited patients not approached by discharge via a letter from the attending neurosurgeon and telephone calls. Trained research personnel used structured telephone interviews to assess participants monthly from 1–6 and at 8, 10, and 12 months following injury. Patients were required to pass a standardized orientation examination16 prior to consent. We followed disoriented patients for up to one year to determine if they had become oriented and could be assessed.
Demographic, medical, radiologic and ICD-9 code data were obtained via participant interviews, chart reviews and the Harborview Trauma Registry. Race was obtained via self-report and chart review because depression prevalence may vary by race. Other system injury severity was based on the Injury Severity Score-excluding head.17 Serum BAL (mg/dL) and toxicology screening results (cocaine and amphetamine) were available on 80% of the sample.
At the initial assessment, we conducted a structured interview to assess preinjury history of psychiatric disorders and treatment. Participants were coded as depressed at injury if they reported any of the following within six months prior to TBI: diagnosis of depression, depression related antidepressant use, depression related counseling or a suicide attempt. Preinjury history of depression was defined as ever receiving a diagnosis of or treatment for depression or making a suicide attempt. Lifetime history of other mental health diagnoses was based on whether participants indicated they had ever been diagnosed with bipolar disorder or manic depression, generalized anxiety disorder, panic disorder, post-traumatic stress disorder (PTSD), obsessive compulsive disorder, any phobia, schizophrenia, schizoaffective disorder or any psychotic disorder. For descriptive purposes, we segregated out lifetime history of depression or PTSD and collapsed the remainder of the diagnoses into “other mental health diagnoses.” Lifetime alcohol dependence was based on endorsing at least two items on the CAGE.18 Alcohol or drug abuse was defined as BAL > 100 or positive toxicology screen for cocaine or amphetamine, respectively, upon admission. Participants were asked whether they were involved in or planning a lawsuit related to their injury.
Longitudinal interviews focused on assessment of MDD as well as panic and other anxiety disorders and treatment. Cases with MDD were identified using a structured interview based on the Patient Health Questionnaire 9-item depression scale (PHQ-9).19 A telephone administered PHQ-9 has excellent inter-rater reliability (r = .99) and good diagnostic sensitivity (.93) and specificity (.89)20 in people with TBI compared to the Structured Diagnostic Interview for DSM-IV (SCID).21 Participants were positive for MDD if they endorsed either depressed mood or anhedonia and a total of 5 or more symptoms of MDD at least several days during the prior two-week period. Current panic disorder and other anxiety disorder were assessed on the same schedule using validated screening modules from the PHQ.22 At each contact, participants were asked about receipt of antidepressants or counseling for depression.
Outcomes assessed at 12 months included health related quality of life (one item General Health Scale from the SF-36),23 the European Quality of Life Measure (EQ-5D) population based weighted summary score24 and five EQ-5D subcomponents. We measured social role impairment attributed to depression symptoms as described by Kroenke and colleagues19 as well as current employment status and subjective percent back to normal (preinjury functioning).25
Post-injury MDD rates are estimated as the proportion of cases ascertained with MDD for the first time post-TBI at each assessment among the total sample of 559. Point prevalence is the proportion of participants positive for MDD, regardless of whether it was new, persisting or recurrent, among those interviewed at that assessment. Participants were classified as MDD+ if they qualified as depressed at any screening call and MDD− if they never qualified. Likewise, a person was considered to have a comorbid condition or treatment if they qualified at any interview. Both underestimate the true rates as participants may have had a condition only when they missed an interview. Binomial regression with a log-linear link (Proc GENMOD, SAS 9.2, SAS Institute, Inc., Cary, NC) was used for comparing the risk of MDD and relating MDD to binary outcomes with or without adjustment for other factors. To assess independent predictors of MDD, a backward stepwise procedure was used starting with a model containing all predictors in Table 1. Separate multivariate models were built for all participants and for those who were not depressed at injury. T-tests were used to assess the bivariate relationship between MDD and continuous outcomes. We adjusted for full-sample-predictors of MDD, using linear or log-binomial regression, to see whether MDD independently predicted outcomes. Months depressed was calculated as the number of positive monthly screens plus twice the number of positive bi-monthly screens. All probabilities are 2-tailed. Nominal p-values are presented, but the Bonferroni-corrected significance level is given in footnotes.
We identified 1080 eligible patients, 559 of whom consented and underwent at least one interview. Those interviewed were significantly younger 42.5 (17.9) vs. 46.8 (21.5) years old, more likely to have completed high school (89% vs. 84%) and less likely to have Medicare insurance (16% vs. 25%) compared to the non-recruited group (data not shown). The two groups were equivalent in terms of gender ratio, race, marital status, cause of injury, coma severity, other system injury severity, BAL, toxicology findings and length of hospital stay. Participant interview rates among those eligible for interview at the nine assessment points ranged from 79–90% (Figure 1). Fewer participants were interviewed at month 1 (n = 289) versus subsequent months (n = 358–432), primarily because more participants at month 1 were not eligible for interview, e.g. pending consent (n = 182) or not yet oriented (n = 30).
During the first year after TBI 297/559 (53%) met criteria for MDD at least once (Figure 2). The point prevalence of MDD was highest the first month after TBI. Point prevalence ranged from 21% to 31% with no trend (eFigure 1). Among those screening positive for MDD in the first 3 months and interviewed at least twice, the median time depressed was 4 months, 27% screened positive only once while 36% screened positive for 6 or more months (eFigure 2). Excluding those depressed at the time of injury, the rate of new (incident) MDD was 49% (233/471).
Table 1 shows the composition of the 559 participants interviewed as well as the percent depressed during the study period in various subgroups based on demographics and injury characteristics and the univariate risk ratio (RR) for depression. Participants were mostly males injured in vehicular crashes who sustained complicated mild injuries. Factors closely related to MDD when considered individually include age, gender, cocaine intoxication, lifetime alcohol dependence and preinjury history of depression, PTSD or other mental health diagnosis. Independent predictors of MDD in the multivariable models (Table 2), were age and pre-injury depression for both the full sample and the sample that excluded those depressed at injury. Lifetime alcohol dependence was independently associated with MDD only in the full sample model and gender was associated with MDD only in the sample not depressed at injury. Figure 3 and eFigures 3–5 display the cumulative rate of MDD depending on prior history of depression, PTSD, alcohol dependence, and other mental health diagnosis. The group with a prior history of depression was comprised of those with a history of depression diagnosis (n=61, 41%) or a history of suicide attempt (n=41, 28%) or treatment for depression including antidepressants (n=121, 81%), inpatient treatment (n=17, 11%) or outpatient counseling (n=52, 35%). TBI patients with or without these co-morbid conditions appear to be at risk of MDD throughout the 12 months (eFigure 5).
MDD was associated with increased risk of meeting criteria for post-TBI panic disorder (27% versus 1%; RR = 23.82, 95% CI, 7.62–74.50) and other anxiety disorder (54% versus 6%; RR = 8.82, 95% CI, 5.42–14.35) (eTable 1).
People with MDD were more likely to receive antidepressants (41% versus 18%; RR = 2.26; 95% CI, 1.67–3.05) and counseling (20% versus 5%; RR = 3.92; 95% CI, 2.20–7.00) during the year after TBI compared to those without MDD (excluding participants in the treatment trial) (eTable 1).
MDD within the first year after TBI was associated with greater problems with mobility, usual activities and pain/discomfort and greater difficulty with role functioning at 12 months post-TBI, after controlling for MDD related risk factors (eTable 2).
The one year cumulative rate of MDD in this study sample is 7.9 (53.1%/6.7%) times greater than would be expected in the general population.26 Previous high quality studies may have underestimated the rates of MDD during the first year after TBI by reporting rates in the 12% to 42.3% range.7, 27, 28 Our rate estimate may be higher because we conducted frequent assessments and were able to capture the cases with transient (one month) major depressive episodes. In addition, the sample was characterized by high rates of depression related risk factors such as alcohol dependence and other preinjury mental health diagnoses. Nevertheless, due to incomplete data at each assessment time point, the rate and depression duration estimates are likely conservative.
Our data indicate that 15.7% of the sample was depressed at the time of injury and that 26.8% had a preinjury history of depression but were not depressed when injured (Table 1). Of the total sample, 11.4% had a major depressive episode both at injury and after the injury, 18.4% experienced a recurrence of major depressive episode after the injury, and 23.3% experienced MDD for the first time after the injury. Preinjury depression and depression at the time of injury heralded higher post-TBI rates of MDD compared to those with no depression history.
Nevertheless, by 12 months 41% of those with no preinjury depression history also had an episode of MDD. High rates of preinjury depression in this and other samples7, 29 compared to the lifetime prevalence of MDD in the general population (16.2%)30 is consistent with the notion that depression is a risk factor for TBI.29 Our estimate of preinjury depression may be higher than other studies because we included prior antidepressant treatment, prior psychotherapy for depression and history of suicide attempt as indicators of depression history.
Several features of MDD after TBI are pertinent to future detection and treatment efforts. About half of the cases that became depressed were identified by 3 months. These data contradict the theory that poor awareness of impairment precludes depressive reactions during the first 6 months after injury31 and suggest a window of opportunity for early identification and treatment or prevention efforts. Nevertheless, TBI survivors remained at risk of MDD throughout the first year regardless of preinjury depression history. Risk of post-TBI MDD probably persists beyond one year since the curves (Figure 3, eFigures 3–5) do not seem to level off by 12 months. In 27% of cases MDD lasted only one month and may not have required treatment. Depression after TBI was complicated by a history of substance abuse disorders and PTSD as well as cooccurring anxiety, conditions that can limit the efficacy of antidepressants.32
Multivariate risk factors for MDD following TBI are similar to those for primary MDD in the general population.33 History of depression around the time of injury and history of depression prior to that time were the strongest predictors of post-TBI depression. These data disconfirm the notion that prior history of psychiatric disorder is either unrelated to28 or inversely related to MDD following TBI.4 The relationship of alcohol dependence to both TBI34, 35 and depression merits particular attention as a potentially modifiable risk factor. We did not find a relationship between injury characteristics and rate of MDD. Severity of TBI as a predictor of MDD has been controversial.13 Other biological markers such as the APOE-ε4 allele, neurotransmitter and neuroendocrine changes, genetic polymorphisms, as well as psychosocial risk factors, merit further study,35
Depression after TBI was associated with comorbid anxiety and poorer functional outcomes in multiple domains one year after injury. After controlling for all variables associated with depression after TBI, MDD remained a significant predictor of poorer self-reported health and lower quality of life. These results are correlational; therefore, causality cannot be inferred. Prior research has linked post-TBI depression with a host of poorer subjective and objective outcomes.5–7 Effective depression treatment may reduce disability36 and this hypothesis deserves further research.
Depression was under-treated in the study sample. Moreover, based on primary care research, we suspect that an even smaller proportion received guideline level depression treatment.37 The dearth of rigorous pharmacotherapy and psychotherapy trials likely contributes to the inadequate treatment of MDD after TBI. Only one negative but underpowered Class I antidepressant (sertraline) treatment trial has been published.38 A randomized placebo-controlled depression prevention trial found that 50 mg of sertraline daily for 3 months after TBI resulted in significantly lower depression severity in the treated group versus controls at the end of the trial but not beyond.39
Psychotherapy was especially underutilized in our sample, possibly due to poor access to counseling. A trial of proactive telephone counseling has demonstrated that treated subjects reported less depressive symptomatology one year after TBI compared to usual care controls.40 Additionally, survey research indicates that people with TBI favor counseling and physical exercise over other depression treatment modalities.41 In-person or telephone counseling was preferred over Internet delivered depression treatment.
Characteristics and comorbidities of TBI related depression may influence treatment efficacy.35 For example, executive dysfunction, which is common following TBI, predicts poor response to selective serotonin reuptake inhibitors in non-TBI samples.42 Cognitive impairments may affect the feasibility and efficacy of standard psychotherapeutic interventions. Integrated medical and psychosocial interventions, including substance abuse interventions, might be required to produce satisfactory outcomes.
Systematic integration of mental health services into standard care of patients with TBI may be needed to improve long-term outcomes after TBI. Within inpatient rehabilitation, integrated clinical pathways can be used to organize early identification, risk assessment, diagnosis and guideline-driven treatment of MDD.43 Systematic depression screening and stepped care treatment protocols should be integrated into routine outpatient care. For those without or beyond routine follow-up, novel case-finding programs, possibly via scheduled telephone contacts,44 Internet based screening45 or other technology-assisted methods46 may be useful. The manner in which substance abuse treatment has been integrated into trauma care47 and depression treatment integrated into primary care48 may provide models of how to incorporate depression treatment into TBI care.
Several study limitations should be highlighted. First, the presence or absence of MDD was based upon structured telephone interviews using the PHQ-9, not more traditional diagnostic interviews such as the SCID. Nevertheless, we have reported excellent inter-rater reliability and good diagnostic sensitivity and specificity when comparing the PHQ-9 to the SCID in people with TBI.20 Caution should be exercised comparing these results to studies that have used other diagnostic approaches.
Next, the study was conducted at a single Level I trauma center serving the Northwestern United States. The patient population was characterized by high rates of Medicaid recipients and somewhat limited ethnic/racial diversity. The results of this study may not be generalizable to other regions or populations with different socioeconomic or ethnic/racial characteristics.
The recruitment rate for this study was 52%. While this rate seems low, other widely referenced prevalence studies were based on convenience or referral samples or did not report recruitment rates and did not assess selection bias.13 Trauma patients, especially persons with TBI, are difficult to recruit and follow49 resulting in unrepresentative samples. Our study sample was comparable to the non-recruited group on most dimensions, though they were younger, more likely to have completed high school and less likely to be on Medicaid.
We found no differences in rate of MDD among those with complicated mild, moderate or severe TBI. However, caution is advised extrapolating these results to persons with uncomplicated mild TBI, which constitute the majority of those who sustain TBI.1 Although a significant number of such cases seek medical attention, adequate information about rates of complicated recoveries is lacking and deserves future research.
In conclusion, MDD after TBI is highly prevalent and associated with increased comorbidity and disability. Because MDD after TBI is an invisible disorder within an often invisible injury, aggressive efforts are needed to educate healthcare providers about the importance of MDD in this population, to promote integrated systems of detection and multidisciplinary care, and to conduct intervention studies aimed at overcoming multiple barriers to effective treatment.
Funding/Support: This work was supported by National Institutes of Health Grant R01 HD39415 to Drs Bombardier and Fann (Co-PIs). Pfizer supplied masked sertraline and placebo for the controlled trial.
Role of the Sponsor: Neither the National Center for Medical Rehabilitation Research, National Institute of Child Health and Human Development/National Institutes of Health nor Pfizer had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
We are grateful for the dedication and expert assistance provided by Erika Pelzer, BS, for oversight of data collection efforts. She was compensated for her contributions.
Financial Disclosures: Dr Bombardier reports ownership of Pfizer stock. Dr. Fann reports ownership of Pfizer and Amgen stock. Dr Temkin reports ownership of stock in Amgen and Kimberly-Clark and consultancies with or honoraria from Novartis, Celgene, Eisai, Pfizer, PAR, UCB, Actelion, and GSK. Dr Esselman reports ownership of Eli Lily stock. Mr. Barber reports none. Dr. Dikmen reports none.
Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Medical Rehabilitation Research
Previous Presentations: Parts of this paper were presented at the annual national meetings of the American Psychological Association, Rehabilitation Psychology Division, Charlotte, NC March 2007 and the Academy of Psychosomatic Medicine, Amelia Island, FL November 2007