Depression after Depression after Traumatic Brain Injury:Traumatic Brain Injury:More Than Just the BluesMore Than Just the Blues

Jesse R. Fann, MD, MPHJesse R. Fann, MD, MPHDepartments of Psychiatry & Behavioral Departments of Psychiatry & Behavioral

Sciences and Rehabilitation MedicineSciences and Rehabilitation MedicineSchool of MedicineSchool of Medicine

Department of EpidemiologyDepartment of EpidemiologySchool of Public HealthSchool of Public Health

University of WashingtonUniversity of Washington

AcknowledgmentAcknowledgment Charles Bombardier, PhDCharles Bombardier, PhD

Sureyya Dikmen, PhDSureyya Dikmen, PhD Nancy Temkin, PhDNancy Temkin, PhD Peter Esselman, MDPeter Esselman, MD Jay Uomoto, PhDJay Uomoto, PhD Wayne Katon, MDWayne Katon, MD Kenneth Jaffe, MDKenneth Jaffe, MD Robert Thompson, MDRobert Thompson, MD Theresa Massagli, MDTheresa Massagli, MD David Newell, MDDavid Newell, MD Peter Cummings, MD, MPHPeter Cummings, MD, MPH

Kenneth Marshall, BSKenneth Marshall, BS Erika Pelzer, BSErika Pelzer, BS Cathy Warms, PhD, ARNPCathy Warms, PhD, ARNP Kellye Campbell, ARNPKellye Campbell, ARNP Jason Barber, MSJason Barber, MS Meghan Keough, BSMeghan Keough, BS Heather Romero, PhDHeather Romero, PhD Audrey Jones, BSAudrey Jones, BS Holly Rao, BSHolly Rao, BS Carina Morningstar, BSCarina Morningstar, BS Bart Burington, MSBart Burington, MS Alexandra Leonetti, MSAlexandra Leonetti, MS

Domains of Research InterestDomains of Research Interest

Depression

PsychiatricVulnerability

TBI Severity

PostconcussiveSymptoms

Cognition

PsychiatricComorbidity

Functioning/QOL

Health CareUtilization

Traumatic Brain Injury ModelTraumatic Brain Injury Model

Non-penetrating TBINon-penetrating TBI

Diffuse Axonal Injury

Contusion

Subdural Hemorrhage

Taber et al 2006

Neuropathology in TBI and DepressionNeuropathology in TBI and Depression Left dorsolateral frontal or left basal ganglia lesionsLeft dorsolateral frontal or left basal ganglia lesions are are

associated with MDD in acute TBI and stroke associated with MDD in acute TBI and stroke (Federoff et al., (Federoff et al., 1992, Robinson et al., 1985)1992, Robinson et al., 1985)

Disruption of frontal lobe - basal ganglia circuitsDisruption of frontal lobe - basal ganglia circuits is is associated with MDD in TBI associated with MDD in TBI (Mayberg, 1994)(Mayberg, 1994)

Decreased glucose metabolismDecreased glucose metabolism in orbital-inferior frontal in orbital-inferior frontal and anterior temporal cortex is associated with MDD in and anterior temporal cortex is associated with MDD in TBI, CVA, Parkinson’s TBI, CVA, Parkinson’s (Mayberg, 1994)(Mayberg, 1994)

Frontal lobe damage from TBI is associated with Frontal lobe damage from TBI is associated with reduced reduced brain serotonergic functionbrain serotonergic function (VanWoerkom et al., 1977)(VanWoerkom et al., 1977)

MDD is associated with MDD is associated with reduced left prefrontal gray matter reduced left prefrontal gray matter volumesvolumes, esp. ventrolateral & dorsolateral regions , esp. ventrolateral & dorsolateral regions (Jorge et (Jorge et al., 2004)al., 2004)

Disruption of serotonin or norepinephrine pathwaysDisruption of serotonin or norepinephrine pathways is is thought to predispose to depression thought to predispose to depression (Krishnan & Stephans, (Krishnan & Stephans, 1998)1998)

Copyright restrictions may apply.Chen, J.-K. et al. Arch Gen Psychiatry 2008;65:81-89.

Voxelwise regression analysis showed an inverse relationship between the severity of depression measured

by the Beck Depression Inventory II9 (BDI-II) and gray matter density in the anterior cingulate

Mayberg et al, J Neuropsychiatry Clin Neurosci

Traumatic Brain Injury (TBI)Traumatic Brain Injury (TBI)

Neurobiological InjuryNeurobiological Injury

Traumatic Event Traumatic Event

Chronic Medical ConditionChronic Medical Condition

TBI-associated DisabilityTBI-associated Disability

““Postconcussive Symptoms”Postconcussive Symptoms”

CognitiveCognitive Physical: sensory and motorPhysical: sensory and motor EmotionalEmotional

VocationalVocational SocialSocial FamilyFamily

DSM-IV Major Depressive Disorder DSM-IV Major Depressive Disorder (MDD)(MDD)

1.1. Depressed mood*Depressed mood*2.2. Loss of interest/pleasure*Loss of interest/pleasure*3.3. Sleep disturbanceSleep disturbance4.4. Poor energyPoor energy5.5. Motor change agitation or slownessMotor change agitation or slowness6.6. Weight/appetite change increase/decreaseWeight/appetite change increase/decrease7.7. Impaired concentration or indecisionImpaired concentration or indecision8.8. Excessive worthlessness or guiltExcessive worthlessness or guilt9.9. Recurrent thoughts of death or suicideRecurrent thoughts of death or suicide At least one of the essential criteria* and a At least one of the essential criteria* and a

total of at least 5 symptoms endorsed most of total of at least 5 symptoms endorsed most of the day most days for at least 2 weeksthe day most days for at least 2 weeks

Must cause clinically significant impairmentMust cause clinically significant impairmentAPA, Diagnostic & Statistical Manual of Mental Disorders, 4th ed, 2000

Transdiagnostic SymptomsTransdiagnostic Symptoms

TBITBI

1.1. Depressed moodDepressed mood

2.2. AnhedoniaAnhedonia

3.3. Weight loss/gainWeight loss/gain

4.4. Insomnia/hypersomniaInsomnia/hypersomnia X X

5.5. Psychomotor changesPsychomotor changes X X

6.6. FatigueFatigue X X

7.7. Worthlessness/guiltWorthlessness/guilt

8.8. Poor concentrationPoor concentration X X

9.9. Thoughts of death/suicideThoughts of death/suicide

Other Common Symptoms of Other Common Symptoms of Depression to Watch ForDepression to Watch For

Feeling sad or blueFeeling sad or blue Feeling helpless, guilty or worthlessFeeling helpless, guilty or worthless Feeling overwhelmedFeeling overwhelmed Feeling irritable or angryFeeling irritable or angry Feeling anxious or on edgeFeeling anxious or on edge Trouble solving problems or making decisionsTrouble solving problems or making decisions Trouble ‘getting going,’ especially in the morningTrouble ‘getting going,’ especially in the morning Thoughts that life isn’t worth the trouble anymoreThoughts that life isn’t worth the trouble anymore Tearfulness, sighingTearfulness, sighing Flat affectFlat affect Slowed or latent speechSlowed or latent speech

Handling Transdiagnostic SymptomsHandling Transdiagnostic Symptoms

There is controversy about including There is controversy about including overlapping symptoms when diagnosing overlapping symptoms when diagnosing depression in neurological conditionsdepression in neurological conditions

Etiologic ApproachEtiologic Approach: Counts symptoms : Counts symptoms only if not clearly and fully accounted for only if not clearly and fully accounted for by a medical condition (DSM IV).by a medical condition (DSM IV).

Inclusive ApproachInclusive Approach: Count depressive : Count depressive symptoms regardless of presumed symptoms regardless of presumed etiology. More reliable, possibly more etiology. More reliable, possibly more sensitive.sensitive.

Williams, 2002, JAMA

Prevalence of Major Depression after TBIPrevalence of Major Depression after TBIOutpatient/Referral CasesOutpatient/Referral Cases 54% 33 months post-TBI 54% 33 months post-TBI (Fann et al, 1995)(Fann et al, 1995)

42% 2.5 years post-TBI42% 2.5 years post-TBI (Kreutzer et al, 2001) (Kreutzer et al, 2001)

Unselected/Consecutive CasesUnselected/Consecutive Cases 26% MDD within 1 mo; 38% 26% MDD within 1 mo; 38% (Federoff et al, 1992)(Federoff et al, 1992)

13% mostly mild TBI at 1 yr 13% mostly mild TBI at 1 yr (Deb et al., 1999)(Deb et al., 1999)

17% mild-mod TBI at 3 mos vs. 6% in 17% mild-mod TBI at 3 mos vs. 6% in general trauma general trauma (Levin et al., 2001)(Levin et al., 2001)

27% mod-severe TBI at mean of 35 months 27% mod-severe TBI at mean of 35 months (Seel et al., 2003(Seel et al., 2003

11%-27% TBI 30-50 yrs ago 11%-27% TBI 30-50 yrs ago (Holsinger 2002, (Holsinger 2002, Koponen 2002)Koponen 2002)

Seven Year Prevalence of SCID* Diagnosed Seven Year Prevalence of SCID* Diagnosed Psychiatric Disorders After TBIPsychiatric Disorders After TBI

0

10

20

30

40

50

60

70

MDE Dysth BPD PTSD OCD PD GAD Phob S/A

Hibbard et al., 1998

Per

cent

SCID=Structured Clinical Interview for DSM-IV

One Year Cumulative Incidence of One Year Cumulative Incidence of Mood Disorders After TBIMood Disorders After TBI

0%

9%

15%

10%7%

33%

0%

10%

20%

30%

40%

Trauma Controls (n=27) TBI (n=91)

Cu

mu

lati

ve

Inc

ide

nc

e

Manic/Mixed

Other Depression

Major Depression

0%

9%

15%

10%7%

33%

0%

10%

20%

30%

40%

Trauma Controls (n=27) TBI (n=91)

Cu

mu

lati

ve

Inc

ide

nc

e

Manic/Mixed

Other Depression

Major Depression

Jorge et al., 2004

Rates of Major Depression in Chronic Rates of Major Depression in Chronic Diseases/Disabling ConditionsDiseases/Disabling Conditions

Traumatic brain injury Traumatic brain injury 11-61%11-61% Multiple sclerosisMultiple sclerosis 16-36%16-36% Spinal cord injurySpinal cord injury 23-30%23-30% StrokeStroke 16-30%16-30% CADCAD 17-27%17-27% DiabetesDiabetes 10-15%10-15% Primary care patientsPrimary care patients 5-10%5-10% General populationGeneral population 2-4%2-4%

Katon & Ciechanowski, 2002; Rudisch & Nemeroff, 2003; Turner-Stokes & Hassan, 2002; Bombardier et al, 2004; Patten, 2003; Dikmen et al., 2004

An estimated 31% of troops returning from An estimated 31% of troops returning from Iraq and Afghanistan have a mental health Iraq and Afghanistan have a mental health

condition or reported having a TBIcondition or reported having a TBI

MDD & PTSD MDD & PTSD after TBIafter TBI

Among Among Army soldiersArmy soldiers with (Hoge et al, 2008) with (Hoge et al, 2008)– Mild TBI with LOC:Mild TBI with LOC: 22.9% MDD22.9% MDD – Mild TBI w/o LOC:Mild TBI w/o LOC: 8.4% MDD8.4% MDD – Other injuries:Other injuries: 6.6% MDD6.6% MDD

Civilian studiesCivilian studies::– MDD Point prevalenceMDD Point prevalence 26-31%26-31% – MDD Period prevalenceMDD Period prevalence 42-53% within the first 42-53% within the first

year, 61% within the first 7 years after TBIyear, 61% within the first 7 years after TBI– Rates of depression are not associated with TBI Rates of depression are not associated with TBI

severityseverity

Importance of Depression & Importance of Depression & PTSDPTSD

Hoge et al, Hoge et al, New Engl J MedNew Engl J Med 2008 2008– Many putative mild TBI-related symptoms may Many putative mild TBI-related symptoms may

overlap with and be mediated, at least in part, overlap with and be mediated, at least in part, by depression and PTSD by depression and PTSD ▪Overall HealthOverall Health▪Missed Workdays due to illnessMissed Workdays due to illness▪Medical Visits due to physical conditionMedical Visits due to physical condition▪Somatic & post-concussive symptoms Somatic & post-concussive symptoms

(including memory & concentration (including memory & concentration problems)problems)

Correlates of Depression in TBICorrelates of Depression in TBI

Depression after TBI is associated withDepression after TBI is associated with: : increased increased aggressive behavioraggressive behavior and and anxietyanxiety

(Tateno et al., 2003; Jorge et al., 2004; Fann et al., 1995)(Tateno et al., 2003; Jorge et al., 2004; Fann et al., 1995) higher rates of higher rates of suicidal planssuicidal plans (Kishi et al., 2001)(Kishi et al., 2001)

8 times more 8 times more suicidesuicide attemptsattempts (Silver et al., (Silver et al., 2001)2001)

3-4 times more 3-4 times more completed suicidescompleted suicides than in than in the general population and non-brain the general population and non-brain injured controls injured controls (Teasdale and Engberg, 2001)(Teasdale and Engberg, 2001)

Correlates of Depression in TBICorrelates of Depression in TBI

Depression after TBI contributes toDepression after TBI contributes to: : Poorer Poorer cognitive functioningcognitive functioning (Rappoport et (Rappoport et

al., 2005)al., 2005)

Lower Lower health status and QOLhealth status and QOL and and greater greater functional disabilityfunctional disability (Levin et al (Levin et al 2001; Fann et al., 1995; Hibbard et al., 2004; Bombardier et al, 2001; Fann et al., 1995; Hibbard et al., 2004; Bombardier et al, 2010)2010)

Poorer Poorer recoveryrecovery (Mooney et al., 2005)(Mooney et al., 2005)

More More post-concussive symptomspost-concussive symptoms (Fann (Fann et al., 1995; Rapoport et al., 2005)et al., 1995; Rapoport et al., 2005)

Major Depression and Cognitive Functioning

Rappoport et al., 2005

Postconcussive SymptomsPostconcussive Symptoms Depressed Nondepressed Depressed Nondepressed

(n=10) (n=10) (n=22) (n=22)

HeadacheHeadache 50%50% 27%27%

DizzinessDizziness 4040 3232

Blurred VisionBlurred Vision 4040 2727

Bothered by NoiseBothered by Noise 5050 3232

Bothered by LightBothered by Light 3030 1818

Loss of Temper EasilyLoss of Temper Easily 7070 3232

Memory DifficultiesMemory Difficulties 7070 5555

FatigueFatigue 6060 3232

Trouble ConcentratingTrouble Concentrating 6060 4141

IrritabilityIrritability 8080 3232

AnxietyAnxiety 9090 3232

Sleep DisturbanceSleep Disturbance 6060 2727

Fann et al, 1995

Depression Influences the Course Depression Influences the Course and Prognosis of Chronic Diseasesand Prognosis of Chronic Diseases

Increased medical utilizationIncreased medical utilization Higher cost of medical careHigher cost of medical care Symptom amplificationSymptom amplification Greater functional disabilityGreater functional disability Poor treatment adherence and self-Poor treatment adherence and self-

carecare Increased mortalityIncreased mortality

Katon and Ciechanowski, 2002Katon and Ciechanowski, 2002

Depression Risk Factors in TBIDepression Risk Factors in TBI

Age (30-44 vs. > 60)Age (30-44 vs. > 60) Female GenderFemale Gender Less than high school educationLess than high school education Violent etiologyViolent etiology Medicaid insuranceMedicaid insurance Litigation involvementLitigation involvement Lifetime alcohol dependenceLifetime alcohol dependence Cocaine/Methamphetamine intoxicationCocaine/Methamphetamine intoxication Preinjury major depressionPreinjury major depression Unstable pre-injury work historyUnstable pre-injury work history

Unrelated to: injury severity, raceUnrelated to: injury severity, race

Bombardier, Fann et al., unpublished; Dikmen et al., 2002 Arch PM&R

Impact of Prior Psych IllnessImpact of Prior Psych IllnessAdults Adults >> 15 yo (N=939) 15 yo (N=939)

Psych Illness Cumulative IncidencePsych Illness Cumulative Incidence

0.000.100.200.300.400.500.600.700.800.90

0.000.100.200.300.400.500.600.700.800.90

6 12 18 24 30 36 6 12 18 24 30 36Month

Pred

icted

Cum

ulat

ive In

ciden

ce

Psychiatric Illness by TBI*nonemild

mod./severe

No Prior Psychiatric Illness Prior Psychiatric Illness

* Predicted proportions for a women of age 40-44 with median index month (6), median log cost and no comorbid injuries

Median Costs (TBI Patients)Median Costs (TBI Patients)

0 to 6 months after TBI

0100200300400500600

OP Prim

Car

e

OP Med

Spec

Emer

gency

OP Phar

mac

y

OP Lab

/Rad

Psych Ill Non-Psych Ill

Prospective Cohort Study & Prospective Cohort Study & Randomized Controlled TrialRandomized Controlled Trial

FundingFunding:: NCMRR (National Institutes of Health)NCMRR (National Institutes of Health) SettingSetting:: Harborview Medical Center: Level I trauma Harborview Medical Center: Level I trauma

center covering Washington, Alaska, Montana, Idahocenter covering Washington, Alaska, Montana, Idaho PatientsPatients:: Consecutive adults admitted with moderate to Consecutive adults admitted with moderate to

severe TBI (Head CT evidence of acute brain injury and/or severe TBI (Head CT evidence of acute brain injury and/or GCSGCS<<12)12)

Data collectionData collection::

Surveillance PhaseSurveillance Phase

Telephone Interview monthlyTelephone Interview monthly

Treatment PhaseTreatment Phase

In-person InterviewIn-person Interview InterventionIntervention:: 12-week, randomized, double-blind, 12-week, randomized, double-blind,

placebo controlled trial of sertralineplacebo controlled trial of sertraline

Study SchemaStudy SchemaConsent consecutive admissions with Moderate to Severe TBIConsent consecutive admissions with Moderate to Severe TBI

Screen for Depression monthly with PHQ-9 for 12 months after TBIScreen for Depression monthly with PHQ-9 for 12 months after TBI

Diagnose MDD with SCIDDiagnose MDD with SCID

__________________________________________________________________________________________________

Eligibility and consent for Treatment Phase randomizationEligibility and consent for Treatment Phase randomization

Baseline Assessment and MeasuresBaseline Assessment and Measures

Randomize to Sertraline or PlaceboRandomize to Sertraline or Placebo

Sertraline 12 wk trialSertraline 12 wk trial Placebo 12 wk trialPlacebo 12 wk trial

Outcome AssessmentOutcome Assessment

Su

rvei

llan

ce

Ph

ase

Tre

atm

en

t P

ha

se

Patient Health Questionnaire - 9Patient Health Questionnaire - 9 Over the Over the last 2 weekslast 2 weeks, how often have you , how often have you

been bothered by any of the following been bothered by any of the following problems?problems?

Not Not at allat all

SeveralSeveraldaysdays

MoreMorethanthan

half thehalf thedaysdays

NearlyNearlyeveryevery dayday

1. Little interest or pleasure in doing things1. Little interest or pleasure in doing things 00 11 22 33

2. Feeling down, depressed, or hopeless2. Feeling down, depressed, or hopeless 00 11 22 33

3. Trouble falling or staying asleep, or sleeping too 3. Trouble falling or staying asleep, or sleeping too muchmuch

00 11 22 33

4. Feeling tired or having little energy4. Feeling tired or having little energy 00 11 22 33

5. Poor appetite or overeating5. Poor appetite or overeating 00 11 22 33

6. Feeling bad about yourself — or that you are a 6. Feeling bad about yourself — or that you are a failure or have let yourself or your family downfailure or have let yourself or your family down

00 11 22 33

7. Trouble concentrating on things, such as reading 7. Trouble concentrating on things, such as reading the newspaper or watching televisionthe newspaper or watching television

00 11 22 33

8. Moving or speaking so slowly that other people 8. Moving or speaking so slowly that other people could have noticed? Or the opposite — being so could have noticed? Or the opposite — being so fidgety or restless that you have been fidgety or restless that you have been moving .around a lot more than usualmoving .around a lot more than usual

00 11 22 33

9. Thoughts that you would be better off dead or of 9. Thoughts that you would be better off dead or of hurting yourself in some wayhurting yourself in some way

00 11 22 33Spitzer et al. JAMA 1999

PHQ-9 vs. SCID ROC in TBIPHQ-9 vs. SCID ROC in TBI

Fann et al., 2005

Demographic CharacteristicsDemographic Characteristics

31% were aged 18-2931% were aged 18-29 72% were male72% were male 85% were non-Hispanic white; 5% African 85% were non-Hispanic white; 5% African

American, 4% Hispanic/Latino; 3% Asian American, 4% Hispanic/Latino; 3% Asian American; 2% otherAmerican; 2% other

10% had less than high school education10% had less than high school education 41% were single41% were single Insurance: 57% Commercial; 27% Insurance: 57% Commercial; 27%

Medicaid; 16% MedicareMedicaid; 16% Medicare

Causes of InjuryCauses of Injury

Fall 33%

Violence 11%

Other 9%

Motor Vehicle

Crash 47%

Injury Severity IndicatorsInjury Severity Indicators Coma severity (Worst GCS Score)Coma severity (Worst GCS Score)

– 52% Complicated Mild (GCS 13-15)52% Complicated Mild (GCS 13-15)– 23% Moderate (GCS 9-12)23% Moderate (GCS 9-12)– 25% Severe (GCS 3-8)25% Severe (GCS 3-8)

29% had cortical contusion(s)29% had cortical contusion(s) 68% had intracerebral hemorrhage68% had intracerebral hemorrhage Non-head (other system) injury severityNon-head (other system) injury severity

– 27% none27% none– 34% minor to moderate34% minor to moderate– 38% serious to critical38% serious to critical

Psychiatric HistoryPsychiatric History

Depression historyDepression history– 16% depressed at injury16% depressed at injury– 27% prior history of depression (not at injury)27% prior history of depression (not at injury)– 57% no history of depression57% no history of depression

6% had a history of PTSD6% had a history of PTSD 11% had a history of other mental health 11% had a history of other mental health

diagnosisdiagnosis 41% screened positive for lifetime history 41% screened positive for lifetime history

of alcohol dependenceof alcohol dependence

Rates Of Major Depression After TBIRates Of Major Depression After TBI

N = 559

53%

Months With MDD (n=154)Months With MDD (n=154)

Data includes only those first depressed within 3 months of TBI and with at least 2 subsequent assessments

Median = 4 months depressed27% depressed for one month36% depressed at least 6 months

57%52% 52%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Complicated Mild Moderate Severe

1 Y

ear

Cu

mu

lati

ve R

ate

Rate of MDD by Coma Severity

All comparisons ns

Rate of MDD by Age

52.6%

69.1%

52.6%

31.0%

0%

10%

20%

30%

40%

50%

60%

70%

80%

18-29 30-44 45-59 60+

Age Category

1 Y

ear

Cu

mu

lati

ve R

ate

*

* P = .002 after adjusting for all other potential predictors

Cumulative Rate of MDD as a Cumulative Rate of MDD as a Function of Depression HistoryFunction of Depression History

73%*69%*

41%

*P < .001; independent predictors after adjusting for all other variables

Rate of MDD by History of Lifetime Rate of MDD by History of Lifetime Alcohol DependenceAlcohol Dependence

70%*

45%

*P < .001; independent predictor after adjusting for all other variables

Comorbidity of Anxiety and MDDComorbidity of Anxiety and MDD

1

27

6

54

0

10

20

30

40

50

60

70

80

90

100

Cu

mu

lati

ve

Pe

rce

nt

Panic Disorder Other Anxiety Disorder

MD-MD+

Any comorbid anxiety disorder in MDD+ vs. MDD- (60% vs. 7%; RR, 8.77; CI, 5.56-13.83)

Association of MDD with Problems on Association of MDD with Problems on EuroQol 5D at 12 months EuroQol 5D at 12 months

24

41

8

2226

51

16

68

49

73

0

10

20

30

40

50

60

70

80

90

100

Per

cen

t w

ith

pro

ble

ms

Mobility Self-Care UsualActivity

Anx/Dep Pain

MD-MD+

****

* Significant after adjusting for all predictors of MDD

Association of MDD with 12 Month Association of MDD with 12 Month Outcomes Outcomes

7

25

87

74

4254

88

74

010

20

30

40

50

60

70

80

90100

Per

cen

t o

f sa

mp

le

% Poor-FairHealth

% Back toNormal

% NotWorking

Mean HealthState

MD-MD+

* * *

* Significant after adjusting for predictors of MDD

Depression TreatmentDepression Treatment

Among those with a major depressive Among those with a major depressive episode (53%):episode (53%):

41% received any antidepressant 41% received any antidepressant 20% received any psychotherapy20% received any psychotherapy 44%44% received any antidepressant or received any antidepressant or

psychotherapypsychotherapy Results overestimate adequate treatment Results overestimate adequate treatment

because based on research in primary because based on research in primary care, less than 50% of those who get any care, less than 50% of those who get any treatment receive guideline level caretreatment receive guideline level care

Simon, Fleck et al Am J Psychiat 2004

Proposed Depression ModelProposed Depression Model

TBI

BiopsychosocialVulnerability

PostconcussiveSymptoms

Cognition

DepressionHealth CareUtilization

Functioning/QOL

+

+/-

+/-

Correlates w/ TBI Severity?

+,-

Modifiable Risk FactorsModifiable Risk Factors

NeurobiologicalFactors

CognitiveDistortions

No PleasantActivities Sedentary LifestylePsychosocial

Adversity

Depression

Depression Treatment PreferencesDepression Treatment Preferences Table 2: Subjects Likely To Participate In Treatment

Treatment Modality Depressed

n=37 Non-Depressed

n=108 Total Sample

n=145 Physical Exercise (PE) 33 (89.2%)a 88 (82.2%)c 121 (84.0%)c Counseling/Psychotherapy (CP) 29 (78.4%)a 69 (63.9%)a,b 98 (67.6%)b Alternative or Herbal (AH)* 25 (67.6%) 66 (61.1%)b 91 (62.8%)a Self-Help Materials (SH) 23 (62.2%) 68 (63.0%)a,b 91 (62.8%)a Antidepressants (AD) 27 (73.0%) 42 (38.9%) 69 (47.6%) Group Therapy (GT) 16 (43.2%) 47 (43.5%) 63 (43.4%) * p<.001 between depressed and non-depressed subjects Note: Differences reported are among treatment modalities within each column. a: Favored over Group Therapy b: Favored over Antidepressants c: Favored over all modalities

0%

10%

20%

30%

40%

50%

60%

70%

80%

Clinicianover

telephone

PCP inClinic

Psych inClinic

Clinicianin Home

Clinicianover

Internet

TBI Depression Treatment Delivery Preferences

Pharmacotherapy Trials in TBIPharmacotherapy Trials in TBI 13 studies One class I study (Ashman et al., 2009), N=52

– showed trends toward superiority of sertraline over placebo

– temporally far removed from TBI (18 yrs)– underpowered to examine predictors of

response. Cannot assume standard treatments have same

efficacy and tolerability in TBI SSRIs were the best tolerated 6 studies of electroconvulsive tx, acupuncture,

magnetic field exposure, biofeedbackFann et al, J Neurotrauma 2009Fann et al, J Neurotrauma 2009

Psychotherapy/Rehab Trials in TBIPsychotherapy/Rehab Trials in TBI

8 studies One class I study (Powell et al., 2002), N=110

– comprehensive, community based, interdisciplinary team intervention targeted to multiple outcomes.

– demonstrated improvements in general psychological wellbeing, but not depressive symptoms specifically

None selectively studied depressed patients Difficult to identify active ingredients Cognitive behavioral approaches showed the

most promise Problem-solving approaches may also be helpful

Fann et al, J Neurotrauma 2009Fann et al, J Neurotrauma 2009

SSRI AntidepressantsSSRI Antidepressants

The selective serotonin The selective serotonin (5-H%) re-uptake (5-H%) re-uptake inhibitors (SSRIs) inhibitors (SSRIs) prevent the re-uptake prevent the re-uptake and degradation of and degradation of serotonin by binding serotonin by binding at the serotonin re-at the serotonin re-uptake transporter. uptake transporter. This leads to This leads to accumulation of accumulation of serotonin in the serotonin in the synaptic cleft.synaptic cleft.

Open Trial of SertralineOpen Trial of Sertraline

0

5

10

15

20

25

30

HAM

-D S

core

0102030405060708090

SF-3

6 Sc

ore

baseline week 8

15 subjects within 2 years of mild TBI, single-blind, placebo-run-in trial

Fann et al., 2000

Brief Anger / Aggression Brief Anger / Aggression Questionnaire (BAAQ)Questionnaire (BAAQ)

0

1

2

3

4

5

6

7

8

9

10

baseline week 8

p=.05

Neuropsychological TestingNeuropsychological Testing baselinebaseline week week

88Wechsler Adult Intelligence Wechsler Adult Intelligence Scale - Revised (WAIS-R)Scale - Revised (WAIS-R)

Digit Symbol Digit Symbol ** 9.13 9.13 10.010.0

Finger TappingFinger Tapping Dominant Dominant ** 41.5 41.5 48.2 48.2Trails BTrails B ** 69.2 69.2

57.757.7Wechsler Memory Scale (WMS)Wechsler Memory Scale (WMS) Logical MemoryLogical Memory

– Initial Initial **** 16.5 16.5 20.5 20.5– 30 min delay 30 min delay **** 12.6 12.6 18.1 18.1– % retention % retention **** 71.3 71.3 84.9 84.9

Selective Reminding Test (SRT)Selective Reminding Test (SRT) Long Term Recall Long Term Recall ** 66.4 66.4 78.4 78.4

* p<.05 ** p<.005* p<.05 ** p<.005

1080 complicated mild to severe TBI admitted to HMC

584 Consented25 Not able to interview

496 Not consented

559 Screened

408 Screened positive

234 Completed SCID90 Not eligible, 84 Refused/Missed

60 with MDD Randomized144 Excluded, 30 Refused

30 sertraline 30 placebo

6.7%

30.0%

0%

10%

20%

30%

40%

50%

60%

Perc

en

t o

f sam

ple

Placebo (n=31) Sertraline (n=31)

Dropouts

Change in Change in HAM-DHAM-D

23.0 + 5.1

15.5 + 8.2

Final dose:Placebo: 127.5 mgSertraline: 115.0 mg

43.0%

23.0%

30.0%

17.0%

0%

10%

20%

30%

40%

50%

60%

Perc

en

t o

f sam

ple

Placebo (n=30) Sertraline (n=30)

Response (p=NS) Remission (HAM-D<9; p=NS)

Preliminary HAM-D Outcomes at 12 WeeksIntent-to-Treat Analysis

37.0%

11.0%

50.0%

31.0%

0%

10%

20%

30%

40%

50%

60%

Perc

en

t o

f sam

ple

Placebo (n=19) Sertraline (n=16)

Response (p=NS) Remission (p=NS)

Preliminary HAM-D Outcomes at 12 WeeksInitial HAM-D>20 Completers Analysis

35.0%

24.0%

54.0%

38.0%

0%

10%

20%

30%

40%

50%

60%

Perc

en

t o

f sam

ple

Placebo (n=17) Sertraline (n=13)

Response (p=NS) Remission (p=NS)

Preliminary HAM-D Outcomes at 12 WeeksHistory of Depression Completers Analysis

Lessons LearnedLessons Learned Recruitment: Significant barriers to care / enrollment Tolerability: 30% dropout in sertraline group versus only

6.7% in placebo High Placebo Response: 43% overall, 30% in severely

depressed (HAM-D > 20) Depression Severity: Better response / remission in

sertraline group if more severely depressed or history of depression

Adherence: Completers had better response / remission rates

Psychosocial risk factors: Do factors such as social adversity (e.g., unemployment), lifestyle, low education, addiction, pending litigation overwhelm some drug effect?

Symptom overlap: Persistent TBI symptoms may limit reductions in “depression” symptoms

Effect of telephone counseling on Effect of telephone counseling on depression severitydepression severity

-10

-8

-6

-4

-2

0

2

4

6

8

Cha

nge

in B

SI-D

epre

ssio

n

Treatment

Control

Bombardier et al, 2009

(p = .006)

(p = .014)

All Subjects Depressed Subjects

LLifeifeIImprovement mprovement FFollowing ollowing TTraumatic Brain Injury:raumatic Brain Injury:A Trial of A Trial of Cognitive-Behavioral Therapy for Depression after TBI

Charles H. Bombardier, PhDCharles H. Bombardier, PhDSteven Vannoy, PhDSteven Vannoy, PhDPeter Esselman, MDPeter Esselman, MDKathy Bell, MDKathy Bell, MDNancy Temkin, PhDNancy Temkin, PhD University of WashingtonUniversity of WashingtonEvette Ludman, PhDEvette Ludman, PhD Group Health Research InstGroup Health Research Inst

Jesse R. Fann, MD, MPHJesse R. Fann, MD, MPHDepartments of Psychiatry & Departments of Psychiatry &

Behavioral Sciences and Behavioral Sciences and Rehabilitation MedicineRehabilitation Medicine

School of MedicineSchool of MedicineDepartment of EpidemiologyDepartment of EpidemiologySchool of Public HealthSchool of Public HealthUniversity of WashingtonUniversity of Washington

LIFT StudyLIFT StudyLife Improvement following TBILife Improvement following TBI

FundingFunding: NIH & NIDRR (DOE) – 5 years: NIH & NIDRR (DOE) – 5 yearsSitesSites: UW, : UW, 50 United States50 United StatesDesignDesign: 3-arm RCT (: 3-arm RCT (phone CBT, in-phone CBT, in-

person CBT, Usual Careperson CBT, Usual Care) for MDD w/in ) for MDD w/in 10 10 yearsyears after moderate to severe TBI after moderate to severe TBI (N=90)(N=90)

RandomizationRandomization: : Choice-stratifiedChoice-stratifiedInterventionIntervention: 12-session modified CBT, : 12-session modified CBT,

TBI Care Management TBI Care Management There are no published RCTs of There are no published RCTs of

psychotherapy for MDD after TBIpsychotherapy for MDD after TBI

EligibilityEligibility

at least 18 years oldat least 18 years old speaks English fluentlyspeaks English fluently Had a complicated mild to severe TBI less Had a complicated mild to severe TBI less

than 10 years ago than 10 years ago lives in Washington, Alaska, Montana, or lives in Washington, Alaska, Montana, or

Idaho (WAMI)Idaho (WAMI) appears depressed (Major Depression will appears depressed (Major Depression will

be confirmed by LIFT staff)be confirmed by LIFT staff)

Note: All criteria are confirmed via phoneNote: All criteria are confirmed via phone

What the Study Can Help WithWhat the Study Can Help With

Mood, depression, anxietyMood, depression, anxiety Associated symptoms, such as sleep, Associated symptoms, such as sleep,

energy, appetite, painenergy, appetite, pain Thinking, concentrationThinking, concentration Making decisionsMaking decisions Solving problemsSolving problems Getting back to doing the things you want Getting back to doing the things you want

to doto do Relating to othersRelating to others

““Choice-Stratified” RandomizationChoice-Stratified” Randomization

Subjects Subjects choosechoose a randomization option that a randomization option that includes treatment groups that are includes treatment groups that are acceptable to them:acceptable to them:

Option 1:Option 1: In-person CBT – vs – usual care In-person CBT – vs – usual care Option 2:Option 2: Telephone CBT – vs – usual care Telephone CBT – vs – usual care Option 3:Option 3: In-person CBT – vs – Telephone In-person CBT – vs – Telephone

CBT – vs – usual careCBT – vs – usual care

Patients are paid up to $100 during studyPatients are paid up to $100 during study

Study DesignStudy Design

Eligibility and Randomization

Usual CarePhone CBT In-Person CBT

Outcome assessment (2, 4, & 6 months)

12 weeks of modified CBT w/ TBI Care Management

ReasonReason AccommodationsAccommodations

Slowed Slowed information information processing & processing & respondingresponding

Present information at slower rate Present information at slower rate Allow client more time to respondAllow client more time to respondProvide written summary of session beforehandProvide written summary of session beforehand

Impaired attention Impaired attention & concentration& concentration

Minimize environmental stimulation and distractions during Minimize environmental stimulation and distractions during sessionsessionFocus on one topic at a time, Use shorter sessionsFocus on one topic at a time, Use shorter sessionsAvoid need for multi-tasking e.g., no note taking while listeningAvoid need for multi-tasking e.g., no note taking while listening

Impaired learning Impaired learning & recall& recall

Provide written summary of session (patient workbook)Provide written summary of session (patient workbook)Assign simple written homework Assign simple written homework Provide written educational materials or workbook Provide written educational materials or workbook Plan additional practice of CBT skills within session (over-learn Plan additional practice of CBT skills within session (over-learn skills)skills)

Impaired verbal Impaired verbal abilitiesabilities

Minimize emphasis on verbally mediated aspects of CBT Minimize emphasis on verbally mediated aspects of CBT Emphasize behavioral activation and pleasant events schedulingEmphasize behavioral activation and pleasant events scheduling

Impaired initiation Impaired initiation & generalization& generalization

Include family or friend in treatment planning and homework Include family or friend in treatment planning and homework assignmentsassignments Provide 2 sessions devoted to generalization and relapse Provide 2 sessions devoted to generalization and relapse prevention at endprevention at end

Impaired Impaired motivationmotivation

Use motivational interviewing techniques to engage subjects in Use motivational interviewing techniques to engage subjects in therapytherapyProvide care management activities aimed at return to work, Provide care management activities aimed at return to work, school or other meaningful roles and finding effective school or other meaningful roles and finding effective rehabilitation resourcesrehabilitation resources

Other Unique FeaturesOther Unique Features

Concurrent treatments allowed (e.g., Concurrent treatments allowed (e.g., Rehab counseling, antidepressants at Rehab counseling, antidepressants at stable dose)stable dose)

TBI Care Management componentTBI Care Management component Highly flexible schedulingHighly flexible scheduling Option to include Support PersonOption to include Support Person Written summary sent after each sessionWritten summary sent after each session Flexible protocol to respond to individual’s Flexible protocol to respond to individual’s

needs, strengths, deficits, etcneeds, strengths, deficits, etc

““Usual Care” is non-restrictiveUsual Care” is non-restrictive

Referring to LIFTReferring to LIFT

Kenneth MarshallKenneth Marshall

Research Coordinator Research Coordinator

Department of Psychiatry & Behavioral SciDepartment of Psychiatry & Behavioral Sci

University of Washington, Box 356560University of Washington, Box 356560

Seattle, WA 98195Seattle, WA 98195

Email:Email: mars2087@uw.edu mars2087@uw.edu

Phone: Phone: (206) 543-4213 (206) 543-4213

Toll Free:  (866) 577-1925Toll Free:  (866) 577-1925

ConclusionsConclusionsDepression after TBI:Depression after TBI: is common following mild to severe TBIis common following mild to severe TBI often begins early after TBI, but increased often begins early after TBI, but increased

risk continues beyond the first year after TBIrisk continues beyond the first year after TBI Is often associated with comorbid anxietyIs often associated with comorbid anxiety is associated with functional and cognitive is associated with functional and cognitive

impairment, poorer health status, and impairment, poorer health status, and worsening postconcussive symptomsworsening postconcussive symptoms

is associated with increased health care is associated with increased health care utilizationutilization

can be validly screenedcan be validly screened

ConclusionsConclusions

Depression after TBI:Depression after TBI: Is undertreatedIs undertreated may be most responsive to antidepressants in may be most responsive to antidepressants in

more severe cases – adherence is criticalmore severe cases – adherence is critical needs further treatment studiesneeds further treatment studies

– PharmacotherapyPharmacotherapy– PsychotherapyPsychotherapy Address Barriers to CareAddress Barriers to Care

– Multi-faceted approachesMulti-faceted approaches

ImplicationsImplications

Need improved recognition of Need improved recognition of MDDMDD

In acute, post-acute and chronic care In acute, post-acute and chronic care settingssettings

Clinician educationClinician education Patient education (reduce stigma)Patient education (reduce stigma) Routine screening and novel case-findingRoutine screening and novel case-finding

ImplicationsImplications

Need improved prevention and treatmentNeed improved prevention and treatment Test the efficacy of standard medical and Test the efficacy of standard medical and

psychosocial treatmentspsychosocial treatments Test novel and adapted interventions*Test novel and adapted interventions* Reduce barriers to treatmentReduce barriers to treatment

– Integrate mental health into rehabilitationIntegrate mental health into rehabilitation– Provide proactive, collaborative, chronic careProvide proactive, collaborative, chronic care– Novel treatment delivery---telephone, InternetNovel treatment delivery---telephone, Internet– Access to qualified providers, insurance coverageAccess to qualified providers, insurance coverage

*Bombardier et al J Head Trauma Rehabil, 2009; Novack et al J Neurotrauma 2009; Ashman et al Arch Phys Med Rehabil, 2008; Fann et al., J Neurotrauma 2009 (review)

Thank you!Thank you! fann@uw.edufann@uw.edu

www.clinicaltrials.gov (search NCT00878150)

www.washington.edu/healthresearch

www.tbiwashington.edu