Neurobiology, Diagnosis & Treatment of PTSD & TBI in Veterans

Diana Glendinning, Ph.D. Department of Neuroscience and Cell Biology

Rutgers, Robert Wood Johnson Medical School

Anthony Tobia, MD Department of Psychiatry


Mei T. Liu, Pharm.D., BCPP Department of Psychiatry, Jersey City Medical Center

Neurobiology, Diagnosis and Treatment of Post-traumatic Stress Disorder and TBI in

Veterans

1-DescribethebrainregionsandmechanismsassociatedwiththePTSD.2-ListtheprimaryfeaturesanddiagnosisofPTSD.3-Discusspharmaceu?calandtherapeu?cinterven?onsforPTSD.

LearningObjec?ves

C.B.isa45year-oldofficerwhoreportedhewasinvolvedin“almostdaily”combatwhileservinginOpera?onIraqiFreedomin2006-2007.Whiledeployed,hewasfrequentlyexposedtorocketandmortaraUacks,oVentravelledinconvoysthatwerevulnerabletoroadsidebombsandpoten?alsuicidebombers.Hesawbothmilitaryandciviliancasual?es.Heexperiencedapar?cularlytrauma?cincidentwhenamortarexploded100feetfromhim,whilehewasnotinprotec?vegear.Hewasthrowntothegroundandmayhavebeenunconscious,butcannotremember.3monthsaVerthisevent,C.B.hadworseningproblemswithaUen?on,memory,andangercontrolthataffectedhisfunc?oningasanofficer.HereceivedtreatmentataU.S.militaryfacility,wherehepar?cipatedingrouptherapiesforPTSD,TBIandchronicpain.2yearslater,CBwasseenforTBIinaVAMedicalCenter.HisaUen?on,workingmemory,verballearning,memoryandexecu?vefunc?oningwereintact,buthereportedanxiety,depressionandirritability.Healsoreportedexperiencingintrusivethoughts,aheightenedstartlereflex,nightmares,socialdetachmentandfeelingsofguilt.

C.B.

Ryanetal.,BrainInjury,(2011)25(10):

PathologicalanxietythatusuallyoccursaVeranindividualexperiencesorwitnessesseveretraumathatcons?tutesathreattothephysicalintegrityorlifeoftheindividualorofanotherperson.

Characteris?cs:Persistentre-experiencingofatrauma?cevent:intrusivethoughts,nightmares,flashbacks,inpresenceofremindersofthetrauma?cevent.

Avoidanceofanythingassociatedwiththetrauma?cevent

Hyperarousal,withirritability,sleepdisturbances

Nega?vethoughts,moodorfeelings

WhatisPTSD?

Post-traumatic Stress Disorder

An estimated 7.7 million U.S. adults have PTSD during any given year. This may arise from any type of traumatic experience. Lifetime prevalence of 8-10% Females are at higher risk for PTSD (10% vs. 5%) PTSD can occur at any age Trauma history increases vulnerability Individual history increases vulnerability

US Department of Veterans Affairs: http://www.ptsd.va.gov/professional/PTSD-overview/epidemiological-facts-ptsd.asp

Estimated Lifetime prevalence in Veterans: about 30% of men and women who have spent time in a war zone experience PTSD. Estimates by war: •  23% of Veterans of the Operation Enduring Freedom/Operation

Iraqi Freedom * •  10% from the Gulf War

•  30% of Vietnam Veterans

Prevalence of PTSD in Veterans

*

http://www.defense.gov/home/features/2012/0312_tbi/

The Incidence of Traumatic Brain Injury has increased in Veterans in recent wars

TBI/PTSDLinkandtheMilitary*

•  TBI: 19% of all those returning from Iraq

•  44% of returnees from Iraq who reported TBI with LOC and post concussive symptoms 3 to 4 months after re-deployment met criteria for PTSD

•  27% with altered consciousness met criteria for PTSD

•  16% with other injuries met criteria for PTSD

•  9% with no injuries met criteria for PTSD

* Hoge C et al. (2008) Mild Traumatic Brain Injury in U.S. Soldiers Returning from Iraq. New Eng J of Med 358(5): 453-63

Diana Glendinning, Ph.D. Department of Neuroscience and Cell Biology


Neurobiology of Post-traumatic Stress

Disorder

Whathappensduringatrauma?cexperience?

AdaptedfromMcEwen2016

Neuroendocrine

PVN

Pituitary

Cor?sol,DHEA,NPY

Adrenals

CHR

ACTH

Autonomic

éHRéBPFightorflight/freeze

Trauma,abuse,violence,lifeevents

Ourbrainsremembertrauma:Fear-Learning

face

sound

smell

Emo?onalResponses

“Fear-condi?oning”islikePavloviancondi?oning

WithintheLimbicSystem:Theemo?onalandmemorycentersofthebrain

Emotional-fear learning occurs in the amygdala. The hippocampal formation stores other features of memory (spatial features, environment)

Sensory inputs

FEAR

Trauma or Pain

Stress

Trauma?corpainfulexperienceandcondi?ons

Consolida:onintoLong-termmemory

Memoryretrieval

Short-termmemory

Healthy Fear-memory formation

Adapted from Parksons RG and Ressler KJ. Nature Neuroscience. 2013;16 (2):146-151

Amygdala/hippocampus

Prefrontalcortex

Ex?nc?on/inhibi?onReconsolida:on

Physiological&BehavioralResponses

Periodofmemorylability

Increasedautonomicreac?vitywhenpeoplearestudiedduringstartle,atrest,orduringrecollec?onofevents:

Pitmanetal.NatureReviews-Neuroscience(2012)13:769

éHeartRateéSkinConductanceéFacialmuscularresponsivenesséStartletoloudsounds

Referredtoasgeneralnervoussystemsensi0za0on:OVentreatedwithbeta-blockers



Memoryretrieval

Short-termmemory




Prefrontalcortex




Onlyabout5-30%ofpeopleexperiencingtraumagetPTSD.Pre-exis?ngfactorsappeartoplayarole.

EtkinandWager(2007)AmJPsychiary164:1476-1488

Increasedfearresponses,anddecreasedex?nc?oniscorrelatedwith:•  Hyperac?va?onofamygdala•  Underac?va?onofprefrontalcortex(vPFC)duringfearcondi?oningtrials.

ü  regulatesemo?onsü  enableex?nc?on

*frontallobeisoVenaffectedinmildTBI

PrefrontalCortex

BrainNeurotrauma:Molecular,Neuropsychological,andRehabilita?onAspects.KobeissyFH,editor.BocaRaton(FL):CRCPress/Taylor&Francis;2015.

MildTBIisassociatedwithPTSD

•  PathologynotwellunderstoodDiffuseaxonalinjuryBrainswellingCerebralatrophy(withrepeatedtrauma)

Symptoms•  Lossofconsciousness•  Headache•  Memoryproblems•  SleepDisturbance

AnisotropyofwhitemaUer(fromDiffusionTensorImagingStudies)inUSMilitaryPersonnelwhohadsustainedmTBI(1-90dayspost-injury)

InFrontalloberegionsassociatedwithmanagingemo?onalmemories



Memoryretrieval

Short-termmemory




Prefrontalcortex




ExposuretherapyDrugtreatmentsCBT

ExposuretherapyEye-movementdesensi?za?on

ExposureTherapyCBTDrugtreatments(experimental)

Experimental only: β-blockerNMDAantagonistsProteinsynthesisinhibitors


Thisneuroplas?cityenablespeoplesufferingfromPTSD,withtheappropriateguidance,treatmentandsupport,torecoverfromPTSD.

Neuroplas:cityisamajorfeatureofthebrainregionsthatproducePTSD

2yearslater,CBwasseenforTBIinaVAMedicalCenter.HisaUen?on,workingmemory,verballearning,memoryandexecu?vefunc?oningwereintact,buthereportedanxiety,depressionandirritability.Healsoreportedexperiencingintrusivethoughts,aheightenedstartlereflex,nightmares,socialdetachmentandfeelingsofguilt.

C.B.


ImportantPoints:RecognizethesymptomsofPTSDRecognizethatthesearemorelikelytooccuraVermTBI

Treatment:•  ImmediatereferraltogrouptherapyforTBIandPTSD•  15monthslater,medicalrecordsindicate“concussivesymptoms”•  24monthslater,referredtoVAforTBI•  TreatedforPTSD,withtherapyforangermanagement.•  ReportedbeUermood,newdesiretoreturntowork,lesspain,decreasedheadaches

Rutgers, The State University of New Jersey

Posttraumatic Stress Disorder

Anthony Tobia, MD Associate Professor

Department of Psychiatry Rutgers Robert Wood Johnson Medical School

Risk and Prognostic Factors

•  Pretraumatic factors (predisposing)

•  Peritraumatic factors (precipitating)

•  Posttraumatic factors (perpetuating)

Pretraumatic Factors

Female gender Family history of mental disorder Younger adult age at the at time of trauma Children and adolescents have lower rates1

Childhood emotional problems by 6 years of age Premorbid mental disorders

Lower SES Lower intelligence Lower education Childhood adversity Cultural characteristics Minority/ethnic status Lack of social support

1. May reflect previous criteria were insufficiently developmentally informed

Bio Psycho Social

•  Severity of trauma •  Perceived life threat •  Personal injury •  Interpersonal violence •  Dissociation •  Being a perpetrator •  Witnessing atrocities •  Killing the enemy

Peritraumatic Factors (psychosocial)

Psychological •  Negative appraisals •  Inappropriate coping

strategies •  Development of ASD

Social •  Subsequent exposure to

cues •  Subsequent adverse life

events •  Financial losses •  Other losses •  Lack of social support

Posttraumatic Factors (psychosocial)

Posttraumatic Stress Disorder (PTSD)

http://www.ptsd.va.gov/

DSM-5

Ø  Can occur after you have been through a traumatic event (something terrible and scary that you see, hear about, or that happens to you):

Ø  Terrorist attack Ø  Combat exposure Ø  Serious accidents

•  Exposure to actual or threatened death, serious injury or sexual violence

•  Experienced directly, witnessed or indirectly

Posttraumatic Stress Disorder (PTSD)

http://www.ptsd.va.gov/ Ø During a traumatic

event, you think that your life or others' lives are in danger.

Ø You may feel afraid or feel that you have no control over what is happening around you.

•  How the individual experienced event no longer defining

•  Removed from DSM •  Peritraumatic social

factor

DSM-5

Comorbidity


DSM-5

Ø  Feelings of hopelessness, shame, or despair

Ø  Depression or anxiety Ø  Drinking or drug

problems Ø  Physical symptoms or

chronic pain Ø  Employment problems Ø  Relationship problems,

including divorce

•  80% more likely than “controls” to have comorbidity

•  Co- occurrence of PTSD and TBI in recent wards is 48%

THE SYMPTOMS

Reliving the event (Re-experiencing symptoms)

•  You may have bad memories or nightmares.

•  You even may feel like you're going through the event again (this is called a flashback).

•  Dissociative sx such as nightmares, flashbacks

•  Ongoing psychological distress at exposure

•  NE/sympathetic/ physiological reactivity on exposure

•  Thoughts and memories that are recurrent, intrusive, distressing


DSM-5 One or more intrusion:

Avoiding situations that remind you of the event

•  You may try to avoid situations or people that trigger memories of the traumatic event.

•  You may even avoid talking or thinking about the event.

•  Avoidance •  External

–  People –  Places

•  Internal (things) –  Memories –  Thoughts –  Feelings


DSM-5

Negative changes in beliefs and feelings

http://www.ptsd.va.gov/ DSM-5 Two or more:

•  The way you think about yourself and others may change because of the trauma.

•  You may feel fear, guilt, or shame.

•  Or, you may not be interested in activities you used to enjoy.

•  Hard time experiencing positive emotions

•  Out of body experience: Feelings of detachment

•  Negative emotional states •  Organism’s cognitions about

the cause of trauma distorted •  Recall of important aspects... •  Impaired •  Negative beliefs exaggerated •  Reduced interest (anhedonia)

Feeling keyed up (Hyperarousal)

http://www.ptsd.va.gov/ DSM-5 Two or more arousal:

•  You may be jittery, or always alert and on the lookout for danger.

•  Or, you may have trouble concentrating or sleeping.

•  Hypervigilance •  Early morning

awakenings •  Reduced concentration •  Outbursts of anger or

irritability •  Exaggerated startle •  Self-destructive

behavior


Don’t avoid honorin’ heroes!!!

The Role of the Psychologist

Non-Pharmacologic Treatments

•  Cognitive behavioral therapy (CBT)

•  Eye Movement Desensitization and Reprocessing (EMDR)

Cognitive Behavioral Therapy (CBT)

•  Most effective treatment for PTSD

•  Learn skills to understand how trauma changed your thoughts and feelings

•  Exposure therapy (variant): talk about your trauma repeatedly until memories are no longer upsetting

•  You also go to places that are safe, but that you have been staying away from because they are related to the trauma

Movement Desensitization and Reprocessing (EMDR)

•  Involves focusing on sounds or hand movements while you talk about the trauma

The Role of the Psychiatrist (biological)

•  Guidelines

•  The art of medicine

•  You are treating a person, not a cookbook

Overview

Clinical Focus Alcohol or Substance Use Disorder

Short-term (6-8 weeks)

Long-term (>8 weeks)

No •  Clonazepam

•  Alprazolam prn

•  Paroxetine or Sertraline1

•  Gabapentin or Lamotrigine

(adjunct)

Yes •  Atypical AP (SGA)2

•  Antihistamine prn

•  Paroxetine or Sertraline1

•  Gabapentin or Lamotrigine

(adjunct)

1.  If first-line agents are ineffective, try Fluoxetine, Venlafaxine (A) or Mirtazapine (B) 2.  Off-label use of sedating SGA (Quetiapine or Olanzapine)


Mei T. Liu, Pharm.D., BCPP Psychiatry Clinical Pharmacist

Jersey City Medical Center RWJBarnabas Health

Pharmacological Treatment Options of Post-traumatic Stress Disorder

PTSD Treatment

• No evidence of support pharmacological treatment to prevent ASD or PTSD

•  Treatment can be divided into 3 categories: –  Evidence-based psychotherapies –  Evidence-based pharmacotherapies –  Adjunctive or supplemental treatment

VA/DoDClinicalPrac?ceGuideline.ManagementofPost-Trauma?cStressGuidelineSummary.Version2.2010.

PTSD Pharmacotherapy

A(Strongrecommenda:on)

SignificantBenefit• SSRI–paroxe?ne,sertraline(FDAapproved)andfluoxe?ne• SNRI–venlafaxine

B(Fairevidence)

SomeBenefit• Mirtazapine• Prazosin(useforsleep/nightmares)• Tricyclican?depressants*• Nefazodone*• Monoamineoxidaseinhibitors*

C(Fairevidencebutnogeneralrecommenda:on)

Unknown• Prazosin(forglobalPTSDsymptoms)


PTSD Pharmacotherapy

D (Ineffective or harmful)

No benefit • Benzodiazepines (harm) • Tiagabine • Guanfacine • Valproate • Topiramate • Risperidone

I (Insufficient evidence)

Unknown • Atypical antipsychotics (mono and adjunct) • Typical antipsychotics • Buspirone • Non-benzodiazepine sedative/hypnotics • Bupropion • Trazodone (as adjunct) • Gabapentin • Lamotrigine • Propranolol • Clonidine

PTSD Treatment

Initial treatment

•  Psychotherapy or SSRI or SNRI •  Reassess at 2 – 4 weeks

Step 1

•  Access and address adherence •  Increase dose and/or add psychotherapy if

patient is not already on it •  Switch to another SSRI or SNRI and /or add

psychotherapy •  Reassess at 4 – 6 weeks from initial

treatment


PTSD Treatment

Step 2

•  Add psychotherapy and/or switch to mirtazapine

•  Reassess at 8 – 12 weeks from initial treatment

Step 3

•  Switch to alternative step 2 or to TCA or nefazodone or MAOI

•  Add psychotherapy •  Reassess at > 12 weeks from initial

treatment

Addprazosinatany?meforsleepornightmareConsiderreferraltospecialtycareatany?meduringtreatment

Pharmacotherapy of co-morbid PTSD and TBI

•  Limitedevidencetoguidetreatmentinpa?entswithco-morbidPTSDandTBI

•  Issuestoconsider–  Cogni?veandothersequelaeofTBIthatmyinterferewith

treatment–  OverlappingsymptomsbetweenPTSDandTBI–  Tradeoffbetweenadverseeffectsversusbenefitprofileswhen

treatmentforonecondi?oncanbepoten?allyharmfulforanother

HowleUJR,SteinMB.Chapter16.Post-Trauma:cStressDisorder:Rela:onshiptoTrauma:cBrainInjuryandApproachtoTreatment.Transla?onalResearchinTrauma?cBrainInjury.Boca

Raton(FL):CRCPress/TaylorandFrancisGroup;2016.hUps://www.ncbi.nlm.nih.gov/books/NBK326723/


•  Startwithlowerdosesduetosensi?vitytosideeffectsinpa?entwithTBI

•  Standardapproachinusingan?depressants•  An?convulsantsfortreatmentmooddisorders,impulsiveanger,irritability,andaggression

•  Uselowdosean?psycho?csforpsycho?csymptoms–  Mayhelpwithreexperiencingandhyperarousal

Tanevetal.BrainInjury2014;28(3):261-270.


•  S?mulantsforfa?gueandaUen?onproblems–  MayworsenhyperarousalinPTSD

•  Medica?onsthatmaycausecogni?vedeficitassociatedinTBI–  An?psycho?cs,an?convulsants,anxioly?cs,andan?cholinergic

medica?ons

•  Monitorforadverseeffectssuchassleepdisturbances,seizures,gaitandbalanceproblems,anddeficitsinsensoryprocessingHowleUJR,SteinMB.Chapter16.Post-Trauma:cStressDisorder:Rela:onshiptoTrauma:cBrainInjuryandApproachtoTreatment.Transla?onalResearchinTrauma?cBrainInjury.

BocaRaton(FL):CRCPress/TaylorandFrancisGroup;2016.hUps://www.ncbi.nlm.nih.gov/books/NBK326723/

McAllisterTW,ZafonteR,etal.Neuropsychopharmacology2016;41:1191-1198.

Neurobiology, Diagnosis & Treatment of PTSD & TBI in Veterans

Health & Medicine

Transcript of Neurobiology, Diagnosis & Treatment of PTSD & TBI in Veterans