neurobiology, diagnosis & treatment of ptsd & tbi in veterans
TRANSCRIPT
Diana Glendinning, Ph.D. Department of Neuroscience and Cell Biology
Rutgers, Robert Wood Johnson Medical School
Anthony Tobia, MD Department of Psychiatry
Rutgers, Robert Wood Johnson Medical School
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
Rutgers, Robert Wood Johnson Medical School
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
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
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
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
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
ExposuretherapyDrugtreatmentsCBT
ExposuretherapyEye-movementdesensi?za?on
ExposureTherapyCBTDrugtreatments(experimental)
Experimental only: β-blockerNMDAantagonistsProteinsynthesisinhibitors
Ryanetal.,BrainInjury,(2011)25(10):
Thisneuroplas?cityenablespeoplesufferingfromPTSD,withtheappropriateguidance,treatmentandsupport,torecoverfromPTSD.
Neuroplas:cityisamajorfeatureofthebrainregionsthatproducePTSD
2yearslater,CBwasseenforTBIinaVAMedicalCenter.HisaUen?on,workingmemory,verballearning,memoryandexecu?vefunc?oningwereintact,buthereportedanxiety,depressionandirritability.Healsoreportedexperiencingintrusivethoughts,aheightenedstartlereflex,nightmares,socialdetachmentandfeelingsofguilt.
C.B.
Ryanetal.,BrainInjury,(2011)25(10):
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
http://www.ptsd.va.gov/
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
http://www.ptsd.va.gov/
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
http://www.ptsd.va.gov/
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
Rutgers, The State University of New Jersey
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)
Rutgers, The State University of New Jersey
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)
VA/DoDClinicalPrac?ceGuideline.ManagementofPost-Trauma?cStressGuidelineSummary.Version2.2010.
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
VA/DoDClinicalPrac?ceGuideline.ManagementofPost-Trauma?cStressGuidelineSummary.Version2.2010.
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/
Pharmacotherapy of co-morbid PTSD and TBI
• Startwithlowerdosesduetosensi?vitytosideeffectsinpa?entwithTBI
• Standardapproachinusingan?depressants• An?convulsantsfortreatmentmooddisorders,impulsiveanger,irritability,andaggression
• Uselowdosean?psycho?csforpsycho?csymptoms– Mayhelpwithreexperiencingandhyperarousal
Tanevetal.BrainInjury2014;28(3):261-270.
Pharmacotherapy of co-morbid PTSD and TBI
• 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.