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Neurobiology, Diagnosis & Treatment of PTSD & TBI in Veterans

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Diana S. Glendinng, PhD
Mei T. Liu, PharmD, BCPP
Anthony Michael Tobia, MD

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Neurobiology, Diagnosis & Treatment of PTSD & TBI in Veterans

  1. 1. 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
  2. 2. 1- Describe the brain regions and mechanisms associated with the PTSD. 2- List the primary features and diagnosis of PTSD. 3- Discuss pharmaceu?cal and therapeu?c interven?ons for PTSD. Learning Objec?ves
  3. 3. C.B. is a 45 year-old officer who reported he was involved in “almost daily” combat while serving in Opera?on Iraqi Freedom in 2006-2007. While deployed, he was frequently exposed to rocket and mortar aUacks, oVen travelled in convoys that were vulnerable to roadside bombs and poten?al suicide bombers. He saw both military and civilian casual?es. He experienced a par?cularly trauma?c incident when a mortar exploded 100 feet from him, while he was not in protec?ve gear. He was thrown to the ground and may have been unconscious, but cannot remember. 3 months aVer this event, C.B. had worsening problems with aUen?on, memory, and anger control that affected his func?oning as an officer. He received treatment at a U.S. military facility, where he par?cipated in group therapies for PTSD, TBI and chronic pain. 2 years later, CB was seen for TBI in a VA Medical Center. His aUen?on, working memory, verbal learning, memory and execu?ve func?oning were intact, but he reported anxiety, depression and irritability. He also reported experiencing intrusive thoughts, a heightened startle reflex, nightmares, social detachment and feelings of guilt. C.B. Ryan et al., Brain Injury, (2011) 25(10):
  4. 4. Pathological anxiety that usually occurs aVer an individual experiences or witnesses severe trauma that cons?tutes a threat to the physical integrity or life of the individual or of another person. Characteris?cs: Persistent re-experiencing of a trauma?c event: intrusive thoughts, nightmares, flashbacks, in presence of reminders of the trauma?c event. Avoidance of anything associated with the trauma?c event Hyperarousal, with irritability, sleep disturbances Nega?ve thoughts, mood or feelings What is PTSD?
  5. 5. 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
  6. 6. 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 *
  7. 7. http://www.defense.gov/home/features/2012/0312_tbi/ The Incidence of Traumatic Brain Injury has increased in Veterans in recent wars
  8. 8. TBI/PTSD Link and the Military* •  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
  9. 9. Diana Glendinning, Ph.D. Department of Neuroscience and Cell Biology Rutgers, Robert Wood Johnson Medical School Neurobiology of Post-traumatic Stress Disorder
  10. 10. What happens during a trauma?c experience? Adapted from McEwen 2016 Neuroendocrine PVN Pituitary Cor?sol, DHEA, NPY Adrenals CHR ACTH Autonomic éHR éBP Fight or flight/freeze Trauma, abuse, violence, life events
  11. 11. Our brains remember trauma: Fear-Learning face sound smell Emo?onal Responses
  12. 12. “Fear-condi?oning” is like Pavlovian condi?oning Within the Limbic System: The emo?onal and memory centers of the brain
  13. 13. 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
  14. 14. Trauma?c or painful experience and condi?ons Consolida:on into Long-term memory Memory retrieval Short-term memory Healthy Fear-memory formation Adapted from Parksons RG and Ressler KJ. Nature Neuroscience. 2013;16 (2):146-151 Amygdala/hippocampus Prefrontal cortex Ex?nc?on/inhibi?on Reconsolida:on Physiological & Behavioral Responses Period of memory lability
  15. 15. Trauma?c or painful experience and condi?ons Consolida:on into Long-term memory Memory retrieval Short-term memory Healthy Fear-memory formation Adapted from Parksons RG and Ressler KJ. Nature Neuroscience. 2013;16 (2):146-151 Amygdala/hippocampus Prefrontal cortex Ex?nc?on/inhibi?on Reconsolida:on Physiological & Behavioral Responses Period of memory lability
  16. 16. Increased autonomic reac?vity when people are studied during startle, at rest, or during recollec?on of events: Pitman et al. Nature Reviews-Neuroscience (2012) 13: 769 éHeart Rate éSkin Conductance éFacial muscular responsiveness éStartle to loud sounds Referred to as general nervous system sensi0za0on: OVen treated with beta-blockers
  17. 17. Trauma?c or painful experience and condi?ons Consolida:on into Long-term memory Memory retrieval Short-term memory Healthy Fear-memory formation Adapted from Parksons RG and Ressler KJ. Nature Neuroscience. 2013;16 (2):146-151 Amygdala/hippocampus Prefrontal cortex Ex?nc?on/inhibi?on Reconsolida:on Physiological & Behavioral Responses Period of memory lability
  18. 18. Only about 5-30% of people experiencing trauma get PTSD. Pre-exis?ng factors appear to play a role.
  19. 19. Etkin and Wager (2007) Am J Psychiary 164:1476-1488 Increased fear responses, and decreased ex?nc?on is correlated with: •  Hyperac?va?on of amygdala •  Underac?va?on of prefrontal cortex (vPFC) during fear condi?oning trials.
  20. 20. ü  regulates emo?ons ü  enable ex?nc?on *frontal lobe is oVen affected in mild TBI Prefrontal Cortex
  21. 21. Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilita?on Aspects. Kobeissy FH, editor. Boca Raton (FL): CRC Press/Taylor & Francis; 2015. Mild TBI is associated with PTSD •  Pathology not well understood Diffuse axonal injury Brain swelling Cerebral atrophy (with repeated trauma) Symptoms •  Loss of consciousness •  Headache •  Memory problems •  Sleep Disturbance
  22. 22. Anisotropy of white maUer (from Diffusion Tensor Imaging Studies) in US Military Personnel who had sustained mTBI (1-90 days post- injury) In Frontal lobe regions associated with managing emo?onal memories
  23. 23. Trauma?c or painful experience and condi?ons Consolida:on into Long-term memory Memory retrieval Short-term memory Healthy Fear-memory formation Adapted from Parksons RG and Ressler KJ. Nature Neuroscience. 2013;16 (2):146-151 Amygdala/hippocampus Prefrontal cortex Ex?nc?on/inhibi?on Reconsolida:on Physiological & Behavioral Responses Period of memory lability Exposure therapy Drug treatments CBT Exposure therapy Eye-movement desensi?za?on Exposure Therapy CBT Drug treatments (experimental) Experimental only: β-blocker NMDA antagonists Protein synthesis inhibitors
  24. 24. Ryan et al., Brain Injury, (2011) 25(10): This neuroplas?city enables people suffering from PTSD, with the appropriate guidance, treatment and support, to recover from PTSD. Neuroplas:city is a major feature of the brain regions that produce PTSD
  25. 25. 2 years later, CB was seen for TBI in a VA Medical Center. His aUen?on, working memory, verbal learning, memory and execu?ve func?oning were intact, but he reported anxiety, depression and irritability. He also reported experiencing intrusive thoughts, a heightened startle reflex, nightmares, social detachment and feelings of guilt. C.B. Ryan et al., Brain Injury, (2011) 25(10): Important Points: Recognize the symptoms of PTSD Recognize that these are more likely to occur aVer mTBI Treatment: •  Immediate referral to group therapy for TBI and PTSD •  15 months later, medical records indicate “concussive symptoms” •  24 months later, referred to VA for TBI •  Treated for PTSD, with therapy for anger management. •  Reported beUer mood, new desire to return to work, less pain, decreased headaches
  26. 26. Rutgers, The State University of New Jersey Posttraumatic Stress Disorder Anthony Tobia, MD Associate Professor Department of Psychiatry Rutgers Robert Wood Johnson Medical School
  27. 27. Risk and Prognostic Factors •  Pretraumatic factors (predisposing) •  Peritraumatic factors (precipitating) •  Posttraumatic factors (perpetuating)
  28. 28. 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
  29. 29. •  Severity of trauma •  Perceived life threat •  Personal injury •  Interpersonal violence •  Dissociation •  Being a perpetrator •  Witnessing atrocities •  Killing the enemy Peritraumatic Factors (psychosocial)
  30. 30. 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)
  31. 31. 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
  32. 32. 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
  33. 33. 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%
  34. 34. THE SYMPTOMS
  35. 35. 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:
  36. 36. 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
  37. 37. 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)
  38. 38. 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
  39. 39. Rutgers, The State University of New Jersey Don’t avoid honorin’ heroes!!!
  40. 40. The Role of the Psychologist
  41. 41. Non-Pharmacologic Treatments •  Cognitive behavioral therapy (CBT) •  Eye Movement Desensitization and Reprocessing (EMDR)
  42. 42. 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
  43. 43. Movement Desensitization and Reprocessing (EMDR) •  Involves focusing on sounds or hand movements while you talk about the trauma
  44. 44. The Role of the Psychiatrist (biological) •  Guidelines •  The art of medicine •  You are treating a person, not a cookbook
  45. 45. 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)
  46. 46. 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
  47. 47. 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/DoD Clinical Prac?ce Guideline. Management of Post-Trauma?c Stress Guideline Summary. Version 2. 2010.
  48. 48. PTSD Pharmacotherapy A (Strong recommenda:on) Significant Benefit • SSRI – paroxe?ne, sertraline (FDA approved) and fluoxe?ne • SNRI – venlafaxine B (Fair evidence) Some Benefit • Mirtazapine • Prazosin (use for sleep/nightmares) • Tricyclic an?depressants* • Nefazodone* • Monoamine oxidase inhibitors* C (Fair evidence but no general recommenda:on) Unknown • Prazosin (for global PTSD symptoms) VA/DoD Clinical Prac?ce Guideline. Management of Post-Trauma?c Stress Guideline Summary. Version 2. 2010.
  49. 49. 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
  50. 50. 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/DoD Clinical Prac?ce Guideline. Management of Post-Trauma?c Stress Guideline Summary. Version 2. 2010.
  51. 51. 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 Add prazosin at any ?me for sleep or nightmare Consider referral to specialty care at any ?me during treatment
  52. 52. Pharmacotherapy of co-morbid PTSD and TBI •  Limited evidence to guide treatment in pa?ents with co-morbid PTSD and TBI •  Issues to consider –  Cogni?ve and other sequelae of TBI that my interfere with treatment –  Overlapping symptoms between PTSD and TBI –  Tradeoff between adverse effects versus benefit profiles when treatment for one condi?on can be poten?ally harmful for another HowleU JR, Stein MB. Chapter 16. Post-Trauma:c Stress Disorder: Rela:onship to Trauma:c Brain Injury and Approach to Treatment. Transla?onal Research in Trauma?c Brain Injury. Boca Raton (FL): CRC Press/Taylor and Francis Group; 2016. hUps://www.ncbi.nlm.nih.gov/books/NBK326723/
  53. 53. Pharmacotherapy of co-morbid PTSD and TBI •  Start with lower doses due to sensi?vity to side effects in pa?ent with TBI •  Standard approach in using an?depressants •  An?convulsants for treatment mood disorders, impulsive anger, irritability, and aggression •  Use low dose an?psycho?cs for psycho?c symptoms –  May help with reexperiencing and hyperarousal Tanev et al. Brain Injury 2014;28(3):261-270.
  54. 54. Pharmacotherapy of co-morbid PTSD and TBI •  S?mulants for fa?gue and aUen?on problems –  May worsen hyperarousal in PTSD •  Medica?ons that may cause cogni?ve deficit associated in TBI –  An?psycho?cs, an?convulsants, anxioly?cs, and an?cholinergic medica?ons •  Monitor for adverse effects such as sleep disturbances, seizures, gait and balance problems, and deficits in sensory processing HowleU JR, Stein MB. Chapter 16. Post-Trauma:c Stress Disorder: Rela:onship to Trauma:c Brain Injury and Approach to Treatment. Transla?onal Research in Trauma?c Brain Injury. Boca Raton (FL): CRC Press/Taylor and Francis Group; 2016. hUps://www.ncbi.nlm.nih.gov/books/NBK326723/ McAllister TW, Zafonte R, et al. Neuropsychopharmacology 2016;41:1191-1198.

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