Health on the Homefront: PTSD, Its Clinical Description, Treatment and Underlying Pathophysiology

Transcription

1 Health on the Homefront: Stephen I. Deutsch, M.D., Ph.D. Eastern Virginia Medical School World War I Shell Shock and Disordered Action of the Heart Tremors Tics Fatigue Memory loss Difficulty in sleeping Nightmares Poor concentration 1

2 Old Sergeant Syndrome (Delayed Onset PTSD) After prolonged combat, experienced soldiers were no longer able to cope with the constant threats of death or serious injury PTSD Stimuli present at time of trauma exposure become associated with the traumatic event Exposure to one or more of these stimuli triggers fear and anxiety Patients develop strategies to avoid traumaassociated contexts and cues Develop symptoms, eg: Cognitive and memory impairments Sleep disturbances 2

3 Diagnostic Criteria (> 6 years) A. Exposure to actual or threatened death, serious injury, or sexual violence 1. Directly experiencing the traumatic event(s) 2. Witnessing, in person, the event(s) as it occurred to others 3. Learning that the traumatic event(s) occurred to a close family member or close friend 4. Experiencing repeated or extreme exposure to aversive details of the traumatic event(s) (eg, first responders collecting human remains; police officers repeatedly exposed to details of child abuse) Diagnostic Criteria (> 6 years) B. Intrusion symptoms associated with the traumatic event(s), beginning after the traumatic event(s) occurred: 1. Recurrent, involuntary, and intrusive distressing memories of the traumatic event(s) (In children > 6 years, repetitive play expressing themes of the traumatic event[s]) 2. Recurrent distressing dreams (content and/or affect related to the traumatic event[s]) 3. Dissociative reactions (eg, flashbacks) feels or acts as if the traumatic event(s) were recurring 4. Intense or prolonged psychological distress at exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event(s) 5. Marked physiological reactions to internal or external cues 3

4 Diagnostic Criteria (> 6 years) C. Persistent avoidance of stimuli associated with the traumatic event(s), beginning after the traumatic event(s) occurred: 1. Avoidance of or efforts to avoid distressing memories, thoughts, or feelings 2. Avoidance of or efforts to avoid external reminders (people, places, conversations, activities, objects, situations) Diagnostic Criteria (> 6 years) D. Negative alterations in cognitions and mood 1. Inability to remember an important aspect of the traumatic event(s) (typically due to dissociative amnesia) 2. Persistent and exaggerated negative beliefs or expectations about oneself, others or the world 3. Persistent, distorted cognitions about the cause or consequences of the traumatic event(s) that lead to blaming him/herself or others 4. Persistent negative emotional state (eg, fear, horror, anger, guilt, or shame) 5. Markedly diminished interest or participation in significant activities 6. Feelings of detachment or estrangement from others 7. Persistent inability to experience positive emotions (eg, inability to experience happiness, satisfaction, or loving feelings) 4

5 Diagnostic Criteria (> 6 years) E. Marked alterations in arousal and reactivity 1. Irritable behavior and angry outbursts with little or no provocation 2. Reckless or self destructive behavior 3. Hypervigilance 4. Exaggerated startle response 5. Problems with concentration 6. Sleep disturbance (eg, difficulty falling asleep, staying asleep or restless sleep) Diagnostic Criteria (> 6 years) F. Duration > 1 month G. Clinically significant distress or impairment in social, occupational, or other important areas of functioning H. The disturbance is not attributable to the physiological effects of a substance or another medical condition 5

6 Diagnostic Criteria (> 6 years) Specifiers: With dissociative symptoms 1. Depersonalization feeling detached from one s mental processes or body 2. Derealization unreality of surroundings With delayed expression full diagnostic criteria are not met until at least 6 months after the event Clinical Presentations and Predominant Signs and Symptoms of PTSD Vary: 1. Fear based re experiencing, emotional and behavioral symptoms 2. Anhedonic or dysphoric mood states and negative cognitions 3. Arousal and reactive externalizing symptoms 4. Dissociative symptoms 6

7 Co Occurring Conditions: Psychiatric Depression Substance Use Disorder Medical Chronic Pain TBI Spinal Cord Injury Co Occurring Conditions (continued): Psychosocial Relationship problems Difficulties in social settings Intimate partner violence (IPV) Child Maltreatment Unemployment/Underemployment Homelessness Incarceration 7

8 Stress An environmental demand exceeds the natural regulatory capacity of an organism Unpredictability Uncontrollability 8

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10 Hypothalamic Pituitary Adrenal (HPA) Axis Excessive release of cortisol from the adrenal glands Elevation in circulating glucose Activates immune cell migration to injured or infected areas 10

11 Chronically Elevated Cortisol Concentrations Impairs forms of memory dependent on the hippocampus or prefrontal cortex eg, extinction memories Favors memories that trigger fear and dependent on the amygdala eg, fear memories Extinction Exposure to conditioned cues leads to expression of intense fear and anxiety Repeated exposure to conditioned cues in the absence of additional negative reinforcement will lead to gradual reduction of emotion associated with the traumatic event 11

12 Extinction Training Does not ERASE memory traces; it does not cause forgetting Forms inhibitory learning that prevents the expression of the original memory Fear Extinction is NEW inhibitory learning rather than erasure or forgetting! Fear Extinction Learning that the conditioned stimulus no longer predicts the unconditioned stimulus 12

13 Persistence of PTSD Symptoms The inability to extinguish a conditioned fear response. Fear Conditioning and Extinction Circuits Prefrontal Cortex Ventromedial Prefrontal Cortex Orbitofrontal Cortex Dorsal Anterior Cingulate Cortex Amygdala Hippocampus Insula Brain Stem 13

14 Dorsal Anterior Cingulate Cortex Center for processing cognitive stimuli Error processing and detection Fear expression Ventromedial Prefrontal Cortex Inhibiting fear expression and promoting extinction Experience dependent plasticity Experience actively drives alterations in CNS gene expression The resulting transcriptional changes are necessary for experience to trigger altered long term behavior 14

15 Epigenetic mechanisms potent regulators of gene transcription in the CNS regulation of chromatin structure DNA methylation DNA methylation Occurs in regions of the genome rich in cytosine guanine (CpG) dinucleotides (CpG islands) Often found in the promoter regions of genes Most often associated with transcriptional silencing 15

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17 Fear Conditioning a commonly used model of associative learning in rodents Context shock association is stabilized via hippocampal dependent consolidation processes Cue shock association is stabilized through amygdala dependent consolidation processes Epigenetic molecular mechanisms underlie the formation and stabilization of context (hippocampal) and cue (amygdala) triggered fear conditioning based in the hippocampus and amygdala, respectively. 17

18 Contextual Fear Conditioning Acetylation of histone H3 in the area CA1 of the hippocampus Histone deacetylase (HDAC) inhibitors improved memory formation 18

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20 Brain Derived Neurotrophic Factor (BDNF) Synaptogenesis Neuroplasticity Cell Survival Neurogenesis 20

21 Stress The gene for BDNF may be repressed Deficient amounts of BDNF expressed Leads to atrophy and apoptosis of neurons in Hippocampus and Prefrontal Cortex 21

22 Hippocampal Atrophy Chronic Stress Major Depression PTSD Antidepressants Restoration of monoamine related signal transduction cascades Increased BDNF expression Restore lost synapses in Hippocampus Promote neurogenesis in Hippocampus 22

23 Hippocampus and Amygdala Normally suppresses the Hypothalamic Pituitary Adrenal (HPA) Axis Hippocampal and Amygdalar Atrophy due to Stress Loss of inhibitory input to the Hypothalamus Overactivity of the HPA axis 23

24 Chronically Elevated Glucocorticoid Levels Insensitivity of HPA Axis to Feedback Inhibition Atrophic Changes of Neurons New Treatments for Depression and Chronic Stress Target HPA Axis Abnormalities Corticotropin Releasing Factor 1 (CRF 1) Receptor Antagonists Vasopressin 1B Receptor Antagonists Glucocorticoid Receptor Antagonists 24

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26 Susceptibility Genes s Variant of the Gene for the Serotonin Transporter Increased Amygdala Activity in Response to Fearful Faces Inefficient Information Processing of Affective Loads in the Amygdala More Likely to Develop Depression when Exposed to Multiple Life Stressors More Hippocampal Atrophy Less Responsive to SSRI/SNRI Treatment Posttraumatic Stress Disorder (PTSD) is one of the signature injuries of the US engagements in Iraq and Afghanistan Of the more than 2.6 million service members deployed to Operation Enduring Freedom (OEF) in Afghanistan since and Operation Iraqi Freedom (OIF) since : 13 20% have or may develop PTSD 26

27 Psychosocial Therapies Exposure therapies are first line treatments designed to reduce PTSD symptoms and related problems, such as depression, anger and guilt Helping patients confront their traumarelated memories, feelings and stimuli Prolonged Exposure Imaginal exposure In vivo exposure 27

28 Cognitive Therapy Identify and modify negative thoughts and beliefs related to the traumatic event, e.g., Survival guilt Self blame for causing the trauma Feelings of personal inadequacy Cognitive Processing Therapy Combines aspects of both Cognitive Therapy and Prolonged Exposure 28

29 Combat Deployments in Iraq and Afghanistan High number and long duration of multiple combat related traumatic stressors Unavoidable reexposure to triggers during training for future combat deployments Combat Deployments in Iraq and Afghanistan Medications should avoid: Sedation Weight Gain Decreased Libido Adverse effects that can interfere with mission performance and quality of life 29

30 Combat Deployments in Iraq and Afghanistan Hyperarousal Cluster of PTSD Symptoms Excessive CNS Adrenergic Activity Combat Deployments in Iraq and Afghanistan Prazosin Generic Alpha 1 Adrenoreceptor Anatagonist Reduces norepinephrine effects at CNS Alpha 1 Adrenoreceptors when administered peripherally 30

31 Combat Deployments in Iraq and Afghanistan Prazosin does NOT produce: Sedation Sexual Dysfunction Dyslipidemia Hyperglycemia Weight Gain Combat Deployments in Iraq and Afghanistan Prazosin Targets: Combat Trauma PTSD Nightmares CAPS Nightmare Item Sleep Disturbance Pittsburgh Sleep Quality Index Global Function in Active Duty Soldiers with PTSD CGI Change Item Self Reported Ability to Function in Daily Activities 17 Item CAPS Total Score CAPS Hyperarousal Cluster 31

32 Stress Affects Multiple Neurotransmitters, Neuropeptides and Hormones GABA Glutamate Serotonin Norepinephrine BDNF CRF Cortisol Stress Affects Gene Expression via Chromatin Compaction and Epigenetic Mechanisms DNA Methylation Histone Acetylation 32

33 Treatment Strategies Prolonged Exposure SSRIs/SNRIs Prazosin Epigenetic Interventions 33