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PTSD: Neurobiology
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Neurophysiologic Alterations in PTSD
• Stress hormone systems - adrenal gland
» Sympatho-adrenomedullary
» Hypothlamic-pituitary-adrenal
• Neurotransmitter systems
• Thyroid
• Immune system
• Amygdala hyperactivity – fear and anger
• Hippocampal volume loss – memory deficits
• Anterior cingulate – “emotional clutch”
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Adrenergic Alterations
• Exaggerated increases in cardiovascular responses to trauma-specific stimuli
• Increased catecholamines in urine, plasma, CSF
• Decreased platelet -2 receptors
• Yohimbine induced panic attacks
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HPA Axis Alterations
PTSD Major Depression
Cortisol levels Low High
Glucocorticoid receptors Increased Decreased
Dexamethasone Hypersuppression Nonsuppression
Negative feedback Stronger Weaker
CSF CRF levels Increased Increased
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HypothalamusCRF
PosteriorPituitary
AnteriorPituitary
ACTH
AdrenalKidney
Norepinephrine Cortisol
PTSD
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Stress Hormone Systems
•Norepinephrine – “revving up” hormone
•Cortisol – “quieting down” hormone
•Both hormones are released in response to stress. They are normally in balance.
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LeDoux, Scientific American, 1994
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Hiker and Snake
• Immediate response
- Fight or flight
- Quick and dirty
• Delayed response
- Recognition, planning
- Slow and accurate
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SENSORY CORTEX
SENSORY THALAMUS AMYGDALA
EMOTIONAL STIMULUS
EMOTIONAL RESPONSES
“High Road”
“Low Road”
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Why do I get so angry?What’s wrong with my memory?
• Amygdala
» “Reptile brain, dinosaur brain”
» Emotional response
» Fear, anger, fight or flight
• Frontal lobe
» “Executive function”
» Cognitive response
» Working memory, attention, carrying out tasks
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“Battlemind”
• In a dangerous situation you don’t want to sit around and think. You want to act immediately using your amygdala and bypassing your frontal lobe.
• In PTSD the brain acts like you are in a dangerous situation all the time. The amygdala is hyperactive and the frontal lobe functions poorly.
• Anger and poor concentration are related. They are both part of hyperarousal.
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Neuroimaging in PTSD
• Amygdala – hyperactivity, responsivity isassociated with PTSD symptom severity
• Frontal cortex – volume loss, responsivity is inversely associated with PTSD
symptom severity
• Hippocampus – volume loss, decreased neuronal and functional integrity
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Anterior cingulate cortex
• Interprets emotional stimuli and processes responses
• Sympathetic ANS – “accelerator”
• Parasympathetic ANS – “brakes”
• Anterior cingulate – “clutch”
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Anterior cingulate in PTSD
• Emotional Counting Stroop paradigm (pressing buttons)
• Blood oxygenation measured by fMRI
• Recruitment of anterior cingulate increased when counting combat-related words only in controls and not in PTSD subjects
- Shin et al, Biol Psychiatry 2001
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“Speechless Terror”
• Suppression of Broca’s area during traumatic reexperiencing (Rauch et al.)
• Construction of narrative promotes reencoding of traumatic memories
• Subcortical memories - somatosensory
• Cortical memories – verbal, symbolic
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Failure of Extinction in PTSD
• Extinction: Decrease in conditioned response due to nonreinforcement
• PTSD:
» Inability to extinguish conditioned fear responses
» Inability to distinguish between dangerous and safe situations
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Extinction is an Active Cortical Process
• Cortical ablation studies – LeDoux
» Acquisition of conditioned fear responses requires only subcortical structures
» Cortical ablation greatly prolongs or prevents extinction of fear responses
• “Indelibility of subcortical emotional memories”
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AMYGDALA
Medial Prefrontal CortexAnterior Cingulate Cortex
Hippocampus
Thalamus
SightsSounds
SmellsCoordinated
Response
+
+
+
_
_
Coordination of Threat Response
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Salient Features of PTSD
• Hyperresponsiveness to stimuli that are reminders of the trauma
? Amygdalar hyperactivity
• Overgeneralization of stimuli
? Hippocampal dysfunction
• Anger dyscontrol, Failure of extinction
? Medial prefrontal cortex dysfunction
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Individual Differences in a Husband and WifeWho Developed PTSD After a Motor Vehicle Accident: A Functional MRI Case Study
Lanius RA, Hopper JW, Menon RS.
Am J Psychiatry 160:4, April 2003 667-669
“Both subjects were trapped in their car forseveral minutes, during which they witnessed a child burn to death and feared that they toowould die.”
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Trauma Response - Husband
• Extremely aroused, actively involved in rescue – broke windshield
• Nightmares and flashbacks started next day, often felt as if accident were recurring
• Psychological and physiological arousal when thinking or talking about accident
• Severely impaired, unable to function at work
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Trauma Response - Wife
• Felt “in shock, frozen”
• Nightmares and flashbacks started next day, often felt as if accident were recurring
• Reexperiencing involved feeling numb and frozen
• Severely impaired, unable to function at work
• H/O early parental loss, postpartum depression, mild panic disorder
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Script-Driven Imagery - Husband
• Intense anxiety, arousal, escape-focused cognitions
• Increased heart rate
• Increased activation of multiple regions including anterior frontal, anterior cingulate, thalamus, amygdala
Exposure therapy x 6 mos - No PTSD
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Script-Driven Imagery - Wife
• Felt extremely “numb” and “frozen”
• No increase in heart rate
• Increased activation only in occipital region
Exposure therapy x 6 mos - Still had PTSD
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Husband
Wife
Functional MRI Responses to Traumatic Imagery
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PTSD: Treatment
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Treatment Components
• Coping skills
• Medication
• Psychotherapy
• Alternative therapies
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Institute of Medicine
“…scientific evidence on treatment modalities for PTSD does not reach the level of certainty that would be desired for such a common and serious condition among veterans… additional high quality research is essential for every treatment modality.”
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Treating people with PTSD is challenging and rewarding. Success requires creativity, flexibility, compassion, and clinical skill.
Be aware of secondary traumatization.
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Sri Lanka
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“Dream Bubbles of Smoke and Blood” Ray-Paul Nielsen
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When to Refer for Specialized Psychiatric Care
• Medication failures or side effects
• Suicidal or homicidal ideation
• Comorbid psychiatric problems including substance abuse
• Other life stressors, limited social support
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Basic Skills
• Relaxation, meditation, mindfulness training, coping skills training, anger management, grounding, etc.
» Tolerate negative emotion
» Use social support
» Calm/soothe self
» Moderate self-loathing
» Control destructive impulses (self-harm, violence, substance abuse)
» Articulate feelings
» Maintain hope
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Approach to Medication Treatment
Literature extremely limited, few controlled trials
No specific agent for PTSD
Treat prominent symptoms
Treat comorbidity
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Therapeutic Relationship
Common barriers to alliance
problems with authority, feelings of powerlessness, fear of being exploited
intense mistrust and/or isolation
Support concurrent psychotherapy
Initial pharmacotherapy may allow later psychotherapy and vice versa
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Explore the Meaning of Medication
Defective, weak, or damaged self
Drugging or numbing – don’t want to listen to complaints
Failure in psychotherapy
Unrealistic wish for med to erase traumatic event
> Assess fears and fantasies as you monitor benefits and side effects
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Symptomatic Treatment
• Inventory all symptoms
• Identify target symptoms for a given medication
• Focus initial therapy on one or two most distressing symptoms
• Often significant resistance to improvement, e.g. hypervigilance
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Psychoeducation and Control Issues
• Give patient (and family) information
» handouts, internet
» spark of recognition
• Give the patient control
» titration decisions
» meds like trazodone, hydroxyzine useful in this regard
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SSRIs
• Sertraline (Zoloft), Paroxetine (Paxil), Fluoxetine (Prozac), Citalopram (Celexa)
• All 3 symptom clusters may respond
• Sexual dysfunction
• Arousal - “Jitteriness”
• Nausea, diarrhea, headache, insomnia
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Other Antidepressants
• Nefazodone (Serzone)» lower sexual dysfunction, liver toxicity?
• Venlafaxine (Effexor)» dual mechanism of action
• Mirtazapine (Remeron)» sedation, weight gain
• Buproprion (Wellbutrin)» activation, increased energy, smoking cessation
• Tricyclic Antidepressants: Amitriptyline, Nortriptyline, Desipramine, Imipramine
» chronic pain, many side effects
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Benzodiazepines: Anxiety and Sleep
• Alprazolam (Xanax) - short acting
• Clonazepam (Klonopin) - long acting
• Lorazepam (Ativan)
• Diazepam (Valium)
• Temazepam (Restoril) - sleep
• Chlordiazepoxide (Librium) – alcohol withdrawal
• GABAA receptor binding and potentiation
• Caution - high addiction potential
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Trazodone and Hydroxyzine
• Trazodone (Desyrel) - 50-200 mg for sleep, 25-100 for anxiety
• Hydroxyzine (Vistaril, Atarax) - 25-100 mg for sleep and anxiety, also Diphenhydramine (Benadryl)
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Newer Sleep Agents
• Zolpidem (Ambien)
• Zaleplon (Sonata)
• Eszopiclone (Lunesta)
• Different binding site on GABAA receptor
• Less addictive, expensive
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Anticonvulsants
- Valproic Acid, Divalproex (Depakote)
- Carbamazepine (Tegretol)
- Lamotrigine (Lamictal)
- Anger, moodswings, violent behavior
- Comorbid bipolar disorder
- Antidepressant augmentation
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Antipsychotics
• Risperidone (Risperdal), Olanzapine (Zyprexa), Ziprasidone (Geodon), Quetiapine (Seroquel), Aripiprazole (Abilify)
• “Psychotic” symptoms including prominent hallucinations, paranoia
• Affective instability (Borderline PD)
• Antidepressant augmentation
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Prazosin for Nightmares
• Alpha-1 adrenergic antagonist commonly used to treat high blood pressure and enlarged prostate
• Lipid soluble – crosses blood-brain barrier
• Slow titration
• Orthostatic dizziness, including first dose effect
• Headache, nausea, congestion, tachycardia
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Approach to Psychotherapy
• Three stages: safety, remembering, reconnection
• Education about trauma and PTSD
• Normalization and validation
• Relieve irrational guilt
• Determine ability to tolerate memories without decompensation or intolerable self-loathing
• Group therapy
• Evidence-based therapy
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Effective Therapies
• Exposure Therapy: Desensitization
• Cognitive Therapy: Dysfunctional beliefs and behaviors
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PFC -L PFC -M
thought extinction
AMYGDALADRUGS
side effects
AMYGDALA
Therapy for Fear/Anxiety Problems
(After LeDoux)
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VA Therapeutic Menu
• Cognitive Behavioral Skills (CBT)
• Prolonged Exposure (PE)
• Cognitive Processing Therapy (CPT)
• Acceptance and Commitment Therapy (ACT)
• Eye Movement Desensitization and Reprocessing (EMDR)
• Addictions Treatment
• Behavioral Activation
• Interpersonal Skills
• Imagery Rehearsal Therapy
• Sleep Improvement
• Mindfulness
• Wellness (Diet, Exercise, Smoking Cessation)
• Work Readiness
• Life Transitions
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Alternative therapies
• Art therapy
• Somatic therapies/bodywork
• Acupuncture
• Yoga
• Tai Chi
• Religious/spiritual practices
• Virtual reality
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Traditional Sweat Lodge
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D-Cycloserine
• Extinction is an active cortical process – requires learning – Joseph LeDoux
• NMDA receptor mediated calcium influx underlies learning and memory
• NMDA receptor agonist at the glycine site, potentiates neurotransmission, facilitates extinction of conditioned fear
• Increases effectiveness of treatment when paired with exposure therapy.
• Drug development company – Mike Davis
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