Docstoc

Prazosin Reduces Nightmares and - PowerPoint

Document Sample
Prazosin Reduces Nightmares and - PowerPoint Powered By Docstoc
					PTSD: Neurobiology




                     1
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”
                                              2
           Adrenergic Alterations

• Exaggerated increases in cardiovascular
  responses to trauma-specific stimuli
• Increased catecholamines in urine, plasma,
  CSF
• Decreased platelet a-2 receptors
• Yohimbine induced panic attacks

                                               3
                    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



                                                                  4
           CRF   Hypothalamus



   Anterior           Posterior
   Pituitary          Pituitary

          ACTH
                                       PTSD
Adrenal
Kidney
                      Norepinephrine    
                      Cortisol          
        Stress Hormone Systems


•Norepinephrine – “revving up” hormone

•Cortisol – “quieting down” hormone

•Both hormones are released in response to
stress. They are normally in balance.


                                             6
LeDoux, Scientific American, 1994




                                    7
                Hiker and Snake


• Immediate response
  - Fight or flight
  - Quick and dirty



• Delayed response
  - Recognition, planning
  - Slow and accurate

                                  8
            SENSORY CORTEX
              “High Road”



SENSORY
                             AMYGDALA
THALAMUS
              “Low Road”



EMOTIONAL                    EMOTIONAL
STIMULUS                     RESPONSES


                                         9
         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
                                                    10
11
12
                    “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.


                                                            13
         Neuroimaging in PTSD

• Amygdala – hyperactivity, responsivity is
     associated with PTSD symptom severity
• Frontal cortex – volume loss, responsivity
     is inversely associated with PTSD
     symptom severity
• Hippocampus – volume loss, decreased
     neuronal and functional integrity

                                               14
           Anterior cingulate cortex

• Interprets emotional stimuli and processes
  responses


• Sympathetic ANS – “accelerator”
• Parasympathetic ANS – “brakes”
• Anterior cingulate – “clutch”

                                               15
             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


                                                             16
               “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
                                                     17
       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

                                                     18
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”
                                                          19
      Coordination of Threat Response
                                                Sights
Medial Prefrontal Cortex                        Sounds
Anterior Cingulate Cortex
                            _ +

                                 AMYGDALA +    Thalamus
                            +
                             _
     Hippocampus

                                                Smells
                                 Coordinated
                                  Response
                                                          20
         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


                                            21
Individual Differences in a Husband and Wife
Who 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 for
  several minutes, during which they witnessed
  a child burn to death and feared that they too
  would die.”
                                                   22
       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

                                                  23
           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

                                                  24
     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

                                                    25
        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




                                                  26
 Functional MRI Responses to Traumatic Imagery




Husband




Wife

                                                 27
PTSD: Treatment




                  28
29
   Treatment Components

• Coping skills
• Medication
• Psychotherapy
• Alternative therapies


                          30
          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.”


                                               31
Treating people with PTSD is challenging
and rewarding. Success requires creativity,
flexibility, compassion, and clinical skill.


Be aware of secondary traumatization.




                                               32
Sri Lanka
            33
“Dream Bubbles of Smoke and Blood” Ray-Paul Nielsen
                                                      34
35
       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


                                                 36
                            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



                                                                            37
      Approach to Medication Treatment



 Literature extremely limited, few controlled trials
 No specific agent for PTSD
 Treat prominent symptoms
 Treat comorbidity




                                                        38
          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


                                             39
     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

                                                      40
          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


                                                 41
   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



                                                      42
                        SSRIs
• Sertraline (Zoloft), Paroxetine (Paxil), Fluoxetine
  (Prozac), Citalopram (Celexa)
• All 3 symptom clusters may respond
• Sexual dysfunction
• Arousal - “Jitteriness”
• Nausea, diarrhea, headache, insomnia


                                                        43
                  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


                                                               44
     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
                                                      45
        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)




                                                   46
            Newer Sleep Agents

• Zolpidem (Ambien)
• Zaleplon (Sonata)
• Eszopiclone (Lunesta)

• Different binding site on GABAA receptor
• Less addictive, expensive

                                             47
             Anticonvulsants

- Valproic Acid, Divalproex (Depakote)
- Carbamazepine (Tegretol)
- Lamotrigine (Lamictal)


- Anger, moodswings, violent behavior
- Comorbid bipolar disorder
- Antidepressant augmentation



                                         48
                 Antipsychotics
• Risperidone (Risperdal), Olanzapine (Zyprexa),
  Ziprasidone (Geodon), Quetiapine (Seroquel),
  Aripiprazole (Abilify)


• “Psychotic” symptoms including prominent
  hallucinations, paranoia
• Affective instability (Borderline PD)
• Antidepressant augmentation

                                                   49
             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

                                                       50
             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

                                                      51
              Effective Therapies


• Exposure Therapy: Desensitization

• Cognitive Therapy: Dysfunctional beliefs and
  behaviors




                                                 52
Therapy for Fear/Anxiety Problems



 PFC -L      PFC -M         AMYGDALA

 thought    extinction



          DRUGS             AMYGDALA


                   side
                  effects        (After LeDoux)
                                              53
                  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
                                                           54
            Alternative therapies

• Art therapy
• Somatic therapies/bodywork
• Acupuncture
• Yoga
• Tai Chi
• Religious/spiritual practices
• Virtual reality
                                    55
Traditional Sweat Lodge

                          56
57
                    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

                                                               58
59