Prazosin (and Other Medications) for PTSD and mTBI

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Prazosin (and Other Medications) for PTSD and mTBI

• Murray A. Raskind, MD
• Director, VISN-20 Mental Illness Research,
  Education, and Clinical Center
• Professor and Vice-Chair
• Dept. of Psychiatry Behavioral Sciences
• University of Washington School of Medicine

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Prazosin

• A generic lipid-soluble alpha-1 adrenoreceptor
  (AR) antagonist introduced in 1973 as Minipress
  for treatment of hypertension
• Short duration of action (6-10 hours)
• Costs pennies per day

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Neurobiologic Model of PTSD

• Brain adrenaline rush that saves lives in
  combat becomes persistent and maladaptive.
• Long-lasting upregulation of brain postsynaptic
  adrenoreceptor (AR) response to norepinephrine at
  the alpha1 AR (in prefrontal cortex, amygdala?)
  contributes to reexperiencing and hyperarousal
  symptoms.

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Two Prazosin RCTs in Vietnam Veterans with PTSD
CAPS Recurrent Distressing Dreams (Nightmares)
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Two Prazosin RCTs in Vietnam Veterans with PTSD
Clinical Global Impression of Change (CGIC)
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Individual PTSD Symptoms Responsive to Prazosin
in Crossover Study

• CAPS Item
• Recurrent distressing dreams
• Difficulty falling/staying asleep
• Physiological reactivity to trauma reminders
• Irritability or anger outbursts
• Intrusive trauma recollections
• Diminished interest/participation in activities
• Restricted affectnumbing
• Hypervigilance

p value lt 0.001 lt 0.01 lt0.01 lt 0.05 lt 0.05 lt
0.05 lt 0.05 lt 0.1
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Sleep Physiology of Trauma Nightmares and PTSD

• Trauma nightmares arise from disrupted REM sleep
  and light sleep (stages 1 and 2).
• In animals, alpha-1 stimulation with methoxamine
  disrupts REM sleep and lengthens light sleep.
  These effects are reversed by prazosin.

Taylor FB, et al., Biol Psychiatry 63629-32,
2008.
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Prazosin and Sleep Physiology A
Placebo-Controlled Crossover Study

• REMview device recorded sleep vs. wake and REM
  vs. non-REM.
• 10 of 13 participants provided a full three
  nights of REMview data in both maintenance
  prazosin condition (3.1 1.3 mg hs) and placebo
  condition.

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Effects of Prazosin vs. Placebo on Sleep Measures
in PTSD Subjects with Nocturnal Symptoms
500
Placebo

Prazosin
400
300
Mean Sleep time (Minutes SD)

200
100


0
Total Sleep Time
REM Sleep Time
Sleep Latency
REM Latency
Mean REM Period Duration
Significant difference between prazosin and
placebo group by repeated measures ANOVA p lt
0.05, p lt 0.01
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Placebo-Controlled Trial of Prazosin in Alcohol
Dependent Persons Seeking Abstinence Subjects
and Methods

• 17 alcohol dependent men without PTSD (46 7
  years).
• Two week titration to target dose of prazosin (or
  placebo) 4 mg BID, 8 mg HS.
• Maintained at target dose for 4 weeks.

Simpson, TL et al., Alcohol Clin Exp Res 3160A,
2007.
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Mean Drinking Days Per Week by Condition (Male
Completers Only)
Controlling for drinking days per week at
baseline and week number, the prazosin group
reported fewer drinking days per week than the
placebo group during the final 3 weeks of the
study (ß -1.84 95 CI -2.74, -.93 p lt
0.001).