1. 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

2. 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

3. 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 alpha 1 AR (in prefrontal cortex, amygdala?) contributes to reexperiencing and hyperarousal symptoms.

5. Two Prazosin RCTs in Vietnam Veterans with PTSD: CAPS Recurrent Distressing Dreams (“Nightmares”)

6. Two Prazosin RCTs in Vietnam Veterans with PTSD: Clinical Global Impression of Change (CGIC)

7. 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 affect…numbing Hypervigilance p value < 0.001 < 0.01 < 0.05 < 0.1

8. 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 63:629-32, 2008.

9. 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.

10. Effects of Prazosin vs. Placebo on Sleep Measures in PTSD Subjects with Nocturnal Symptoms Placebo Prazosin Total Sleep Time REM Sleep Time Sleep Latency REM Latency Mean REM Period Duration Mean Sleep time (Minutes ± SD) 500 400 300 200 100 0 ** * *Significant difference between prazosin and placebo group by repeated measures ANOVA *p < 0.05, **p < 0.01

11. 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 31:60A, 2007.

12. 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 (β = -1.84; 95% CI = -2.74, -.93; p < 0.001). Mean Drinking Days Per Week by Condition (Male Completers Only)