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-ChairDept. of Psychiatry & Behavioral Sciences

University of Washington School of Medicine

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

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.

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

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

Individual PTSD Symptoms Responsive to Prazosin in Crossover Study

CAPS ItemRecurrent distressing dreamsDifficulty falling/staying asleepPhysiological reactivity to

trauma remindersIrritability or anger outburstsIntrusive trauma recollectionsDiminished interest/participation

in activitiesRestricted affect…numbingHypervigilance

p value< 0.001< 0.01

<0.01< 0.05< 0.05

< 0.05< 0.05< 0.1

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.

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.

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

Mea

n S

leep

tim

e (M

inut

es ±

SD

) 500

400

300

200

100

0

**

**

** *

*Significant difference between prazosin and placebo group by repeated measures ANOVA*p < 0.05, **p < 0.01

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.

0

1

2

3

4

5

6

0 1 2 3 4 5 6

study week

mean

(± 1

SE

M)

dri

nkin

g d

ays p

er

week

placebo (n=10) prazosin (n=7)

final titr

ation

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)