PTSD and Substance Use Disorders: Implications for Assessment and Treatment

Full text

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DEAN KRAHN, MD CHIEF, MH SERVICE VA-MADISON

WARNING/WARNING

LOTS OF OFF-LABEL USES DISCUSSED AS WELL AS NOT USING SO READILY SUBSTANCES THAN ARE ON-LABEL

NO FINANCIAL DISCLOSURES

PTSD and Substance Use Disorders:

Implications for Assessment and

Treatment

PTSD: Psychiatric Comorbidity

yMajor Depression yOther Anxiety Disorders ySubstance Use Disorders

{Up to 30-50% in combat populations (mostly male); elevated over general population by about double in other traumatized populations.

yPersonality Disorders: Cluster B

PTSD: Physical Comorbidity

yPain: headache, TBI

yPain: musculoskeletal/fibromyalgia (number one

complaint in OIF/OEF/OND veterans).

yBackache: (80 pound packs on and off of helicopters leads to chronic pain and opiate use)

yCardiac and GI sx like somatization disorder

Definition of PTSD in DSM-IV

yA1: traumatic event (life threatening to self or those

close)

yA2: emotional reaction (horrified, overwhelmed, etc—not useful in most soldiers)

yB: reexperiencing

yC: hyperarousal

yD: numbing/withdrawal

yDysfunction/distress

Relationship of Trauma, PTSD, SUD

yNot completely clear

yIn studies in which a given order “wins”, the order is trauma-ÆPTSD-ÆSUD, with those who experience trauma but don’t develop PTSD developing no more SUD than those with no trauma

yBut, PTSD is linked with many types of comorbidities

Neural Mechanisms of PTSD

yPTSD characterized by decreased prefrontal cortical activity (therefore, amygdala overactivity isn’t regulated; with faster fear conditioning and slower extinguishing)

yElevated amygdala activity (associated with fear, anxiety, and startle)

yDecreased hippocampal activity (“misfiled” memories that are potently imprinted due to high levels of Norepinephrine)

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The amygdala is critical in fear

conditioning and response to stress

Pathophysiology of PTSD

yHow do we understand the mechanism by which trauma results in reexperiencing sx?

{Traumatic stress results in an amygdala that is

hyperresponsive to threat-related stimuli

{But to some extent that is a good thing//where does it go

wrong such that the pt with PTSD keeps on responding in non-threat conditions

ÙPotentially, inadequate functioning by the anterior paralimbic cortex which mediates habituation (in other words, learning not to respond in non-threat situations)

ÙAlso, decreased hippocampal function might lead to the overgeneralization of fear response to non-threatening stimuli

Pathophysiology of PTSD

yStartle response and irritability {Amygdala and startle

ÙThe neurology of startle ÙFear-potentiated startle

ÙIncreased by yohimbine; decreased by prazosin ÙAlcohol and benzodiazepines help acutely but increase it

chronically

Pathophysiology of PTSD

yHyperresponsiveness to corticosteroid feedback {Often have low resting cortisols but intact response to

stressors

yHigh levels of Norepinephrine

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Pathophysiology of PTSD & Implications

for Treatment

yHow does one get over “learned alarm”

{The process of extinction

ÙRe-experiencing on purpose, under control, and nothing bad results over and over again

{Diminishing CRH and NE effects ÙSSRI’s, prazosin

{Learning new coping strategies

Patients with PTSD and SUD

yAre particularly likely to drop out

yThe frequently-given advice that “you should get

sober so you can get treatment for your PTSD” drives many away

ySimultaneous care is the way to go

Seeking Safety

yCombination of relapse prevention for substance

abuse and cognitive processing therapy for PTSD developed by Najavits

{Aimed at improvement as opposed to abstinence only

ySome studies (mostly in women rape victims) show benefit for decreased PTSD sx and less drinking

yLots of available training and manuals

Other effective treatments that can be easily used yNTX plus sertraline

yMotivational enhancement (often for both disorders) yPrazosin (looks to be good for both disorders)

The Evidence Base for Prazosin Treatment of Military Operations PTSD in United States Veterans and Service Members

Murray A. Raskind, MD Director, VISN 20 Northwest Network Mental Illness Research, Education and Clinical

Center (MIRECC)

Prazosin

yA generic lipid-soluble alpha-1

adrenoreceptor (AR) antagonist introduced in 1973 as “Minipress” for treatment of hypertension.

yCosts pennies per day.

yNon-sedating.

yOnly alpha-1 AR antagonist that crosses blood brain barrier.

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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)

Prazosin and Sleep Physiology: A

Placebo-Controlled Crossover Study

yWe evaluated the effects of bedtime prazosin

vs. placebo on sleep physiology and PTSD symptoms in 13 civilian trauma PTSD subjects with persistent trauma nightmares and sleep disturbance.

yPrazosin increased total sleep time by 94

minutes with no effect on sleep latency.

Prazosin: Adverse Effects

Generally, very well tolerated.

“First dose” hypotension avoided with low dose initiation - but some vets need titration to 20 mg or more.

Orthostatic dizziness more common in young women and persons already on a beta-blocker or ED drug.

Concurrent use with trazodone may increase priapism risk.

Nasal congestion, peripheral edema, headache, palpitations.

Two Large Randomized Controlled Trials

for Combat Operations PTSD Currently

Well Underway

Ongoing Prazosin RCTs

yA Placebo-Controlled Augmentation Trial for Combat Trauma PTSD. A DoD funded RCT in OIF/OEF active duty soldiers.

yCSP 563. Prazosin and Combat Trauma PTSD (PACT). VA funded. For combat Veterans of any war at 13 VA sites.

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Active Duty OIF/OEF Prazosin RCT

yParallel group RCT (1:1) at Joint Base Lewis

McChord, WA

yActive duty OIF/OEF soldiers with combat

operations PTSD (CAPS > 50) and distressing trauma nightmares (at least two nights/week)

yMaintenance psychotropic medications and psychotherapy OK.

Design and Methodology

y6-week dose titration to maximum 20 mg HS and 5

mg midmorning.

yStudy duration 15 weeks.

yPrimary outcome measures – CAPS “distressing

dreams,” PSQI and CGIC

ySecondary outcome measures – total CAPS, PHQ-9, QOLI, and Penn Alcohol Craving Scale

Prazosin for PTSD in OIF/OEF Soldiers, Baseline to Week 15, Midstudy Analysis (n=68)

Prazosin Placebo Significance (2 tailed)

CAPS Total -23 vs. -11 p < 0.05

CAPS Nightmare -3.2 vs. -1.4 p < 0.01

CGIC, moderate and marked improvement (sense of well being and ability to function)

18/25 vs. 5/26 p = 0.02

PSQI -6 vs. -2 p < 0.05

For Alcohol Comorbidity

yAt least one study in vets shows benefit for alcohol

abuse.

yRaskind personal communication indicates benefit in his opinion for comorbids

yPush dose (eg 5/5/10) and use in daytime.

Prazosin vs. Quetiapine for Nighttime PTSD Symptoms in Veterans: Long-Term Comparative Effectiveness

and Safety

A Retrospective Chart Review Study Melanie G. Byers, et al. J Clin Psychopharmacology

30:225-229, 2010

Subjects

Subjects

237 veterans (mean age 54) prescribed

237 veterans (mean age 54) prescribed

prazosin

prazosin

(n=62) or quetiapine

(n=62) or

quetiapine

(n=175) for

(n=175) for

PTSD nighttime symptoms

PTSD nighttime symptoms

First Prescribed

First Prescribed End PointEnd Point Oct 2002 to Oct 2005

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Questions

yShort-term effectiveness: Did percentage improved within 6 months differ between drugs?

yLong-term effectiveness: Did percentage treatment continued to October 2008 endpoint (3 to 6 years of medication continuity) differ between drugs? yLong-term safety: Did adverse effects leading to

drug discontinuation differ between drugs?

Prazosin vs. Quetiapine in Veterans:

Mean Doses

Baseline (2002-2005)

6 Months End Study (2008)

Prazosin 1.4 mg 3.2 mg 6.3 mg

Quetiapine 41 mg 101 mg 135 mg

Prazosin vs. Quetiapine in Veterans: Short and Long Term Effectiveness for

PTSD Nighttime Symptoms

Prazosin vs. Quetiapine in Veterans: Reasons for Discontinuation

Prazosin vs. Quetiapine in Veterans: Adverse Effects Leading to Discontinuation

Prazosin vs. Quetiapine for Nighttime PTSD Symptoms in Veterans: Investigators Conclusions and Recommendations yEquivalent short-term effectiveness.

yPrazosin superior long-term effectiveness.

yPrazosin safe than quetiapine.

“We recommend that prazosin be used first line for treating nighttime PTSD symptoms in veterans.”

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Proposed Symptom-Based Approach to Pharmacologic Treatment of Military Operations PTSD

PTSD with Prominent Depressive Symptoms and/or Irritability

PTSD with Prominent Sleep Disruption with (or without) Recalled Trauma Nightmares and Daytime Hypervigilance

SSRI/SNRI Start prazosin @ 1-2 mg HS

Titrate over 4-8 weeks per clinical response* to 5 mg bid and 20 mg HS (*achieved effective prazosin dose highly variable)

*Effective prazosin dose highly, range from 2 mg to 40 mg/day

Proposed Symptom-Based Approach to Pharmacologic Treatment of Military Operations PTSD - Continued

yStarting an SSRI/SNRI and prazosin simultaneously

is reasonable.

yAdd zolpidem (or other sedative) for persistent

distressing sleep initiation insomnia.

yAdd low dose quetiapine for persistent psychotic symptoms.

Hamner Quetiapine Trial

Mark Hamner, Jose Canive, Sophie Robert, Lawrence A. Calais,  Gerardo Villarreal , Valerie Durkalski

‰INTRODUCTION:Psychotherapy and antidepressants are mainstay treatments for PTSD. Atypical antipsychotics may also be effective in reducing symptoms of PTSD. The following study investigated the efficacy of monotherapy with quetiapine in patients with chronic PTSD using a double‐blind, randomized, placebo‐controlled trial.

‰METHODS:There was a 1‐week placebo phase followed by a 12‐week randomized phase. Eighty patients entered the study and 77 had > 1 efficacy assessment. The primary outcome measure was the CAPS. A number of secondary rating instruments were also administered including PANSS, CGI‐S, CGI‐I, HAM‐D, HAM‐A, and other psychosocial and safety measures.

‰RESULTS:There was a highly significant (3‐fold) decline in CAPS composite scores in quetiapine‐treated patients as compared with placebo (ITT analysis, LOCF, P=0.0070, 2‐tailed) and on re‐experiencing (P=0.0019) and hyperarousal symptom (P=0.030) subscales but not on the avoidance subscale (P=0.56). Greater improvement was observed in the CGI‐S (P=0.0030), the CGI‐I (P=0.030), and the PANSS composite scores (P=0.0135). HAM‐A (P=0.020) and HAM‐D (P=0.0093) total scores also declined versus placebo. The average dose of quetiapine was 258 mg/d (range, 50‐800 mg/d).

‰CONCLUSIONS:These results suggest that quetiapine monotherapy is efficacious in the treatment of PTSD. Larger controlled trials are needed to better define the role of quetiapine and other atypical antipsychotics alone or as adjuncts in treating patients suffering from PTSD.

Krystal, et al Risperidone Add-On RCT in Vets yPlacebo controlled in 100’s of Vets

yAdd-on in treatment-resistant Vets

yNo significant decrease in CAPS or depression scales yLots of se’s (mostly metabolic) in risperidone vs.

placebo

yBut small, significant decreases in hyperarousal and re-experiencing symptoms

yExtremely bad press right now re: this medication.

SSRI

SSRI

s

s

Sertraline

Sertraline

Ù

ÙRandomized, doubleRandomized, double--blind, veterans, blind, veterans,

multicenter

multicenter, n=169 (Friedman et al., , n=169 (Friedman et al., 2007)

2007)

|

| No significant differences in mean change No significant differences in mean change

of CAPS

of CAPS--2 total severity score, IES total 2 total severity score, IES total score, or CGI severity or improvement

score, or CGI severity or improvement

scales

scales

|

| No consistent effects of gender, illness No consistent effects of gender, illness

duration, illness severity

duration, illness severity

(

(

Sertraline

Sertraline

cont.)

cont.)

{

{ RCT in Israeli veterans, n=23 (RCT in Israeli veterans, n=23 (ZoharZoharet al., 2002)et al., 2002)

Ù

ÙNo statistically significant difference between No statistically significant difference between

sertraline

sertralineand placebo on CAPS-and placebo on CAPS-2 total 2 total severity and symptom cluster scores severity and symptom cluster scores

{

{2 2 RCTRCT’’ssin nonin non--veterans, n=187 (Brady et veterans, n=187 (Brady et al., 2000); n=208 (Davidson et al., 2001) al., 2000); n=208 (Davidson et al., 2001)

|

|Significant drugSignificant drug--placebo differences in CAPSplacebo differences in CAPS- -2 total severity score, and CGI change and

2 total severity score, and CGI change and

mean

mean

|

|Significant changes in avoidance/numbing Significant changes in avoidance/numbing and

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Fluoxetine

Fluoxetine

{ Vast majority of RCT’s with civilians

{ Mixed study of veterans and civilians, n=31 veterans (van der Kolk et al., 1994)

Ù Fluoxetine superior to placebo in reducing CAPS total score, and avoidance and hyperarousal clusters, but not intrusion Ù Differences between drug and placebo much smaller in

veterans

{ Non-North American study on 3 continents, n=226, (Martenyi et al., 2002) 48% combat veterans, 47% civilian war trauma

Ù Significantly greater improvement, fluoxetine vs. placebo, (younger veterans with recent war trauma), in CAPS total score and hyperarousal subscore (inter-rater reliability?)

Paroxetine

Paroxetine

{

{No No RCTRCT’’ssspecifically with veteransspecifically with veterans {

{RCTRCT’’sswith civilians, mostly women with civilians, mostly women

(n=307, n=365), show efficacy (n=307, n=365), show efficacy measured by CAPS

measured by CAPS --2 total score, 3 2 total score, 3 symptom clusters , and CGI symptom clusters , and CGI { {CitalopramCitalopram--no no RCTRCT’’ss { {FluvoxamineFluvoxamine--no no RCTRCT’’ss

Venlafaxine

Venlafaxine

ER

ER

{ { No No RCTRCT’’ssin veteransin veterans {

{ 12 week, double12 week, double--blind, blind, multicentermulticenter(n=538) v. (n=538) v.

sertraline

sertralineand placebo (multiple traumas , <9% and placebo (multiple traumas , <9%

combat)

combat)

Ù

Ù Significantly greater improvement compared to Significantly greater improvement compared to placebo in CAPS

placebo in CAPS--Sx17, and avoidance/numbing and Sx17, and avoidance/numbing and

hyperarousal

hyperarousalsubscales, but not resubscales, but not re--experiencingexperiencing Ù

Ù Relatively small effect sizeRelatively small effect size

Ù

Ù No significant differences between No significant differences between venlafaxinevenlafaxineand and sertraline

sertraline

(

(

Venlafaxine

Venlafaxine

ER cont.)

ER cont.)

{

{ 6 month, double6 month, double--blind, blind, multicentermulticenterinternational international

(none U.S.), n=329, 12% combat

(none U.S.), n=329, 12% combat

Ù

ÙSignificantly greater improvement Significantly greater improvement compared to placebo in CAPS

compared to placebo in CAPS--Sx17, and Sx17, and avoidance/numbing and re

avoidance/numbing and re--experiencing, experiencing, but not

but not hyperarousalhyperarousal

Ù

ÙNo measure of interNo measure of inter--rater reliabilityrater reliability

Ù

ÙSmall effect size Small effect size

(

(

Venlafaxine

Venlafaxine

ER cont.)

ER cont.)

{2 pooled analyses of the previous 2 studies

ÙEarliest onset of response (week 2):

irritability/anger and physiological reactivity to cues

ÙNumbing and hyperarousal took longer to

respond

ÙInconsistent efficacy for distressing dreams and

insomnia

ÙNo significant effects of gender

ÙTreatment effects smaller in subjects with combat

trauma

Duloxetine

Duloxetine

{ Binds both serotonin and norepinephrine receptors with equal affinity even at lower doses

{ 12 week open-label trial, veterans, n=20 (Villarreal et al., 2010)

ÙSignificant improvement in CAPS total and all

subscales

Ù9 subjects (45%) classified as responders (defined

as more than 20% improvement in total CAPS score)

ÙMost improvement by week 2

ÙSignificant improvement in sleep quality (PSQI)

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(

(

Duloxetine

Duloxetine

cont.)

cont.)

{ 8 week open-label trial, veterans, n=21 (Walderhaug et al.,

2010)

Ù Treatment refractory; co-morbid major depression; 80% Vietnam veterans

Ù Primary outcome measure – PTSD checklist (PCL-C) – significant drop from 64.1 (+/- 10.2) to 48.1 (+/- 11.9) Ù Increase in pleasant dream activity; “rapid and sustained

improvement of nightmares” Ù Rapid onset of action

Mirtazapine

Mirtazapine

{ 2 studies with veterans in Korea { Open label, sertraline-controlled study

Ù No significant differences between mirtazapine and sertraline Ù Both decreased CAPS-2 total score

{ Open-label continuation study

Ù Effects of mirtazapine on PTSD may appear later than with depression

{ 2 small randomized controlled trials in civilians: some suggestions of effectiveness, but limited power of small sample sizes

Conclusions

yImportant comorbidity given returning troops and a

dangerous world

yDeveloping treatments based on improving understanding of physiology

yPsychotherapy has more support for PTSD than does pharmacotherapy

Figure

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References

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