DIAGNOSIS AND PHARMACOTHERAPY OF PTSD

Murray B. Stein, MD, MPH;

University of California San Diego;

INjury and TRaumatic STress (INTRuST) Consortium;

and VA San Diego Healthcare System

AACP Mood and Anxiety Disorders MeetingChicago, IL April 8, 2010

Disclosure Statement

Dr. Stein has in the past 3 years:Received research support from

○ Department of Defense, Hoffmann-La Roche, National Institute of Mental Health, Veterans Administration

Been a consultant for ○ AstraZeneca, Bristol-Myers Squibb, Comprehensive

NeuroScience, Hoffmann-La Roche, Jazz Pharmaceuticals, Johnson & Johnson

Been on the speaker’s bureau of○ None

Learning ObjectivesUpon the completion of this activity, participants will be able

to:

1) Consider diagnostic issues in posttraumatic stress disorder (PTSD)

2) List FDA approved treatments for PTSD.

3) Identify the different classes of psychotropic agents that may be useful in the treatment of PTSD

4) Discuss the limitations of the available evidence base for PTSD pharmacotherapy and of the need for more studies and better therapeutics

Posttraumatic Stress Disorder (1) Traumatic Exposure

experienced, witnessed, or was confronted with…○ events that involved actual or threatened

death or serious injury, or a threat to the physical integrity of self or others

the person’s response involved intense fear, helplessness, or horror

Posttraumatic Stress Disorder (2) Reexperiencing

intrusive thoughts, nightmares, flashbacks Avoidance

avoids relationships, reminders of event Numbing

feels emotionally “numbed” or “cut off” Hyperarousal

startle, trouble concentrating, insomnia

Criterion A Event?

Trauma Types Causing PTSD

Criminal Victimization Rape, intimate

partner violence, robbery

Motor vehicle accidents

Childhood abuse Natural disasters Unexpected death of

relative/friend Terrorism War Other…

PTSD Symptoms

Reexperiencing Hyperarousal

Avoidance

PTSD Symptoms

Reexperiencing

ActiveAvoidance

EmotionalNumbing

Hyperarousal

GUILT

ANGER

PTSD Prevalence

US general population3.5% (se 0.3) in NCS-R1

○ Lifetime 6.8% (se 0.4) in NCS-RFemale:Male ~ 2:1

Prevalence higher in some US subpopulations2-3X in American Indians on reservations2

○ Most prevalent disorder in women is PTSD (~20%)Cambodian refugees in US 20 years later3

○ 12-month prevalence 62%

1Kessler RC et al., Arch Gen Psychiatry 2005;2Beals J et al., Arch Gen Psychiatry 2005;3Marshall G et al., JAMA 2005

PTSD Comorbidity

PTSDMajorDepression

SubstanceAbuse

TBI

Pain

Stein MB & McAllister TW. Am J Psychiatry 2009

Frank JB et al. Am J Psychiatry, 1988

0

5

10

15

20

25

30

35

40

Week 0 Week 8

Phenelzine

Imipramine

Placebo

Imp

act

of

Eve

nts

Sca

leRandomized Trial of Phenelzine, Imipramine and Placebo (N=60)

Completed 4 Weeks of Treatment (N=40)

0

10

20

30

40

0 4 8

Weeks of Treatment

IES Amitriptyline

Placebo

Davidson et al. Arch Gen Psychiatry. 1990

Amitriptyline vs. Placebo

Pharmacotherapy of PTSD

FDA-ApprovedSertraline [Zoloft]Paroxetine [Paxil]

Non FDA-Approved but Probably EfficaciousOther SSRIsVenlafaxine ER [Effexor XR]

Non FDA-Approved but Possibly EfficaciousBupropion [Wellbutrin SR]Mirtazapine [Remeron]

Pharmacotherapy of PTSD

Non FDA-Approved but PromisingAnticonvulsants

○ Topiramate [Topamax]○ Lamotrigine [Lamictal]○ Tiagabine [Gabitril]

Others○ Prazosin [Minipress]○ Olanzapine [Zyprexa]○ Risperidone [Risperdal]

0

10

20

30

40

50

60

70

80

90

0 2 4 6 8 10 12

Fluoxetine

Placebo

Dav

idso

n T

rau

ma

Sca

le

WeekConnor et al, Br J Psychiatry, 1999

Fluoxetine vs. Placebo (N=53)

Sertraline in PTSD

Week 12 Response Rate (%)0

10

20

30

40

50

6032

53

Placebo

Sertraline

Brady et al., JAMA, 2000

CA

PS

-2 T

ota

l Sev

eri

ty S

co

re

Acute Phase Study Open-Label Continuation Study

Londborg PD et al. J Clin Psychiatry, 2001

The Effect of Continuation Treatment with Sertraline on Core Symptoms of PTSD

01020304050607080

Baseline Week 12 Week 20 Week 28 Week 36 Endpoint(LOCF)

05101520253035

Imp

act of E

vent To

tal Sco

re

CAPS-2 scoreIES score

Paroxetine Fixed-Dose PTSD StudyResponder Analysis

Series10

10

20

30

40

50

60

70 Paroxetine 20 mg

Paroxetine 40 mg

PlaceboPercent

Responders Based on CGI-I

PercentResponders

Based on CGI-I

Week 12Week 12

****

Marshall et al., Am J Psychiatry, 2001

Trauma

Target Symptoms of PTSD

Re-experiencing Avoidance Numbing Hyperarousal

insomnia (Anger)

CAPS-2: Symptom ClustersA

dju

sted

Mea

n C

han

ge

fro

m B

asel

ine†

**p<0.001; Marshall et al. Am J Psychiatry, 2001

Paroxetine 20 mg/day Paroxetine 40 mg/day Placebo

-18

-16

-14

-12

-10

-8

-6

-4

-2

0Re-experiencing Avoidance/Numbing Hyperarousal

** ** ****

****

Davidson, J. et al. Arch Gen Psychiatry 2006;63:1158-1165.

Change in score on the Clinician-Administered Posttraumatic Stress Disorder Scale

Venlafaxine ER in PTSD

Predictors of Response?

Largely unknown Clinical lore

Chronicity○ Elapsed time since trauma exposure

Type of Trauma○ Combat○ Childhood maltreatment

Confounded by chronicity?

Institute of Medicine 2007

At the request of the Department of Veterans Affairs, the Institute of Medicine’s Committee on Treatment of Posttraumatic Stress Disorder (PTSD) undertook a systematic review of the PTSD literature. After nearly 2,800 abstracts were identified, the application of inclusion criteria narrowed the list down to 90 randomized clinical trials, 37 pharmacotherapy studies, and 53 psychotherapy studies. The principal finding of the committee (2007) is that the 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.

The committee finds that the evidence is sufficient to conclude the efficacy of exposure therapies in the treatment of PTSD.The committee finds that the evidence is inadequate to determine efficacy of all forms of pharmacotherapy

The committee reached a strong consensus that additional high quality research is essential for every treatment modality.

Utility of Rx in PTSD

Core symptoms of PTSD Comorbid disorders Associated features

affective instability aggressive dyscontrol

In combination with psychotherapy? Prior to psychotherapy?

Unmet Needs in PTSD Rx

Polypharmacy rampant Response frequently incomplete

○ Sleep disturbance○ Psychotic symptoms

Non-response commonChronicity

Psychopharmacologic Treatment of PTSD in the VA

ICD-9 PTSD (N = 274,297) in FY 2004Most (80%) of veterans with PTSD get Rx

○ 89% antidepressants○ 61% anxiolytics/sedative-hypnotics○ 34% antipsychotics

Medication-appropriate comorbid diagnoses predicted use of each of these 3 classes○ But most uses not associated with a diagnostic indication

e.g., 77% of antipsychotic use not in presence of a psychotic dx

Substantial Rx use targeted at specific symptoms○ e.g., insomnia, anxiety, nightmares, flashbacks

Mohamed S & Rosenheck RA, J Clin Psychiatry, 2008

Prazosin for Combat-Related PTSD

Reexper Baseline

Reexper Endpoint

Total Base-line

Total Endpoint

0102030405060708090

Placebo

Prazosin

Raskind et al., Am J Psychiatry, 2003

N=10 D-B, Crossover, Add-On to Current Rx

CA

PS

*

* Mean dose10 mg qhs

Prazosin for PTSD Sleep Problems

Outcome at 8 weeks(N = 34 veterans)

Prazosin Placebo P

CAPS distressing dreams 3.2 ± 2.6 5.5 ± 2.2 .02

PSQI 9.7 ± 3.9 12.6 ± 4.1 .008

CGIC 2.41 ± 1.1 3.65 ± 1.2 .002

Raskind MA et al., Biol Psychiatry 2007;61:928-934;Taylor FB et al., Biol Psychiatry 2008;63:629-632

N = 10 civilians, DB Crossover

Guanfacine for PTSD 8 week RCT (adjunctive or monotherapy)

N = 34 guanfacine○ start 0.5 mg; median dose 2.4 mg/d

N = 29 placebo

Neylan TC et al., Am J Psychiatry 2006; 163:2186-2188

Rx of SSRI-Resistant PTSD

CAPS PSQI CES-D-20

-15

-10

-5

0

5

10

Olanzapine

Placebo

All p < 0.05

Change from baseline

Stein MB et al., Am J Psychiatry, 2002

Adjunctive Risperidone forChronic Combat-Related PTSD

PANSS Positive

HAM-D

HAM-A

CAPS-D (Arousal)

CAPS-C (Avoidance)

CAPS-B (Re-experiencing)

CAPS Total*

-16 -14 -12 -10 -8 -6 -4 -2 0

Placebo

Risperidone

Change in Score

Improvement

*P < 0.05 vs placebo

*

*

*

Bartzokis G et al., Biol Psychiatry, 2005

Topiramate for PTSD Open-label studies promising

N = 40 DB RCT○ Flexible dose topiramate vs placebo

In a residential treatment program

○ High drop-out rates 55% topiramate;25% placebo

○ No significant (or hint of) treatment benefits of topiramate over placebo

N = 38 DB RCT○ Flexible dose topiramate vs placebo

Outpatients

○ Modest advantage for topiramate (ns)Additional studies warranted?

○ Power faux pas…Lindley SE et al., J Clin Psychopharmacol, 2007;Tucker P et al., J Clin Psychiatry, 2007

Tiagabine for PTSD Tiagabine is a selective GABA reuptake

inhibitor (SGRI) Open-label trial of tiagabine (N=29)

Double-blind, randomized placebo-substitution○ N = 18 subjects responding to open-label tx

“response” = at least minimal improvement

No greater incidence of relapse with placeboNeed for larger RCTs

Connor KM et al. Psychopharmacology 2006

RCT of Tiagabine in PTSD N = 232 patients with DSM-IV PTSD

12 week RCT○ Flexible dosing up to 16 mg/d (as 8 mg bid)

Mean dose 11.2 mg/d tiagabine (range 2-16 mg/d)○ Completion rates 66% tiagabine v 55% placebo

AE-related dropouts low (8%; 8%)

Response rates 49% tiagabine v 54% placeboNo differences on secondary outcomes

○ Davidson Trauma Scale; ○ Pittsburgh Sleep Quality Inventory

Davidson JRT et al. J Clin Psychopharmacol 2007

Divalproex Monotherapy in PTSD

DB PC RCT male combat veteransN = 82, 8 weeks

Primary outcome hyperarousal (CAPS)No significant difference vs. placebo

○ For primary or secondary endpoints

Ineffective in this populationUseful for less chronic PTSD?Useful as adjunctive Rx?

Davis LL et al. J Clin Psychopharmacol 2008

Combining Pharmacotherapy and Psychotherapy to Augment Response in PTSD

Str

uct

ure

d Inte

rvie

w P

TSD

1Rothbaum BO et al., J Traum Stress 2006;2Simon NM et al., J Clin Psychiatry 2008

-- Prolonged exposure (PE) augments SSRI partial response1

-- SSRIs do not augment prolonged exposure (PE) partial response2

Low-dose Cortisol for PTSD Small double-blind, placebo-controlled

crossover study3 patients with chronic PTSD

○ 10 mg/d cortisol or placebo1 month each with taper in-between

Beneficial effects on intrusive thoughts during cortisol treatment

Larger RCT warranted?

Aerni A et al., Am J Psychiatry 2004; 161:1488-1490

PTSD Rx Prevention: Challenges Uncharted territory

No previous large scale trials ○ Few trials of any kind

Whom to treat?○ Critical Incident Stress Debriefing a failure

“selective prevention”- After exposure to risk (i..e, trauma)

○ PTSD-like symptoms after traumatic stressor “indicated prevention”

- When showing early symptoms

PTSD and Opiates Observational studies suggest impact of morphine on

PTSD prevention 24 children admitted to burn service

○ Morphine dose in hospital correlates negatively with PTSD symptoms at 6 months1

120 adults admitted to burn service○ Morphine dose during first 48 hours of hospitalization negatively

predicted PTSD at 3 months2

696 navy-marine personnel injured in combat○ 61% of PTSD + had received morphine vs. 76% of PTSD –3

Specific opiate effect vs. pain relief? observation of similar ketamine association4

RCTs needed But difficult to design and probably unethical to conduct

1Saxe G et al. JAACAP 2001; 2Bryant RA et al. Biol Psychiatry 2009;3Holbrook TL et al. NEJM 2010; 4McGhee LL et al. J Trauma 2008

PTSD Pharmacoprevention D-B RCT

Patients admitted to UCSD Level 1 Surgical Trauma Center with acute physical injury○ Excluded serious head injury, spinal cord

injury…Rx 24-48 hours of injury for 14 days

○ N = 48 randomizedPropranolol (N = 17) 40 mg tidGabapentin (N = 14) 300 mg tidPlacebo (N = 17) tid

Outcomes 1, 4, and 8 months post-injury

Stein MB et al., J Traum Stress 2007

PTSD Diagnostic Outcomes

4-month follow-up CIDI by telephone

Blind to treatment assignment Rates of Past-Month PTSD:

Gabapentin: 20% observed cases (43% max*)

Propranolol: 25% observed cases (47% max*)

Placebo: 25% observed cases (29% max*)○ p = 0.95*Assuming all lost to follow-up developed PTSD

Stein MB et al., J Traum Stress 2007

Summary Growing evidence base for PTSD treatments

Exposure-based psychotherapies Pharmacotherapies

○ SSRIs and SNRIs○ MAOIS ○ Other antidepressants ○ Anticonvulsants○ Adjuncts

Prazosin Atypical antipsychotics

Pharmacotherapy alone usually inadequate to obtain optimal outcomes Combined Rx + exposure-based therapy

○ Studies ongoing (e.g., D-cycloserine) Novel treatments… including early intervention