Post on 18-Dec-2015
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
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 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
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