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Murray B. Stein, MD, MPH; University of California San Diego; INjury and TRaumatic STress (INTRuST) Consortium; and VA San Diego Healthcare System. Diagnosis and Pharmacotherapy of PTSD. AACP Mood and Anxiety Disorders Meeting Chicago, IL April 8, 2010. Disclosure Statement.

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Diagnosis and Pharmacotherapy of PTSD


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    1. Murray B. Stein, MD, MPH; University of California San Diego; INjury and TRaumatic STress (INTRuST) Consortium; and VA San Diego Healthcare System Diagnosis and Pharmacotherapy of PTSD AACP Mood and Anxiety Disorders Meeting Chicago, IL April 8, 2010

    2. 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

    3. Learning Objectives Upon 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

    4. 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

    5. 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

    6. Criterion A Event?

    7. 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…

    8. PTSD Symptoms Avoidance Reexperiencing Hyperarousal

    9. PTSD Symptoms GUILT Active Avoidance Emotional Numbing ANGER Reexperiencing Hyperarousal

    10. PTSD Prevalence • US general population • 3.5% (se 0.3) in NCS-R1 • Lifetime 6.8% (se 0.4) in NCS-R • Female:Male ~ 2:1 • Prevalence higher in some US subpopulations • 2-3X 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

    11. PTSD Comorbidity TBI Pain Major Depression PTSD Substance Abuse Stein MB & McAllister TW. Am J Psychiatry 2009

    12. Randomized Trial of Phenelzine, Imipramine and Placebo (N=60) 40 35 Placebo 30 Imipramine 25 20 Impact of Events Scale Phenelzine 15 10 5 0 Week 0 Week 8 Frank JB et al. Am J Psychiatry, 1988

    13. Amitriptyline vs. Placebo Completed 4 Weeks of Treatment (N=40) 40 Placebo 30 Amitriptyline IES 20 10 0 0 4 8 Weeks of Treatment Davidson et al. Arch Gen Psychiatry. 1990

    14. Pharmacotherapy of PTSD • FDA-Approved • Sertraline [Zoloft] • Paroxetine [Paxil] • Non FDA-Approved but Probably Efficacious • Other SSRIs • Venlafaxine ER [Effexor XR] • Non FDA-Approved but Possibly Efficacious • Bupropion[Wellbutrin SR] • Mirtazapine [Remeron]

    15. Pharmacotherapy of PTSD • Non FDA-Approved but Promising • Anticonvulsants • Topiramate [Topamax] • Lamotrigine [Lamictal] • Tiagabine [Gabitril] • Others • Prazosin [Minipress] • Olanzapine [Zyprexa] • Risperidone [Risperdal]

    16. Fluoxetine vs. Placebo (N=53) 90 80 70 60 Placebo 50 Davidson Trauma Scale 40 30 Fluoxetine 20 10 0 0 2 4 6 8 10 12 Week Connor et al, Br J Psychiatry, 1999

    17. Sertraline in PTSD Brady et al., JAMA, 2000

    18. The Effect of Continuation Treatment with Sertraline on Core Symptoms of PTSD CAPS-2 score IES score 80 35 70 30 60 25 50 20 CAPS-2 Total Severity Score 40 15 30 10 20 Impact of Event Total Score 5 10 0 0 Baseline Week 12 Week 20 Week 28 Week 36 Endpoint (LOCF) Acute Phase Study Open-Label Continuation Study Londborg PD et al. J Clin Psychiatry, 2001

    19. Paroxetine Fixed-Dose PTSD StudyResponder Analysis * * Percent Responders Based on CGI-I Week 12 Marshall et al., Am J Psychiatry, 2001

    20. Trauma Target Symptoms of PTSD • Re-experiencing • Avoidance • Numbing • Hyperarousal • insomnia • (Anger)

    21. ** ** ** ** ** ** CAPS-2: Symptom Clusters Paroxetine 20 mg/day Paroxetine 40 mg/day Placebo Re-experiencing Avoidance/Numbing Hyperarousal 0 -2 -4 -6 Adjusted Mean Change from Baseline† -8 -10 -12 -14 -16 -18 **p<0.001; Marshall et al. Am J Psychiatry, 2001

    22. Venlafaxine ER in PTSD Change in score on the Clinician-Administered Posttraumatic Stress Disorder Scale Davidson, J. et al. Arch Gen Psychiatry 2006;63:1158-1165.

    23. Predictors of Response? • Largely unknown • Clinical lore • Chronicity • Elapsed time since trauma exposure • Type of Trauma • Combat • Childhood maltreatment • Confounded by chronicity?

    24. 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.

    25. Utility of Rx in PTSD • Core symptoms of PTSD • Comorbid disorders • Associated features • affective instability • aggressive dyscontrol • In combination with psychotherapy? • Prior to psychotherapy?

    26. Unmet Needs in PTSD Rx • Polypharmacy rampant • Response frequently incomplete • Sleep disturbance • Psychotic symptoms • Non-response common • Chronicity

    27. Psychopharmacologic Treatment of PTSD in the VA • ICD-9 PTSD (N = 274,297) in FY 2004 • Most (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

    28. Prazosin for Combat-Related PTSD N=10 D-B, Crossover, Add-On to Current Rx * Mean dose 10 mg qhs CAPS * Raskind et al., Am J Psychiatry, 2003

    29. Prazosin for PTSD Sleep Problems N = 10 civilians, DB Crossover Raskind MA et al., Biol Psychiatry 2007;61:928-934; Taylor FB et al., Biol Psychiatry 2008;63:629-632

    30. 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

    31. Rx of SSRI-Resistant PTSD Change from baseline All p < 0.05 • Stein MB et al., Am J Psychiatry, 2002

    32. Improvement Adjunctive Risperidone forChronic Combat-Related PTSD * * * *P < 0.05 vs placebo Bartzokis G et al., Biol Psychiatry, 2005

    33. Abstract TOP Background: Topiramate, a novel anticonvulsant, has been reported to rapidly reduce symptoms of posttraumatic stress disorder (PTSD) in an open-label trial. The present study was designed as a test of topiramate's efficacy as adjunctive therapy in a 7-week, randomized, double-blind, placebo-controlled trial. Methods: Forty male veterans with PTSD in a residential treatment program were randomized to flexible-dose topiramate or placebo augmentation. The primary outcome measures were PTSD symptom severity and global symptom improvement. Results: Baseline Clinician-Administered PTSD Scale scores were 62.1 ± 13.9 for placebo and 61.0 ± 22.2 for topiramate. There was a high dropout rate from the study (55% topiramate; 25% placebo), with 40% of topiramate and 10% of placebo dropping because of adverse events (AEs). No significant treatment effects of topiramate versus placebo were observed for the primary treatment outcomes. Subjects reporting central nervous system-related AEs and with higher baseline severity of depression were more likely to discontinue because of AEs. Conclusions: Primary outcome measures failed to demonstrate a significant effect for topiramate over placebo; however, high dropout rate in the treatment group prohibits definitive conclusions about the efficacy of topiramate in this population. Topiramate for PTSD • Open-label studies promising • N = 40 DB RCT • Flexible dose topiramatevs 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 topiramatevs placebo • Outpatients • Modest advantage for topiramate (ns) • Additional studies warranted? • Power faux pas… Lindley SE et al., J ClinPsychopharmacol, 2007; Tucker P et al., J Clin Psychiatry, 2007

    34. 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 placebo • Need for larger RCTs Connor KM et al. Psychopharmacology2006

    35. 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% placebo • No differences on secondary outcomes • Davidson Trauma Scale; • Pittsburgh Sleep Quality Inventory Davidson JRT et al. J ClinPsychopharmacol2007

    36. DivalproexMonotherapy in PTSD • DB PC RCT male combat veterans • N = 82, 8 weeks • Primary outcome hyperarousal (CAPS) • No significant difference vs. placebo • For primary or secondary endpoints • Ineffective in this population • Useful for less chronic PTSD? • Useful as adjunctive Rx? Davis LL et al. J ClinPsychopharmacol2008

    37. Combining Pharmacotherapy and Psychotherapy to Augment Response in PTSD -- Prolonged exposure (PE) augments SSRI partial response1 Structured Interview PTSD -- SSRIs do not augment prolonged exposure (PE) partial response2 1Rothbaum BO et al., J Traum Stress 2006; 2Simon NM et al., J Clin Psychiatry 2008

    38. Low-dose Cortisol for PTSD • Small double-blind, placebo-controlled crossover study • 3 patients with chronic PTSD • 10 mg/d cortisol or placebo • 1 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

    39. 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

    40. 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. JAACAP2001; 2Bryant RA et al. BiolPsychiatry 2009; 3Holbrook TL et al. NEJM 2010; 4McGhee LL et al. J Trauma 2008

    41. 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 randomized • Propranolol (N = 17) 40 mg tid • Gabapentin (N = 14) 300 mg tid • Placebo (N = 17) tid • Outcomes 1, 4, and 8 months post-injury Stein MB et al., J Traum Stress 2007

    42. 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

    43. 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