Diagnosing and Treating Posttraumatic Stress Disorder

James W. Jefferson, MD Clinical Professor of Psychiatry

University of Wisconsin

School of Medicine and Public Health

Distinguished Senior Scientist

Madison Institute of Medicine

Disclosures

Generalized AnxietyDisorder

Panic Disorder

Obsessive-Compulsive

DisorderSocial Anxiety

Disorder

PosttraumaticStress

Disorder

Anxiety Disorders

Anxiety Disorders (NCS-R) Lifetime Prevalence

• Social Phobia 12.1 %

• Posttraumatic Stress Disorder 6.8%

• Generalized Anxiety Disorder 5.7 %

• Panic Disorder 4.7 %

• Obsessive-Compulsive Disorder 1.6 %

Kessler et al. Arch Gen Psychiatry 2005;62:593-602; 617-627

National Comorbidity Survey Replication- Adolescent

• Face-to-face, ages 13 to 18, n=10,123

• PTSD lifetime: Total 5.0% Female: 8.0%

Male: 2.3%

Merikangas et al, J Am Acad Child Adolesc Psychiatry 2010;49:980-989

PTSD: Adult 12-Month Prevalence

• National Comorbidity Survey Replication*

3.5%

• European Epidemiology Study (ESEMeD) 1.1%

*Kessler et al, Arch Gen Psychiatry 2005;62:617-627Darves-Bornoz et al, J Traumatic Stress 2008;21:455-462

Prevalence Depends on the Population Studied

• PTSD in refugees and asylum seekers as high as 10 times that of the general population of the new country

Crumlish et al, J Nervous and Mental Dis 2010;198:237-251Fazel et al, Lancet 2005;365:1309-1314

National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) – Anxiety Disorders

• Very Common Comorbidities: Major Depressive Disorder Other Anxiety Disorders Substance Use Disorders

Conway et al., J Clin Psychiatry 2006;67:247-257

PTSD Lifetime Axis I Comorbidities From Wave 2, NESARC, n=34,653

• Odds ratios increased for: -MDD, Dysthymia, Bipolar I and II -GAD, Panic, Agoraphobia, SAD, Specific Phobia -Alcohol and Drug Abuse/Dependence, Nicotine Dependence -Lifetime Suicide Attempt

Pietrzak et al, J Anxiety Disorders 2011;25:456-465

PTSD Lifetime Axis II Comorbidities From Wave 2, NESARC, n=34,653

• Odds ratios increased 2.1-2.5 times for schizotypal, narcissistic, and borderline personality disorders

• 32.0% with BPD had PTSD

• 24.2% with PTSD had BPD

Pietrzak et al, J Psychiatric Research 2011;45:678-686Pagura et al, J Psychiatric Research 2010;44:1190-1198

Why So Much Axis I Comorbidity?

• Preexisting disorders increase risk

• Complications of PTSD

• Over lapping diagnostic criteria

• Traumatic stressors trigger PTSD and comorbid conditions

Pietrzak et al, J Anxiety Disorders 2011;25:456-465

Easy Ways to Miss Diagnoses

• If the patient doesn’t bring it up, it doesn’t exist

• Don’t interview significant others

• Don’t review records

• Don’t use diagnostic tools

• Don’t take the time

• Don’t think

Now It’s Called PTSD, but Back Then…

• Civil War: Soldier’s Heart• World War I: Shell Shock• World War II: Battle Fatigue• DSM-I: Gross Stress Reaction• DSM-II: Situational Reaction • DSM-III: Post-Traumatic Stress Disorder• DSM-IV: Posttraumatic Stress Disorder

PTSD: DSM-IV-TR

• Extreme traumatic stressor, response with intense fear, helplessness, or horror

• Characteristic symptoms– Reexperiencing (images, dreams,

flashbacks, etc)– Avoidance and numbing– Increased arousal

• Duration: > 1 month• Acute, chronic, delayed

PTSD: DSM-V Proposed Criteria

• A. Exposure to traumatic event• B. Intrusion symptoms• C. Persistent avoidance• D. Negative cognitions and mood• E. Alterations in arousal and reactivity• F. Duration ˃ 1 month• G. Causes significant distress or impairment• H Not due a substance or general medical

condition

PTSD: DSM-V

• Is it an anxiety disorder, a stress-induced fear circuitry disorder, an internalizing disorder, or a trauma- and stressor-related disorder?

• Trauma- and Stressor-Related Disorders: A new diagnostic category?

• Read all about it! See Friedman et al, Depression and Anxiety 2011;28:737-749

Some Brain Areas implicated in PTSD

Anterior Cingulate Cortex (ACC)

reward anticipation, empathy, and emotion1

Amygdala

memory of emotional reactions1

Hippocampus

memory and feedback to HPA

axis1

Charney et al, Neurobiol of Mental Illness, 2nd ed, 2004Garfinkel and Liberzon, Psychiatric Annals 2009;39:370-381

Prefrontal Cortex (PFC)

decision-making, planning, judgment1

Decreased Hippocampal Volume in PTSD Causation or Predisposition?

• Monozygotic twin study: Twin with PTSD, trauma-unexposed co-twin • Both had smaller hippocampi• Both had impaired hippocampal-mediated

spatial processing

Gilbertson et al, Nature Neuroscience 2002;5:1242-1247Gilbertson et al, Biol Psychiatry 2007;62:513-520

Long-Term Paroxetine for PTSD Increases Hippocampal Volume

• 9-12 months of treatment (n=20) increasedhippocampal volume by 4.6%

• And significantly improved verbal declarative memory• But clinical improvement not associated with volume

Vermetten et al, Biol Psychiatry 2003;54:693-702

Serotonin Transporter Gene Polymorphism and Sertraline Response in PTSD

• 12-week open-label, completer analysis, n= 330 entered, 226 completed (68.5%)

• Sertraline 100 mg/day

• CAPS total improvement SS 26.8%SL 25.2%LL 45.8%

Mushtaq etal, J Affective Disorders 2011, Sep 28, ePub

Mushtaq et al, J Affective Disorders 2011, Sep 28, ePub

Serotonin Transporter Gene Polymorphism and Sertraline Response in PTSD

PTSD Clinical Practice Guidelines

• 7 published since 2004 (VA/DoD, APA, NICE, NHMRC, ISTSS, AACAP, IOM)

• Conclusions: 1) Trauma-focused CBT is first-line 2) Pharmacotherapy (SSRIs) either alternative first-line or second-line 3) Avoid psychological debriefing as early intervention

Forbes et al., J Traumatic Stress 2010;23:537-552, Oct.

FDA-Approved for Posttraumatic Stress Disorder

• Paroxetine

• Sertraline

Of Possible Interest for PTSD

• SNRIs as SSRI alternatives

• Atypical antipsychotic augmentation

• Antiepileptics

• Prazosin for nightmares

• Propranolol for prevention

• D-Cycloserine for extinction learning

Venlafaxine for PTSD

1. 12-week vs. sertraline and placebo, n=538 VEN˃PBO, SER=PBO, VEN=SER Cluster scores: VEN˃PBO for hyperarousal, avoidance/numbing

2. 6-month vs. placebo, n=329 VEN ˃PBO Cluster scores: VEN˃PBO for reexperiencing, avoidance/numbing

1. Davidson et al, J Clin Psychopharmacology 2006;26:259-2672. Davidson et al, Arch Gen Psychiatry 2006;63:1158-1165

Atypical Antipsychotics for PTSD: A Review

• 10 double-blind, 8 open-label studies (monotherapy or add-on)

• At least 1 positive double-blind for risperidone, olanzapine, quetiapine

• Short-term, small sample sizes, small effect sizes

• Larger, longer, better studies needed.

Ahearn et al., Int Clin Psychopharmacology 2011;26:193-200

Adjunctive Risperidone for Military-Related Antidepressant-

Resistant PTSD

• 6-month, double-blind, n=247

• Dose: up to 4 mg/day

• Primary efficacy measure: CAPS total (Clinician-Administered PTSD Scale)

• Secondary measures: MADRS, HAM-A

Krystal et al, JAMA 2011;306:493-502, Aug 3

In this chronic, severely ill, predominately male military

population, risperidone

• Did not reduce overall PTSD severity

• Did not improve quality of life

• Did not improve depression

• Did not improve anxiety

Krystal et al, JAMA 2011;306:493-502, Aug 3

Topiramate for PTSD

• 3 small, short-duration, double-blind, placebo-controlled studies

• 1 monotherapy, 2 adjunctive

• High dropout rates

• Only 1 adjunctive was positive

Andrus and Gilbert, Ann Pharmacother 2010;44:1810-1816

Treating Nightmares and Insomnia in PTSD

• Behavioral treatments: Inconclusive

• SSRIs: No published studies

• Venlafaxine: No benefit in 2 RCTs

• Antipsychotics: Limited data

• Anticonvulsants: Weak support

• Alpha-1 blockers: Prazosin promising

Nappi et al, Neuropharmacology 2012;62:576-585

Prazosin for Nightmares and Insomnia in PTSD

• Alpha-1 adrenergic receptor blocker

• Effective open-label, in RCTs, more studies underway

• The only drug rated “recommended” by the American Academy of Sleep Medicine

• Optimal dose: To be determined

• Not FDA-approved for PTSD

Nappi et al, Neuropharmacology 2012;62:576-585

Eszopiclone for PTSD and Associated Insomnia

• 7-week, double-blind, placebo-controlled, 3 mg qhs, n=24

• Significantly ˃ improvement on -Short PTSD Rating Interview (SPRINT) -Clinician-Administered PTSD Scale (CAPS) -Pittsburgh Sleep Quality Index (PSQI)

Pollack et al, J Clin Psychiatry 2011;72:892-897

Propranolol to Prevent Traumatic Stress Disorders

• Beta-adrenergic receptor antagonist

• Interference with consolidation of fear memories

• Results remain controversial despite over 2 decades of study

Sharp S et al, J Trauma 2010;68:193-197; Hoge et al, CNS Neurosci & Therap 2012;18:21-27;Cohen et al, Eur Neuropsychopharmacol 2011;21:230-240; Nugent et al, J Traumatic Stress 2011;23:282-287

D-Cycloserine (DCS) Plus Exposure for Posttraumatic Stress Disorder

• Fear extinction may be mediated through NMDA receptors in the amygdala

• DCS: a partial agonist of the NMDA receptor glycine binding site

• 2010 International Society for Traumatic Stress: Several studies find “underwhelming” results

Johnson K, Internal Medicine News, Nov 18,2010

Psychotherapies for PTSD

1. Cognitive behavior therapy (CBT)

2. Eye movement desensitization and reprocessing (EMDR)

3. Psychological debriefing

4. Psychodynamic psychotherapy

5. Something else? If so, what?

APA Practice Guideline for the Treatment of Patients with Acute Stress Disorderand Posttraumatic Stress Disorder. Am J Psychiatry 2004;11:1-31, Nov supplement

Cognitive Behavioral Therapy for Anxiety Disorders

• Effective • Lower relapse rates than meds when

stopped• Few side effects• Can be combined with meds• Limited availability• Requires investment of time and effort

Exposure Habituation

Prolonged Exposure for PTSDMeta-analysis in Adolescents and Adults

• 13 studies (n=675) met criteria for analysis• Robust benefit vs. controls post-study and follow-up• But no significant difference from other active treatments (CPT 1 study, EMDR 3 studies, SIT 2 studies)

Powers et al, Clin Psychology Rev 2010;30:635-641

CPT=Cognitive Processing Therapy; SIT=Stress Inoculation Therapy; EMDR=Eye Movement Desensitization and Reprocessing

CBT for Pediatric PTSD Review and Meta-Analysis

• 21 RCTs, 8 met criteria for meta-analysis• Strong evidence for effectiveness• Child Behavior Checklist: Significant benefit for Total Problems, Internalizing, Externalizing, but not for Total Competence

Kowalik et al, J Behav Ther & Exp Psychiatr 2011;42:405-413

CBT+Meds vs. Either Alone For PTSD

• 4 studies (1 in kids), n=124

• 2 vs. meds alone, 2 vs. CBT alone

Hetrick et al, Cochrane Database of Systematic Reviews 2010;issue 7, July

CBT+Meds vs. Either Alone For PTSD

• 4 studies (1 in kids), n=124

• 2 vs. meds alone, 2 vs. CBT alone

• Not enough evidence support or reject the benefit of combination therapy

Hetrick et al, Cochrane Database of Systematic Reviews 2010;issue 7, July

CBT for Medication Non-Remitters: Systematic Review

• 4 PTSD studies, all in Cambodian or Vietnamese refugees• Small sample sizes, variable designs, • CBT added to medication• Effective in all studies

Rodrigues et al, 2011;129:219-228

PTSD: Conclusions

• A common psychiatric disorder• Often comorbid with Axis I and I disorders • SSRIs and SNRIs: effective for PTSD and

comorbid depression

• CBT and its variants effective for PTSD and comorbid depression