PTSD and Substance Use Disorders: Implications for Assessment and Treatment

Transcription

1 PTSD and Substance Use Disorders: Implications for Assessment and Treatment 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: Psychiatric Comorbidity Major Depression Other Anxiety Disorders Substance Use Disorders Up to 30-50% in combat populations (mostly male); elevated over general population by about double in other traumatized populations. Personality Disorders: Cluster B PTSD: Physical Comorbidity Definition of PTSD in DSM-IV Pain: headache, TBI Pain: musculoskeletal/fibromyalgia (number one complaint in OIF/OEF/OND veterans). Backache: (80 pound packs on and off of helicopters leads to chronic pain and opiate use) Cardiac and GI sx like somatization disorder A1: traumatic event (life threatening to self or those close) A2: emotional reaction (horrified, overwhelmed, etc not useful in most soldiers) B: reexperiencing C: hyperarousal D: numbing/withdrawal Dysfunction/distress Relationship of Trauma, PTSD, SUD Neural Mechanisms of PTSD Not completely clear In studies in which a given order wins, the order is trauma- PTSD- SUD, with those who experience trauma but don t develop PTSD developing no more SUD than those with no trauma But, PTSD is linked with many types of comorbidities PTSD characterized by decreased prefrontal cortical activity (therefore, amygdala overactivity isn t regulated; with faster fear conditioning and slower extinguishing) Elevated amygdala activity (associated with fear, anxiety, and startle) Decreased hippocampal activity ( misfiled memories that are potently imprinted due to high levels of Norepinephrine)

2 The amygdala is critical in fear conditioning and response to stress Pathophysiology of PTSD How 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 Potentially, inadequate functioning by the anterior paralimbic cortex which mediates habituation (in other words, learning not to respond in non-threat situations) Also, decreased hippocampal function might lead to the overgeneralization of fear response to non-threatening stimuli Pathophysiology of PTSD Pathophysiology of PTSD Startle response and irritability Amygdala and startle The neurology of startle Fear-potentiated startle Increased by yohimbine; decreased by prazosin Alcohol and benzodiazepines help acutely but increase it chronically Hyperresponsiveness to corticosteroid feedback Often have low resting cortisols but intact response to stressors High levels of Norepinephrine Overreactions and amplified memories of stressors

3 Pathophysiology of PTSD & Implications for Treatment How does one get over learned alarm The process of extinction Re-experiencing on purpose, under control, and nothing bad results over and over again Diminishing CRH and NE effects SSRI s, prazosin Learning new coping strategies Patients with PTSD and SUD Are particularly likely to drop out The frequently-given advice that you should get sober so you can get treatment for your PTSD drives many away Simultaneous care is the way to go Seeking Safety Other effective treatments that can be easily used Combination of relapse prevention for substance abuse and cognitive processing therapy for PTSD developed by Najavits Aimed at improvement as opposed to abstinence only Some studies (mostly in women rape victims) show benefit for decreased PTSD sx and less drinking Lots of available training and manuals NTX plus sertraline Motivational enhancement (often for both disorders) Prazosin (looks to be good for both disorders) The Evidence Base for Prazosin Treatment of Military Operations PTSD in United States Veterans and Service Members Prazosin Murray A. Raskind, MD Director, VISN 20 Northwest Network Mental Illness Research, Education and Clinical Center (MIRECC) A generic lipid-soluble alpha-1 adrenoreceptor (AR) antagonist introduced in 1973 as Minipress for treatment of hypertension. Costs pennies per day. Non-sedating. Only alpha-1 AR antagonist that crosses blood brain barrier.

4 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 We 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. Prazosin 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 betablocker or ED drug. Concurrent use with trazodone may increase priapism risk. Nasal congestion, peripheral edema, headache, palpitations. Ongoing Prazosin RCTs Two Large Randomized Controlled Trials for Combat Operations PTSD Currently Well Underway A Placebo-Controlled Augmentation Trial for Combat Trauma PTSD. A DoD funded RCT in OIF/OEF active duty soldiers. CSP 563. Prazosin and Combat Trauma PTSD (PACT). VA funded. For combat Veterans of any war at 13 VA sites. 194 randomized.

5 Active Duty OIF/OEF Prazosin RCT Design and Methodology Parallel group RCT (1:1) at Joint Base Lewis McChord, WA Active duty OIF/OEF soldiers with combat operations PTSD (CAPS > 50) and distressing trauma nightmares (at least two nights/week) Maintenance psychotropic medications and psychotherapy OK. 6-week dose titration to maximum 20 mg HS and 5 mg midmorning. Study duration 15 weeks. Primary outcome measures CAPS distressing dreams, PSQI and CGIC Secondary 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) For Alcohol Comorbidity Prazosin Placebo Significance (2 tailed) CAPS Total -23 vs. -11 p < 0.05 CAPS Nightmare -3.2 vs 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 At least one study in vets shows benefit for alcohol abuse. Raskind personal communication indicates benefit in his opinion for comorbids Push dose (eg 5/5/10) and use in daytime. Prazosin vs. Quetiapine for Nighttime PTSD Symptoms in Veterans: Long-Term Comparative Effectiveness and Safety Subjects A Retrospective Chart Review Study Melanie G. Byers, et al. J Clin Psychopharmacology 30: , veterans (mean age 54) prescribed prazosin (n=62) or quetiapine (n=175) for PTSD nighttime symptoms First Prescribed End Point Oct 2002 to Oct 2005 Oct 2008

6 Questions Short-term effectiveness: Did percentage improved within 6 months differ between drugs? Long-term effectiveness: Did percentage treatment continued to October 2008 endpoint (3 to 6 years of medication continuity) differ between drugs? Long-term safety: Did adverse effects leading to drug discontinuation differ between drugs? Prazosin vs. Quetiapine in Veterans: Mean Doses Baseline ( ) 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 Equivalent short-term effectiveness. Prazosin superior long-term effectiveness. Prazosin safe than quetiapine. We recommend that prazosin be used first line for treating nighttime PTSD symptoms in veterans.

7 Proposed Symptom-Based Approach to Pharmacologic Treatment of Military Operations PTSD Proposed Symptom-Based Approach to Pharmacologic Treatment of Military Operations PTSD - Continued PTSD with Prominent Depressive Symptoms and/or Irritability SSRI/SNRI PTSD with Prominent Sleep Disruption with (or without) Recalled Trauma Nightmares and Daytime Hypervigilance Start 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) Starting an SSRI/SNRI and prazosin simultaneously is reasonable. Add zolpidem (or other sedative) for persistent distressing sleep initiation insomnia. Add low dose quetiapine for persistent psychotic symptoms. *Effective prazosin dose highly, range from 2 mg to 40 mg/day Hamner Quetiapine Trial Mark Hamner, Jose Canive, Sophie Robert, Lawrence A. Calais, Gerardo Villarreal, Valerie Durkalski Krystal, et al Risperidone Add-On RCT in Vets 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, 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. Placebo controlled in 100 s of Vets Add-on in treatment-resistant Vets No significant decrease in CAPS or depression scales Lots of se s (mostly metabolic) in risperidone vs. placebo But small, significant decreases in hyperarousal and re-experiencing symptoms Extremely bad press right now re: this medication. SSRI s Sertraline Randomized, double-blind, blind, veterans, multicenter,, n=169 (Friedman et al., 2007) No significant differences in mean change of CAPS-2 2 total severity score, IES total score, or CGI severity or improvement scales No consistent effects of gender, illness duration, illness severity (Sertraline cont.) RCT in Israeli veterans, n=23 (Zohar( et al., 2002) No statistically significant difference between sertraline and placebo on CAPS-2 2 total severity and symptom cluster scores 2 RCT s in non-veterans, n=187 (Brady et al., 2000); n=208 (Davidson et al., 2001) Significant drug-placebo differences in CAPS- 2 total severity score, and CGI change and mean Significant changes in avoidance/numbing and hyperarousal,, but not re-experiencing experiencing

8 Fluoxetine Vast majority of RCT s with civilians Mixed study of veterans and civilians, n=31 veterans (van der Kolk et al., 1994) Fluoxetine superior to placebo in reducing CAPS total score, and avoidance and hyperarousal clusters, but not intrusion 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 Significantly greater improvement, fluoxetine vs. placebo, (younger veterans with recent war trauma), in CAPS total score and hyperarousal subscore (inter-rater reliability?) Paroxetine No RCT s specifically with veterans RCT s with civilians, mostly women (n=307, n=365), show efficacy measured by CAPS -22 total score, 3 symptom clusters, and CGI Citalopram- no RCT s Fluvoxamine- no RCT s Venlafaxine ER (Venlafaxine ER cont.) No RCT s in veterans 12 week, double-blind, blind, multicenter (n=538) v. sertraline and placebo (multiple traumas, <9% combat) Significantly greater improvement compared to placebo in CAPS-Sx17, Sx17, and avoidance/numbing and hyperarousal subscales, but not re-experiencing experiencing Relatively small effect size No significant differences between venlafaxine and sertraline 6 month, double-blind, blind, multicenter international (none U.S.), n=329, 12% combat Significantly greater improvement compared to placebo in CAPS-Sx17, Sx17, and avoidance/numbing and re-experiencing, experiencing, but not hyperarousal No measure of inter-rater rater reliability Small effect size (Venlafaxine ER cont.) Duloxetine 2 pooled analyses of the previous 2 studies Earliest onset of response (week 2): irritability/anger and physiological reactivity to cues Numbing and hyperarousal took longer to respond Inconsistent efficacy for distressing dreams and insomnia No significant effects of gender Treatment effects smaller in subjects with combat trauma 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) Significant improvement in CAPS total and all subscales 9 subjects (45%) classified as responders (defined as more than 20% improvement in total CAPS score) Most improvement by week 2 Significant improvement in sleep quality (PSQI) (no specific mention of change in nightmares)

9 (Duloxetine cont.) Mirtazapine 8 week open-label trial, veterans, n=21 (Walderhaug et al., 2010) Treatment refractory; co-morbid major depression; 80% Vietnam veterans Primary outcome measure PTSD checklist (PCL-C) significant drop from 64.1 (+/- 10.2) to 48.1 (+/- 11.9) Increase in pleasant dream activity; rapid and sustained improvement of nightmares Rapid onset of action 2 studies with veterans in Korea Open label, sertraline-controlled study No significant differences between mirtazapine and sertraline Both decreased CAPS-2 total score Open-label continuation study 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 Important comorbidity given returning troops and a dangerous world Developing treatments based on improving understanding of physiology Psychotherapy has more support for PTSD than does pharmacotherapy Prazosin