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Emerging Pharmacotherapy Options for PTSD: We Need Backup!

Cole Larsen, PharmD, BCPS PGY2 Ambulatory Care/Behavioral Health Pharmacy Resident

South Texas Veterans Health Care System Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy

Pharmacotherapy Education and Research Center, University of Texas Health Science Center at San Antonio

January 29th, 2016

Learning Objectives 1. Describe the prevalence of Posttraumatic Stress Disorder (PTSD) and risk factors for

developing the disorder.2. List currently recommended pharmacotherapy per the Veterans Affairs/Department of

Defense (VA/DoD) and American Psychiatric Association (APA) guidelines in order ofpreference.

3. Describe the effectiveness of currently recommended therapies for PTSD.4. Discuss theoretical and clinical benefits of baclofen, methylphenidate, and topiramate in

patients with PTSD who fail to respond to currently recommended therapies.

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PTSD Background

I. Epidemiology1,2,3 a. Fifth most common psychiatric condition in the United States (U.S.)b. Lifetime prevalence estimated between 7-9% in the general population2,4

c. Compared with U.S. non-Latino whites, higher rates reported in U.S. Latinos, AfricanAmericans, and American Indians; lower rates reported in Asian Americans

d. Overall lifetime prevalence found to be doubled in women compared to men4

e. 18.7% lifetime risk in Vietnam War vets, and current risk of 9.1%f. 15-17% current risk in Iraqi and Afghanistan war veterans

Iraqi/Afghanistan war vets seek mental health services at higher ratesthan vets from previous wars5

II. Risk Factors for Development3

a. Severe trauma (high perceived threat, interpersonal in nature)b. Physical injury to self or other that can serve as a reminder of the trauma (i.e. TBI)c. Ongoing life stress or vocations that involve regular risk2

a. Lack of social support before and/or after the eventb. Female genderc. Young age at time of traumad. Pre-existing psychiatric disorders, substance misuse, or traumae. Low socioeconomic status, low education level, and lower level of intelligencea. Peri-traumatic dissociation and interpersonal traumaa. Bereavement or traumatic griefb. Negative social support (i.e. shaming or blaming environment, distressed spouse)

Marriage may confer some protective benefit4

c. Poor coping skills

III. Personal and Social Costs2

a. Employment difficultiesb. Inability to connect with othersc. Comorbid disorders: PTSD prevalence ranges 11-30% in medical settings due to

increased risk for other disease states1,6

i. Depression and anxiety Can worsen pre-existing chronic pain

ii. Increased risk of metabolic disorders such as diabetes7 and cardiovasculardisease8

iii. Patients frequently suffer from insomnia and/or nightmaresiv. Substance use disorders

1. PTSD increased peri-/post-deployment risk of alcohol use disorder(AUD) in military personnel by 22.6% (43.8% if comorbid majordepressive disorder [MDD])9

2. Withdrawal from alcohol can increase sympathetic stimulation andworsen PTSD symptoms

3. Increased risk nicotine and illicit substance abuse10

v. Sexual dysfunction11

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IV. Diagnosis and Clinical Features3 a. Acute stress reactions immediately following the exposure are common and

generally resolve within days to weeks i. Symptoms include depression, fatigue, anxiety, decreased

concentration/memory, irritability, agitation, and exaggerated startle response

ii. Diagnosis of acute stress disorder if PTSD criteria met within one month of traumatic event

b. Considered acute PTSD if symptoms persist 1-3 months c. Chronic PTSD if symptoms persist beyond 3 months

Diagnosis often difficult due to shared features with depression and traumatic brain injury (TBI)1

Figure 1: Stress Reaction Timeline

Table 1: DSM-5 Criteria for PTSD Diagnosis2

*Symptoms must be present for >1 month, cause significant distress in daily functioning, and not be attributable to another substance or medication

Direct, witnessed, or close contact with actual/threatened death, serious injury, or sexual violence + ≥1 sign of each of the following:

Intrusion Symptoms Recurrent, involuntary,

and intrusive distressing memories of the event(s)

Recurrent distressing dreams of the traumatic event(s)

Dissociative reactions (i.e. flashbacks)

Internal or external cues causing intense or prolonged psychological stress and/or physiologic reactions

Avoidance Avoidance or efforts

to avoid distressing thoughts, memories or feelings related to the traumatic event(s)

Avoidance or efforts to avoid external reminders that arouse distressing memories, thoughts or feelings associated with the traumatic event(s)

Negative alterations in mood and cognition

Inability to remember an important aspect of the traumatic event(s) (not due to head injury, alcohol, or drugs)

Persistent and exaggerated negative beliefs in general or related to the cause/consequences of the traumatic event(s) that lead to blame of self or others

Persistent negative emotional state and inability to experience positive emotion

Diminished interest Feelings of detachment or

estrangement from others

Hyperarousal Irritable with

angry outbursts despite minimal provocation

Reckless/self-destructive behavior

Hypervigilance Exaggerated

startle response Impaired

concentration Sleep disturbance

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V. Neurologic Pathology16

Figure 2: Brain structures involved in PTSD

a. Brain stem structures responsible for releasing neurotransmitters to various regions of the brain

i. Locus ceruleus – norepinephrine (NE) to amygdala, hippocampus, prefrontal cortex, and hypothalamus

ii. Dorsal and raphe nuclei – serotonin (5-HT) to amygdala and hippocampus, exerts inhibitory tone on locus ceruleus via 5-HT

b. Abnormal labs and drug responses in PTSD i. Adrenergic findings

1. ↑ NE in urine and central nervous system (CNS) spinal fluid 2. Yohimbine, an 𝛂𝛂-2 antagonist that potentiates sympathetic activity,

was found to induce panic attacks/flashbacks in PTSD patients 3. Propranolol blunts stress responses in normal patients

ii. Glutaminergic findings 1. Glutamate considered essential for memory formation but also

excitatory 2. Pre-treatment with N-methyl-D-aspartic acid (NMDA)-antagonists

blunted stress response (measured by corticotropin [ACTH] release) 3. Animal models suggest NMDA antagonism plays a role in fear

extinction as well, case series with memantine yielded positive results17

iii. Serotonergic findings 1. Paroxetine found to promote hippocampal neurogenesis 2. Citalopram associated with activation of medial prefrontal cortex

(PFC), leading to greater control over the amygdala 3. Escitalopram found to decrease activation of amygdala 4. Selective serotonin reuptake inhibitors (SSRI’s) attenuate

corticotropin releasing hormone (CRH) secretion and subsequent pituitary release of ACTH

iv. 𝛾𝛾-amino butyric acid (GABA) findings Lower plasma GABA levels associated with PTSD development18

v. Hypothalamic-Pituitary Axis (HPA) findings 1. ↓cortisol (COR) in urine, plasma, and saliva 2. PTSD patients had higher numbers of glucocorticoid receptors that

were more sensitive to cortisol as demonstrated by greater adrenocorticotropic hormone suppression from the pituitary compared to controls during a low-dose dexamethasone-suppression test19 (see Figure 3)

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Figure 3: Cortisol regulation

Treatment

I. Severity Scales (see appendix)

a. Clinician-Administered PTSD Scale (CAPS)20 i. Used for diagnosis

ii. 30-question assessment iii. Questions subdivided according to symptom clusters

1. CAPS-B (Re-experiencing) 2. CAPS-C (Avoidance/numbing) 3. CAPS-D (Hyperarousal)

iv. Scores range 0-136, with higher scores corresponding with more severe symptoms

v. Change in score ≥15 points considered clinically significant vi. CAPS-5 now available

1. Requires single index trauma rather than up to three events allowed under DSM-IV

2. Incorporates new symptoms from DSM-5 into scoring 3. Rated using a single severity score rather than separate frequency

and intensity b. PTSD Symptoms Checklist (PCL)21

i. Useful for tracking symptom progression ii. Shorter than CAPS, easier to administer on subsequent visits

iii. Under DSM-IV, score >50 usually suggestive of PTSD (range 17-85) 1. Available in military, civilian, and specific formats 2. Change in score ≥10 points considered clinically significant

iv. PCL-5 now available 1. Now available in one format (scores range 0-80) 2. Updated to reflect language used in DSM-5 3. Score >38 suggestive of PTSD

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II. Management of Chronic PTSD3

Figure 4: PTSD Treatment Algorithm

a. First-line recommendation to initiate psychotherapy and/or pharmacotherapy b. Psychotherapy

i. May be initiated alongside side or in absence of pharmacotherapy ii. Trauma-focused and stress management psychotherapy found to be most

beneficial 1. Exposure-based therapies, cognitive-based therapies, stress

inoculation training, and eye movement desensitization and reprocessing

2. Often required to correct underlying source of the trauma iii. Group therapies may also be beneficial iv. Often required to reduce frequency/severity of angry outbursts1 v. Proper sleep hygiene and/or Cognitive Behavioral Therapy (CBT) for

insomnia encouraged vi. Anger Management therapy or training in relaxation exercises beneficial for

patients experiencing irritability, agitation, or anger vii. Eye Movement Desensitization and Reprocessing (EMDR) useful for

decreasing fear response c. Pharmacotherapy1

i. SSRI’s and venlafaxine considered first line 1. Proven in RCT’s to improve the three core symptom clusters of re-

experiencing, hyperarousal, and avoidance22,23,24 2. Only paroxetine and sertraline FDA-labeled for PTSD but all SSRI’s

and venlafaxine considered equally efficacious ii. Other antidepressants

1. Tricyclic antidepressants (TCA’s) (amitriptyline and imipramine) and monoamine oxidase (MAOI’s) (phenelzine) – generally considered equally efficacious but use limited by side effects and low therapeutic index

2. Mirtazapine – weaker level of evidence a. Advantages: lack of sexual dysfunction and sedation b. Disadvantage: weight gain

Initial TX

•Psychotherapy•SSRI, SNRI

Step 1 •Switch SSRI or SNRI•Add psychoterapy

Step 2•Mirtazapine, nefazodone, TCA•Add psychotherapy

Step 3

•Switch to alternative in step 2•TCA or phenelzine•Add psychotherapy

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3. Nefazodone a. Useful in targeting hyperarousal symptoms, insomnia, and

anxiety b. Recommended with caution due to black box warning for

hepatotoxicity leading to liver failure iii. Prazosin is useful as adjunct therapy for combat-related nightmares iv. Benzodiazepines (BZDs)

No accepted role in the management of PTSD as monotherapy or adjunct therapy

a. Improve anxiety symptoms without addressing underlying issues

b. Delay more effective care and interfere with fear extinction during prolonged exposure therapy

c. Patients with pre-existing substance use disorder at higher risk for developing addiction to BZDs

v. Other pharmacotherapies have been trialed as adjunct and/or monotherapy with limited success (Tabel 2)

Table 2: Pharmacotherapy in PTSD3

Summary of Recommendations Significant Benefit (Grade A)

SSRI’s SNRI’s

Some Benefit (Grade B)

Mirtazapine Prazosin (for sleep/nightmares) TCA’s Nefazodone (caution for hepatotoxicity risk) MAOI’s (caution for DDI’s and Drug-Food Interactions)

No Benefit (Grade D)

BZDs (Harm) Tigabine Guanfacine Valproate Topiramate Risperidone

Unknown Benefit (Grade I)

Antipsychotics Buspirone Non-BZD hypnotics Bupropion Trazodone (adjunct) Gabapentin Lamotrigine Propranolol Clonidine

VI. Effectiveness of Current therapy

a. Over 40% of patients fail to respond to initial pharmacotherapy (defined as “much” or “very much” improved) according to a Cochrane meta-analysis12

APA 2009 guideline update concluded antidepressants may not be as effective for combat-related trauma as originally thought13

b. Half of patients retain their PTSD diagnosis following psychotherapy14 c. JAMA meta-analysis found psychotherapy for combat-related PTSD improved

symptoms in majority of patients, but 60-72% failed to go into remission15 Based on ITT analysis, dropout rates ranged 13-39%

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III. Emerging therapies a. Baclofen

i. Proposed to counteract PTSD symptoms via stimulation of GABAB ii. Given as monotherapy in open-label study for 14 combat vets over 8 weeks25

1. Significant improvements in CAPS total, avoidance, and hyperarousal 2. No change in re-experiencing symptoms

b. Methylphenidate i. Studied in TBI and recognized as an effective therapy26,27

ii. Stimulant use during time of traumatic event found to increase risk for PTSD by 500% in large, retrospective study28

iii. Methylphenidate shown to be beneficial in animal models and proposed to alleviate PTSD symptoms by allowing patients to concentrate on the present moment29

c. Topiramate i. Currently not recommended in guidelines due to lack of proven benefit

ii. Past trials have found mixed results30 iii. GABAA agonist and glutamate antagonist iv. Majority of benefit seen for re-experiencing symptoms

d. Cannabinoids and 3,4-methylenedioxy-methamphetamine (MDMA) currently an active area of investigation

Literature Review

Manteghi et al. Baclofen Add-on to Citalopram in Treatment of Posttraumatic Stress Disorder. J Clin Psychopharm. 2014;34(2):240-243.31

Objectives To evaluate the effectiveness of baclofen when added to citalopram for the treatment of PTSD

Design 8 week, double-blind randomized, placebo-controlled trial Population 40 Iranian combat veterans (Iran-Iraq War) with PTSD, enrolled as inpatients

Inclusion Exclusion Age 25-65 PTSD diagnosis established by 2

independent psychiatrists per DSM-IV criteria

Altered mental status Unstable medical conditions History of seizure Active psychosis History of suicide/homicide attempt Substance abuse/dependence Use of long-acting psychotropic

medications in the last 2 weeks Allergy to baclofen Lack of interest in follow-up

Interventions Randomized to baclofen or placebo 2-week washout period Citalopram ± baclofen for 8 weeks

o Citalopram initiated at 10 mg/day and able to be titrated up to 60 mg/day o Baclofen initiated at 10 mg/day and able to be titrated up to 40 mg/day over 3

divided doses Trazodone or hydroxyzine allowed for treatment of insomnia BZDs or injectable antipsychotics allowed for acute agitation/anxiety

Endpoints Change in the following rating scales at weeks 0, 2, 4, 6, and 8 CAPS total (CAPS-T), re-experience (CAPS-B), avoidance (CAPS-C), and hyperarousal

(CAPS-D) GAF HAM-A HAM-D

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Statistics Independent t-test to compare between groups Paired t-test to compare within groups at different time points

Results Baseline characteristics Placebo (n=10) Baclofen (n=13) p-value

Age, mean (SD) 46.61 (9.31) 42.50 (3.40) 0.06 % married 100% 100% -

% unemployed 61.53% 70% - MMSE, mean (SD) 26.89 (1.21) 27 (0.92) 0.234

Reasons for not completing the study

Reason for Dropout # Patients Lost to follow-up as outpatient 4

Change in SSRI medication as outpatient 2 Use of illicit drugs after discharge from inpatient 2

Nursing mistake in administration of medications 3 Rebound symptoms due to discontinuation of the initial

medication 3

Gastrointestinal bleeding 1 Change in diagnosis 2

Change in rating scales:

Rating scale Group Baseline Week 8 p-value (between groups)

CAPS-T (Total)

Baclofen 61 (16.1) 38.0 (11.7) 0.040 Placebo 61.8 (14.38) 46.2 (7.9)

CAPS-B (Re-experiencing)

Baclofen 19.8 (5.7) 10.9 (3.2) 0.740 Placebo 18.5 (5.0) 10.5 (3.13)

CAPS-C (Avoidance)

Baclofen 20.1 (7.1) 13.8 (5.6) 0.02 Placebo 21.0 (7.5) 18.5 (4.5)

CAPS-D (Arousal)

Baclofen 21.1 (5.3) 13.3 (4.3) 0.020 Placebo 22.4 (4.0) 16.9 (1.9)

GAF Baclofen 53.1 (12.1) 64.5 (12.5) 0.001 Placebo 50.8 (8.7) 54.4 (7.4)

HAM-A Baclofen 26.7 (6.3) 17.2 (4.8) <0.001 Placebo 27.6 (5.7) 22.1 (3.3)

HAM-D Baclofen 24.4 (6.0) 16.2 (4.1) <0.001 Placebo 24.3 (4.9) 20.0 (2.5)

*No significant differences between groups in any of the rating scales at baseline Author’s Conclusions

Baclofen was well-tolerated and can enhance treatment response of PTSD symptoms, comorbid anxiety and depression, and global level of functioning when added to the SSRI citalopram

Patients initially inpatient, which improved adherence compared to real world scenarios Limited by number of subjects, short duration of follow-up, high dropout rate, and did

not base analysis off of intention-to-treat (ITT) population Critique Advantages

Randomized, blinded, and placebo-controlled

Disadvantages Baclofen initiated simultaneously with

SSRI Previous therapies not disclosed Did not define reason for dropout by

groups Take Home Baclofen may hold promise as adjunct therapy to SSRI’s, limitations and study design make

interpretation difficult

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McAllister et al. Randomized Placebo-Controlled Trial of Methylphenidate or Galantamine for Persistent Emotional and Cognitive Symptoms Associated with PTSD and/or Traumatic Brain Injury. Neuropsychopharmacology. 2015.29

Objectives To compare the effectiveness of methylphenidate compared to galantamine for improving cognitive and emotional symptoms associated with PTSD and/or TBI

Design 12 week, multi-site, randomized, double-blind, placebo-controlled trial conducted through the Injury and Traumatic Stress (INTRuST) collaborative network established by the US DoD

Population 32 civilian and military patients with PTSD and/or TBI Inclusion Exclusion Age 18-55 years Diagnosis of PTSD and/or history of

mild TBI (mTBI or complicated mTBI as established by clinical interview)

Clinically significant cognitive complaints (T-score ≥60 on the Postmorbid Cognitive Scale of the Ruff Neurobehavioral Inventory [RNBI])

Hypersensitivity adverse reaction to galantamine, methylphenidate, or other acetylcholinesterase inhibitor or stimulant

Current or recent use of MAOIs or other cholinergic medications (other psychotropic meds allowed if on stable dose for ≥4 weeks)

Women who were pregnant, planning to become pregnant, or lactating

History of glaucoma, cardiac conditions, seizure conditions, or neurosurgery

Non-English speaking persons with score <70 on the Wide Range Achievement Test-Reading subtest (WRAT-3 Reading)

Lifetime history of: psychotic disorder, BP disorder type 1, stimulant abuse or dependence, tic disorder, alcohol use disorder, substance use disorder in past 6 months, current active suicidal ideation, and severe depressive symptoms (PHQ score >20)

Interventions Participants randomized to receive methylphenidate (MPH), galantamine (GAL), or placebo over 12 weeks Assessments conducted at weeks 4, 8, and 12 weeks. Brief, face-to-face visits occurred weekly to monitor tolerability MPH titrated from 5 mg BID to 20 mg BID during weeks 0-8, tapered off over 2 weeks GAL titrated from 4 mg BID to 12 mg BID during weeks 0-8, tapered off over 2 weeks

Endpoints Primary outcome measure Mean 12-week change in cognitive symptoms as measured by the Postmorbid Cognitive

Scale of the Ruff Neurobehavioral Inventory (RNBI) Secondary outcome measures PTSD symptoms (PCL-S) Depressive symptoms (PHQ-9) Change in cognitive performance (Rey Verbal Learning Test [RVLT] [, Digit Symbol,

Trails A, etc) Post-concussive (PCS) symptoms (Rivermead Post Concussive Symptoms Questionnaire

[RPCSQ]) Statistics Demographic and baseline characteristics

Categorical variables analyzed via Fisher-Freeman-Halton Test Continuous variables analyzed using analysis of variance test or Kruskal-Wallis test, as

appropriate Primary and secondary outcomes MMRM using a modified intent-to-treat population (participants administered ≥1 dose

of study medication with baseline score and ≥1 follow up assessment) Independent variables included treatment, visit, treatment-by-visit interaction Covariates included education, gender, age at baseline, and diagnosis A p-value of 0.05 considered statistically significant for all tests performed

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Results Enrollment

*All participants included in modified ITT Baseline characteristics Middle-aged, average 41.2 years 56% male 72% white 15 of the 32 participants (47%) were civilians without military backgrounds and were

equally distributed across groups 22% mixed mTBI/PTSD, 44% mTBI only, 34% PTSD only No significant differences between groups Most participants excluded due to comorbid medical conditions and not having severe

enough cognitive complaints/deficits

Primary outcome MPH-treated patients exhibited significant improvements in RNBI score at all 3 time

points compared to placebo (p=0.004; 0.03; 0.036 at weeks 4, 8, and 12, respectively; effect size=0.337 [95% CI=−0.642 to 1.304] at week 12)

GAL did not improve RNBI score compared with placebo Secondary outcomes PTSD symptoms (PCL-S)

o MPH associated with significant improvement at weeks 4, 8, and 12 (p=0.003; 0.014; 0.007 respectively; effect size=0.881 [95% CI=−0.148 to 1.883 at week 12])

Depressive symptoms (PHQ-9) o MPH associated with significant improvement in PHQ-9 at weeks 4, 8, and 12

(p=0.01; 0.01; 0.001, respectively; effect size=0.497 [95% CI=−0.493 to 1.471] at week 12).

o GAL was associated with improvement in depressive symptoms at 12 weeks (p=0.01; effect size=0.157 [95% CI=−0.893 to 1.228])

Cognitive measures o MPH improvement on measure of attention (Digit Symbol, p=0.011). o GAL improvement on episodic memory (long-delay recall of the RVLT, p=0.011)

PCS (PRQ13) o MPH associated with significant RPQ13 score reduction at weeks 4, 8, and 12

(p=0.047; 0.01; 0.01, respectively; effect size=0.886 [95% CI=−0.329 to 2.061] at week 12)

Safety and tolerability

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Yeh et al. Double-blind randomized controlled trial to study efficacy of topiramate in a civilian sample of PTSD. CNS Neuroscience Therapy. 2011; 17:305–310.32

Objectives To assess the efficacy and tolerability of topiramate in civilian-related PTSD Design 12-week, randomized, double-blind, placebo-controlled trial in 31 Brazilian outpatients with

civilian PTSD Methods Inclusion Exclusion

Aged 18-62 years Diagnosed with PTSD per DSM-IV criteria

Lifetime history of bipolar, psychosis, or borderline personality disorder

Substance dependence/abuse (excluding nicotine or caffeine) in the last 6 months

Serious or unstable concurrent illness History of nephrolithiasis Use of psychotropic medication in the

previous 2 weeks (6 weeks for fluoxetine) BMI <20 kg/m2 Current suicidal ideation

Participants recruited from the violence program at the Federal University of Sâo Paulo (PROVE)

Survey sent to random sample of 3000 individuals in Sâo Paulo to assess relationship between exposure to violence of prevalence of PTSD o Cases of potential PTSD were referred to the PROVE program

CAPS, Beck Depression Inventory (BDI), and CGI performed at baseline and 12 weeks Patients were given placebo for 1 week and excluded if found to have a significant

improvement in symptoms defined as “minimally improved” (CGI-I score <3) Topiramate initiated at 25 mg/d and titrated to effect or to max dose of 200 mg/d Symptoms and side effects assessed at weeks 1, 2, 3, 4, 6, 8, and 12 Participants showing a 1-point decrease in CGI-I or serious adverse effect were withdrawn Zolpidem was the only concomitant psychotropic medication allowed

62.5% of participants experienced an adverse effect with no difference between groups No serious adverse effects recorded

Author’s Conclusions

MPH, but not GAL, resulted in a significant reduction relative to placebo in cognitive complaints based on the primary outcome measure, the RNBI Postmorbid Cognitive Scale

Improvements in PCL-S scores were much larger than expected and PHQ-9 improvements were unexpected

Both medications were well tolerated with similar rates of adverse effects compared to placebo and did not worsen PTSD hyperarousal symptoms & sleep difficulties as feared o Treatment discontinuation due to adverse events occurred in the placebo group but

not in the treatment groups Limitations

o Small study size, noted that enrollment difficulties may limit generalizability to the larger population

Critique Advantages Randomized and placebo-controlled Increased generalizability by

allowing other psychotropic medications

Disadvantages Psychotropic medication usage

rates not reported Did not separate results by PTSD vs

mTBI Inclusion of patients with mTBI

confounds benefit in PTSD Take Home Methylphenidate appears safe in patients with PTSD and may improve cognitive function

as well as PTSD symptoms Replication is needed in patients without TBI

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Endpoints Primary Outcome Change in CAPS total score from baseline to final visit Secondary Outcomes Change from baseline in PTSD symptoms clusters (CAPS-B, CAPS-C, and CAPS-D) Change from baseline BDI

Statistics ITT analysis for participants with baseline and ≥1 post-baseline CAPS assessment Change in CAPS and BDI scores calculated using nonparametric test for repeated ordinal

measure similar to ANOVA Response defined as ≥30% improvement on CAPS and CAPS subtest scores Remission defined as CAPS total score <20 Chi-square test used to determine between-group differences in response and remission

rates All tests were 2-sided with a significance level of 0.05

Results Enrollment 31 out of 36 enrolled participants completed the study and included in the ITT analysis

o 1 excluded during placebo washout period o Placebo arm:

4 did not return to first visit and were excluded from analysis 2 did not complete the study (1 for worsening symptoms, 1 dropped out)

o Topiramate arm: 3 participants did not complete the study (2 for worsening of symptoms, 1 for

adverse event) o 26 participants completed the entire study and were included in the efficacy analysis

Baseline Characteristics

Topiramate (n=17) Placebo (n=14) Age (mean SD) 43.7 (13.44) 36.5 (7.97) Male, n (%) 5 (29.41) 5 (35.71) PTSD duration, months (SD) 48.52 (66.21) 37.92 (45.62)

*No significant clinical or baseline differences between groups at baseline Results of ITT analysis

Efficacy analysis (participants who completed full 12 week treatment) N=14 for topiramate, n=12 for placebo Compared to placebo, topiramate group showed significant reduction in CAPS total

score (-57.78 vs -32.41; p=0.007), CAPS-B (-19.5 vs -13.16; p=0.04) CAPS-C (-23.5 vs -7; p=0.0001)

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Safety Mean topiramate dose was 102.04 mg/day (range 50-200 mg/day) Adverse events in the topiramate group included somnolence (23%), insomnia (23%),

paresthesia (17%), headache (11%), irritability (11%), dyspepsia (17%), and difficulty with concentration (11%)

Adverse events reported in the placebo group included somnolence (35%), headache (21%), and insomnia (7%)

Author’s Conclusions

Topiramate may be effective in the treatment of PTSD and was well tolerated Improved findings in efficacy analysis may have been influenced by the fact that 2

topiramate and 1 placebo-treated participant had already failed other medications and were considered “treatment-resistant”

Limitations include small sample size, possible confounding by comorbid depression, unclear compliance (pill counts were performed), and possible confounding by comorbid depression

Critique Advantages Placebo washout period may have

eliminated individuals predisposed to a potent placebo effect

Excluded alcohol abuse

Disadvantages Patients with negative outcomes

withdrawn Reasons for dropout suggest blind may

have been difficult to maintain Mean topiramate dose not compared

between groups Take Home Points

Topiramate may improve numbing/avoidance symptoms in civilian PTSD in the absence of AUD

Batki et al. Topiramate treatment of alcohol use disorder in veterans with posttraumatic stress disorder: a randomized controlled pilot trial. Alcohol Clin Exp Res. 2014;38(8):2169-2177.33

Objective To determine whether topiramate is effective in improving PTSD symptoms and reducing alcohol consumption in patients with co-occurring PTSD and AUD

Design 12-week randomized, double-blind, placebo-controlled trial in 30 veterans of Vietnam, Gulf, Iraq, and Afghanistan wars with combat and/or civilian-related trauma exposure

Methods Inclusion Exclusion Meet DSM-IV criteria for alcohol

dependence and PTSD Report “at-risk” or “heavy” drinking per

NIH/NIAAA criteria (≥15 drinks/week averaged over 4 weeks for men ≥8 drinks/week for women)

Express desire to reduce alcohol consumption with possible long-term goal of abstinence

Psychotic disorders Bipolar disorder Dementia Clinically significant unstable

medical/psychiatric conditions History of suicide attempt or ideation in

the past 6 months Acute alcohol withdrawal Narrow angle glaucoma Seizure disorder Concurrent anticonvulsant use or

topiramate use within the past 4 weeks Randomization in 1:1 fashion to topiramate or placebo Topiramate dosed from 25-300 mg/day, with weekly titrations to maximum tolerated

dose Participants free to access any other standard psychological or pharmacologic

treatments for PTSD with the exception of AUD pharmacotherapy All patients received weekly counseling to promote medication adherence and reduction

in alcohol use Endpoints Primary Outcome

% Drinking days (DD) within topiramate group at baseline compared with average over weeks 1-12

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Secondary Outcome Psychiatric outcomes

o PTSD Checklist (PCL) o Obsessive Compulsive Drinking Scale (OCDS) measured thoughts and compulsions

associated with alcohol cravings at baseline and weeks 4, 8, and 12 Alcohol consumption/cravings

o % DD between topiramate and placebo group at baseline compared with average over weeks 1-12 Time Line Follow Back (TLFB) interview conducted at baseline and then weekly

to assess number of alcohol drinking days (DD), heavy drinking days (HDD) and drinks per each day of drinking

Safety Hopkins Verbal Learning Test-Revised (HVLT-R) to assess whether cognition impacted

by topiramate at baseline and weeks 6 and 12 Statistics T-Test for continuous variables

Fisher’s exact for categorical variables Powered to detect within-group changes in number of drinking days

o Within-topiramate group analysis applied a random-intercept repeated subject negative binomial model, modeling week (baseline - week 12) as a continuous variable

Powered to detect a between-group “signal” with a statistical trend (p<0.10) o Model with fixed effect for week, treatment group (topiramate and placebo), and the

interaction between treatment group and week to analyze % drinking days/week, % heavy drinking days, drinks/week, and average per drinking day

Random-intercept linear mixed models to analyze reduction in PTSD symptomatology, craving, and effects on measure of learning and memory

Analyses were ITT and p<0.05 considered statistically significant Results Population

Topiramate (n=14) Placebo (n=16) Male, n (%) 13 (92.9) 15 (93.8) Age, years 49.5 ± 13.9 50.4 ± 12.8

Education, years 12.9 ± 3.1 14.4 ± 1.9 Caucasian (Hispanic/Latino) 8 (2) 8

African American 2 5 Other 4 3

Combat exposed, n (%) 10 (71.4) 12 (75) Comorbid Substance Use Disorder, n (%) 5 (35.7) 5 (31.3)

PTSD Pharmacotherapy TX, n (%) • Antidepressants (%)

• Sedatives (%)

5 (35.7) 4 (28.6)

0 (0)

9 (56.3) 7 (43.8) 3 (0.2)

CAPS 72.8 ± 14.3 83.1 ± 17.3 CAPS-B 18.2±4.3 21.9±6.9 CAPS-C 31.1±6.1 34.8±8.9 CAPS-D 23.5±6.7 26.4±4.1

*No significant differences between groups at baseline 4 topiramate and 2 placebo-treated participants attended a 30-day community based

residential rehabilitation treatment program 27 of the 30 participants completed the trial (13/14 topiramate, 14/16 placebo)

o Topiramate-treated participants attended more study visits (94.2% vs 83.1%; p=0.002)

Average dose achieved in treatment group was 286 ± 20 mg/day vs 281 ± 45 mg/day (p=0.248)

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% DD o Primary analysis: DD significantly decreased within topiramate group (73.3 ± 30.3 at

baseline vs 19.5 ± 34.2 mean weeks 1-12; P=0.019) o Secondary analysis: no significant treatment-by-week interaction (p=0.063)

Significant main effect (p=0.036) with topiramate-treated participants had 51% fewer DD’s than placebo averaged over weeks1-12

Between-group results

Topiramate (mean ± SD)

Placebo (mean ± SD)

p-value %Diff.

% DD 19.5 ± 34.2 39.7 ± 36.5 0.036 51% % HDD 11.1 ± 27.1 16.8 ± 26.3 0.342 34%

Std. drinks per week

8.7 ± 19.0 19.3 ± 30.5 0.099 55%

Drinks per DD 1.9 ± 3.3 4.8 ± 6.5 0.057 60% PCL Total 42.3 ± 16.0 49.0 ± 16.5 0.100 14%

PCL-B (Re-experiencing)

12.3 ± 5.4 14.3 ± 5.5 0.155 14%

PCL-C (Avoidance) 17.6 ± 7.2 19.9 ± 6.9 0.272 12% PCL-D (Arousal) 12.4 ± 4.9 14.9 ± 5.0 0.071 17%

OCDS Total 5.53 ± 6.55 11.08 ± 8.12 0.025 50%

Author’s Conclusions

Reductions in alcohol use generally agree with previous studies in patients without PTSD First study of topiramate in PTSD to note a trend toward improved arousal symptoms

(other positive studies showed reductions in re-experiencing and avoidance) o Hypothesize that topiramate may target PTSD symptom clusters differently in

patients with comorbid AUD Topiramate was well-tolerated and reductions in verbal/auditory learning and memory

that occurred mid-study recovered by week 12 Limitations included small sample size and reliance on self-report for alcohol

consumption Critique Advantages

Randomized, blinded, placebo-controlled design

Psychotropic medication use allowed and reported by group

Similar doses achieved in each group suggests effective blinding

Disadvantages Pilot study, PTSD findings not properly

powered Primary outcome measured change within

treatment group rather than against placebo

Baseline PCL not reported More psychotropic medication use in

placebo group Take Home First study to evaluate topiramate in patients with comorbid PTSD and AUD

Results suggest benefit

Recommendations

I. Baclofen (Grade I) a. May hold promise as adjunct therapy in combat-related PTSD when combined with

an SSRI b. Larger, better designed trials needed to determine if appropriate for routine adjunct

therapy c. Potential therapeutic applications include:

i. Comorbid AUD who have failed topiramate therapy ii. Patients requiring treatment for muscle spasticity

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II. Methylphenidate (Grade I) a. Safe in mTBI with comorbid PTSD with unexpected benefit in PTSD symptoms,

needs replication in patients with PTSD and without TBI b. Consider as adjunct therapy in patients with significant cognitive complaints despite

optimized therapy with 2nd or 3rd trial of first-line agents

III. Topiramate (Grade B) a. Appears to improve PTSD symptoms in some patients, especially re-experiencing

symptoms i. Consider as adjunct or monotherapy in treatment-resistant patients

ii. Recommend as adjunct therapy in treatment-resistant patients with comorbid

1. AUD 2. Migraines

Summary

I. Pharmacotherapy options have demonstrated limited efficacy in PTSD

a. Trials are frequently small with many design limitations b. Enrollment often difficult due to reluctance of patients to seek treatment c. Following trials with SSRI’s and/or venlafaxine, pharmacotherapy options in

treatment-resistant patients should be selected based on patient-specific factors

II. Psychotherapy should be encouraged at each visit a. Difficult for patients to confront their trauma so patients often reluctant to

participate b. More directly addresses the trauma

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Appendix A: Additional Brain Structure Abnormalities in PTSD

Biologic function Abnormal findings Neurotransmitters involved

Amygdala Responsible for emotional regulation, memory consolidation, and stress response

Interconnected with hippocampus and prefrontral cortex

Increased activity of locus ceruleus (5-HT) and decreased dorsal & raphe nuclei (NE) activity lead to augmented function

Decreased 5-HT transporter expression in the amygdala34

NE augments fear response 5-HT attenuates fear

response GC augments fear response

Hippocampus Role in formation and retrieval of episodic and declarative memories

Reduced hippocampal volume and ↑GC sensitivity, suggested as a risk factor for developing PTSD

NE suppresses ability to blunt fear response from amygdala

5-HT enhances ability to blunt fear response from amygdala

GC possibly damaging to the hippocampus, works in conjunction with NE to consolidate traumatic memories

Glu possibly damaging to hippocampus

Prefrontal cortex (PFC)

Perform decision-making, problem-solving, and judgment tasks such as mediating stress signals from the amygdala

Dendritic atrophy following exposure to chronic stress

NE/GC lessen ability of higher brain function to suppress fear responses

Hypothalamic-pituitary Axis

Regulates body’s stress response

Receives input from amygdala, regulates motor and autonomic responses to emotionally arousing stimuli

↑number of lymphocyte GC receptors and ↑pituitary GC receptor sensitivity

GC modulates NE/5-HT regulation to augment stress response

Glu augments stress response

*NE=Norepinephrine, 5-HT=Serotonin, DA=Dopamine, Glu=Glutamate, GC=Glucocorticoid

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Appendix B:

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Appendix C:

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Appendix D: Andrus M et al. Treatment of Civilian and Combat-Related Posttraumatic Stress Disorder with Topiramate. Annals of Pharmacotherapy. 2010;44(11):1810-1816.

Study Design Monotherapy or Adjunct

Duration (weeks)

Dose Range (mg/ day)

Outcome Measures

Results

Civilian studies Berlant et al (2002)

Open label (n=35)

Monotherapy or adjunct

3 (range 1-119)

12.5-500

Change in PCL-C score

from baseline to 4

weeks

Significant reduction in PCL-C score

(baseline 60 ± 10, 4 wk 39 ± 11; p <

0.001) Berlant et al (2002)

Open label (n=33)

Monotherapy or adjunct

12 12.5-200

Change in PCL-C score

from baseline to 4

weeks

Significant reduction in PCL- C score

(baseline 62.6, 4 wk 40.3, no SD provided; p < 0.001); n = 30 for

those completing both assessments

Tucker et al (2007)

Double-blind,

placebo controlled

(n=38)

Monotherapy 12 25-400 Change in CAPS score

from baseline to 12 weeks

No significant difference in change in

total CAPS score; re-experiencing

improved (74.9% vs 50.2% decrease;

p=0.038)

Combat Studies Akuchekian et al (2004)

Double-blind,

placebo- controlled

(n=67)

Adjunct 12 12.5-500

11-item severity score of

CAPS from baseline to 12 weeks

Significant difference in CAPS score

(placebo baseline 50.7 ± 7.7, 12 wk 46.62 ±

8.82; topiramate baseline 48.9 ± 9.13,

12 wk 32.75 ± 8.2; p = 0.00)

Lindley et al (2007)

Double-blind,

placebo- controlled

(n=40)

Adjunct 7 50-200 CAPS score at baseline, week 4 and

week 7

No significant difference in CAPS

score Significant reduction

in CAPS re-experiencing subscore

(p<0.05) Alderman et al (2009)

Open-label (n=43)

Adjunct 8 50-200 Changes in CAPS score

and M-PTSD score from

baseline to 8 weeks

Significant reduction in CAPS score

(baseline 86.3 ± 21.1; 8 week 76.1 ± 25.1; p < 0.01); no significant reduction in M-PTSD

score