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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