Atypical Antipsychotic Monotherapy: A Game Changer for Post-

Traumatic Stress Disorder?

Julienne Pauly, PharmD

PGY2 Psychiatric Pharmacy Resident

South Texas Veterans Health Care System, San Antonio, TX
Division of Pharmacotherapy, the University of Texas at Austin College of Pharmacy
Pharmacotherapy Education and Research Center
The University of Texas Health Science Center at San Antonio

March 3, 2017

Learning Objectives
1. Discuss the clinical presentation, pathophysiology, and consequences of post-traumatic stress
disorder (PTSD)
2. Analyze treatment guideline recommendations for PTSD and recognize limitations in current therapy
3. Describe the evidence for safety and efficacy of atypical antipsychotics as monotherapy in PTSD
 Post-Traumatic Stress Disorder (PTSD) Overview

I. Introduction
A. Clinically significant condition with complex cognitive, somatic, affective, and behavioral symptoms
1-3
continuing more than one month after a traumatic experience
1-3
B. Examples of traumatic or stressful events that can lead to development of PTSD:
i. Sexual violence rape, childhood sexual abuse, partner violence
ii. Interpersonal network traumatic event of loved one
iii. Interpersonal violence childhood physical abuse, physical assault
iv. Exposure to organized violence kidnapped, civilian war zone, refugee
v. Participation in organized violence combat exposure, witnessing death/injury
vi. Other natural disaster, car accident, toxic chemical exposure

II. Epidemiology
1,4-7
A. Prevalence of PTSD in the United States (US)
i. Projected lifetime risk is 8.7%
ii. Twelve-month prevalence is 3.5%
iii. Men 3.6% vs. women 9.7%
iv. Service members deployed to Afghanistan or Iraq: 13.8%
v. Veterans who served in Vietnam: 18.7% lifetime war-related
1
B. Highest rates among:
i. Veterans
ii. Policemen, firefighters, emergency medical personnel
iii. Survivors of rape

III. Prognostic Outcomes

1
A. Impairment in social, occupational, or other important areas of functioning
1
B. People with PTSD are 80% more likely to have comorbid mental health diagnosis
1,4
C. Substance abuse is 2-4 times more prevalent in patients with PTSD
1
D. Increased likelihood of suicide attempts

IV. Risk Factors

Table 1: Risk Factors for Developing PTSD
Pre-traumatic
Female gender
Younger age
Emotional problems in youth
Mental health disorders
Lower socioeconomic class
Lower education
Exposure to prior trauma
Childhood adversity
Cultural characteristics
Lower intelligence
Minority status
Family psychiatric history
1-2
Peri-traumatic Post-traumatic
Severity of trauma Negative appraisals
Perceived life threat or Negative coping strategies
personal injury Development of acute
Perceived threat to another stress disorder
Killing the enemy Exposure to repeated
Dissociation that occurs upsetting reminders
during the trauma and Adverse life events
persists after the trauma Financial or trauma-related
losses

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V. Diagnosis
th 1
A. Diagnostic and Statistical Manual of Mental Disorders, 5 edition (DSM-V)
i. Criteria A: Exposure to actual or threatened death, serious injury, or sexual violence in 1 of the
following ways: directly experiencing the event, witnessing the event, traumatic event occurring to
family member/friend (violent or accidental), or experiencing repeated/extreme exposure to aversive
events
ii. Criteria B: 1 intrusive symptoms associated with the event (s)
iii. Criteria C: 1 avoidance of stimuli associated with the event(s)
iv. Criteria D: 2 negative alterations in cognitions/mood associated with the event(s)
v. Criteria E: 2 alterations in arousal and activity
vi. Criteria F: Duration of presentation is > 1 month
vii. Criteria G: Causes clinically significant distress/impairment in ability to function
viii. Criteria H: Not attributed to effects of substance or another medication
ix. Specifiers: with dissociative symptoms or delayed expression

VI. Presentation
1,2
Table 2: Symptom Clusters Following Trauma Exposure
Intrusive Distressing memories/dreams, flashbacks, psychological and physiological distress
(re-experiencing) towards with triggers
Avoidant Avoidance of distressing memories, thoughts, feelings, external reminders
Negative cognition / Blackouts, negative views of self/world, distorted cognition of the distressing event,
mood (numbing) negative emotional state, anhedonia, feelings of detachment from others, inability to
experience positive emotions, persistent negative beliefs/expectations about self,
others, and the world
Hyperarousal Irritable, easily angered, reckless, self-destructive, exaggerated startle response,
difficulty concentrating, sleep disturbance

VII. Time Frame

2
A. Acute: >1 month but < 3 months after trauma exposure
2
B. Chronic: Symptoms last 3 months after trauma exposure
2
C. Delayed onset: 6-month presentation after trauma exposure

VIII. Rating Scales

8
Table 3: Common Rating Scales Used for PTSD
Name Description Results / Interpretation
Clinician 30 items Likert scoring: 0 (absent) 4
Administered Clinician administered (extreme/incapacitating)
PTSD Scale Used for diagnosis, assessment Total score range 0-150
revised of symptoms, treatment response Remission: 70% of symptoms sustained
(CAPS-5) Takes 45-60 minutes over 3 months
Reviews symptom clusters Adequate response: in 50% of
symptoms
Partial response: in 25-50% of symptoms
Non-response: <25% of symptoms
PTSD 20 items Likert scoring: 0 (not at all) 4 (extremely)
Checklist for Patient-reported Total symptom severity score: 0-80
DSM-5 Used for screening, diagnosis, Response to treatment: by 5 points
(PCL-5) treatment response Clinically significant change: by 10
Takes 5-10 minutes points
Reviews symptoms / past month
Treatment 8 items Scoring: 0 (not at all) 4 (extremely severe)
Outcome Self-rated Total score range 0-32
PTSD Scale Simplified version of CAPS-2 Higher score = higher severity of illness
(TOP-8) Reviews symptom clusters Threshold for PTSD=score of 8-12
Takes 5-10 minutes Response: in 40% of symptoms

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 9
PTSD Pathophysiology

I. Norepinephrine (NE) Role

A. Under normal conditions, the sympathetic nervous system (SNS) releases NE in response to stress,
producing the physiologic fight or flight response
B. PTSD patients have NE
i. NE in the amygdala, hippocampus, and prefrontal cortex (PFC) = intensification of fear conditioning,
formation of memories, hyperarousal, nightmares

II. Serotonin (5HT) Role

A. Unclear, however PTSD symptoms relieved by pro-serotonergic agents
B. Selective serotonin reuptake inhibitors (SSRIs) may promote hippocampal neurogenesis and modulate
PFC inhibition of the amygdala

III. Hypothalamic-Pituitary-Adrenal (HPA) Axis

A. Regulates physiological response to stress
B. Dysfunction = stress response
C. cortisol, which could be due to adrenal exhaustion and negative feedback in the setting of chronic stress

IV. Glutamate Role

A. Primary excitatory CNS neurotransmitter
B. Modulates corticotropin-releasing factor (CRF) in response to stress and thought to play a role in memory

V. Other potential causes of PTSD

A. Disruptions in diurnal sleep cycle, thyroid function, dysregulation of the opioid system, suppressed
immunologic function, kindling/behavioral desensitization in limbic nuclei

Treatment of PTSD

I. Guideline Recommendations
2,10-11
Table 4: PTSD Treatment Algorithms
Guideline Initial Second-line Third-line Fourth-line
Veterans Affairs (VA) / Psychotherapy Alternative + psychotherapy, Switch to
Department of Defense or SSRI/SNRI SSRI/SNRI switch to mirtazapine, TCA,
2
(DoD), 2010 psychotherapy mirtazapine, nefazodone or
augment with phenelzine; +
prazosin psychotherapy
American Psychiatric Psychotherapy TCAs, Risperidone, Tiagabine,
Association (APA), or SSRI/SNRI nefazodone, olanzapine divalproex,
10
2004 mirtazapine carbamazepine,
lamotrigine
National Institute for Psychotherapy; Different class of
Health and Clinical mirtazapine or antidepressant or
Excellence (NICE), paroxetine for adjunctive
11
2009 patients who olanzapine
refuse trauma-
focused
therapy
Key: SNRI: serotonin norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitors; TCA: tricyclic
antidepressants

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 2
A. Psychotherapy
Table 5: Evidenced-Based Psychotherapies for PTSD
Exposure-Based Emphasize oral or written exposure along with cognitive restructuring,
Therapies relaxation techniques, and self-monitoring of anxiety
Cognitive-Based Challenge acquired beliefs connected to the traumatic event, also include
Therapies relaxation techniques and discussion of traumatic event
Stress Inoculation Emphasizes breathing retraining, muscle relaxation, cognitive elements
Training and exposure techniques
Eye Movement Emphasizes exposure and cognitive components, relaxation techniques,
Desensitization and and alternating eye movements
Reprocessing
2
B. Pharmacotherapy
Table 6: VA/DoD Pharmacotherapy Interventions for the Treatment of PTSD (appendix I)
Much Some benefit Unknown benefit No benefit
benefit
SSRIs Mirtazapine Atypical Buspirone BZDs
SNRIs Prazosin antipsychotics NBRA Tiagabine
TCAs monotherapy Bupropion Guanfacine
Nefazodone Atypical Trazodone Valproate
MAOIs antipsychotics (adjunct) Topiramate
(phenelzine) adjunctively Gabapentin Risperidone
(recommend Lamotrigine
against Propranolol
risperidone Clonidine
adjunct) Prazosin
Conventional (global PTSD)
antipsychotics
Key: BZDs: benzodiazepines; MAOI: monoamine oxidase inhibitor; NBRA: non-benzodiazepine receptor
agonists

2
C. Treatment Response for PTSD Symptom Clusters
Table 7: Symptom Response by Drug Class and Individual Drug
Global Intrusive Avoidance / Hyperarousal
Improvement (Re-experiencing) Numbing
SSRI Fluoxetine X X X X
Sertraline X X X X
Paroxetine X X X X
SNRI Venlafaxine X X X X
TCAs Amitriptyline X X X
/ Imipramine
MAOIs Phenelzine X X X
Sympatholytic Prazosin X X X
Other Mirtazapine X X X
Nefazodone X X X

II. Limitations of Current Standards of Care

12
A. 60-72% of patients do not go into remission after psychotherapy
12
B. Drop-out rates for psychotherapy range from 13-39%
13-16
C. SSRI response rates between 53-62% (vs. 32-38% placebo), and ~30% of patients reach remission
17
D. SSRIs might not be as effective in combat-related PTSD as they are in civilian-related PTSD
18
E. Venlafaxine ER response rate 78% and ~40% achieve remission
2
F. Non-SSRI/SNRI therapies do not cover avoidance/numbing symptom clusters

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 Atypical Antipsychotics

I. Atypical Antipsychotics
19
Table 8: Atypical Antipsychotics
Aripiprazole Asenapine Brexpiprazole Cariprazine
Clozapine Iloperidone Lurasidone Olanzapine
Paliperidone Risperidone Quetiapine Ziprasidone
19
A. All Food and Drug Administration (FDA) approved for schizophrenia, amongst other indications

B. Agents studied in PTSD include aripiprazole, olanzapine, risperidone, and quetiapine

19,20
C. Mechanism of Action
i. Dopamine-2 (D2) receptor antagonism
ii. Serotonin-2A (5-HT2A) receptor antagonism
iii. Varying receptor binding affinities lead to different clinical action across agents (appendices II and III)
19-22
D. Safety
i. Black box warning: mortality in elderly with dementia-related psychosis
ii. Black box warning for Aripiprazole/quetiapine: suicidality in patients taking antidepressants
iii. Table 9: Side Effect Incidence of Atypical Antipsychotics
QTc Sedation Extra- Anticholinergic Orthostasis Weight Prolactin
pyramidal Gain
Symptoms
(EPS)
Aripiprazole - + + + + + -
Olanzapine + ++ ++ ++/+++ ++ ++++ +
Quetiapine ++/+++ ++/+++ - ++ ++/+++ ++/+++ +
Risperidone ++ + +++ + ++ +++ ++/+++
Key: - = negligible; + = low; ++ = moderate; +++ = moderately high; ++++ = high
iv. Other: sexual dysfunction, neuroleptic malignant syndrome, decreased seizure threshold,
hematologic abnormalities, increased liver function tests
v. Side effects vary per individual agent based on receptor binding (appendices II and III)
19
E. Monitoring
Table 10: Required Monitoring for Atypical Antipsychotics
Vital signs Hematology Blood chemistries
Pregnancy Metabolic Parameters (appendix IV) Electrocardiogram
EPS Hyperprolactinemia Eye exams

Atypical Antipsychotic Use in PTSD

I. General
23
A. 40% of off-label atypical antipsychotic prescriptions within the VA are for PTSD
23
B. 19.4% of patients with PTSD prescribed an atypical antipsychotic
C. Broad receptor effects (appendix II and III) allow for improvements in PTSD symptoms and are
24-25
theoretically positive for comorbid mental health illness and possibly substance abuse

II. Psychotic Features

26
A. Psychotic symptoms occur in ~40% of severe PTSD cases
B. Chronic combat-related PTSD with comorbid depression has been associated with auditory or visual
27
hallucinations related to combat phenomenon
C. Meta-analysis of open-label trials in treatment-resistant PTSD patients with psychotic features showed
28
atypical antipsychotic monotherapy allowed for at least a partial response in symptoms
D. D2 antagonism and 5-HT2A antagonism allow for antipsychotic action

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III. Nightmares / Sleep
A. Prospective cohort study comparing quetiapine to prazosin found that short-term both agents had similar
29
efficacy but long term prazosin was superior and had less side effects
30
B. Adjunctively used atypical antipsychotics have shown improvements in PTSD-related sleep disturbance
C. Theoretical impact on nightmares due to action on 1 antagonism and on sleep due to H1 antagonism

IV. Irritability, severe agitation, or anger

A. VA/DoD Guidelines recommend low-dose risperidone/quetiapine when evidence-based interventions fail
2
due to theoretical anti-adrenergic properties
B. Theoretical impact due to D2, 5-HT2A, 5-HT2C, 1, and H1 antagonism

V. Core PTSD Symptom Clusters

31-38
A. Adjunctive use to standards of care has conflicting data (appendix V)
39-41
B. Monotherapy use has conflicting data
Table 11: Trials of Atypical Antipsychotics as Monotherapy for PTSD
Study Design Population Intervention Primary Outcome
Aripiprazole
Mello et 16 week N=32, men Flexible A 30% improvement in mean CAPS scores
39
al. 2008 open-label and women dose from baseline (82.7 23.1) to endpoint
trial with civilian aripiprazole (51.431.4) was achieved, p = 0.001
trauma up to 15mg
(from daily
Brazil)
Youssef et 12 week N=10, men Flexible in CAPS total score
40
al. 2012 open-label and women dose Baseline: 78.08 (24.60 SD)
trial Veterans aripiprazole Endpoint: 58.25 (27.33 SD)
with PTSD 5-30mg p < 0.01
daily
Olanzapine
Butterfield 10 week N=15, Olanzapine baseline in SIP and Baseline SPRINT
et al. randomized majority up to 20mg SPRINT scores Olanzapine: 31.5 5.7
41 Placebo: 34.8 2.1
2001 control trial females, daily vs.
(RCT) civilian and placebo Baseline SIP Week 10 SPRINT
Olanzapine: 39.7 9.7 Olanzapine: 17.9 7.8
combat Placebo: 20.5 11.1
PTSD Placebo: 45.9 8.2
Week 10 SIP
Olanzapine: 19.2 8.7 P>0.05
Placebo: 17.0 17.5
Key: SIP=structured interview for PTSD; SPRINT=short PTSD rating interview
C. Response in studies mainly in the re-experiencing/intrusive and hyperarousal symptom clusters

Clinical Question

Is atypical antipsychotic monotherapy safe and efficacious in the treatment of PTSD?

Literature Review

Padala PR, Madison J, Monnahan et al. Risperidone monotherapy for post-traumatic stress disorder
42
related to sexual assault and domestic abuse in women. Int Clin Psychopharmacol. 2006; 21(5):275-80
Purpose To determine the efficacy of risperidone monotherapy in females with chronic PTSD
secondary to domestic violence or sexual assault
Design 12-week, randomized, double-blind, placebo-controlled trial from October 2001 until August
2004 conducted in the United States
Population Inclusion Criteria Exclusion Criteria
Females Lifetime history of bipolar I disorder or schizophrenia
19-65 years Unstable medically
Symptoms of Abnormal laboratory values
PTSD Significant suicidality
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 determined by Prior risperidone treatment
Mini International Enrollment in recent research
Neuropsychiatric Pregnant / breastfeeding
Interview (MINI) Substance abuse/dependence diagnosis within previous 2
(appendix VI) months
Outcome Primary: TOPS-8 score
Methods Intervention
- Subjects randomized (randomization methods not stated) to flexible-dose risperidone
or placebo for 10-week acute phase (visits 2-12)
- Risperidone initial dose of 0.5mg BID up to target of 4-6mg/day
- Optional diphenhydramine 25-50mg daily for EPS
- Weekly meetings with psychiatrist or research assistant
Procedures
- Baseline and at each study visit: TOP-8 score preformed
- Baseline, weeks 7, 11, 13: CAPS, Clinical Global Impressions Severity (CGI-S),
Hamilton Rating Scale for Anxiety (HAM-A), Hamilton Rating Scale for Depression
(HAM-D), Positive and Negative Syndrome Scale (PANSS), Abnormal Involuntary
Movement Scale (AIMS) (appendix VI)
- Baseline, weeks 7, 11, 13: physical examination, laboratory parameters, vitals
- Patients tapered off of medications at week 12
- Concomitant psychiatric medications not allowed
- Psychotherapy allowed if initiated prior to study start
Statistical Outcome measures: group x visit repeated measures ANOVA
Analysis - Post-hoc Newman-Keuls test
Results Patient Demographics / Baseline Characteristics
- n=20 randomized, n=11 risperidone, n=9 placebo
Acute phase completers: n=9 risperidone, n=6 placebo
- Table 12: Baseline Characteristics Between Groups
Risperidone Group Placebo Group
Age (years) 39.2 43.8
Race Caucasian 55% Caucasian 89%
African American 36% African American 11%
Mixed 9%
Mean TOP-8 Score 20.1 20
Mean CAPS Score 79.3 80.6
No p-values provided

- Domestic abuse, sexual assault, and rape most common trauma

15
Number

10

0
Rape Sexual Domestic Physical Childhood Violent death
molestation abuse assault physical of a loved
abuse one
Types of Abuse

Figure 1: Types of Trauma Experienced by Study Participants

- Mean risperidone dose was 2.62mg

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 Primary Outcome

Figure 2: TOP-8 Change in Visits 1-11

p=0.0999

CAPS

Figure 3: CAPS Change in Visits 1, 7, 11

p=0.33

Safety
- No major safety concerns noted per authors, no data reported
- n=1 withdrew due to rash in the risperidone group
Authors Risperidone monotherapy is a safe and effective treatment option for management of PTSD in
Conclusion women who experienced domestic violence and/or sexual assault
Critique Pros Cons
Inclusion of Limited sample size
comorbid Unclear randomization methods
depression and Participant recruitment / compensation
anxiety disorders Diagnosis using MINI
Population studied Close follow-up not indicative of clinical practice
Appropriate scale Unknown reasons for discontinuation
utilized for primary Safety data / use of diphenhydramine not available
outcome No reported data for CGI-S, HAM-D, PANSS, AIMS
Raw data not provided for outcome measures
Critiquers Risperidone monotherapy appears to allow for short-term treatment response according
Conclusion to TOP-8 and partial response according to CAPS, however PTSD symptoms persisted
Authors should have provided safety data, reasons for treatment discontinuation, and
reasons risperidone did not reach target doses; no conclusions on safety

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Carey P, Suliman S, Ganesan K et al. Olanzapine monotherapy in posttraumatic stress disorder:
efficacy in a randomized, double-blind, placebo-controlled study. Hum. Psychopharmacol Clin Exp.
43
2012;27:386-91
Purpose Evaluate the efficacy of olanzapine monotherapy in non-combat related PTSD
Design 8-week, randomized, placebo-controlled, double-blind, parallel group study taking place in
South Africa
Population Inclusion Criteria Exclusion Criteria
Adults 18 years Major depressive disorder
Chronic non-combat PTSD Baseline Montgomery Asberg Rating Scale (MADRS)
meeting DSM-IV criteria score 20
Minimum CAPS of 50 Presence of suicide risk
Provide informed consent Substance use disorder within 6 months of
Free of disallowed randomization
psychotropic medications Positive urine drug screen
History of personality disorder
Lifetime history of schizophrenia or psychotic disorder
Pregnant / breastfeeding, or of child-bearing age without
contraception
Unstable medical condition
Intolerance/treatment failure on past atypical
antipsychotic
Treatment failure with 2 adequate trials of SSRI/SNRI
Initiation/change of psychotherapy within 8 weeks of
screening
Electroconvulsive therapy within 3 months of screening
Participation in clinical trial in the 6 months before
screening
Improvement in 2 points on the CGI-S from screening
to randomization
Outcome Primary: Mean change from baseline in CAPS at week 8
Secondary: CAPS symptom cluster subscales, Davidson Trauma Scale (DTS), Sheehan
Disability Scale (SDS) (appendix VI)
Methods Intervention
- Randomization via computer-generated 10 number
- n=14 assigned to olanzapine and n=14 to placebo
- Olanzapine group: 5mg x 1 week, then 7.5mg x 1 week, then 10mg x 2 weeks
- If CGI-S 3 at week 4 and olanzapine tolerated, groups uptitrated to 15mg
- Single 2.5mg dose reductions allowed
Procedures
- Diagnosis confirmed using MINI
- Baseline, week 4, week 8: CAPS, DTS, SDS
- CGI assessed at every visit
- Patients assessed weekly for the first 4 weeks, then every 2 weeks
- 1 week of single-blind placebo run-in to exclude placebo responders
Statistical Repeated measures ANOVA
Analysis Intention-to-treat (ITT) with last observation carried forward (LOCF)
Two-tailed tests with p values < 0.05 considered significant
Cohens d to calculate effect size
Adverse effects: chi-squared tests
Results Patient Demographics / Baseline Characteristics
- n=34 randomized, n=28 with data, n=24 completers
- Dropouts: loss to follow-up, poor compliance, lack of efficacy, withdrawn consent
- n=17 were female, mean age of all participants 40.75 11.59 years
- Mean (SD) CAPS total: olanzapine 79.4 (16) and placebo 81.6 (11.3)
- Other measurements overall similar between groups, however baseline DTS higher in
the placebo groups (appendix VII)

Pauly | 10
 Primary Outcome
- Table 13: Mean Scores by Treatment Group
Scale Baseline Week 4 Week 8 Effect
(Mean, SD) (Mean, SD) (Mean, SD) size, r
O P O P O P
CAPS 79.4 81.6 49.1 73.21 33.6 62.3 0.43
(16) (11.3) (27.2) (20.5) (8.2) (31.9)
p-value 0.686 0.014 0.018
Key: O =olanzapine, P=placebo
Secondary Outcomes:
- Olanzapine had statistically significant reductions over placebo for the CAPS
avoidance symptom cluster (weeks 4 and 8, r=0.51), DTS (weeks 4 and 8, r=0.5), and
SDS (week 8, r=0.57) (appendix VII)
Other Outcomes (appendix VII)
- Olanzapine had statistically significant reductions over placebo for CGI-S (r=0.4)
- Olanzapine had a greater proportion of CAPS responders (10/14) compared to
placebo (3/14), (r=0.43)
- Olanzapine had greater numbers of individuals either improved or very much
improved (11/14 olanzapine, 4/14 placebo) on CGI-improvement (CGI-I), (p=0.027)
Safety
- 100% of patients in the olanzapine group had weight gain (n=8, 0-5kg, n=6, 5-10kg),
compared to 33% (n=5, 0-5kg) in the placebo group, p=0.001
- Sedation was the second most common side effect for olanzapine
- One withdrawal in the olanzapine group due to excessive sedation
- Adverse effects in the olanzapine group included headache, increased appetite,
tremor, insomnia, muscle ache, diarrhea, dizziness, dry mouth, amongst others
Authors Olanzapine monotherapy is efficacious over placebo in non-combat related chronic PTSD
Conclusion
Critique Pros Cons
Use of CAPS score / DSM diagnosis Short-term
to determine eligibility Small sample size
Efforts to eliminate confounders Extensive exclusion criteria
Randomization efforts defined Diagnosis confirmation using MINI
Disallowed medications not defined
Doses reached not provided
Critiquers Olanzapine may have utility as monotherapy in PTSD treatment
Conclusion Extensive eligibility criteria may not allow for application of results to patients with PTSD
with comorbid mental health illness
Adverse effects limit olanzapines use

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Villarreal G, Hamner MB, Canive JM et al. Efficacy of quetiapine monotherapy in posttraumatic stress
44
disorder: A randomized, placebo-controlled trial. Am J Psychiatry. 2016; 173(12):1205-12
Purpose Determine efficacy of quetiapine as monotherapy in military-related PTSD
Design 12-week, randomized, placebo-controlled, double-blind trial taking place between 2004-2008
in the United States
Population Inclusion Exclusion
18-65 years old Females not on contraceptives or of childbearing age
Met DSM-IV criteria for Hypersensitivity to quetiapine
PTSD as established Use of psychotropic medications/herbals within one week of
by the CAPS- randomization and throughout study duration
Diagnostic Version Certain medical disorders (not diabetes) that may preclude
(CAPS-DX) use of quetiapine or exacerbate anxiety symptoms
Minimum CAPS of 50 Substance abuse/dependence within 1 month of study
Schizophrenia, schizoaffective and bipolar disorders
Dementia
Suicidal or homicidal ideation
Current pursuit of compensation for trauma
Psychotherapy initiation/change within 3 months
Outcome Primary: Total CAPS Score
Secondary: CAPS subscale symptom clusters, DTS, PANSS, CGI-S/CGI-I, HAM-D, HAM-
A, Pittsburg Sleep Quality Index (PSQI) (appendix VI)
Methods 1 week placebo lead-in, after which non-responders were assigned to intervention
Randomization 1:1 to quetiapine or placebo x 12 weeks
- Quetiapine: 25mg initially, titrated to 400mg/day by the end of week 2
- Increases/decreases in dose allowed (range allowed was 50mg 800mg)
- Rescue medications allowed during placebo lead-in and in the first 2 weeks
- Evaluated at weeks 1,2,4,8,12
Outcome measures evaluated at weeks 2,4,8,12
AIMS, Simpson-Angus Scale (SAS), Barnes Akathisia Scale (BAS), Arizona Sexual
Experiences Scale (ASEX) (appendix VI): baseline, week 12
PANSS: baseline, week 12
Lab tests at baseline; vital signs and adverse effects at each visit
Statistical Primary: ANOVA; ITT with LOCF
Analysis Secondary and safety: Mixed-model ANOVA
Two-sided with significance of 0.05
Results Patient Demographics / Baseline Characteristics
- n=80 randomized, n=42 to quetiapine, n=38 to placebo
- Doses range: 50-800mg, quetiapine mean 258mg/day and placebo mean 463mg/day
- Baseline CAPS scores, CAP re-experiencing scores, and DTS scores were higher in
the quetiapine group, all other outcome measures similar (appendix VIII), (not all p-
values provided)
- Baseline safety measures overall similar in both groups

Table 14: Baseline measures between groups

Variable Quetiapine Placebo p-value
Mean SD Mean SD
Age (years) 52 12 54 10 0.36
Education years 14.2 2.4 13.1 2.3 0.04
Weight (lb) 224.5 50.3 196.3 39.2
N % N %
Male 38 90 37 97 0.20
Dropouts 13 31 20 52 0.07
Caucasian 21 50 21 55 0.68
African American 12 29 9 24
American Indian 9 21 8 21

- Six patients required rescue medications but did not discontinue study
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 Primary Outcome
Table 15: CAPS Total Score Change at Study Endpoint
Measure Group Baseline Score at week P-value
Score (mean) 12 (mean)
CAPS Quetiapine 75.40 53.85 0.02
total Placebo 70.60 65.66
Secondary Outcome (appendix VIII)
- Quetiapine had higher reductions in scores from baseline over placebo with the
following: CAPS re-experiencing, CAPS hyperarousal, Davidson Trauma Scale, HAM-
D (p < 0.05)
- Other outcome measures: quetiapine had modestly higher reductions in scoring from
baseline over placebo (p < 0.05), except for CAPS avoidance/numbing, PANSS
negative symptoms
- Quetiapine had reductions in PSQI scores at week 4, but not thereafter
Safety
- Common ADRs in the quetiapine group included dry mouth (15.8%), somnolence
(13.4%), and sedation (7.4%)
- Dropout in quetiapine group due to adverse effects (n=9), dropout in placebo group
due to inefficacy (n=9) and adverse effects (n=3)
- Safety outcomes similar between treatment groups, p > 0.05
Authors Quetiapine is safe and effective monotherapy for the treatment of PTSD and associated
Conclusion anxiety and depressive symptoms
Critique Pros Cons
Use of CAPS score / No data on adverse drug reactions / drug discontinuation
DSM criteria to No data on lab tests
determine eligibility Not all p-values for baseline characteristics provided
Measurement of Safety measures favorable for quetiapine outcomes
PANSS Unclear which group required rescue medications
Gold standard scale
Critiquers Quetiapine monotherapy allowed for treatment response, however patients continued to
Conclusion be symptomatic after week 12 of treatment
Extensive eligibility criteria may not allow for application of results to patients with PTSD
who have comorbid mental health illness
Unable to draw conclusions from this study regarding adverse effects

Conclusions

I. Summary of Literature Review

A. Atypical antipsychotic monotherapy allowed for treatment response across studies
B. PTSD symptoms persisted at 12 weeks for two of the three studies (civilian and combat-related PTSD)
C. The agents studied did not cover all PTSD symptom clusters and offered modest global improvement
Table 16: Atypical Antipsychotic Effect on PTSD Symptom Clusters
Global Re-experiencing Avoidance Hyperarousal
Improvement / Intrusive / Numbing
Risperidone (civilian PTSD) ? ? ? ?
Olanzapine (civilian PTSD) X - X -
Quetiapine (combat-related PTSD) X X - X
D. Data not applicable to patients with psychotic features or comorbid mental health illness/substance abuse
E. Unclear safety of risperidone and quetiapine, olanzapine had more weight gain and sedation than placebo

II. Recommendations
A. May consider atypical antipsychotic monotherapy in individuals with civilian and combat-related PTSD who
have inadequate response to standards of care, however risks versus benefits should be weighed

Pauly | 13
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 Appendices
2,19
Appendix I: Evidenced-Based Pharmacotherapy for the Treatment of PTSD
Medication Mechanism of Action Side Effects
Class / Agents
SSRIs 5HT reuptake transporter inhibition Somnolence, insomnia, diaphoresis, sexual
Fluoxetine dysfunction, gastrointestinal upset, nervousness,
Paroxetine* agitation, anxiety, hyponatremia/syndrome of
Sertraline* inappropriate anti-diuretic hormone (SIADH),
serotonin syndrome
SNRIs 5HT and NE reuptake inhibition As above for SSRIs and hypertension at high
Venlafaxine doses
2 antagonist 5HT2, 5HT3, histamine, and 2 Increased appetite, weight gain, somnolence, dry
Mirtazapine antagonism mouth
TCAs 5HT, NE reuptake inhibition; , Dry mouth, dry eyes, constipation, orthostatic
Amitriptyline histamine, and muscarinic hypotension, increased heart rate, ventricular
Imipramine antagonism arrhythmias, weight gain, drowsiness
SARI 5HT and NE reuptake inhibition; 5HT2 As above for SSRI and hepatotoxicity
Nefazodone receptor antagonist
MAOIs NE, DA, 5HT through inhibition of Hypertensive crisis, bradycardia, orthostatic
Phenelzine monoamine oxidase hypotension, insomnia, dry eyes, constipation
Sympatholytics 1 antagonism; disrupts REM sleep, First dose syncope
Prazosin NREM sleep, cortisol stress
response
*Food and Drug Administration Approved
Key: BZDs: benzodiazepines; MAOI: monoamine oxidase inhibitor; NBRA: non-benzodiazepine receptor agonists; SNRI:
serotonin norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitors; TCA: tricyclic antidepressants

45-48
Appendix II: Receptor Binding Affinities of Individual Antipsychotic Agents
Drug D2 D3 5- 5-HT2A 5- 5- 1 2 M1 M3 H1
HT1A HT2C HT7
Aripiprazole +++* +++ +++* ++ ++ +++ ++ ++ ++
Olanzapine ++ ++ +++ ++ + ++ + ++ ++ +++
Risperidone +++ +++ + ++++ ++ +++ +++ ++ ++
Quetiapine + + + ++ + ++ +++ ++ ++ ++ +++
Key: + weak binding affinity (100>Ki<1000), ++moderate binding affinity (10>Ki<100), +++strong binding
affinity (1>Ki<10), ++++very strong binding affinity (Ki<1); *partial agonism

45-48
Appendix III: Receptor Binding Action of Atypical Antipsychotics
D2 antagonism Antipsychotic - improvements in positive symptoms of schizophrenia (delusions,
hallucinations, disorganized speech, disorganized behavior, paranoia), antimanic,
anti-aggression, EPS, tardive dyskinesia, hyperprolactinemia
D3 antagonism positive/negative symptoms, precognitive, antidepressant
5-HT1A partial Antidepressant, anxiolytic, anti-EPS
agonism
5-HT2A antagonism Antipsychotic improvements in negative symptoms of schizophrenia (amotivation,
alogia, avolition, anhedonia, blunted affect), cognitive symptoms (poor concentration,
memory impairment), anti-EPS, hyperprolactinemia, dysphoria, depression
5-HT2C antagonism Antidepressant, weight gain
5-HT7 antagonism circadian rhythm dysfunction, negative symptoms, procognitive
1 antagonism Orthostatic hypotension, dizziness, syncope
2 antagonism Antidepressant, alertness, blood pressure
M1, M3 antagonism Anti-EPS, dry mouth, blurred vision, constipation, tachycardia
H1 antagonism Sedation, weight gain, anti-EPS, anxiolytic

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 49
Appendix IV: Metabolic Monitoring for Atypical Antipsychotics
Baseline 4 weeks 8 weeks 12 Quarterly Annually Q5
weeks year
Personal and family X X
history
Weight (BMI) X X X X X
Waist Circumference X X
Blood Pressure X X X
Fasting Plasma Glucose X X X
Fasting Lipid Panel X X X
31-38
Appendix V: Select Trials of Atypical Antipsychotics as Augmentation Therapy for PTSD Core Symptoms
Study Design Population Intervention Primary Outcome
Risperidone
Bartzokis 16 week DB N=65, male Risperidone baseline CAPS total
et al. RCT Veterans with 3mg daily vs. Risperidone: -14.3
31
2004 chronic PTSD placebo Placebo: -4.6
P<0.001
Rothbaum 16 week N=25, civilian Phase 2, baseline CAPS total from phase 2 to
et al. RCT, 2 PTSD without risperidone study end
32
2008 phases, remission on 0.5-3mg daily Risperidone: -23.1
phase 2 was sertraline entered vs. placebo Placebo: -23.5
DB phase 2 risperidone P=0.8
augmentation
Krystal et 6 month DB N=267, treatment Risperidone baseline CAPS total
33
al. 2011 RCT resistant combat up to 4mg Risperidone: -16.3
related PTSD daily vs. (95% CI, -19.7 to -12.9)
placebo Placebo: -12.5
(95% CI, -15.7 to -9.4)
P=0.11
Olanzapine
Stein et al. 12 week DB N=19 male Olanzapine baseline CAPS total
34
2002 RCT Veterans with 10mg daily Olanzapine: -14.80
combat-PTSD who vs. placebo Placebo: -2.67
did not respond to P<0.05
SSRI therapy
Quetiapine
Hamner et 6 week N=20 patients, Quetiapine baseline CAPS total
35
al. 2003 open-label, mainly combat- 25-300mg Baseline: 89.8 15.7
no control related PTSD daily Week 6: 67.5 21/0
P<0.0005
Ahearn et 8 week N=15, combat and Quetiapine: baseline CAPS total
36
al. 2008 open-label, civilian PTSD 100-400mg Baseline: 80 (SD 21)
no control daily Week 8: 46 (SD 31)
P0.0010

Aripiprazole
Lambert Case series N=5, majority male Sertraline 4/5 cases had symptom improvements
37
2005 in Veterans with CBT with
combat-related flexible dose
PTSD aripiprazole
up to 30mg
daily
Richardson 12 week N=27, majority Flexible dose Beck Depression Inventory and PCL-M
et al. retrospective male with combat- aripiprazole BDI: 9.77
38
2011 chart review, related PTSD up to 30mg PCL-M: 9.26
open-label daily P<0.0001

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 50
Appendix VI: Additional PTSD/Psychiatric Rating Scales Used in Studies
Name Description Results / Interpretation
Abnormal Clinician-administered; 12 item Scoring: 0 (none) 4 (severe)
Involuntary Qualifies involuntary movements Items 11/12 are yes/no
Movement Scale Measurements include facial/oral Score range: 0-40
(AIMS) movements, extremity Higher scores = more involuntary
movements, trunk movements, movement
global judgement and dental
status
Arizona Sexual Self-rated; 5 item Score range: 5-30
Experiences Quantifies sex drive, arousal, Higher scores = sexual dysfunction
Scale (ASEX) ability to orgasm, erection
Barnes Clinician-administered; 4 item Objective akathisia: score 0-3
Akathisia Scale Determines akathisia presence Subjective awareness: score 0-3
(BAS) Distress of patient: score 0-3
Global: score 0-5
2 indicates akathisia
Clinical Global Clinician or patient administered CGI-S: 1 (normal) 7 (amongst the
Impressions Rated relative to the past week most extremely ill)
Scale (CGI) CGI-Severity: how mentally ill is CGI-I: 1 (very much improved since
the patient at this time? initiation of medication) 7 (very much
CGI-Improvement: measures worse since initiation of medication)
response after medication
initiated
Davidson Self-reported; 19 item Frequency of symptoms scoring: 0 (not
Trauma Scale Assesses DSM-IV PTSD at all) 4 (every day)
(DTS) symptoms Severity of symptoms scoring: 0 (not
distressing) 4 (extremely distressing)
Total score range from 0-168
Hamilton Rating Clinician-administered; 14 items Scoring: 0 (not present) 4 (Severe)
Scale for Assesses severity of anxiety Total range 0-56
Anxiety (HAM-A) symptoms 0-17: Mild
18-24: Mild - Moderate
25-30 Moderate - Severe
Hamilton Clinician-administered; 17 item Scoring: 0 (absent) 4 (very severe)
Depression Used to assess response to 0-7: Normal
Scale (HAM-D, treatment 8-13: Mild depression
HDRS) Reviews patient-reported 14-18: Moderate depression
symptoms over the past week 19-22: Severe depression
23: Very severe depression
Mini- Clinician-administered Yes or no responses to symptom criteria
International Assesses 16 mental health Scoring varies per module measured
Neuropsychiatric disease states (modules)
Interview (MINI) Assesses symptoms based on
DSM-IV criteria

Montgomery- Clinician-administered; 10 item Scoring: 0 (absent) 6 (severe)

Asberg Assesses response to depression 0-6: No symptoms
Depression treatment 7-19: Mild depression
Rating Scale Also used for measuring severity 20-34: Moderate depression
(MADRS) of bipolar depression 35-60: Severe depression
Pittsburgh Sleep Clinician-administered; 19 item Scoring: 0 (no occurrence) 3 ( 3 times
Quality Index Used to assess sleep quality per week)
(PSQI) 5: good sleep quality
5: poor sleep quality

Pauly | 18
Positive and Clinician-administered; 30 item
Negative Assesses psychosis symptoms
Syndrome Scale and response
(PANSS) Subscales: positive, negative,
general psychopathology
Sheehan Clinician-administered; 10 item
Disability Scale Assess functional impairment in
(SDS) work/school, social, family life
Simpson Angus Clinician-administered; 10 item
Scale (SAS) Used to screen Parkinsons
disease and other EPS
Assess gait, arm drooping,
shoulder shaking, elbow rigidity,
wrist rigidity or fixation of position,
leg pendulousness, head
dropping, glabella tap, tremor
Scoring: 1 (not present) 7 (extremely
severe)
Score range: 30-210 (usual scores 60-150)
Response: 20-30% in sx
Remission: Score 3 for 6 months on
each selected item
Scoring: 0 (not at all) 10 (extremely)
Score of 0 = not impaired
Score of 30 = highly impaired
Scoring: 0 (absent) 4 (most extreme
form) Global score: sum of score/total items
< 0.3: normal range

43
Appendix VII: Carey et al. Outcome Measures
Measure Olanzapine Placebo p-value Effect size, r
(mean, SD) (mean, SD)
CAPS total score Baseline 79.4 (16) 81.6 (11.3) 0.686 0.43
Week 4 49.1 (27.2) 73.21 (20.5) 0.014
Week 8 33.6 (28.2) 62.3 (31.9) 0.018
% CAPS score 57.7% 23.7%
CAPS re-experiencing Baseline 21.4 (6.9) 21.6 (5.1) 0.926 0.36
symptom cluster Week 4 12.9 (8) 17.86 (10.7) 0.173
Week 8 9.5 (8.7) 16.9 (10.3) 0.052
CAPS avoidance Baseline 32.7 (7.1) 35.8 (5.3) 0.208 0.51
symptom cluster Week 4 18.9 (12.1) 30.71 (8.1) 0.005
Week 8 11.5 (12.3) 26.6 (13) 0.004
CAPS hyperarousal Baseline 25.3 (5.5) 24.1 (5.2) 0.553 0.31
symptom cluster Week 4 17.4 (8.6) 23.9 (5.4) 0.022
Week 8 12.6 (9.1) 18.9 (9.9) 0.092
DTS Baseline 75 (16.3) 88.1 (22.5) 0.088 0.5
Week 4 54.8 (27.7) 86.2 (22.3) 0.003
Week 8 37.9 (32) 75.8 (34.5) 0.006
% DTS score 51% 16%
CGI severity Baseline 4.7 (0.8) 5 (0.8) 0.356 0.4
Week 8 2.9 (1.4) 4.1 (1.3) 0.027
CGI responders 11 (78.5%) 4 (28.5%)
MADRS Baseline 15.9 (4) 15.3 (2.9) 0.631 0.29
Week 8 10.3 (6.8) 15.3 (9.8) 0.137
SDS Baseline 18.3 (7.1) 24.1 (4.2) 0.032 0.57
Week 8 10.6 (6.9) 20.6 (7.4) 0.004

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 44
Appendix VIII: Villareal et al. Outcome Measures
Measure (total Quetiapine Placebo (n=38) p-value Effect size,
score) (n=42) (mean, SD) cohens d
(mean, SD)
CAPS total Baseline 75.40 (16) 70.60 (11.7) 0.45
Endpoint 53.85 (26.4) 65.66 (20.8) 0.02 0.49
CAPS re-experiencing Baseline 20.66 (6.8) 17.18 (6.1) 0.02
symptom cluster Endpoint 11.71 (8.2) 16.06 (7.9) 0.0004 0.54
CAPS Baseline 30.02 (7.4) 29.55 (7.5)
avoidance/numbing Endpoint 25.54 (12.2) 28.30 (10.5) 0.13 0.24
symptom cluster
CAPS hyperarousal Baseline 24.71 (5.3) 23.86 (4.7)
symptom cluster Endpoint 16.60 (9.7) 21.30 (6.8) 0.007 0.56
DTS Baseline 91.38 (22.6) 84.47 (22.5)
Endpoint 63.82 (35.3) 73.73 (29.6) 0.03 0.30
HAM-D Baseline 20.40 (5.2) 19.76 (6.4)
Endpoint 13.40 (7.1) 18.00 (7.3) 0.02 0.64
HAM-A Baseline 19.97 (6.3) 18.78 (5.7)
Endpoint 13.57 (7.6) 16.60 (6.9) 0.01 0.41
Pittsburgh sleep quality Baseline 11.00 (4.3) 10.44 (4.7)
index Endpoint 7.69 (6.2) 8.64 (4.2) 0.20 0.17
PANSS, global Baseline 34.81 (6.4) 34.68 (7.5)
psychopathology Endpoint 28.97 (5.7) 32.46 (7.7) 0.005 0.50
PANSS, positive Baseline 12.71 (2.9) 11.89 (3.2)
symptoms Endpoint 11.05 (2.6) 12.03 (3.4) 0.002 0.32
PANSS, negative Baseline 14.28 (4.1) 13.73 (4.0)
symptoms Endpoint 13.11 (4.0) 13.40 (3.8) 0.16 0.07
CGI severity Baseline 4.85 (0.7) 4.76 (0.7)
Endpoint 3.97 (1.1) 4.43 (0.9) 0.01 0.45
CGI improvement Endpoint 2.57 (1.2) 3.50 (1.3) <0.01 0.75

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