All study procedures are approved and monitored by the University of Texas Health Science Center at San Antonio Institutional Review Board and South Texas Veterans Health Care System (STVHCS) Research and Development Committee. In addition, all study participants complete a written informed consent prior to any study procedure and are eligible to receive other standard of care treatments within their VA.
2.2 Study Procedures
This is a double-blind, placebo-controlled 14- week pilot study in which participants will be randomized to receive quetiapine (n = 10) or placebo (n = 10). Prescreening will be accomplished by review of patient’s medical record, speaking to the patient’s treating clinician, and interview by the study coordinator in person (if possible) or by telephone to eliminate any obviously ineligible participants and determine the likelihood of eligibility. During chart review, lab data from clinical care will also inform study coordinator regarding an individual’s likely eligibility. After prescreening, potentially eligible individuals will be scheduled for written informed consent and a formal screening visit. Participants who pass the eligibility screening will be scheduled for randomization as soon as possible after screening. Sequentially eligible participants will be assigned to receive either 1) placebo or 2) quetiapine by the Research Pharmacist to a randomized sequence established prior to the study. The participants, study physician, clinical prescribers and psychologists, and study coordinator will remain blinded to treatment assignment. After randomization, all patients will begin a 2-week stabilization period before beginning CPT. During this time, patients will receive a flexible dose regimen based upon tolerability and clinical response to maximize engagement in rehabilitation treatment by initiating quetiapine or placebo treatment 2 weeks before starting CPT treatment. Flexible dosing will begin with 25 mg at bedtime and titration up to 200 mg daily if needed. Matching placebo will permit apparent dose adjustments to be accomplished by adjusting the number of tablets prescribed. Medication treatment will be maintained throughout 14-week study period including the 12 session CPT. Doses will be adjusted as clinically indicated (see Fig. 2).
Assessments
A full list of study measures and assessment procedures is outlined in Table 1.
Notes: Shown are procedures completed at visits (V#) / weeks (WK) of study. Screening (Scr) occurs at V0 and medication initiation occurs at V1. Abbreviations: CAPS-5, Clinician-Administered PTSD Scale for DSM-5; PCL-5, PTSD Checklist for DSM-5; ISI, Insomnia Sleep Index; GAD-7, Generalized Anxiety Disorder-7; WHODAS 2.0, World Health Organization Disability Assessment Schedule 2.0; WHOQOL-BREF, World Health Organization Quality of Life-BREF; PHQ-9, Patient Health Questionnaire; PTGI, Post Traumatic Growth Inventory; AUDIT, Alcohol Use Disorders Identification Test; DUDIT, Drug Use Disorders Identification Test; TSQM-9, Treatment Satisfaction Questionnaire for Medication-9; ECG, 12-lead electrocardiogram.
Primary outcome measures
The primary outcome measures for this study are: (1) trial feasibility, (2) engagement in CPT, anxiety, and insomnia, and (3) recovery.
Feasibility
We will collect information on number of potentially eligible veterans approached, the number screened, and the number randomized. This information will allow us to determine patient acceptability, and the logistic feasibility of recruiting participants into a full-scale, randomized, double-blind, placebo-controlled trial that requires antipsychotic medication versus placebo in combination with CPT.
Measures of Engagement in CPT treatment
After 2 weeks of quetiapine or placebo dosing, participants will begin CPT. CPT lasts for 12 weekly sessions but trauma exposure doesn’t begin until session #3 (Visit 4) when participant is asked to write a full account of the most traumatic event with sensory details. A significant number of PTSD patients terminate treatment prior to session #4, in which the completed account is reviewed and read aloud by the patient, which suggests strongly that the emotional difficulty of directly engaging with trauma content is a substantial barrier to treatment engagement. We have established two measures of engagement in CPT treatment. The first is continuing CPT treatment at least until session # 4 (i.e., when trauma account is due). The second measure is the participant’s self-report on engagement in therapy measured by emotional engagement graded on a scale from 0 (not very engaged) to 10 (fully engaged) at every visit by the participant; a score of 7 or higher is the desired response and self-reported completion of homework. We also will record the number of sessions of CPT completed by the participants. Non-compliance with the CPT treatment reported by the therapist will also be documented. The completions status will be confirmed after discussion with the therapist and number of sessions of CPT completed by the participants will also be recorded.
Anxiety
Change in anxiety will be assessed using a well validated and quick and easy to administer self-administered, the Generalized Anxiety Disorder 7 item (GAD-7) scale.[30]
Insomnia
Change in insomnia will be assessed using the Insomnia Severity Index (ISI).[31] The ISI is short (7 items), easy to complete, and it has been used in evaluating insomnia in veteran populations.[32] We considered several alternative primary outcome measures for this study and dismissed them for the following reasons: polysomnography is too burdensome and costly. Sleep diaries are equally valid and sensitive, but they are more burdensome. The ISI has been validated against both polysomnography and sleep diary assessments in clinical trials.[33] Lastly, although the Pittsburgh Sleep Quality Index is a popular measure of overall sleep disturbances however ISI is preferred for insomnia.[34]
PTSD Symptom Severity
PTSD Checklist for DSM-5 (PCL-5) is a 20-item validated self-report measure which is widely implemented throughout the VA clinics to screen individuals for PTSD, make a provisional PTSD diagnosis, and monitor symptom change during and after treatment.[35] A PCL-5 score of 34 is considered an optimal cutoff level for the diagnosis of PTSD.[36] Evidence has suggested that 10 point change in PCL score represents reliable and clinically significant change.[35]
Quality of Life
The World Health Organization Quality of Life (WHOQOL) BREF is a 26 item self-report questionnaire to assess functioning and quality of life from the patient’s perspective over the past 2-week period.[37] It is a measure of conceptual domains of quality of life: material and physical well-being, relationships with other people, social, community and civic activities, personal development and fulfillment, independence, and recreation. It is a reliable and valid instrument utilized in physically and psychologically disabling conditions including PTSD.
Disability
The World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) is a 12 item self-report to measure functional disability over the past 30-day period.[38] It assesses 6 domains of functioning: cognition, mobility, self-care, getting along, life activities, and participation.
Secondary Outcome Measures
The secondary outcomes include: (1) The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) [39] will be used to establish PTSD diagnostic status at the screening and end of study (Visit 11). CAPS-5 is a gold standard diagnostic interview for PTSD, developed by National Center for PTSD. We will enroll participants who meet diagnostic criteria for PTSD and who have a CAPS-5 score of ≥ 25 and will repeat assessment at end of treatment to determine clinically significant change in the scores. PTSD diagnosis will be determined using the PTSD diagnosis algorithm recommended by the National Center of PTSD which requires at least moderate ratings (2 or more) on at least 1 B item (items #1–5), 1 C item (items #6–7), 2 D items (#8–14), and 2 E items (items #15–20) of the CAPS-5. (2) The Patient Health Questionnaire (PHQ)-9 will monitor for change in depressive symptoms, suicidality by the item # 9, and homicidality by an added question.[40] (3) The Post Traumatic Growth Inventory (PTGI) will measure change in cognition about positive outcomes.[41] (4) Substance use will be assessed by Alcohol Use Disorders Identification Test (AUDIT) [42],.and Drug Use Disorders Identification Test (DUDIT) [43] and treatment satisfaction by the Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9).[44]
Quetiapine has risks and side effects. Quetiapine may cause sedation and extra-pyramidal symptoms. The medications in the atypical antipsychotic class prescribed at high dose, for longer duration of treatment, in severely mentally ill individuals increase the risk for diabetes and heart diseases by causing metabolic dysregulation. We will thoroughly screen for metabolic risk factors by medical history and physical examination, vital signs, ECG, and basic laboratory tests. Basic laboratory tests to assess metabolic parameters and ECG will be repeated at the end of study (Visit 14) to verify whether or not adverse changes were observed in these parameters. Quetiapine has also been shown to cause prolongation of QTc interval which can contribute to cardiac arrhythmias therefore we will exclude veterans with prolonged QTc ≥ 450 milliseconds. Quetiapine use has been associated with respiratory dysfunction in patients with obstructive sleep apnea. Study participants will be screened for sleep apnea and compliance with continuous positive airway pressure use will be assessed and encouraged at every visit. At risk non-compliant participants will be discontinued from further participation in the study.
Participant safety will be monitored at each weekly visit and Adverse Events (AEs) will be documented. The study coordinator will collect and record side effects, worsening of PTSD symptoms, or suicidal ideations data from participants every week and the study physician will be alerted to clinically manage side effects and implement remedial procedures as indicated.
We will assess blind integrity at the end of each subject’s treatment (i.e. visit 13) by asking the participants and the investigator to guess the placebo or quetiapine treatment assignment.[45] Assessments will be completed by asking: “Which pills do you think you (or participants) were taking in this study, quetiapine or placebo (sugar pill)?” “And why do you think that?”
2.3 Materials
Medication Dosing
All the participants will continue their standard care prescribed medication. Study drug will be initially dispensed to participants soon after randomization, occurring on the same day as randomization (i.e., Visit 1) so that participants can start taking study medication on the first night immediately following randomization. Initial dose titration will occur during the first two weeks of the study. A participant’s initial titration will be accomplished during one to three dose evaluation telephone calls by the study physician. Using information gathered from participant feedback regarding tolerance of study medication and potentially supplemented by results of clinical assessment, the prescriber will sequentially titrate study medication upward or downward as tolerated. This dose escalation method is comparable to what would be utilized in clinical practice and could therefore be generalized to the intended treatment population. Quetiapine vs. placebo will be initiated at the dose 25 mg at bedtime and then increased up to 200 mg daily as clinically indicated. Dose adjustments will be made in 25–50 mg increments and after at least 14 days of dosing, participants will begin CPT with a VA trained therapist for 12 weekly sessions. Participants will be maintained on their maximally tolerated dose until completion of Visit 13, at which point study medication will be tapered down to the next lower dose for three nights before being discontinued altogether. No taper will be necessary for participants whose maximally tolerated dose was the lowest possible dose. Any change in study medication dose will be documented on the designated Case Report Form. A note will be entered in the CPRS to record the reason for the dose change, document that the change was communicated to the participant and that the participant verbalized an understanding of the change. The participants will be instructed to bring their pill bottles with them to each post-baseline visit to allow pill-count measures of medication compliance. Compliance with the study drug will also be assessed using participant report. The participant will be instructed to return any remaining supply in his/her possession. The Research Pharmacy will maintain the drug accountability log. Participants who does not initiate and continue study medication for at least 2 weeks or first CPT session will be terminated.
Cognitive Processing Therapy (CPT)
All participants will receive individual weekly CPT as a standard of care within the STVHCS. At STVHCS CPT is delivered in twelve 60-minute sessions following the model established by Resick et al.[5] which includes the trauma narrative component. For this study, we will exclude participants who previously completed a course of CPT but will permit those with ongoing PTSD symptoms who previously dropped out with the hypothesis that quetiapine randomization may help them to complete. Our study will use clinical standard of care procedures for participants who miss sessions. In our clinic, 12 sessions of CPT are generally delivered in 16–20 weeks. Thus, we have defined treatment endpoints as having completed CPT treatment or until 20 weeks of therapy time elapses. The participants will not be allowed to participate in any other clinical study, start a new medication, or a psychotherapeutic treatment during study participation.
Safety
Participants will be provided with emergency contact information for the study staff. In circumstances such as hospitalization or serious side effects such as suicidal or homicidal ideations, participants will contact the study staff. If the situation requires, the blind will be broken for emergency medical necessity (emergency unmasking), wherein knowledge of the study treatment assignment will influence the medical treatment of the participant, participants will be transferred to an emergency department or inpatient psychiatric unit. Participation in the trial will be terminated and a study discontinuation visit will be scheduled when feasible. Participants will be thanked for study participation and the study physician will coordinate indicated care with the mental health service.
2.4 Analysis Plan
This pilot study is not designed for efficacy or mechanistic hypotheses testing.[46, 47] As a rough guide to future planning, conventional effect sizes will be calculated with 95% confidence limits.[48] For dimensional scales (e.g., PCL-5, ISI, GAD-7, WHOQOL-BREFF, WHODAS 2.0, CAPS-5), effect sizes will be model-based estimates of pre-post treatment change divided by baseline standard deviations (e.g., bias-adjusted Hedges’ g). Cohen’s index (h) [49], odds ratios, and number needed to treat will be calculated for proportions. Although the statistical power of this study is limited, we will perform statistical analyses appropriate for an adequately powered study to identify data analysis issues germane to future planning, e.g., data management and scoring, missing data, data distributions, outliers, nature of trends over time, covariance structures. Statistical analyses will be intent to treat, using all available data from randomized participants regardless of extent of participation in treatment.
For dimensional measures related to clinical outcome (i.e., PCL-5, ISI, GAD-7, and 12-point self and therapist report measure of engagement), comparison of means will be done with general or generalized linear mixed effects regression models with repeated measures, with fixed effects of treatment, time, and the treatment by time interaction (e.g., SAS MIXED, GLIMMIX).When measures are assessed only at two time points, the treatment by time interaction is a test of the difference in pre-post change (i.e., CAPS-5, WHOQOL-BREFF, WHODAS 2.0, PTGI). For dichotomous measures of treatment engagement, statistical analyses will be done using chi-square tests. Either logistic or proportional hazard survival regression analysis will be used to determine if baseline descriptive and clinical characteristics predict treatment completion.
Recovery will be measured by a latent variable analysis using scores of three highly correlated indicator variables including the WHODAS 2.0, WHOQOL-BREF, and PCL-5. To reduce Type I error and account for the substantial overlap among functional disability, quality of life, and PTSD symptoms, we will: i) utilize preliminary factor analysis to create composite functional impairment factor scores for Veterans at three time points. The first time point will be at baseline (screening). Composite factor scores will also be created for their level of functional impairment at the visit 7 (week 8) interview and the end of study (Visit 13 (week 14)); ii) Scores on each of the measures will be standardized on the mean and standard deviation of each across the three time points prior to the factor analyses, so that comparisons can be made across time; iii) For each time point, a single, standardized factor will be extracted that accounts for the majority of the variance in the indicator variables; and iv) We expect that factor loadings for the indicators will be also quite high across all three time points, providing strong empirical support for an overall “functional impairment” factor.
Hypothesis 3
proposes that quetiapine promotes recovery by increasing treatment engagement and reducing insomnia and anxiety. The mediation hypothesis is typically represented in a triangular diagram (Fig. 3), which depicts a direct causal path from treatment to outcome (path c), and an indirect path from treatment through the mediator (path a) to outcome (path b). If mediation is complete, path c disappears, but partial mediation is also possible. The paths and standard errors are estimated with appropriate (i.e., linear, logistic) regression models or simultaneous equation modeling (SEM), which estimates the causal paths and standard errors simultaneously. The product of those paths (a*b) equals the decrement in the direct path due to mediation. The Figure shows the simplest case with only one mediator, but it is readily expanded to include more. The statistical significance of the indirect effect can be tested parametrically with estimates of its standard error, but bootstrapping is generally considered preferable because the distribution of the indirect effect is typically non-normal. Macros for these computations in SPSS and SAS can be downloaded from the internet (e.g., the PROCESS macro, available at: (reference # 94 is URL).[50]