This parallel-design, double-blind, randomized clinical trial investigates if combination treatment with brexpiprazole and sertraline is efficacious, safe, and well tolerated in patients with posttraumatic stress disorder.
Key Points
Question
Is brexpiprazole and sertraline combination (brexpiprazole + sertraline) treatment an efficacious, safe, and well-tolerated treatment for posttraumatic stress disorder (PTSD)?
Findings
In this phase 3, parallel-design, double-blind, randomized clinical trial including 416 participants, brexpiprazole + sertraline demonstrated a statistically significant reduction in PTSD symptoms (Clinician-Administered PTSD Scale for DSM-5 total score) vs sertraline + placebo from randomization (week 1) to week 10. The proportion of treated participants who discontinued due to adverse events was 3.9% for brexpiprazole + sertraline and 10.2% for sertraline + placebo.
Meaning
Brexpiprazole + sertraline treatment improved PTSD symptoms and was tolerated by most participants.
Abstract
Importance
New pharmacotherapy options are needed for posttraumatic stress disorder (PTSD).
Objective
To investigate the efficacy, safety, and tolerability of brexpiprazole and sertraline combination treatment (brexpiprazole + sertraline) compared with sertraline + placebo for PTSD.
Design, Setting, and Participants
This was a parallel-design, double-blind, randomized clinical trial conducted from October 2019 to August 2023. The study had a 1-week, placebo run-in period followed by an 11-week, double-blind, randomized, active-controlled, parallel-arm period (with 21-day follow-up) and took place at 86 clinical trial sites in the US. Adult outpatients with PTSD were enrolled (volunteer sample).
Interventions
Oral brexpiprazole 2 to 3 mg per day (flexible dose) + sertraline 150 mg per day or sertraline 150 mg per day + placebo (1:1 ratio) for 11 weeks.
Main Outcomes and Measures
The primary end point was change in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total score (which measures the severity of 20 PTSD symptoms) from randomization (week 1) to week 10 for brexpiprazole + sertraline vs sertraline + placebo. Safety assessments included adverse events.
Results
A total of 1327 individuals were assessed for eligibility. After 878 screen failures, 416 participants (mean [SD] age, 37.4 [11.9] years; 310 female [74.5%]) were randomized. Completion rates were 137 of 214 participants (64.0%) for brexpiprazole + sertraline and 113 of 202 participants (55.9%) for sertraline + placebo. At week 10, brexpiprazole + sertraline demonstrated statistically significant greater improvement in CAPS-5 total score (mean [SD] at randomization, 38.4 [7.2]; LS mean [SE] change, −19.2 [1.2]; n = 148) than sertraline + placebo (randomization, 38.7 [7.8]; change, −13.6 [1.2]; n = 134), with LS mean difference, −5.59 (95% CI, −8.79 to −2.38; P < .001). All key secondary and other efficacy end points were also met. Treatment-emergent adverse events with incidence of 5% or greater for brexpiprazole + sertraline (and corresponding incidences for sertraline + placebo) were nausea (25 of 205 [12.2%] and 23 of 196 [11.7%]), fatigue (14 of 205 [6.8%] and 8 of 196 [4.1%]), weight increase (12 of 205 [5.9%] and 3 of 196 [1.5%]), and somnolence (11 of 205 [5.4%] and 5 of 196 [2.6%]). Discontinuation rates due to adverse events were 8 of 205 participants (3.9%) for brexpiprazole + sertraline and 20 of 196 participants (10.2%) for sertraline + placebo.
Conclusions and Relevance
Results of this randomized clinical trial show that brexpiprazole + sertraline combination treatment statistically significantly improved PTSD symptoms vs sertraline + placebo, indicating its potential as a new efficacious treatment for PTSD. Brexpiprazole + sertraline was tolerated by most participants, with a safety profile consistent with that of brexpiprazole in approved indications.
Trial Registration
ClinicalTrials.gov Identifier: NCT04124614
Introduction
Posttraumatic stress disorder (PTSD) is characterized by 4 symptom clusters: intrusive reexperiences of the trauma, avoidance of internal and external associations with the trauma, negative alterations in cognitions and mood, and heightened arousal and reactivity.1,2 PTSD has a high prevalence in the US and worldwide (estimates vary between studies).3,4,5 Traumas with the greatest PTSD risk are those involving interpersonal violence, whether physical or sexual.6 PTSD places a high burden on patients in terms of social and occupational disability, quality of life issues, and suicide.2,7,8
The selective serotonin reuptake inhibitors (SSRIs), sertraline and paroxetine, are the only US Food and Drug Administration–approved pharmacotherapies for PTSD.7 However, in a large meta-analysis, 42% of patients with PTSD did not respond to SSRI treatment.9 Furthermore, individual trials fail to show consistent efficacy on PTSD symptom clusters, particularly intrusion and arousal.9 Polypharmacy with off-label medications is therefore common to address a broader range of symptoms.10 Taken together, this evidence indicates an unmet need for new PTSD treatment options.11
Brexpiprazole is an atypical antipsychotic with broad pharmacological activity across noradrenergic, serotonergic, and dopaminergic neurotransmitter systems implicated in psychiatric disorders, including PTSD.12,13,14,15 In phase 3 randomized clinical trials, brexpiprazole demonstrated efficacy, safety, and tolerability for the treatment of schizophrenia,16,17 the treatment of agitation in Alzheimer dementia,18,19 and the adjunctive treatment of major depressive disorder.20,21,22,23 Given its multimodal mechanism of action and efficacy in other psychiatric disorders, brexpiprazole was investigated in a phase 2 randomized clinical trial in PTSD.24 The combination of brexpiprazole and sertraline (brexpiprazole + sertraline) demonstrated efficacy, with no identified safety concerns.24 Therefore, the aim of the present phase 3 trial was to further investigate the efficacy, safety, and tolerability of brexpiprazole + sertraline in adults with PTSD.
Methods
This was a phase 3, multicenter, 12-week, double-blind, active-controlled, parallel-arm, randomized clinical trial of brexpiprazole + sertraline in patients with PTSD. The trial protocol and statistical analysis plan are available in Supplement 1. The trial was conducted in accordance with the International Council for Harmonisation Good Clinical Practice Consolidated Guideline and local regulatory requirements. The trial was reviewed and approved by the governing institutional review board for each investigational site. All participants provided written or electronic informed consent before initiation of trial procedures and were reimbursed for time and travel. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.
Participants and Study Design
Participants (a volunteer sample) were screened by investigators at 78 of 86 selected trial sites in the US (eTable 1 in Supplement 2). Key inclusion criteria were as follows: outpatient status, age 18 to 65 years, diagnosis of PTSD as defined by DSM-5 criteria25 and confirmed by the Mini-International Neuropsychiatric Interview version 726 with symptoms for 6 or more months before screening, and a Clinician-Administered PTSD Scale for DSM-5 (CAPS-5)27 total score of 33 or greater at screening and baseline (day 0). Enrollment of patients with an index trauma related to combat was limited to 20%. Key exclusion criteria were as follows: receiving disability payments or being engaged in compensation litigation related to PTSD or another psychiatric disorder; an index traumatic event before age 16 years or more than 9 years before screening; a traumatic event within 3 months of screening; currently experiencing trauma, ongoing contact with their assailant/abuser, or ongoing legal matters related to their assault/abuse; considered psychotropic treatment–resistant/refractory by history in the investigator’s opinion; currently receiving sertraline with adequate dose and duration; any previous exposure to brexpiprazole; a change in PTSD treatment within 28 days of screening; a current DSM-5 major depressive episode; a current or recent (within 6 months of screening) anxiety disorder that has been the primary focus of psychiatric treatment; at significant risk of committing suicide; or any other psychiatric or medical condition as listed in the protocol.
Eligible participants entered a 1-week, double-blind, placebo run-in period (period A), followed by an 11-week, double-blind, active-treatment period (period B) in which participants were randomized 1:1 to brexpiprazole + sertraline or sertraline + placebo. To reduce potential bias in efficacy outcomes, aspects of the trial design (eFigure 1 in Supplement 2) were blinded to participants and trial site personnel. Specifically, the existence of the placebo run-in period, the timing and nature of randomization (ie, parallel treatment arms and randomization ratio), and the timing of the primary efficacy end point (week 10) were not revealed, such that the trial appeared to comprise a single, 12-week, double-blind treatment period. Visits occurred weekly from baseline to week 4, then every 2 weeks.
Brexpiprazole was flexibly dosed at 2 to 3 mg per day, whereas sertraline was administered at a fixed 150-mg daily dose to avoid confounding factors (titration was over 2-3 weeks) (eFigure 1 in Supplement 2). Study drugs were taken orally, together, at the same time each day (once daily), without regard to meals. Brexpiprazole tablets (or matching placebo) and sertraline capsules (or matching placebo for the first week) were provided by the sponsor or designated agent in the form of numbered blister cards. Treatments were assigned to participants via a fixed-block (block size 4) computer-generated randomization code provided by the sponsor and stratified by site and enrichment status (as defined in the Statistical Analysis section). Treatment assignments were blinded to participants, investigators, and sponsor personnel, including those involved in data analysis. Prohibited medications, including psychotropic agents (antipsychotics, antidepressants, etc), were washed out during the screening period. Benzodiazepines and nonbenzodiazepine sleep aids were prohibited except in the short term to manage emergent agitation/anxiety and insomnia, respectively. Psychotherapy was permitted provided it was ongoing for 28 days or more before screening, and the participant committed to continue the therapy during the trial.
Assessments
Participant demographics and medical history were recorded at the screening visit. Sex, race (American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, White, other nonspecified), and ethnicity (Hispanic or Latino, not Hispanic or Latino, unknown, other nonspecified) were self-reported using US Census Bureau classifications. The Life Events Checklist for DSM-528 was used to identify index traumatic events. The Emory Treatment Resistance Interview for PTSD29 was used to collect information on prior PTSD treatments.
The CAPS-5,27 an extensively validated structured interview,30,31 was used to assess PTSD diagnostic status and symptom severity. The CAPS-5 includes 20 DSM-5 PTSD-symptom items that are each scored from 0 (absent) to 4 (extreme/incapacitating); total score is calculated by summing the 20 items, and symptom cluster scores are calculated by summing specific items: intrusion (items 1-5), avoidance (items 6-7), negative cognitions and mood (items 8-14), and arousal and reactivity (items 15-20).27 The CAPS-5 past-month version was completed at screening, and the past-week version was completed at baseline (day 0) and weeks 1, 3, 4, 6, 10, and 12, by trained raters. PTSD symptom severity was also assessed using the clinician-reported Clinical Global Impression–Severity of illness (CGI-S) scale32 and the patient-reported PTSD Checklist for DSM-5 (PCL-5).33 Physical, social, emotional, and occupational functioning was assessed using the patient-reported Brief Inventory of Psychosocial Function (B-IPF),34 anxiety and depression symptom severity using the patient-reported Hospital Anxiety and Depression Scale (HADS),35 and health-related quality of life using the patient-reported 36-item Short-Form Health Survey version 2 (SF-36v2, an exploratory measure).36
Safety was assessed via standard variables including treatment-emergent adverse events (TEAEs), body weight, laboratory tests, vital signs, electrocardiograms, the Columbia Suicide Severity Rating Scale (C-SSRS),37 and 3 extrapyramidal symptom rating scales: Simpson–Angus Scale (SAS),38 Abnormal Involuntary Movement Scale (AIMS),32 and Barnes Akathisia Rating Scale (BARS).39
Statistical Analysis
The primary estimand was defined as follows:
Population: outpatients with PTSD, the efficacy sample, which was enriched for participants with CAPS-5 total score of 27 or greater at the randomization visit (week 1) and less than 50% improvement in CAPS-5 total score from baseline (day 0) to week 1, thereby excluding participants who responded during the placebo run-in period.
Treatments: brexpiprazole + sertraline or sertraline + placebo for 11 weeks.
Primary end point: change from randomization (week 1) to week 10 (ie, 9 weeks of active treatment) in CAPS-5 total score.
Measure of intervention effect: mean difference between treatment arms.
Intercurrent events: premature treatment discontinuation.
In the hypothetical strategy that no withdrawals occurred,40 any withdrawal events in practice were considered missing at random, and a mixed model for repeated measures (MMRM) approach based on observed data was used to account for participants who withdrew. Details of the sample size calculation and MMRM methods are provided in the online supplement (eMethods in Supplement 2). Prespecified subgroup analyses of the primary efficacy end point were performed by sex, race, age, and previous PTSD pharmacotherapy. Missing-not-at-random sensitivity analyses were performed.
Key secondary end points were as follows: (1) change from randomization (week 1) to week 10 in CGI-S score and (2) change from baseline (day 0) to week 12 in B-IPF score, both using MMRM. B-IPF was not measured at weeks 1 or 10 to maintain blinding. To control the familywise type I error at the .05 level (2-sided), a stepwise hierarchical testing procedure was applied in the following order: primary efficacy end point, CGI-S key secondary end point, B-IPF key secondary end point. Other efficacy end points (PCL-5 total, HADS Anxiety, HADS Depression, CAPS-5 symptom cluster scores, and CAPS-5 response rate [≥30% improvement from week 1]) and exploratory end points (SF-36v2 physical component, mental component, and subscale scores, and sleep-specific CAPS-5/PCL-5 item scores) were tested at a nominal .05 level (2-sided), with no adjustment for multiplicity. Data analyses were conducted using SAS, version 9.4 (SAS Institute).
Results
Participants
The trial was conducted between October 8, 2019, and August 8, 2023. A total of 1327 individuals were assessed for eligibility. After 878 screen failures, 450 participants (449 distinct patients, as 1 patient was enrolled twice) entered period A. A total of 416 participants (mean [SD] age, 37.4 [11.9] years; 310 female [74.5%]; 106 male [25.5%]) entered period B and were randomized to brexpiprazole + sertraline (n = 214) or sertraline + placebo (n = 202) (Figure 1). Participants self-identified with the following races: 9 American Indian or Alaska Native (2.2%), 13 Asian (3.1%), 88 Black or African American (21.2%), 1 Native Hawaiian or Other Pacific Islander (0.2%), 291 White (70.0%), and 14 other (3.4%). Participants self-identified with the following ethnicities: 61 Hispanic or Latino (14.7%), 350 not Hispanic or Latino (84.1%), and 5 unknown or other (1.2%). Period B completion rates were 137 of 214 participants (64.0%) for brexpiprazole + sertraline and 113 of 202 participants (55.9%) for sertraline + placebo. The most common reasons for discontinuation after randomization (>5% in either treatment group) were, for the brexpiprazole + sertraline and sertraline + placebo groups, respectively, withdrawal by the participant (26 of 214 [12.1%] and 22 of 202 [10.9%]), lost to follow-up (18 of 214 [8.4%] and 25 of 202 [12.4%]), and adverse event (7 of 214 [3.3%] and 22 of 202 [10.9%]) (Figure 1).
Figure 1. Participant Disposition.
aA total of 449 distinct patients, as 1 patient was enrolled twice. After each enrollment, this patient discontinued before randomization (1 withdrawal by participant and 1 lost to follow-up).
bAggregated reasons for discontinuation were as follows: (1) withdrawal by participant + lost to follow-up + adverse event: 23.8% (51 of 214 participants) for brexpiprazole + sertraline and 34.2% (69 of 202 participants) for sertraline + placebo; (2) lost to follow-up + adverse event: 11.7% (25 of 214 participants) for brexpiprazole + sertraline and 23.3% (47 of 202 participants) for sertraline + placebo.
cIncluding 1 participant who reported an adverse event of fatigue (start day 39; resolved day 44), discontinued trial medication on day 60, and discontinued the trial due to withdrawal of consent on day 75.
dThe efficacy sample was enriched for participants with Clinician-Administered Posttraumatic Stress Disorder (PTSD) Scale for DSM-5 (CAPS-5) total score ≥27 at the randomization visit (week 1) and <50% improvement in CAPS-5 total score from baseline (day 0) to week 1.
The randomized sample had a mean (SD) of 4.2 (2.5) years since the index trauma. The most common trauma types were assault, sexual trauma, exposure to sudden death, and vehicle incident. Baseline demographics, clinical characteristics, and treatment history were similar between treatment groups (Table 1). Considering medical history, major depressive disorder was the only psychiatric disorder reported by more than 5% of participants: brexpiprazole + sertraline, 36 of 214 (16.8%); sertraline + placebo, 46 of 202 (22.8%). Most participants (305 [73.3%]) were PTSD-pharmacotherapy naive at baseline (Table 1). SSRIs for PTSD had previously been received by 35 of 214 participants (16.4%) randomized to brexpiprazole + sertraline and 27 of 202 participants (13.4%) randomized to sertraline + placebo.
Table 1. Baseline Demographics, Clinical Characteristics, and Treatment History.
| Characteristic | No. (%) | |
|---|---|---|
| Sertraline + placebo (n = 202) | Brexpiprazole + sertraline (n = 214) | |
| Demographics (randomized sample) | ||
| Age, mean (SD), y | 36.8 (12.1) | 37.8 (11.7) |
| Age group, y | ||
| <55 | 179 (88.6) | 193 (90.2) |
| ≥55 | 23 (11.4) | 21 (9.8) |
| Weight, mean (SD), kg | 85.8 (22.2) | 85.9 (21.2) |
| BMI, mean (SD)a | 30.1 (7.1) | 30.4 (6.7)b |
| Sex | ||
| Female | 152 (75.2) | 158 (73.8) |
| Male | 50 (24.8) | 56 (26.2) |
| Race | ||
| American Indian or Alaska Native | 2 (1.0) | 7 (3.3) |
| Asian | 9 (4.5) | 4 (1.9) |
| Black or African American | 38 (18.8) | 50 (23.4) |
| Native Hawaiian or Other Pacific Islander | 0 | 1 (0.5) |
| White | 144 (71.3) | 147 (68.7) |
| Other nonspecified | 9 (4.5) | 5 (2.3) |
| Ethnicity | ||
| Hispanic or Latino | 32 (15.8) | 29 (13.6) |
| Not Hispanic or Latino | 167 (82.7) | 183 (85.5) |
| Unknown/other | 3 (1.5) | 2 (0.9) |
| Clinical (randomized sample) | ||
| Time since index traumatic event, mean (SD), y | 4.1 (2.4) | 4.2 (2.5) |
| Time since onset of symptoms, mean (SD), y | 3.9 (2.4) | 4.1 (2.5) |
| Index traumatic event | ||
| Assault | 79 (39.1) | 75 (35.0) |
| Sexual trauma | 39 (19.3) | 55 (25.7) |
| Exposure to sudden death | 21 (10.4) | 33 (15.4) |
| Motor vehicle/transportation incident | 28 (13.9) | 16 (7.5) |
| Other | 35 (17.3) | 35 (16.4) |
| PTSD treatment history (randomized sample) | ||
| Prescription medication for PTSD | ||
| Yes | 50 (24.8) | 61 (28.5) |
| No | 152 (75.2) | 153 (71.5) |
| Psychotherapy for PTSD | ||
| Yes | 59 (29.2) | 79 (36.9) |
| No | 143 (70.8) | 135 (63.1) |
| Any PTSD treatment (prescription medication or psychotherapy) | ||
| Yes | 84 (41.6) | 105 (49.1) |
| No | 118 (58.4) | 109 (50.9) |
| Psychiatric scales at week 1 (efficacy sample) | ||
| No. | 137 | 149 |
| CAPS-5 total, mean (SD) | 38.8 (8.0) | 38.3 (7.2) |
| Intrusion | 9.4 (3.4) | 9.2 (3.3) |
| Avoidance | 4.8 (1.6) | 4.5 (1.6) |
| Negative cognitions and mood | 14.7 (4.0) | 14.5 (3.8) |
| Arousal and reactivity | 10.0 (3.0) | 10.1 (2.9) |
| CGI-S, mean (SD) | 4.6 (0.6) | 4.6 (0.6)c |
| B-IPF at baseline, mean (SD) | 64.3 (22.9)d | 65.2 (21.1)e |
| PCL-5 total, mean (SD) | 48.0 (13.4)f | 47.4 (12.9)g |
| HADS Anxiety, mean (SD) | 14.1 (3.3)f | 14.0 (3.9)g |
| HADS Depression, mean (SD) | 10.7 (3.8)f | 11.0 (3.7)g |
Abbreviations: B-IPF, Brief Inventory of Psychosocial Function; BMI, body mass index; CAPS-5, Clinician-Administered PTSD Scale for DSM-5; CGI-S, Clinical Global Impression–Severity of illness; HADS, Hospital Anxiety and Depression Scale; PCL-5, PTSD Checklist for DSM-5; PTSD, posttraumatic stress disorder.
Calculated as weight in kilograms divided by height in meters squared.
N = 213.
N = 148.
N = 129.
N = 142.
N = 130.
N = 138.
During the placebo run-in period, mean (SD) CAPS-5 total score change from baseline (day 0) to randomization (week 1) was −8.8 (9.0) points overall (n = 379), and −5.2 (5.8) in participants who met the enrichment criteria (n = 286).
The mean (SD) brexpiprazole dose at each participant’s last visit was 2.2 (0.6) mg (n = 205).
Efficacy
Primary End Point
From randomization (week 1) to week 10, brexpiprazole + sertraline demonstrated statistically significant greater improvement in CAPS-5 total score (mean [SD] at randomization, 38.4 [7.2]; LS mean [SE] change, −19.2 [1.2]; n = 148) than sertraline + placebo (randomization, 38.7 [7.8]; change, −13.6 [1.2]; n = 134), with LS mean difference, −5.59 (95% CI, −8.79 to −2.38; P <.001). Greater improvement for brexpiprazole + sertraline was observed from week 6 onward (Figure 2A). Subgroup analyses (eFigure 2 in Supplement 2), missing-not-at-random sensitivity analyses (eTable 2 in Supplement 2), and full-analysis-set analyses (eFigure 3 in Supplement 2) were generally consistent with the results of the primary analysis.
Figure 2. Change in Clinician-Administered Posttraumatic Stress Disorder (PTSD) Scale for DSM-5 (CAPS-5) Total Score (Primary End Point), Clinical Global Impression–Severity of Illness (CGI-S) and Brief Inventory of Psychosocial Function (B-IPF) Scores and CAPS-5 Response Rate.
Mean CAPS-5 total score at randomization (week 1): brexpiprazole + sertraline, 38.4; sertraline + placebo, 38.7. Mean CGI-S score at randomization (week 1): brexpiprazole + sertraline, 4.6; sertraline + placebo, 4.6. Mean B-IPF score at baseline (day 0): brexpiprazole + sertraline, 64.8; sertraline + placebo, 63.5. Mixed model for repeated measures (A-C); last observation carried forward, Cochran-Mantel-Haenszel general association test (D); efficacy sample.
aP < .05 vs sertraline + placebo (nominal P values with no adjustment for multiplicity).
bP < .01 vs sertraline + placebo (nominal P values with no adjustment for multiplicity).
cFor sertraline + placebo, n = 95 at week 8 and n = 79 at week 12. For brexpiprazole + sertraline, n = 101 at week 8 and n = 87 at week 12.
dFor sertraline + placebo, n = 128 at week 3 and n = 137 at weeks 4 onward. For brexpiprazole + sertraline, n = 141 at week 3 and n = 149 at weeks 4 onward.
eP < .001 vs sertraline + placebo (nominal P values with no adjustment for multiplicity).
Key Secondary End Points
Brexpiprazole + sertraline demonstrated statistically significant greater improvement vs sertraline + placebo on the LS mean change in CGI-S score from randomization (week 1) to week 10: treatment difference: −0.47 (95% CI, −0.76 to −0.17; P = .002) (Figure 2B). Brexpiprazole + sertraline also demonstrated statistically significant greater improvement vs sertraline + placebo on the LS mean change in B-IPF total score from baseline (day 0) to week 12: treatment difference: −12.0 (95% CI, −19.4 to −4.62; P = .002) (Figure 2C).
Other Efficacy and Exploratory End Points
Brexpiprazole + sertraline showed greater improvement vs sertraline + placebo on all other efficacy end points at week 10: PCL-5 total (eFigure 4 in Supplement 2), HADS Anxiety, HADS Depression, and CAPS-5 symptom cluster scores (Table 2), and CAPS-5 response rate (Figure 2D). CAPS-5 response rates at week 10 were 102 of 149 (68.5%) for brexpiprazole + sertraline and 66 of 137 (48.2%) for sertraline + placebo (P <.001). Exploratory end points are presented in eTable 3 in Supplement 2.
Table 2. Summary of Primary, Key Secondary, and Other Efficacy Results (Efficacy Sample).
| End pointa | Treatment group | No. | Mean (SD) score at week 1 | LS mean (SE) change from week 1 to week 10 | Treatment difference at week 10 | ||
|---|---|---|---|---|---|---|---|
| LS mean (95% CI) | P value | Cohen d | |||||
| Clinician-reported | |||||||
| CAPS-5 total (primary)b | Brexpiprazole + sertraline | 148 | 38.4 (7.2) | −19.2 (1.2) | −5.59 (−8.79 to −2.38) | <.001 | 0.41 |
| Sertraline + placebo | 134 | 38.7 (7.8) | −13.6 (1.2) | ||||
| Intrusion | Brexpiprazole + sertraline | 148 | 9.3 (3.3) | −5.3 (0.4) | −1.69 (−2.76 to −0.62) | .002 | 0.37 |
| Sertraline + placebo | 134 | 9.3 (3.4) | −3.6 (0.4) | ||||
| Avoidance | Brexpiprazole + sertraline | 148 | 4.5 (1.6) | −2.3 (0.2) | −0.74 (−1.32 to −0.15) | .01 | 0.30 |
| Sertraline + placebo | 134 | 4.8 (1.6) | −1.6 (0.2) | ||||
| Negative cognitions and mood | Brexpiprazole + sertraline | 148 | 14.5 (3.8) | −7.3 (0.5) | −1.94 (−3.33 to −0.55) | .007 | 0.33 |
| Sertraline + placebo | 134 | 14.6 (3.9) | −5.4 (0.5) | ||||
| Arousal and reactivity | Brexpiprazole + sertraline | 148 | 10.1 (2.9) | −4.3 (0.3) | −1.35 (−2.25 to −0.45) | .004 | 0.35 |
| Sertraline + placebo | 134 | 10.0 (3.0) | −2.9 (0.4) | ||||
| CGI-S (key secondary)c | Brexpiprazole + sertraline | 148 | 4.6 (0.6) | −1.5 (0.1) | −0.47 (−0.76 to −0.17) | .002 | 0.37 |
| Sertraline + placebo | 137 | 4.6 (0.6) | −1.1 (0.1) | ||||
| Patient-reported | |||||||
| B-IPF (key secondary)d | Brexpiprazole + sertraline | 104 | 64.8 (21.2) | −33.8 (2.8) | −12.0 (−19.4 to −4.62) | .002 | 0.45 |
| Sertraline + placebo | 97 | 63.5 (23.2) | −21.8 (3.0) | ||||
| PCL-5 totale | Brexpiprazole + sertraline | 133 | 47.7 (12.7) | −22.7 (1.6) | −7.28 (−11.5 to −3.06) | .001 | 0.42 |
| Sertraline + placebo | 124 | 47.7 (13.4) | −15.4 (1.6) | ||||
| HADS Anxietyf | Brexpiprazole + sertraline | 133 | 14.2 (3.8) | −4.7 (0.4) | −1.56 (−2.72 to −0.41) | .008 | 0.33 |
| Sertraline + placebo | 124 | 14.0 (3.3) | −3.1 (0.4) | ||||
| HADS Depressionf | Brexpiprazole + sertraline | 133 | 11.1 (3.8) | −3.7 (0.4) | −1.34 (−2.49 to −0.19) | .02 | 0.29 |
| Sertraline + placebo | 124 | 10.5 (3.7) | −2.3 (0.4) | ||||
| Response | No. (%) | Response ratio (95% CI) | |||||
| CAPS-5 responseg | Brexpiprazole + sertraline | 149 | NA | 102 (68.5) | 1.40 (1.14 to 1.72) | <.001 | NA |
| Sertraline + placebo | 137 | NA | 66 (48.2) | ||||
Abbreviations: B-IPF, Brief Inventory of Psychosocial Function; CAPS-5, Clinician-Administered PTSD Scale for DSM-5; CGI-S, Clinical Global Impression–Severity of illness; HADS, Hospital Anxiety and Depression Scale; LS, least squares; NA, not available; PCL-5, PTSD Checklist for DSM-5.
Mixed model for repeated measures; n values are for participants with measurements at randomization (week 1), unless stated otherwise; patients in the efficacy sample were excluded from these analyses if they only had unscheduled post-baseline visits.
CAPS-5 total score ranges from 0 (absent) to 80 (extreme/incapacitating); symptom cluster score ranges are as follows: intrusion (0-20), avoidance (0-8), negative cognitions and mood (0-28), arousal and reactivity (0-24).27
CGI-S score ranges from 1 (normal, not at all ill) to 7 (among the most extremely ill patients).32
B-IPF index score ranges from 0 (least impairment) to 100 (greatest impairment).34 B-IPF data are presented for baseline (day 0) and week 12 (assessments were not made at week 1 or week 10); n values are for participants with measurements at baseline (day 0).
PCL-5 total score ranges from 0 (not at all) to 80 (extremely).33
HADS Anxiety and Depression scores range from 0 (absent) to 21 (maximum severity).35
Defined as 30% or greater improvement from randomization (week 1) to week 10. Last observation carried forward, Cochran-Mantel-Haenszel general association test.
Safety
After randomization, 123 of 205 participants (60.0%) in the brexpiprazole + sertraline group and 114 of 196 participants (58.2%) in the sertraline + placebo group reported 1 or more TEAEs. TEAEs with incidence of 5% or greater for brexpiprazole + sertraline (and corresponding incidences for sertraline + placebo) were nausea (25 of 205 [12.2%] and 23 of 196 [11.7%]), fatigue (14 of 205 [6.8%] and 8 of 196 [4.1%]), weight increase (12 of 205 [5.9%] and 3 of 196 [1.5%]), and somnolence (11 of 205 [5.4%] and 5 of 196 [2.6%]). TEAEs with incidence of 5% or greater for sertraline + placebo (and corresponding incidences for brexpiprazole + sertraline) were nausea (23 [11.7%] and 25 [12.2%]), headache (17 [8.7%] and 10 [4.9%]), diarrhea (13 [6.6%] and 9 [4.4%]), and tremor (10 [5.1%] and 8 [3.9%]) (Table 3). Most TEAEs were mild or moderate in severity. Extrapyramidal symptom–related TEAEs were reported by 18 participants (8.8%) taking brexpiprazole + sertraline and 24 participants (12.2%) taking sertraline + placebo. Discontinuation rates due to adverse events were 8 of 205 participants (3.9%) for brexpiprazole + sertraline and 20 of 196 participants (10.2%) for sertraline + placebo. Akathisia was the only TEAE leading to discontinuation in more than 2 participants in either group (brexpiprazole + sertraline, 0; sertraline + placebo, 3 [1.5%]). One participant died during the trial, in the sertraline + placebo group, from the toxic effects of a cocaine overdose (considered unrelated to study drug).
Table 3. Postrandomization Treatment-Emergent Adverse Events (TEAEs) Week 1 to Week 12 (Safety Sample)a.
| Event | No. (%) | |
|---|---|---|
| Sertraline + placebo (n = 196) | Brexpiprazole + sertraline (n = 205) | |
| At least 1 TEAE | 114 (58.2) | 123 (60.0) |
| At least 1 potentially drug-related TEAE | 80 (40.8) | 90 (43.9) |
| At least 1 serious TEAE | 4 (2.0)b | 1 (0.5)c |
| At least 1 severe TEAE | 6 (3.1) | 6 (2.9) |
| Discontinuation due to adverse event | 20 (10.2) | 8 (3.9)d |
| Death | 1 (0.5)e | 0 |
| TEAEs with an incidence ≥5% in either treatment group | ||
| Nausea | 23 (11.7) | 25 (12.2) |
| Fatigue | 8 (4.1) | 14 (6.8) |
| Weight increase | 3 (1.5) | 12 (5.9) |
| Somnolence | 5 (2.6) | 11 (5.4) |
| Headache | 17 (8.7) | 10 (4.9) |
| Diarrhea | 13 (6.6) | 9 (4.4) |
| Tremor | 10 (5.1) | 8 (3.9) |
| Other TEAEs of interest | ||
| Insomnia | 9 (4.6) | 8 (3.9) |
| Dizziness | 9 (4.6) | 6 (2.9) |
| Akathisia | 9 (4.6) | 5 (2.4) |
| Sedation | 7 (3.6) | 5 (2.4) |
| Anxiety | 6 (3.1) | 4 (2.0) |
| Agitation | 2 (1.0) | 3 (1.5) |
| Restlessness | 1 (0.5) | 2 (1.0) |
| Hypersomnia | 1 (0.5) | 0 |
| Orthostatic hypotension | 0 | 0 |
In the placebo run-in period (baseline [day 0] to randomization [week 1]), 89 of 401 participants (22.2%) reported at least 1 adverse event.
Cerebrovascular accident, diverticulitis, hepatic enzyme increased, toxicity to various agents (toxic effects of cocaine).
Gastroenteritis.
Including 1 participant who reported an adverse event of fatigue (start day 39; resolved day 44), discontinued trial medication on day 60, and discontinued the trial due to withdrawal of consent on day 75.
Toxicity to various agents (toxic effects of cocaine).
Mean (SD) change in body weight from randomization (week 1) to each participant’s last visit was +1.3 (4.8) kg in the brexpiprazole + sertraline group and 0.0 (4.9) kg in the sertraline + placebo group (details in eTable 4 in Supplement 2). At last visit, weight gain of 7% or greater from week 1 was experienced by 16 of 197 participants (8.1%) in the brexpiprazole + sertraline group and 9 of 190 participants (4.7%) in the sertraline + placebo group; the corresponding values for weight loss of 7% or greater were 5 of 197 participants (2.5%) and 6 of 190 participants (3.2%), respectively.
No clinically meaningful differences between treatment groups were observed for changes in laboratory test parameters, vital signs, or electrocardiograms (eTable 4 in Supplement 2). No participants reported TEAEs related to suicidality. On the C-SSRS, there was no treatment-emergent suicidal behavior, and the incidence of treatment-emergent suicidal ideation at any visit was less than 5% in both treatment groups. Changes in SAS, AIMS, and BARS scores were minimal in both treatment groups (eTable 4 in Supplement 2).
Discussion
In adults with PTSD, treatment with brexpiprazole + sertraline resulted in statistically significant greater improvement of PTSD symptoms vs treatment with sertraline + placebo at week 10, as measured by change in CAPS-5 total score (primary end point), supported by all key secondary and other efficacy end points, both clinician-reported (CGI-S, CAPS-5 symptom clusters, CAPS-5 response) and patient-reported (B-IPF, PCL-5 total, HADS Anxiety, HADS Depression). Greater improvement in PTSD symptoms for brexpiprazole + sertraline vs sertraline + placebo was observed from week 6 and maintained to the end of the trial (week 12). Importantly, brexpiprazole + sertraline treatment showed improvement across the 4 CAPS-5 PTSD symptom clusters, as well as HADS depressive and anxious symptoms, which have not been consistently demonstrated for currently approved treatments.9 Finally, brexpiprazole + sertraline treatment was associated with improvements in B-IPF psychosocial functioning (key secondary end point).
Although there is no widely agreed threshold for clinically meaningful change in CAPS-5 total score, the observed within-group mean change of −19.2 points for brexpiprazole + sertraline at week 10 (vs −13.6 for sertraline + placebo) is above existing estimates of greater than or equal to 12 to 14 points for reliable change (ie, beyond what may be attributed to measurement error).41,42,43,44 The treatment difference at week 10 in this phase 3 trial (−5.59) was similar to that in the phase 2 trial (−5.08).24 At the individual-patient level, a greater proportion of participants receiving brexpiprazole + sertraline achieved 30% or greater improvement at week 10 (68.5%, vs 48.2% for sertraline + placebo), which is a common definition of clinically meaningful change in PTSD trials.42,45 Finally, although this trial was not powered for analyses of subgroups and sample sizes were small, subgroup analyses were generally consistent with the primary analysis.
The rate of discontinuation due to adverse events in this trial was low (3.9% for brexpiprazole + sertraline vs 10.2% for sertraline + placebo), indicating that most participants tolerated brexpiprazole and sertraline combination treatment. Of note, almost three-quarters of participants were PTSD-pharmacotherapy naive at baseline, which is not uncommon in PTSD due to various treatment barriers.46,47 The safety profile of brexpiprazole + sertraline was generally similar to that of sertraline + placebo. In both treatment arms the only TEAE with incidence greater than 10% was nausea, a known adverse effect of sertraline treatment.48 Weight gain (objectively, and as a TEAE) was greater among participants receiving brexpiprazole + sertraline than sertraline + placebo; previous analyses in schizophrenia and major depressive disorder show that brexpiprazole is associated with moderate weight gain (+3-4 kg over 1 year).49,50 The incidence of activating and sedating TEAEs (a concern with some antipsychotics51) was generally low, although fatigue (6.8% vs 4.1%) and somnolence (5.4% vs 2.6%) had a higher incidence with brexpiprazole + sertraline than sertraline + placebo. Overall, brexpiprazole + sertraline had a safety profile consistent with that of brexpiprazole in approved indications.49,50,52,53,54,55,56
Strengths and Limitations
Strengths of this trial include the enrollment of participants with different traumas representative of the patient population, the predominantly PTSD pharmacotherapy–naive sample, the placebo run-in period to reduce placebo response,57 the blinding of trial design elements, and the concurrent use of clinician- and patient-reported outcomes.
Limitations include the patient eligibility criteria, restrictions on concomitant therapy, and the lack of non-US sites, which mean that the results may not be generalizable to a broader population with PTSD. Specifically, the exclusion of patients with a current major depressive episode is both a strength (to show a specific effect on PTSD) and a limitation (given the high prevalence of comorbid depression in PTSD58). Results of this trial support starting patients on combination therapy; however, the effect of adding brexpiprazole to existing sertraline therapy was not evaluated. This trial cannot be used to advise on duration of treatment, and longer-term efficacy and safety data are needed.
Conclusions
In this randomized clinical trial, brexpiprazole + sertraline demonstrated efficacy on overall PTSD symptoms and on each of the 4 PTSD symptom clusters compared with treatment with sertraline + placebo. Brexpiprazole + sertraline was also associated with improvements in depression, anxiety, and psychosocial functioning. No new safety signals were identified relative to trials of brexpiprazole in approved indications. A low rate of discontinuation due to adverse events indicated that brexpiprazole + sertraline treatment was tolerated by most participants. Overall, this trial demonstrated the utility of the combination of brexpiprazole + sertraline as a new efficacious treatment for PTSD.
Trial Protocol and Statistical Analysis Plan.
eMethods. Statistical Analysis
eFigure 1. Trial Design
eFigure 2. Change in CAPS-5 Total Score From Randomization (Week 1) to Week 10 by Subgroup (Efficacy Sample)
eFigure 3. Change in CAPS-5 Total Score (Full Analysis Set)
eFigure 4. Change in PCL-5 Total Score (Efficacy Sample)
eTable 1. List of Principal Investigators and Trial Sites
eTable 2. CAPS-5 Total Score Sensitivity Analysis—MNAR Using Pattern Mixture Model With Multiple Imputation—Assume All Dropouts as MNAR (Efficacy Sample)
eTable 3. Summary of Exploratory Efficacy Results (Efficacy Sample)
eTable 4. Body Weight, Metabolic Parameters, Vital Signs, QT Interval, and Extrapyramidal symptoms (Safety Sample)
eReferences
Data Sharing Statement.
References
- 1.Lancaster CL, Teeters JB, Gros DF, Back SE. Posttraumatic stress disorder: overview of evidence-based assessment and treatment. J Clin Med. 2016;5(11):105. doi: 10.3390/jcm5110105 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.American Psychiatric Association . Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition, Text Revision. American Psychiatric Association; 2022. [Google Scholar]
- 3.Kilpatrick DG, Resnick HS, Milanak ME, Miller MW, Keyes KM, Friedman MJ. National estimates of exposure to traumatic events and PTSD prevalence using DSM-IV and DSM-5 criteria. J Trauma Stress. 2013;26(5):537-547. doi: 10.1002/jts.21848 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Schein J, Houle C, Urganus A, et al. Prevalence of posttraumatic stress disorder in the US: a systematic literature review. Curr Med Res Opin. 2021;37(12):2151-2161. doi: 10.1080/03007995.2021.1978417 [DOI] [PubMed] [Google Scholar]
- 5.Koenen KC, Ratanatharathorn A, Ng L, et al. Posttraumatic stress disorder in the World Mental Health Surveys. Psychol Med. 2017;47(13):2260-2274. doi: 10.1017/S0033291717000708 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Kessler RC, Aguilar-Gaxiola S, Alonso J, et al. Trauma and PTSD in the WHO World Mental Health Surveys. Eur J Psychotraumatol. 2017;8(suppl 5):1353383. doi: 10.1080/20008198.2017.1353383 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Yehuda R, Hoge CW, McFarlane AC, et al. Posttraumatic stress disorder. Nat Rev Dis Primers. 2015;1:15057. doi: 10.1038/nrdp.2015.57 [DOI] [PubMed] [Google Scholar]
- 8.Wilcox HC, Storr CL, Breslau N. Posttraumatic stress disorder and suicide attempts in a community sample of urban American young adults. Arch Gen Psychiatry. 2009;66(3):305-311. doi: 10.1001/archgenpsychiatry.2008.557 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Williams T, Phillips NJ, Stein DJ, Ipser JC. Pharmacotherapy for posttraumatic stress disorder (PTSD). Cochrane Database Syst Rev. 2022;3(3):CD002795. doi: 10.1002/14651858.CD002795.pub3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Davis LL, Urganus A, Gagnon-Sanschagrin P, et al. Patient journey before and after a formal posttraumatic stress disorder diagnosis in adults in the US—a retrospective claims study. Curr Med Res Opin. 2023;39(11):1523-1532. doi: 10.1080/03007995.2023.2269839 [DOI] [PubMed] [Google Scholar]
- 11.Krystal JH, Davis LL, Neylan TC, et al. It is time to address the crisis in the pharmacotherapy of posttraumatic stress disorder: a consensus statement of the PTSD Psychopharmacology Working Group. Biol Psychiatry. 2017;82(7):e51-e59. doi: 10.1016/j.biopsych.2017.03.007 [DOI] [PubMed] [Google Scholar]
- 12.Lee JH, Lee S, Kim JH. Amygdala circuits for fear memory: a key role for dopamine regulation. Neuroscientist. 2017;23(5):542-553. doi: 10.1177/1073858416679936 [DOI] [PubMed] [Google Scholar]
- 13.Pan X, Kaminga AC, Wen SW, Liu A. Catecholamines in posttraumatic stress disorder: a systematic review and meta-analysis. Front Mol Neurosci. 2018;11:450. doi: 10.3389/fnmol.2018.00450 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Maeda K, Sugino H, Akazawa H, et al. Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator. J Pharmacol Exp Ther. 2014;350(3):589-604. doi: 10.1124/jpet.114.213793 [DOI] [PubMed] [Google Scholar]
- 15.Krystal JH, Neumeister A. Noradrenergic and serotonergic mechanisms in the neurobiology of posttraumatic stress disorder and resilience. Brain Res. 2009;1293:13-23. doi: 10.1016/j.brainres.2009.03.044 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Kane JM, Skuban A, Ouyang J, et al. A multicenter, randomized, double-blind, controlled phase 3 trial of fixed-dose brexpiprazole for the treatment of adults with acute schizophrenia. Schizophr Res. 2015;164(1-3):127-135. doi: 10.1016/j.schres.2015.01.038 [DOI] [PubMed] [Google Scholar]
- 17.Correll CU, Skuban A, Ouyang J, et al. Efficacy and safety of brexpiprazole for the treatment of acute schizophrenia: a 6-week randomized, double-blind, placebo-controlled trial. Am J Psychiatry. 2015;172(9):870-880. doi: 10.1176/appi.ajp.2015.14101275 [DOI] [PubMed] [Google Scholar]
- 18.Lee D, Slomkowski M, Hefting N, et al. Brexpiprazole for the treatment of agitation in Alzheimer dementia: a randomized clinical trial. JAMA Neurol. 2023;80(12):1307-1316. doi: 10.1001/jamaneurol.2023.3810 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Grossberg GT, Kohegyi E, Mergel V, et al. Efficacy and safety of brexpiprazole for the treatment of agitation in Alzheimer dementia: two 12-week, randomized, double-blind, placebo-controlled trials. Am J Geriatr Psychiatry. 2020;28(4):383-400. doi: 10.1016/j.jagp.2019.09.009 [DOI] [PubMed] [Google Scholar]
- 20.Hobart M, Skuban A, Zhang P, et al. A randomized, placebo-controlled study of the efficacy and safety of fixed-dose brexpiprazole 2 mg/d as adjunctive treatment of adults with major depressive disorder. J Clin Psychiatry. 2018;79(4):17m12058. doi: 10.4088/JCP.17m12058 [DOI] [PubMed] [Google Scholar]
- 21.Hobart M, Skuban A, Zhang P, et al. Efficacy and safety of flexibly dosed brexpiprazole for the adjunctive treatment of major depressive disorder: a randomized, active-referenced, placebo-controlled study. Curr Med Res Opin. 2018;34(4):633-642. doi: 10.1080/03007995.2018.1430220 [DOI] [PubMed] [Google Scholar]
- 22.Thase ME, Youakim JM, Skuban A, et al. Efficacy and safety of adjunctive brexpiprazole 2 mg in major depressive disorder: a phase 3, randomized, placebo-controlled study in patients with inadequate response to antidepressants. J Clin Psychiatry. 2015;76(9):1224-1231. doi: 10.4088/JCP.14m09688 [DOI] [PubMed] [Google Scholar]
- 23.Thase ME, Youakim JM, Skuban A, et al. Adjunctive brexpiprazole 1 and 3 mg for patients with major depressive disorder following inadequate response to antidepressants: a phase 3, randomized, double-blind study. J Clin Psychiatry. 2015;76(9):1232-1240. doi: 10.4088/JCP.14m09689 [DOI] [PubMed] [Google Scholar]
- 24.Behl S, Lee D, Zeng H, et al. Efficacy of brexpiprazole in combination with sertraline for patients with post-traumatic stress disorder: summary of data from Phase 2 and Phase 3 randomized clinical trials. Poster presented at ASCP Annual Meeting; May 30, 2024; Miami Beach, FL. Accessed September 4, 2024. https://ascpp.org/ascp-meetings/ascp-annual-meeting/
- 25.American Psychiatric Association . Diagnostic and Statistical Manual of Mental Disorders. Fifth edition. American Psychiatric Association; 2013. [Google Scholar]
- 26.Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59(suppl 20):22-33. [PubMed] [Google Scholar]
- 27.Weathers FW, Blake DD, Schnurr PP, Kaloupek DG, Marx BP, Keane TM. Clinician-administered PTSD Scale for DSM-5 (CAPS-5). Updated April 13, 2018. Accessed March 13, 2024. https://www.ptsd.va.gov/professional/assessment/adult-int/caps.asp
- 28.Weathers FW, Blake DD, Schnurr PP, Kaloupek DG, Marx BP, Keane TM. The Life Events Checklist for DSM-5 (LEC-5)-Extended. Updated April 12, 2018. Accessed March 13, 2024. https://www.ptsd.va.gov/professional/assessment/te-measures/life_events_checklist.asp
- 29.Dunlop BW, Kaye JL, Youngner C, Rothbaum B. Assessing treatment-resistant posttraumatic stress disorder: the Emory Treatment Resistance Interview for PTSD (E-TRIP). Behav Sci (Basel). 2014;4(4):511-527. doi: 10.3390/bs4040511 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Weathers FW, Bovin MJ, Lee DJ, et al. The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5): development and initial psychometric evaluation in military veterans. Psychol Assess. 2018;30(3):383-395. doi: 10.1037/pas0000486 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Weathers FW, Keane TM, Davidson JRT. Clinician-administered PTSD scale: a review of the first 10 years of research. Depress Anxiety. 2001;13(3):132-156. doi: 10.1002/da.1029 [DOI] [PubMed] [Google Scholar]
- 32.Guy W. ECDEU Assessment Manual for Psychopharmacology, Revised. National Institute of Mental Health; 1976. [Google Scholar]
- 33.Weathers FW, Litz BT, Keane TM, Palmieri PA, Marx BP, Schnurr PP. The PTSD Checklist for DSM-5 (PCL-5) – Extended Criterion A. Updated August 29, 2023. Accessed March 13, 2024. https://www.ptsd.va.gov/professional/assessment/adult-sr/ptsd-checklist.asp
- 34.Kleiman SE, Bovin MJ, Black SK, et al. Psychometric properties of a brief measure of posttraumatic stress disorder-related impairment: the Brief Inventory of Psychosocial Functioning. Psychol Serv. 2020;17(2):187-194. doi: 10.1037/ser0000306 [DOI] [PubMed] [Google Scholar]
- 35.Zigmond AS, Snaith RP. The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand. 1983;67(6):361-370. doi: 10.1111/j.1600-0447.1983.tb09716.x [DOI] [PubMed] [Google Scholar]
- 36.Ware JE Jr, Gandek B. Overview of the SF-36 Health Survey and the International Quality of Life Assessment (IQOLA) project. J Clin Epidemiol. 1998;51(11):903-912. doi: 10.1016/S0895-4356(98)00081-X [DOI] [PubMed] [Google Scholar]
- 37.Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168(12):1266-1277. doi: 10.1176/appi.ajp.2011.10111704 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Simpson GM, Angus JWS. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl. 1970;212:11-19. doi: 10.1111/j.1600-0447.1970.tb02066.x [DOI] [PubMed] [Google Scholar]
- 39.Barnes TRE. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672-676. doi: 10.1192/bjp.154.5.672 [DOI] [PubMed] [Google Scholar]
- 40.US Food & Drug Administration . E9(R1) Statistical Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials Guidance for Industry. US Food & Drug Administration; 2021. [Google Scholar]
- 41.Marx BP, Lee DJ, Norman SB, et al. Reliable and clinically significant change in the clinician-administered PTSD Scale for DSM-5 and PTSD Checklist for DSM-5 among male veterans. Psychol Assess. 2022;34(2):197-203. doi: 10.1037/pas0001098 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Halvorsen JØ. Defining clinically significant change. Br J Psychiatry. 2016;209(1):85. doi: 10.1192/bjp.209.1.85 [DOI] [PubMed] [Google Scholar]
- 43.Halvorsen JØ, Stenmark H. Narrative exposure therapy for posttraumatic stress disorder in tortured refugees: a preliminary uncontrolled trial. Scand J Psychol. 2010;51(6):495-502. doi: 10.1111/j.1467-9450.2010.00821.x [DOI] [PubMed] [Google Scholar]
- 44.Monson CM, Schnurr PP, Resick PA, Friedman MJ, Young-Xu Y, Stevens SP. Cognitive processing therapy for veterans with military-related posttraumatic stress disorder. J Consult Clin Psychol. 2006;74(5):898-907. doi: 10.1037/0022-006X.74.5.898 [DOI] [PubMed] [Google Scholar]
- 45.Institute of Medicine . Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence. The National Academies Press; 2008. [Google Scholar]
- 46.Kantor V, Knefel M, Lueger-Schuster B. Perceived barriers and facilitators of mental health service utilization in adult trauma survivors: a systematic review. Clin Psychol Rev. 2017;52:52-68. doi: 10.1016/j.cpr.2016.12.001 [DOI] [PubMed] [Google Scholar]
- 47.Nobles CJ, Valentine SE, Gerber MW, Shtasel DL, Marques L. Predictors of treatment utilization and unmet treatment need among individuals with posttraumatic stress disorder from a national sample. Gen Hosp Psychiatry. 2016;43:38-45. doi: 10.1016/j.genhosppsych.2016.09.001 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48.Almatica Pharma LLC . Sertraline hydrochloride capsules, for oral use. Prescribing information (US). Accessed May 24, 2024. https://www.sertralinecaps.com/static/documents/prescribing-information.pdf
- 49.Newcomer JW, Eriksson H, Zhang P, Meehan SR, Weiss C. Changes in metabolic parameters and body weight in patients with major depressive disorder treated with adjunctive brexpiprazole: pooled analysis of phase 3 clinical studies. J Clin Psychiatry. 2019;80(6):18m12680. doi: 10.4088/JCP.18m12680 [DOI] [PubMed] [Google Scholar]
- 50.Newcomer JW, Eriksson H, Zhang P, Weiller E, Weiss C. Changes in metabolic parameters and body weight in brexpiprazole-treated patients with acute schizophrenia: pooled analyses of phase 3 clinical studies. Curr Med Res Opin. 2018;34(12):2197-2205. doi: 10.1080/03007995.2018.1498779 [DOI] [PubMed] [Google Scholar]
- 51.Citrome L. Activating and sedating adverse effects of second-generation antipsychotics in the treatment of schizophrenia and major depressive disorder: absolute risk increase and number needed to harm. J Clin Psychopharmacol. 2017;37(2):138-147. doi: 10.1097/JCP.0000000000000665 [DOI] [PubMed] [Google Scholar]
- 52.Newcomer JW, Meehan SR, Chen D, Brubaker M, Weiss C. Changes in metabolic parameters and body weight in patients with prediabetes treated with adjunctive brexpiprazole for major depressive disorder: pooled analysis of short- and long-term clinical studies. J Clin Psychiatry. 2023;84(5):23m14786. doi: 10.4088/JCP.23m14786 [DOI] [PubMed] [Google Scholar]
- 53.Clayton AH, Ivkovic J, Chen D, George V, Hobart M. Effect of brexpiprazole on prolactin and sexual functioning: an analysis of short- and long-term study data in major depressive disorder. J Clin Psychopharmacol. 2020;40(6):560-567. doi: 10.1097/JCP.0000000000001297 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54.Ivkovic J, Lindsten A, George V, Eriksson H, Hobart M. Effect of brexpiprazole on prolactin: an analysis of short- and long-term studies in schizophrenia. J Clin Psychopharmacol. 2019;39(1):13-19. doi: 10.1097/JCP.0000000000000979 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55.Kane JM, Skuban A, Hobart M, et al. Overview of short- and long-term tolerability and safety of brexpiprazole in patients with schizophrenia. Schizophr Res. 2016;174(1-3):93-98. doi: 10.1016/j.schres.2016.04.013 [DOI] [PubMed] [Google Scholar]
- 56.Thase ME, Zhang P, Weiss C, Meehan SR, Hobart M. Efficacy and safety of brexpiprazole as adjunctive treatment in major depressive disorder: overview of 4 short-term studies. Expert Opin Pharmacother. 2019;20(15):1907-1916. doi: 10.1080/14656566.2019.1638913 [DOI] [PubMed] [Google Scholar]
- 57.Chen YF, Yang Y, Hung HMJ, Wang SJ. Evaluation of performance of some enrichment designs dealing with high placebo response in psychiatric clinical trials. Contemp Clin Trials. 2011;32(4):592-604. doi: 10.1016/j.cct.2011.04.006 [DOI] [PubMed] [Google Scholar]
- 58.Rytwinski NK, Scur MD, Feeny NC, Youngstrom EA. The co-occurrence of major depressive disorder among individuals with posttraumatic stress disorder: a meta-analysis. J Trauma Stress. 2013;26(3):299-309. doi: 10.1002/jts.21814 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol and Statistical Analysis Plan.
eMethods. Statistical Analysis
eFigure 1. Trial Design
eFigure 2. Change in CAPS-5 Total Score From Randomization (Week 1) to Week 10 by Subgroup (Efficacy Sample)
eFigure 3. Change in CAPS-5 Total Score (Full Analysis Set)
eFigure 4. Change in PCL-5 Total Score (Efficacy Sample)
eTable 1. List of Principal Investigators and Trial Sites
eTable 2. CAPS-5 Total Score Sensitivity Analysis—MNAR Using Pattern Mixture Model With Multiple Imputation—Assume All Dropouts as MNAR (Efficacy Sample)
eTable 3. Summary of Exploratory Efficacy Results (Efficacy Sample)
eTable 4. Body Weight, Metabolic Parameters, Vital Signs, QT Interval, and Extrapyramidal symptoms (Safety Sample)
eReferences
Data Sharing Statement.