PTSD

Evidence-based psychotherapy (EBP) for posttraumatic stress disorder (PTSD), such as prolonged exposure (PE), is supported by multiple clinical practice guidelines and is expected to be available to veterans served by the Veterans Health Administration (VHA).^1-5 However, traditional models of EBP delivery with 1 or 2 sessions weekly have high dropout rates.^6,7 Few veterans who could benefit from such EBPs receive them, and those who do have low completion rates.^8,9 Over a 15-year period, VHA records review of > 265,500 veterans with PTSD showed only 9.1% completed EBP treatment that included but was not limited to PE.¹⁰

One empirically supported solution that has yet to be widely implemented is delivering EBPs for PTSD in a massed or accelerated format of ≥ 3 sessions weekly.¹¹ While these massed models of EBP delivery for PTSD are promising, their implementation is limited in federal health care settings, such as the VHA.¹² PE therapy is a first-line treatment for PTSD that has been evaluated in numerous clinical trials since the early 1990s and in a wide range of trauma populations.^13,14 Massed PE is effective and PE has been found to be effective both in-person and via telehealth.^11,15,16

Another approach to accelerated PE is the inclusion of a massed PE course within a broader treatment context that includes augmentation of the massed PE with additional services, this is referred to as an intensive outpatient model (IOP).¹⁷ PE-IOP has also been shown to be feasible, acceptable, and effective with increased completion rates in comparison to the traditional (1 or 2 sessions weekly) model of PE.^12,16,18,19 Ragsdale et al describe a 2-week IOP with multiple treatment tracks, including a PTSD track. The PTSD treatment track includes massed PE and additional standard services including case management, wellness services, family services, and a single session effective behaviors group. Additional augmentation services are available when clinically indicated (eg, repetitive transcranial magnetic stimulation, transcranial direct current stimulation treatment, psychoeducation, motivational interviewing, and/or relapse prevention).¹⁷

Rauch et al studied the first 80 patients completing an IOP program that consisted of PE (5 sessions weekly) and complementary interventions (eg, mindfulness and yoga) and reported a 96% retention rate, significant reductions of self-reported PTSD symptoms, significant reduction in self-reported co-occurring depression symptoms, and significant increase in self-reported satisfaction with social functioning. ¹⁸ In another study, Sherril et al explored patient reactions to participation in massed PE (5 sessions weekly) and found that patients reported significantly more positive than negative reactions. Sherrill et al noted that according to patients, the benefits of massed PE included a structured format that limits avoidance and distraction. The resulting fast pace of progress enhanced motivation; however, drawbacks included short-term discomfort and time demands.¹⁹ Yamokoski et al explored the feasibility of massed PE in a larger study of PTSD treatment in an intensive outpatient track (IOT) in a VHA PTSD clinic with minimal staffing. The 48 patients who completed IOT PTSD treatment in 2 or 4 weeks (including 35 patients who received massed PE) had high retention rates (85%), reported high satisfaction, and had significantly reduced PTSD and depression symptoms.¹²

The massed IOT PE model implemented by Yamokoski et al included the primary EBP intervention of massed PE with adjunctive groups. The addition of these groups increased both retention and patient-reported satisfaction. The PE-IOP model implemented by Rauch et al and Sherrill et al also included wellness and educational groups, as well as access to complementary interventions such as mindfulness and yoga.^18,19 The addition of wellness education along with a primary EBP aligned with the VHA focus on whole health well-being and wellness. The whole health approach includes understanding the factors that motivate a patient toward health and well-being, provision of health education, and providing access to complementary interventions such as mindfulness.²⁰ Dryden et al describe the whole health transformation within VHA as a proactive approach to addressing employee and patient wellness and health. Their research found that the whole health model promoted well-being in patients and staff and was sustained even during the COVID-19 pandemic.²¹ Dryden et al also noted that use of virtual technologies facilitated and promoted continued whole health implementation. The literature illustrates that: (1) massed PE can be provided with complementary education and wellness offerings, and that such offerings may increase both retention and satisfaction by enriching the massed PE treatment (eg, delivering PE-IOP); (2) whole health including wellness education and complementary interventions (eg, mindfulness, motivational enhancement) promotes well-being in both patients and mental health professionals; and (3) whole health education and complementary interventions can be delivered virtually.

Health Care Need

Prior to the implementation of a massed EBP for PTSD program at US Department of Veterans Affairs (VA) Pacific Islands Health Care System (VAPIHCS), our setting included a traditional outpatient program for treatment of PTSD and a 12- bed residential program for treatment of PTSD for male-identified (self-identified and identified as male in the electronic medical record) veterans via a cohort model with an 8- or 9-week length of stay. Both programs were located on Oahu. Thus, veterans who received care at VAPIHCS had access to PE in both outpatient and residential settings and via in-person and telehealth modalities. However, their access to PE was limited to the traditional models of PE delivery (eg, 1 or 2 session per week) and very few veterans outside of the island of Oahu had accessed PE treatment for PTSD. Moreover, when looking at PE reach within VAPIHCS, in the fiscal year prior to the implementation of the massed EBP program, only 32 of the > 5000 eligible veterans with a PTSD diagnosis had received PE. VAPIHCS serves veterans in a catchment area across the Pacific Basin which includes 3 time zones: Hawaii Standard Time (HST), Chamorro Standard Time (ChST), and Samoa Standard Time (SST). ChST is 20 hours ahead of HST, making service delivery that is inclusive for patients in Guam and Saipan especially challenging when providing care from Hawaii or other US states or territories. Given all of this, implementation of a new program offering accelerated PE virtually to any veterans with PTSD within the VAPIHCS would increase access to and reduce barriers to receiving PE.

PROGRAM DESCRIPTION

The Intensive Virtual EBP Team (iVET) for PTSD consists of an accelerated course of PE therapy and whole health education provided via VA Video Connect (VVC). iVET is a 3-week program and includes 3 parts: (1) massed individual PE therapy for PTSD; (2) group whole health and wellness classes; and (3) individual health coaching to address personal wellness goals. Programming is offered over 10-hour days to increase access across multiple time zones, especially to allow for participation in Guam and Saipan.

When a patient is referred to the iVET, their first contact is a video (or telephone) appointment with a registered nurse (RN) for a screening session. The screening session is designed to educate the patient about the program, including interventions, time commitment, and resources required for participation. In addition, following the educational discussion, the RN completes screening for safety with the patient including suicidal ideation and risk, as well as intimate partner violence risk. If urgent safety concerns are present, a licensed social worker or psychologist will join the screening to complete further assessment of risk and to address any safety concerns. Following screening, patients are scheduled for a VVC intake with a licensed therapist (social worker or psychologist) to complete the Clinician-Administered PTSD Scale (CAPS-5) for the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition), a clinical interview for PTSD assessment. Patients are also sent a secure link to complete a measurement-based care (MBC) battery of self-report measures including measures assessing demographics, PTSD symptoms, anxiety symptoms, depression symptoms, substance use, quality of life (QOL), and satisfaction with mental health care. The results of the CAPS-5 and self-report measures are discussed with the patient during the intake session when planning next steps and engaging in shared decision-making. This initial VVC intake not only allows for diagnostic goodness of fit but also provides the opportunity to troubleshoot any technical difficulties the patients might have with the virtual platforms.

There are minimal exclusion criteria for participation in iVET, which include active unmanaged psychosis or manic symptoms, recent suicidal crises (attempt within 8 weeks), active nonsuicidal self-injurious behaviors (within 8 weeks), and moderate-to-severe cognitive impairment. Following intake, patients are scheduled to begin their course of care with iVET. Upon completion of intake, patients are sent program materials for their individual and group classes, asked to obtain or request a recording device, and told they will receive email links for all VVC appointments. Patients are admitted to the iVET in a rolling admission fashion, thereby increasing access when compared to closed group and/or cohort models of care.

Patients receiving care in iVET attend 2 or 3 telehealth appointments daily with practice exercises daily between telehealth sessions. The primary EBP intervention in the iVET for PTSD program is a massed or accelerated course of PE, which includes 4 primary components: psychoeducation, in-vivo exposure, imaginal exposure, and breathing retraining. Specifically, PE is delivered in 4 90-minute individual sessions weekly allowing completion of the full PE protocol, to fidelity, in 3 weeks. In addition to receiving this primary intervention, patients also participate in four 50-minute group sessions per week of a whole health and wellness education class and have access to one 30- to 60-minute session weekly of individual health coaching should they wish to set wellness goals and receive coaching in support of attaining wellness goals. During iVET, patients are invited to complete MBC batteries of selfreport measures including measures assessing PTSD symptoms, anxiety symptoms, depression symptoms, substance use, QOL, and satisfaction with mental health care at sessions 1, 5, 9, and the final session of PE. Following discharge from the iVET, patients are offered 1-month, 3-month, and 6-month individual postdischarge check-up sessions with a therapist where they are invited to complete MBC measures and review relapse prevention and maintenance of treatment gains. Likewise, they are offered 1-month, 3-month, and 6-month postdischarge check-up sessions with an RN focused on maintaining wellness gains.

The iVET for PTSD staff includes 3 therapists (psychologists or social workers) and an RN. Additionally, the iVET for PTSD is supported by a program manager and a program support assistant. The primary cost of the program is salary for staff. Additional iVET for PTSD resources included computer equipment for staff and minimal supplies. Due to the virtual environment of care, iVET staff telework and do not require physical space within VAPIHCS.

OUTCOMES

All veterans receiving care in iVET for PTSD are invited to complete a MBC at multiple timepoints including pretreatment, during PE treatment, and posttreatment. The MBC measures included self-reported demographics, a 2-item measure of satisfaction with mental health services, the Brief Addiction Monitor-Intensive Outpatient Program questionnaire,²² the Generalized Anxiety Disorder-7 scale,^23, the Patient Health Questionnaire (PHQ-9),²⁴ the QOL Enjoyment and Satisfaction Questionnaire- Short Form,²⁵ and the PTSD Checklist for DSM-5 (PCL-5), both weekly and monthly versions. ^26,27

The retention rate has averaged 81% since the iVET for PTSD opened in 2022. To date, 132 veterans have completed the iVET for PTSD program, including a full course of massed PE (Table 1). Veterans experienced reduced PTSD (P < .005), depression (P < .005), anxiety (P < .005), and substance use risk (P < .005). Veterans experienced improved QOL (P < .005) and reported high satisfaction with mental health care in iVET for PTSD (Table 2). Veterans also experienced reduced thoughts of death or suicidal ideation (SI) based on PHQ-9 item 9 responses. When looking categorically at presence or absence of SI on PHQ-9 item 9, a significant relationship was found between the absence of suicidal ideation and completion of a course of massed PE: X² (1, N = 132) = 13.75, P < .001. In addition, veterans who completed the program showed a significant decrease in severity of SI as measured continuously (range, 0-3) on PHQ-9 item 9 (P < .005).

Another important aspect to consider when implementing massed models of EBP is the impact on employee well-being and job satisfaction. The impact of EBP on staff was assessed following the initial EBP project. To explore this further, all staff members in the iVET for PTSD were invited to engage in a small program evaluation. iVET staff were guided through a visualization meditation intended to recall a typical workday 1 month prior to starting their new position with iVET. After the visualization meditation, staff completed the Professional Quality of Life (ProQOL) scale, a 30-item, self-reported questionnaire for health care workers that evaluates compassion satisfaction, perceived support, burnout, secondary traumatic stress, and moral distress.²⁸ One week later, staff were asked to complete the ProQOL again to capture their state after the first 6 months into their tenure as iVET staff. iVET employees experienced significantly increased perceived support (P < .05), reduced burnout (P < .05), reduced secondary traumatic stress (P < .05), and reduced moral distress (P < .05). Team members also remarked on the rewarding nature of the work and care model.

Future Directions

Future research should aim to sustain these outcomes as the iVET program continues to serve more veterans. Another important line of inquiry is longer-term follow-up, as exploring if outcomes are maintained over time is an important question that has not been answered in this article. In addition, we hope to see the accelerated model of care applied to treatment of other presenting concerns in mental health treatment (eg, anxiety, depression, insomnia). Expansion of accelerated mental health treatment into other federal and non-federal health care settings is another worthy direction. Finally, while short term (6 months) assessment of staff satisfaction in iVET was promising, ongoing assessment staff satisfaction over a longer timeframe (1-5 years) is also important.

CONCLUSIONS

PE for PTSD has been demonstrated to be effective and improve functioning and is supported by multiple clinical practice guidelines.1-5 However, as federal practitioners, we must consider the reality that many of the individuals who could benefit are not engaging in PE and there is a high dropout rate for those that do. It is vital that we envision a future state where access to PE for PTSD is equitable and inclusive, retention rates are dramatically improved, and clinicians providing PE do not experience high rates of burnout.

We must continue exploring how we can better care for our patients and colleagues. We posit that the development of programs, or tracks within existing programs, that provide massed or accelerated PE for PTSD with virtual delivery options is an imperative step toward improved care. Federal health care settings treating trauma-exposed patients with PTSD, such as those within the US Department of Defense, Indian Health Services, Federal Bureau of Prisons, and VA, are well positioned to implement programs like iVET. We believe this model of care has great merit and foresee a future where all patients seeking PTSD treatment have the option to complete an accelerated or massed course of PE should they so desire. The experiences outlined in this article illustrate the feasibility, acceptability, and sustainability of such programs without requiring substantial staffing and financial resources.

Evidence-based psychotherapy (EBP) for posttraumatic stress disorder (PTSD), such as prolonged exposure (PE), is supported by multiple clinical practice guidelines and is expected to be available to veterans served by the Veterans Health Administration (VHA).^1-5 However, traditional models of EBP delivery with 1 or 2 sessions weekly have high dropout rates.^6,7 Few veterans who could benefit from such EBPs receive them, and those who do have low completion rates.^8,9 Over a 15-year period, VHA records review of > 265,500 veterans with PTSD showed only 9.1% completed EBP treatment that included but was not limited to PE.¹⁰

One empirically supported solution that has yet to be widely implemented is delivering EBPs for PTSD in a massed or accelerated format of ≥ 3 sessions weekly.¹¹ While these massed models of EBP delivery for PTSD are promising, their implementation is limited in federal health care settings, such as the VHA.¹² PE therapy is a first-line treatment for PTSD that has been evaluated in numerous clinical trials since the early 1990s and in a wide range of trauma populations.^13,14 Massed PE is effective and PE has been found to be effective both in-person and via telehealth.^11,15,16

Another approach to accelerated PE is the inclusion of a massed PE course within a broader treatment context that includes augmentation of the massed PE with additional services, this is referred to as an intensive outpatient model (IOP).¹⁷ PE-IOP has also been shown to be feasible, acceptable, and effective with increased completion rates in comparison to the traditional (1 or 2 sessions weekly) model of PE.^12,16,18,19 Ragsdale et al describe a 2-week IOP with multiple treatment tracks, including a PTSD track. The PTSD treatment track includes massed PE and additional standard services including case management, wellness services, family services, and a single session effective behaviors group. Additional augmentation services are available when clinically indicated (eg, repetitive transcranial magnetic stimulation, transcranial direct current stimulation treatment, psychoeducation, motivational interviewing, and/or relapse prevention).¹⁷

Rauch et al studied the first 80 patients completing an IOP program that consisted of PE (5 sessions weekly) and complementary interventions (eg, mindfulness and yoga) and reported a 96% retention rate, significant reductions of self-reported PTSD symptoms, significant reduction in self-reported co-occurring depression symptoms, and significant increase in self-reported satisfaction with social functioning. ¹⁸ In another study, Sherril et al explored patient reactions to participation in massed PE (5 sessions weekly) and found that patients reported significantly more positive than negative reactions. Sherrill et al noted that according to patients, the benefits of massed PE included a structured format that limits avoidance and distraction. The resulting fast pace of progress enhanced motivation; however, drawbacks included short-term discomfort and time demands.¹⁹ Yamokoski et al explored the feasibility of massed PE in a larger study of PTSD treatment in an intensive outpatient track (IOT) in a VHA PTSD clinic with minimal staffing. The 48 patients who completed IOT PTSD treatment in 2 or 4 weeks (including 35 patients who received massed PE) had high retention rates (85%), reported high satisfaction, and had significantly reduced PTSD and depression symptoms.¹²

The massed IOT PE model implemented by Yamokoski et al included the primary EBP intervention of massed PE with adjunctive groups. The addition of these groups increased both retention and patient-reported satisfaction. The PE-IOP model implemented by Rauch et al and Sherrill et al also included wellness and educational groups, as well as access to complementary interventions such as mindfulness and yoga.^18,19 The addition of wellness education along with a primary EBP aligned with the VHA focus on whole health well-being and wellness. The whole health approach includes understanding the factors that motivate a patient toward health and well-being, provision of health education, and providing access to complementary interventions such as mindfulness.²⁰ Dryden et al describe the whole health transformation within VHA as a proactive approach to addressing employee and patient wellness and health. Their research found that the whole health model promoted well-being in patients and staff and was sustained even during the COVID-19 pandemic.²¹ Dryden et al also noted that use of virtual technologies facilitated and promoted continued whole health implementation. The literature illustrates that: (1) massed PE can be provided with complementary education and wellness offerings, and that such offerings may increase both retention and satisfaction by enriching the massed PE treatment (eg, delivering PE-IOP); (2) whole health including wellness education and complementary interventions (eg, mindfulness, motivational enhancement) promotes well-being in both patients and mental health professionals; and (3) whole health education and complementary interventions can be delivered virtually.

Health Care Need

Prior to the implementation of a massed EBP for PTSD program at US Department of Veterans Affairs (VA) Pacific Islands Health Care System (VAPIHCS), our setting included a traditional outpatient program for treatment of PTSD and a 12- bed residential program for treatment of PTSD for male-identified (self-identified and identified as male in the electronic medical record) veterans via a cohort model with an 8- or 9-week length of stay. Both programs were located on Oahu. Thus, veterans who received care at VAPIHCS had access to PE in both outpatient and residential settings and via in-person and telehealth modalities. However, their access to PE was limited to the traditional models of PE delivery (eg, 1 or 2 session per week) and very few veterans outside of the island of Oahu had accessed PE treatment for PTSD. Moreover, when looking at PE reach within VAPIHCS, in the fiscal year prior to the implementation of the massed EBP program, only 32 of the > 5000 eligible veterans with a PTSD diagnosis had received PE. VAPIHCS serves veterans in a catchment area across the Pacific Basin which includes 3 time zones: Hawaii Standard Time (HST), Chamorro Standard Time (ChST), and Samoa Standard Time (SST). ChST is 20 hours ahead of HST, making service delivery that is inclusive for patients in Guam and Saipan especially challenging when providing care from Hawaii or other US states or territories. Given all of this, implementation of a new program offering accelerated PE virtually to any veterans with PTSD within the VAPIHCS would increase access to and reduce barriers to receiving PE.

PROGRAM DESCRIPTION

The Intensive Virtual EBP Team (iVET) for PTSD consists of an accelerated course of PE therapy and whole health education provided via VA Video Connect (VVC). iVET is a 3-week program and includes 3 parts: (1) massed individual PE therapy for PTSD; (2) group whole health and wellness classes; and (3) individual health coaching to address personal wellness goals. Programming is offered over 10-hour days to increase access across multiple time zones, especially to allow for participation in Guam and Saipan.

When a patient is referred to the iVET, their first contact is a video (or telephone) appointment with a registered nurse (RN) for a screening session. The screening session is designed to educate the patient about the program, including interventions, time commitment, and resources required for participation. In addition, following the educational discussion, the RN completes screening for safety with the patient including suicidal ideation and risk, as well as intimate partner violence risk. If urgent safety concerns are present, a licensed social worker or psychologist will join the screening to complete further assessment of risk and to address any safety concerns. Following screening, patients are scheduled for a VVC intake with a licensed therapist (social worker or psychologist) to complete the Clinician-Administered PTSD Scale (CAPS-5) for the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition), a clinical interview for PTSD assessment. Patients are also sent a secure link to complete a measurement-based care (MBC) battery of self-report measures including measures assessing demographics, PTSD symptoms, anxiety symptoms, depression symptoms, substance use, quality of life (QOL), and satisfaction with mental health care. The results of the CAPS-5 and self-report measures are discussed with the patient during the intake session when planning next steps and engaging in shared decision-making. This initial VVC intake not only allows for diagnostic goodness of fit but also provides the opportunity to troubleshoot any technical difficulties the patients might have with the virtual platforms.

There are minimal exclusion criteria for participation in iVET, which include active unmanaged psychosis or manic symptoms, recent suicidal crises (attempt within 8 weeks), active nonsuicidal self-injurious behaviors (within 8 weeks), and moderate-to-severe cognitive impairment. Following intake, patients are scheduled to begin their course of care with iVET. Upon completion of intake, patients are sent program materials for their individual and group classes, asked to obtain or request a recording device, and told they will receive email links for all VVC appointments. Patients are admitted to the iVET in a rolling admission fashion, thereby increasing access when compared to closed group and/or cohort models of care.

Patients receiving care in iVET attend 2 or 3 telehealth appointments daily with practice exercises daily between telehealth sessions. The primary EBP intervention in the iVET for PTSD program is a massed or accelerated course of PE, which includes 4 primary components: psychoeducation, in-vivo exposure, imaginal exposure, and breathing retraining. Specifically, PE is delivered in 4 90-minute individual sessions weekly allowing completion of the full PE protocol, to fidelity, in 3 weeks. In addition to receiving this primary intervention, patients also participate in four 50-minute group sessions per week of a whole health and wellness education class and have access to one 30- to 60-minute session weekly of individual health coaching should they wish to set wellness goals and receive coaching in support of attaining wellness goals. During iVET, patients are invited to complete MBC batteries of selfreport measures including measures assessing PTSD symptoms, anxiety symptoms, depression symptoms, substance use, QOL, and satisfaction with mental health care at sessions 1, 5, 9, and the final session of PE. Following discharge from the iVET, patients are offered 1-month, 3-month, and 6-month individual postdischarge check-up sessions with a therapist where they are invited to complete MBC measures and review relapse prevention and maintenance of treatment gains. Likewise, they are offered 1-month, 3-month, and 6-month postdischarge check-up sessions with an RN focused on maintaining wellness gains.

The iVET for PTSD staff includes 3 therapists (psychologists or social workers) and an RN. Additionally, the iVET for PTSD is supported by a program manager and a program support assistant. The primary cost of the program is salary for staff. Additional iVET for PTSD resources included computer equipment for staff and minimal supplies. Due to the virtual environment of care, iVET staff telework and do not require physical space within VAPIHCS.

OUTCOMES

All veterans receiving care in iVET for PTSD are invited to complete a MBC at multiple timepoints including pretreatment, during PE treatment, and posttreatment. The MBC measures included self-reported demographics, a 2-item measure of satisfaction with mental health services, the Brief Addiction Monitor-Intensive Outpatient Program questionnaire,²² the Generalized Anxiety Disorder-7 scale,^23, the Patient Health Questionnaire (PHQ-9),²⁴ the QOL Enjoyment and Satisfaction Questionnaire- Short Form,²⁵ and the PTSD Checklist for DSM-5 (PCL-5), both weekly and monthly versions. ^26,27

The retention rate has averaged 81% since the iVET for PTSD opened in 2022. To date, 132 veterans have completed the iVET for PTSD program, including a full course of massed PE (Table 1). Veterans experienced reduced PTSD (P < .005), depression (P < .005), anxiety (P < .005), and substance use risk (P < .005). Veterans experienced improved QOL (P < .005) and reported high satisfaction with mental health care in iVET for PTSD (Table 2). Veterans also experienced reduced thoughts of death or suicidal ideation (SI) based on PHQ-9 item 9 responses. When looking categorically at presence or absence of SI on PHQ-9 item 9, a significant relationship was found between the absence of suicidal ideation and completion of a course of massed PE: X² (1, N = 132) = 13.75, P < .001. In addition, veterans who completed the program showed a significant decrease in severity of SI as measured continuously (range, 0-3) on PHQ-9 item 9 (P < .005).

Another important aspect to consider when implementing massed models of EBP is the impact on employee well-being and job satisfaction. The impact of EBP on staff was assessed following the initial EBP project. To explore this further, all staff members in the iVET for PTSD were invited to engage in a small program evaluation. iVET staff were guided through a visualization meditation intended to recall a typical workday 1 month prior to starting their new position with iVET. After the visualization meditation, staff completed the Professional Quality of Life (ProQOL) scale, a 30-item, self-reported questionnaire for health care workers that evaluates compassion satisfaction, perceived support, burnout, secondary traumatic stress, and moral distress.²⁸ One week later, staff were asked to complete the ProQOL again to capture their state after the first 6 months into their tenure as iVET staff. iVET employees experienced significantly increased perceived support (P < .05), reduced burnout (P < .05), reduced secondary traumatic stress (P < .05), and reduced moral distress (P < .05). Team members also remarked on the rewarding nature of the work and care model.

Future Directions

Future research should aim to sustain these outcomes as the iVET program continues to serve more veterans. Another important line of inquiry is longer-term follow-up, as exploring if outcomes are maintained over time is an important question that has not been answered in this article. In addition, we hope to see the accelerated model of care applied to treatment of other presenting concerns in mental health treatment (eg, anxiety, depression, insomnia). Expansion of accelerated mental health treatment into other federal and non-federal health care settings is another worthy direction. Finally, while short term (6 months) assessment of staff satisfaction in iVET was promising, ongoing assessment staff satisfaction over a longer timeframe (1-5 years) is also important.

CONCLUSIONS

PE for PTSD has been demonstrated to be effective and improve functioning and is supported by multiple clinical practice guidelines.1-5 However, as federal practitioners, we must consider the reality that many of the individuals who could benefit are not engaging in PE and there is a high dropout rate for those that do. It is vital that we envision a future state where access to PE for PTSD is equitable and inclusive, retention rates are dramatically improved, and clinicians providing PE do not experience high rates of burnout.

We must continue exploring how we can better care for our patients and colleagues. We posit that the development of programs, or tracks within existing programs, that provide massed or accelerated PE for PTSD with virtual delivery options is an imperative step toward improved care. Federal health care settings treating trauma-exposed patients with PTSD, such as those within the US Department of Defense, Indian Health Services, Federal Bureau of Prisons, and VA, are well positioned to implement programs like iVET. We believe this model of care has great merit and foresee a future where all patients seeking PTSD treatment have the option to complete an accelerated or massed course of PE should they so desire. The experiences outlined in this article illustrate the feasibility, acceptability, and sustainability of such programs without requiring substantial staffing and financial resources.

Evidence-based psychotherapy (EBP) for posttraumatic stress disorder (PTSD), such as prolonged exposure (PE), is supported by multiple clinical practice guidelines and is expected to be available to veterans served by the Veterans Health Administration (VHA).^1-5 However, traditional models of EBP delivery with 1 or 2 sessions weekly have high dropout rates.^6,7 Few veterans who could benefit from such EBPs receive them, and those who do have low completion rates.^8,9 Over a 15-year period, VHA records review of > 265,500 veterans with PTSD showed only 9.1% completed EBP treatment that included but was not limited to PE.¹⁰

One empirically supported solution that has yet to be widely implemented is delivering EBPs for PTSD in a massed or accelerated format of ≥ 3 sessions weekly.¹¹ While these massed models of EBP delivery for PTSD are promising, their implementation is limited in federal health care settings, such as the VHA.¹² PE therapy is a first-line treatment for PTSD that has been evaluated in numerous clinical trials since the early 1990s and in a wide range of trauma populations.^13,14 Massed PE is effective and PE has been found to be effective both in-person and via telehealth.^11,15,16

Another approach to accelerated PE is the inclusion of a massed PE course within a broader treatment context that includes augmentation of the massed PE with additional services, this is referred to as an intensive outpatient model (IOP).¹⁷ PE-IOP has also been shown to be feasible, acceptable, and effective with increased completion rates in comparison to the traditional (1 or 2 sessions weekly) model of PE.^12,16,18,19 Ragsdale et al describe a 2-week IOP with multiple treatment tracks, including a PTSD track. The PTSD treatment track includes massed PE and additional standard services including case management, wellness services, family services, and a single session effective behaviors group. Additional augmentation services are available when clinically indicated (eg, repetitive transcranial magnetic stimulation, transcranial direct current stimulation treatment, psychoeducation, motivational interviewing, and/or relapse prevention).¹⁷

Rauch et al studied the first 80 patients completing an IOP program that consisted of PE (5 sessions weekly) and complementary interventions (eg, mindfulness and yoga) and reported a 96% retention rate, significant reductions of self-reported PTSD symptoms, significant reduction in self-reported co-occurring depression symptoms, and significant increase in self-reported satisfaction with social functioning. ¹⁸ In another study, Sherril et al explored patient reactions to participation in massed PE (5 sessions weekly) and found that patients reported significantly more positive than negative reactions. Sherrill et al noted that according to patients, the benefits of massed PE included a structured format that limits avoidance and distraction. The resulting fast pace of progress enhanced motivation; however, drawbacks included short-term discomfort and time demands.¹⁹ Yamokoski et al explored the feasibility of massed PE in a larger study of PTSD treatment in an intensive outpatient track (IOT) in a VHA PTSD clinic with minimal staffing. The 48 patients who completed IOT PTSD treatment in 2 or 4 weeks (including 35 patients who received massed PE) had high retention rates (85%), reported high satisfaction, and had significantly reduced PTSD and depression symptoms.¹²

The massed IOT PE model implemented by Yamokoski et al included the primary EBP intervention of massed PE with adjunctive groups. The addition of these groups increased both retention and patient-reported satisfaction. The PE-IOP model implemented by Rauch et al and Sherrill et al also included wellness and educational groups, as well as access to complementary interventions such as mindfulness and yoga.^18,19 The addition of wellness education along with a primary EBP aligned with the VHA focus on whole health well-being and wellness. The whole health approach includes understanding the factors that motivate a patient toward health and well-being, provision of health education, and providing access to complementary interventions such as mindfulness.²⁰ Dryden et al describe the whole health transformation within VHA as a proactive approach to addressing employee and patient wellness and health. Their research found that the whole health model promoted well-being in patients and staff and was sustained even during the COVID-19 pandemic.²¹ Dryden et al also noted that use of virtual technologies facilitated and promoted continued whole health implementation. The literature illustrates that: (1) massed PE can be provided with complementary education and wellness offerings, and that such offerings may increase both retention and satisfaction by enriching the massed PE treatment (eg, delivering PE-IOP); (2) whole health including wellness education and complementary interventions (eg, mindfulness, motivational enhancement) promotes well-being in both patients and mental health professionals; and (3) whole health education and complementary interventions can be delivered virtually.

Health Care Need

Prior to the implementation of a massed EBP for PTSD program at US Department of Veterans Affairs (VA) Pacific Islands Health Care System (VAPIHCS), our setting included a traditional outpatient program for treatment of PTSD and a 12- bed residential program for treatment of PTSD for male-identified (self-identified and identified as male in the electronic medical record) veterans via a cohort model with an 8- or 9-week length of stay. Both programs were located on Oahu. Thus, veterans who received care at VAPIHCS had access to PE in both outpatient and residential settings and via in-person and telehealth modalities. However, their access to PE was limited to the traditional models of PE delivery (eg, 1 or 2 session per week) and very few veterans outside of the island of Oahu had accessed PE treatment for PTSD. Moreover, when looking at PE reach within VAPIHCS, in the fiscal year prior to the implementation of the massed EBP program, only 32 of the > 5000 eligible veterans with a PTSD diagnosis had received PE. VAPIHCS serves veterans in a catchment area across the Pacific Basin which includes 3 time zones: Hawaii Standard Time (HST), Chamorro Standard Time (ChST), and Samoa Standard Time (SST). ChST is 20 hours ahead of HST, making service delivery that is inclusive for patients in Guam and Saipan especially challenging when providing care from Hawaii or other US states or territories. Given all of this, implementation of a new program offering accelerated PE virtually to any veterans with PTSD within the VAPIHCS would increase access to and reduce barriers to receiving PE.

PROGRAM DESCRIPTION

The Intensive Virtual EBP Team (iVET) for PTSD consists of an accelerated course of PE therapy and whole health education provided via VA Video Connect (VVC). iVET is a 3-week program and includes 3 parts: (1) massed individual PE therapy for PTSD; (2) group whole health and wellness classes; and (3) individual health coaching to address personal wellness goals. Programming is offered over 10-hour days to increase access across multiple time zones, especially to allow for participation in Guam and Saipan.

When a patient is referred to the iVET, their first contact is a video (or telephone) appointment with a registered nurse (RN) for a screening session. The screening session is designed to educate the patient about the program, including interventions, time commitment, and resources required for participation. In addition, following the educational discussion, the RN completes screening for safety with the patient including suicidal ideation and risk, as well as intimate partner violence risk. If urgent safety concerns are present, a licensed social worker or psychologist will join the screening to complete further assessment of risk and to address any safety concerns. Following screening, patients are scheduled for a VVC intake with a licensed therapist (social worker or psychologist) to complete the Clinician-Administered PTSD Scale (CAPS-5) for the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition), a clinical interview for PTSD assessment. Patients are also sent a secure link to complete a measurement-based care (MBC) battery of self-report measures including measures assessing demographics, PTSD symptoms, anxiety symptoms, depression symptoms, substance use, quality of life (QOL), and satisfaction with mental health care. The results of the CAPS-5 and self-report measures are discussed with the patient during the intake session when planning next steps and engaging in shared decision-making. This initial VVC intake not only allows for diagnostic goodness of fit but also provides the opportunity to troubleshoot any technical difficulties the patients might have with the virtual platforms.

There are minimal exclusion criteria for participation in iVET, which include active unmanaged psychosis or manic symptoms, recent suicidal crises (attempt within 8 weeks), active nonsuicidal self-injurious behaviors (within 8 weeks), and moderate-to-severe cognitive impairment. Following intake, patients are scheduled to begin their course of care with iVET. Upon completion of intake, patients are sent program materials for their individual and group classes, asked to obtain or request a recording device, and told they will receive email links for all VVC appointments. Patients are admitted to the iVET in a rolling admission fashion, thereby increasing access when compared to closed group and/or cohort models of care.

Patients receiving care in iVET attend 2 or 3 telehealth appointments daily with practice exercises daily between telehealth sessions. The primary EBP intervention in the iVET for PTSD program is a massed or accelerated course of PE, which includes 4 primary components: psychoeducation, in-vivo exposure, imaginal exposure, and breathing retraining. Specifically, PE is delivered in 4 90-minute individual sessions weekly allowing completion of the full PE protocol, to fidelity, in 3 weeks. In addition to receiving this primary intervention, patients also participate in four 50-minute group sessions per week of a whole health and wellness education class and have access to one 30- to 60-minute session weekly of individual health coaching should they wish to set wellness goals and receive coaching in support of attaining wellness goals. During iVET, patients are invited to complete MBC batteries of selfreport measures including measures assessing PTSD symptoms, anxiety symptoms, depression symptoms, substance use, QOL, and satisfaction with mental health care at sessions 1, 5, 9, and the final session of PE. Following discharge from the iVET, patients are offered 1-month, 3-month, and 6-month individual postdischarge check-up sessions with a therapist where they are invited to complete MBC measures and review relapse prevention and maintenance of treatment gains. Likewise, they are offered 1-month, 3-month, and 6-month postdischarge check-up sessions with an RN focused on maintaining wellness gains.

The iVET for PTSD staff includes 3 therapists (psychologists or social workers) and an RN. Additionally, the iVET for PTSD is supported by a program manager and a program support assistant. The primary cost of the program is salary for staff. Additional iVET for PTSD resources included computer equipment for staff and minimal supplies. Due to the virtual environment of care, iVET staff telework and do not require physical space within VAPIHCS.

OUTCOMES

All veterans receiving care in iVET for PTSD are invited to complete a MBC at multiple timepoints including pretreatment, during PE treatment, and posttreatment. The MBC measures included self-reported demographics, a 2-item measure of satisfaction with mental health services, the Brief Addiction Monitor-Intensive Outpatient Program questionnaire,²² the Generalized Anxiety Disorder-7 scale,^23, the Patient Health Questionnaire (PHQ-9),²⁴ the QOL Enjoyment and Satisfaction Questionnaire- Short Form,²⁵ and the PTSD Checklist for DSM-5 (PCL-5), both weekly and monthly versions. ^26,27

The retention rate has averaged 81% since the iVET for PTSD opened in 2022. To date, 132 veterans have completed the iVET for PTSD program, including a full course of massed PE (Table 1). Veterans experienced reduced PTSD (P < .005), depression (P < .005), anxiety (P < .005), and substance use risk (P < .005). Veterans experienced improved QOL (P < .005) and reported high satisfaction with mental health care in iVET for PTSD (Table 2). Veterans also experienced reduced thoughts of death or suicidal ideation (SI) based on PHQ-9 item 9 responses. When looking categorically at presence or absence of SI on PHQ-9 item 9, a significant relationship was found between the absence of suicidal ideation and completion of a course of massed PE: X² (1, N = 132) = 13.75, P < .001. In addition, veterans who completed the program showed a significant decrease in severity of SI as measured continuously (range, 0-3) on PHQ-9 item 9 (P < .005).

Another important aspect to consider when implementing massed models of EBP is the impact on employee well-being and job satisfaction. The impact of EBP on staff was assessed following the initial EBP project. To explore this further, all staff members in the iVET for PTSD were invited to engage in a small program evaluation. iVET staff were guided through a visualization meditation intended to recall a typical workday 1 month prior to starting their new position with iVET. After the visualization meditation, staff completed the Professional Quality of Life (ProQOL) scale, a 30-item, self-reported questionnaire for health care workers that evaluates compassion satisfaction, perceived support, burnout, secondary traumatic stress, and moral distress.²⁸ One week later, staff were asked to complete the ProQOL again to capture their state after the first 6 months into their tenure as iVET staff. iVET employees experienced significantly increased perceived support (P < .05), reduced burnout (P < .05), reduced secondary traumatic stress (P < .05), and reduced moral distress (P < .05). Team members also remarked on the rewarding nature of the work and care model.

Future Directions

Future research should aim to sustain these outcomes as the iVET program continues to serve more veterans. Another important line of inquiry is longer-term follow-up, as exploring if outcomes are maintained over time is an important question that has not been answered in this article. In addition, we hope to see the accelerated model of care applied to treatment of other presenting concerns in mental health treatment (eg, anxiety, depression, insomnia). Expansion of accelerated mental health treatment into other federal and non-federal health care settings is another worthy direction. Finally, while short term (6 months) assessment of staff satisfaction in iVET was promising, ongoing assessment staff satisfaction over a longer timeframe (1-5 years) is also important.

CONCLUSIONS

PE for PTSD has been demonstrated to be effective and improve functioning and is supported by multiple clinical practice guidelines.1-5 However, as federal practitioners, we must consider the reality that many of the individuals who could benefit are not engaging in PE and there is a high dropout rate for those that do. It is vital that we envision a future state where access to PE for PTSD is equitable and inclusive, retention rates are dramatically improved, and clinicians providing PE do not experience high rates of burnout.

We must continue exploring how we can better care for our patients and colleagues. We posit that the development of programs, or tracks within existing programs, that provide massed or accelerated PE for PTSD with virtual delivery options is an imperative step toward improved care. Federal health care settings treating trauma-exposed patients with PTSD, such as those within the US Department of Defense, Indian Health Services, Federal Bureau of Prisons, and VA, are well positioned to implement programs like iVET. We believe this model of care has great merit and foresee a future where all patients seeking PTSD treatment have the option to complete an accelerated or massed course of PE should they so desire. The experiences outlined in this article illustrate the feasibility, acceptability, and sustainability of such programs without requiring substantial staffing and financial resources.

The US Department of Veterans Affairs (VA) mission is defined by President Abraham Lincoln’s promise “to care for him who shall have borne the battle, and for his widow, and his orphan.” Critically, the biopsychosocial needs of veterans differ from the needs of civilians due to the nature of military service.¹ Veterans commonly experience traumatic brain injury (TBI) due to combat- or training-related injuries.² Psychologically, veterans are disproportionately likely to be diagnosed with mental health conditions, such as posttraumatic stress disorder (PTSD), often linked to military exposures.³ Spiritually, veterans frequently express moral injury after living through circumstances when they perpetrate, fail to prevent, or witness events that contradict moral beliefs/ expectations.⁴ Veterans also have significant social challenges, including high rates of homelessness. ⁵ A critical strength of the VA mission is its awareness of these complex sequelae and its ability to provide well-informed treatment and social services to meet veterans’ unique needs.

Foundational to a well-informed health care system is a robust research and operational quality improvement infrastructure. The VA Office of Research and Development (ORD) has worked tirelessly to understand and address the unique, idiographic needs of veterans. In 2024 the ORD had a budget of $2.4 billion, excluding quality improvement initiatives enhancing VA operations.⁶

The integrated VA health care system is a major strength for providing state-of-the-science to inform veterans’ treatment and social service needs. The VA features medical centers and clinics capable of synergistically leveraging extant infrastructure to facilitate collaborations and centralized procedures across sites. The VA also has dedicated research centers, such as the National Center for PTSD, Centers of Excellence, Centers of Innovation, and Mental Illness, Research, Education and Clinical Centers that focus on PTSD, suicide prevention, TBI, and other high-priority areas. These centers recruit, train, and invest in experts dedicated to improving veterans’ lives. The VA Corporate Data Warehouse provides a national, system-wide repository for patient-level data, allowing for advanced analysis of large datasets.⁷

This special issue is a showcase of the strengths of VA mental health and social service research, aligning with the current strategic priorities of VA research. Topics focus on the unique needs of veterans, including sequelae (eg, PTSD, homelessness, moral injury), with particular attention to veterans. Manuscripts highlight the strengths of collaborations, including those between specialized research centers and national VA operational partners. Analyses highlight the VA research approach, leveraging data and perspectives from inside and outside the VA, and studying new and established approaches to care. This issue highlights the distinct advantages that VA research provides: experts with the tools, experience, and dedication to addressing the unique needs of veterans. Given the passion for veteran care among VA researchers, including those featured in this issue, we strongly believe the VA will continue to be a leader in this research.

The US Department of Veterans Affairs (VA) mission is defined by President Abraham Lincoln’s promise “to care for him who shall have borne the battle, and for his widow, and his orphan.” Critically, the biopsychosocial needs of veterans differ from the needs of civilians due to the nature of military service.¹ Veterans commonly experience traumatic brain injury (TBI) due to combat- or training-related injuries.² Psychologically, veterans are disproportionately likely to be diagnosed with mental health conditions, such as posttraumatic stress disorder (PTSD), often linked to military exposures.³ Spiritually, veterans frequently express moral injury after living through circumstances when they perpetrate, fail to prevent, or witness events that contradict moral beliefs/ expectations.⁴ Veterans also have significant social challenges, including high rates of homelessness. ⁵ A critical strength of the VA mission is its awareness of these complex sequelae and its ability to provide well-informed treatment and social services to meet veterans’ unique needs.

Foundational to a well-informed health care system is a robust research and operational quality improvement infrastructure. The VA Office of Research and Development (ORD) has worked tirelessly to understand and address the unique, idiographic needs of veterans. In 2024 the ORD had a budget of $2.4 billion, excluding quality improvement initiatives enhancing VA operations.⁶

The integrated VA health care system is a major strength for providing state-of-the-science to inform veterans’ treatment and social service needs. The VA features medical centers and clinics capable of synergistically leveraging extant infrastructure to facilitate collaborations and centralized procedures across sites. The VA also has dedicated research centers, such as the National Center for PTSD, Centers of Excellence, Centers of Innovation, and Mental Illness, Research, Education and Clinical Centers that focus on PTSD, suicide prevention, TBI, and other high-priority areas. These centers recruit, train, and invest in experts dedicated to improving veterans’ lives. The VA Corporate Data Warehouse provides a national, system-wide repository for patient-level data, allowing for advanced analysis of large datasets.⁷

This special issue is a showcase of the strengths of VA mental health and social service research, aligning with the current strategic priorities of VA research. Topics focus on the unique needs of veterans, including sequelae (eg, PTSD, homelessness, moral injury), with particular attention to veterans. Manuscripts highlight the strengths of collaborations, including those between specialized research centers and national VA operational partners. Analyses highlight the VA research approach, leveraging data and perspectives from inside and outside the VA, and studying new and established approaches to care. This issue highlights the distinct advantages that VA research provides: experts with the tools, experience, and dedication to addressing the unique needs of veterans. Given the passion for veteran care among VA researchers, including those featured in this issue, we strongly believe the VA will continue to be a leader in this research.

The US Department of Veterans Affairs (VA) mission is defined by President Abraham Lincoln’s promise “to care for him who shall have borne the battle, and for his widow, and his orphan.” Critically, the biopsychosocial needs of veterans differ from the needs of civilians due to the nature of military service.¹ Veterans commonly experience traumatic brain injury (TBI) due to combat- or training-related injuries.² Psychologically, veterans are disproportionately likely to be diagnosed with mental health conditions, such as posttraumatic stress disorder (PTSD), often linked to military exposures.³ Spiritually, veterans frequently express moral injury after living through circumstances when they perpetrate, fail to prevent, or witness events that contradict moral beliefs/ expectations.⁴ Veterans also have significant social challenges, including high rates of homelessness. ⁵ A critical strength of the VA mission is its awareness of these complex sequelae and its ability to provide well-informed treatment and social services to meet veterans’ unique needs.

Foundational to a well-informed health care system is a robust research and operational quality improvement infrastructure. The VA Office of Research and Development (ORD) has worked tirelessly to understand and address the unique, idiographic needs of veterans. In 2024 the ORD had a budget of $2.4 billion, excluding quality improvement initiatives enhancing VA operations.⁶

The integrated VA health care system is a major strength for providing state-of-the-science to inform veterans’ treatment and social service needs. The VA features medical centers and clinics capable of synergistically leveraging extant infrastructure to facilitate collaborations and centralized procedures across sites. The VA also has dedicated research centers, such as the National Center for PTSD, Centers of Excellence, Centers of Innovation, and Mental Illness, Research, Education and Clinical Centers that focus on PTSD, suicide prevention, TBI, and other high-priority areas. These centers recruit, train, and invest in experts dedicated to improving veterans’ lives. The VA Corporate Data Warehouse provides a national, system-wide repository for patient-level data, allowing for advanced analysis of large datasets.⁷

This special issue is a showcase of the strengths of VA mental health and social service research, aligning with the current strategic priorities of VA research. Topics focus on the unique needs of veterans, including sequelae (eg, PTSD, homelessness, moral injury), with particular attention to veterans. Manuscripts highlight the strengths of collaborations, including those between specialized research centers and national VA operational partners. Analyses highlight the VA research approach, leveraging data and perspectives from inside and outside the VA, and studying new and established approaches to care. This issue highlights the distinct advantages that VA research provides: experts with the tools, experience, and dedication to addressing the unique needs of veterans. Given the passion for veteran care among VA researchers, including those featured in this issue, we strongly believe the VA will continue to be a leader in this research.

Posttraumatic stress disorder (PTSD) is the most likely diagnosis considering this patient’s symptoms of anxiety, hypervigilance, recurring nightmares, agitation, flashbacks, and violent outbursts. His experience of being robbed at gunpoint outside his gym seems to have been the triggering event for his PTSD, which may have also been influenced by his history of multiple concussions incurred in a fight setting in which he is forced to defend himself. His avoidance of continued training and appearing at scheduled fights further support this diagnosis. His CT scan, although not diagnostic for PTSD directly, does show evidence of minor brain injury, with the remaining hematomas.

Anxiety disorder may account for the patient’s severe anxiety, agitation, and headaches, but his symptoms are new and started after the robbery, which indicates PTSD and not a long-standing anxiety disorder.

Schizophrenia is an unlikely diagnosis for this patient. Although he is within the typical age range of symptom onset, has had violent outbursts, and is prone to vast changes in mood that come on quickly, he is not psychotic and does not experience any of the hallmark symptoms of schizophrenia: delusions, hallucinations, and disorganized speech/behavior, at least two of which would need to be present to support a diagnosis of schizophrenia.

Given this patient’s circumstances, post-traumatic epilepsy initially may be a potential diagnostic consideration. However, he is not experiencing seizures, but rather mood and behavioral disturbances, the onset of which occurred after a specific event. Additionally, posttraumatic epilepsy results from traumatic brain injury.

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision, an update to the 2017 clinical treatment guidelines published by the American Psychiatric Association (APA), the diagnostic criteria for PTSD in an individual older than 6 years are:

1.    Exposure to actual or threatened death, serious injury or sexual assault
2.    The traumatic event is persistently re-experienced via flashbacks, nightmares, and intrusive thoughts that cause strong emotional reactions and psychological distress
3.    Avoidance behaviors either in thoughts or conversations about the event or of people and places associated with the event
4.    At least two examples of negative alterations in cognition and mood
5.    At least two examples of hyperarousal
6.    Duration of symptoms > 1 month
7.    Significant distress or impairment in function because of these symptoms

Trauma-focused therapy is the gold standard of treatment for patients with PTSD. A recent review of current treatment strategies for PTSD found that cognitive processing therapy, cognitive-behavioral therapy, prolonged exposure therapy, and eye movement desensitization and reprocessing, all with a strong trauma focus, are the most effective treatments for PTSD.

The use of pharmacology to treat PTSD is controversial and varies by guideline. The APA and US Department of Veterans Affairs both recommend the use of antidepressants, particularly selective serotonin reuptake inhibitors, as a first-line treatment of PTSD. This is particularly important for patients who have psychiatric comorbid conditions, such as depression, who may not be able to effectively engage in cognitive- behavioral therapy. However, use of benzodiazepines or hypnotics should be strictly avoided in these patients because these drugs increase intrusive and avoidance symptoms over time. Medication should be continued for 6 to 12 months to help prevent relapse. 

Heidi Moawad, MD, Clinical Assistant Professor, Department of Medical Education, Case Western Reserve University School of Medicine, Cleveland, Ohio.

Heidi Moawad, MD, has disclosed no relevant financial relationships.
 

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

Posttraumatic stress disorder (PTSD) is the most likely diagnosis considering this patient’s symptoms of anxiety, hypervigilance, recurring nightmares, agitation, flashbacks, and violent outbursts. His experience of being robbed at gunpoint outside his gym seems to have been the triggering event for his PTSD, which may have also been influenced by his history of multiple concussions incurred in a fight setting in which he is forced to defend himself. His avoidance of continued training and appearing at scheduled fights further support this diagnosis. His CT scan, although not diagnostic for PTSD directly, does show evidence of minor brain injury, with the remaining hematomas.

Anxiety disorder may account for the patient’s severe anxiety, agitation, and headaches, but his symptoms are new and started after the robbery, which indicates PTSD and not a long-standing anxiety disorder.

Schizophrenia is an unlikely diagnosis for this patient. Although he is within the typical age range of symptom onset, has had violent outbursts, and is prone to vast changes in mood that come on quickly, he is not psychotic and does not experience any of the hallmark symptoms of schizophrenia: delusions, hallucinations, and disorganized speech/behavior, at least two of which would need to be present to support a diagnosis of schizophrenia.

Given this patient’s circumstances, post-traumatic epilepsy initially may be a potential diagnostic consideration. However, he is not experiencing seizures, but rather mood and behavioral disturbances, the onset of which occurred after a specific event. Additionally, posttraumatic epilepsy results from traumatic brain injury.

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision, an update to the 2017 clinical treatment guidelines published by the American Psychiatric Association (APA), the diagnostic criteria for PTSD in an individual older than 6 years are:

1.    Exposure to actual or threatened death, serious injury or sexual assault
2.    The traumatic event is persistently re-experienced via flashbacks, nightmares, and intrusive thoughts that cause strong emotional reactions and psychological distress
3.    Avoidance behaviors either in thoughts or conversations about the event or of people and places associated with the event
4.    At least two examples of negative alterations in cognition and mood
5.    At least two examples of hyperarousal
6.    Duration of symptoms > 1 month
7.    Significant distress or impairment in function because of these symptoms

Trauma-focused therapy is the gold standard of treatment for patients with PTSD. A recent review of current treatment strategies for PTSD found that cognitive processing therapy, cognitive-behavioral therapy, prolonged exposure therapy, and eye movement desensitization and reprocessing, all with a strong trauma focus, are the most effective treatments for PTSD.

The use of pharmacology to treat PTSD is controversial and varies by guideline. The APA and US Department of Veterans Affairs both recommend the use of antidepressants, particularly selective serotonin reuptake inhibitors, as a first-line treatment of PTSD. This is particularly important for patients who have psychiatric comorbid conditions, such as depression, who may not be able to effectively engage in cognitive- behavioral therapy. However, use of benzodiazepines or hypnotics should be strictly avoided in these patients because these drugs increase intrusive and avoidance symptoms over time. Medication should be continued for 6 to 12 months to help prevent relapse. 

Heidi Moawad, MD, Clinical Assistant Professor, Department of Medical Education, Case Western Reserve University School of Medicine, Cleveland, Ohio.

Heidi Moawad, MD, has disclosed no relevant financial relationships.
 

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

Posttraumatic stress disorder (PTSD) is the most likely diagnosis considering this patient’s symptoms of anxiety, hypervigilance, recurring nightmares, agitation, flashbacks, and violent outbursts. His experience of being robbed at gunpoint outside his gym seems to have been the triggering event for his PTSD, which may have also been influenced by his history of multiple concussions incurred in a fight setting in which he is forced to defend himself. His avoidance of continued training and appearing at scheduled fights further support this diagnosis. His CT scan, although not diagnostic for PTSD directly, does show evidence of minor brain injury, with the remaining hematomas.

Anxiety disorder may account for the patient’s severe anxiety, agitation, and headaches, but his symptoms are new and started after the robbery, which indicates PTSD and not a long-standing anxiety disorder.

Schizophrenia is an unlikely diagnosis for this patient. Although he is within the typical age range of symptom onset, has had violent outbursts, and is prone to vast changes in mood that come on quickly, he is not psychotic and does not experience any of the hallmark symptoms of schizophrenia: delusions, hallucinations, and disorganized speech/behavior, at least two of which would need to be present to support a diagnosis of schizophrenia.

Given this patient’s circumstances, post-traumatic epilepsy initially may be a potential diagnostic consideration. However, he is not experiencing seizures, but rather mood and behavioral disturbances, the onset of which occurred after a specific event. Additionally, posttraumatic epilepsy results from traumatic brain injury.

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision, an update to the 2017 clinical treatment guidelines published by the American Psychiatric Association (APA), the diagnostic criteria for PTSD in an individual older than 6 years are:

1.    Exposure to actual or threatened death, serious injury or sexual assault
2.    The traumatic event is persistently re-experienced via flashbacks, nightmares, and intrusive thoughts that cause strong emotional reactions and psychological distress
3.    Avoidance behaviors either in thoughts or conversations about the event or of people and places associated with the event
4.    At least two examples of negative alterations in cognition and mood
5.    At least two examples of hyperarousal
6.    Duration of symptoms > 1 month
7.    Significant distress or impairment in function because of these symptoms

Trauma-focused therapy is the gold standard of treatment for patients with PTSD. A recent review of current treatment strategies for PTSD found that cognitive processing therapy, cognitive-behavioral therapy, prolonged exposure therapy, and eye movement desensitization and reprocessing, all with a strong trauma focus, are the most effective treatments for PTSD.

The use of pharmacology to treat PTSD is controversial and varies by guideline. The APA and US Department of Veterans Affairs both recommend the use of antidepressants, particularly selective serotonin reuptake inhibitors, as a first-line treatment of PTSD. This is particularly important for patients who have psychiatric comorbid conditions, such as depression, who may not be able to effectively engage in cognitive- behavioral therapy. However, use of benzodiazepines or hypnotics should be strictly avoided in these patients because these drugs increase intrusive and avoidance symptoms over time. Medication should be continued for 6 to 12 months to help prevent relapse. 

Heidi Moawad, MD, Clinical Assistant Professor, Department of Medical Education, Case Western Reserve University School of Medicine, Cleveland, Ohio.

Heidi Moawad, MD, has disclosed no relevant financial relationships.
 

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

Editor's Note: This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

Editor's Note: This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

Editor's Note: This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A drug that combines the atypical antipsychotic brexpiprazole and the selective serotonin reuptake inhibitor sertraline provides significantly greater relief of posttraumatic stress disorder (PTSD) symptoms than sertraline plus placebo, results of a phase 3 trial showed.

The medication is currently under review by the Food and Drug Administration (FDA) and if approved, will be the first pharmacologic option for PTSD in more than 20 years.

The trial met its primary endpoint of change in the Clinician Administered PTSD Scale for Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) (CAPS-5) total score at week 10 and secondary patient-reported outcomes of PTSD symptoms, anxiety, and depression.

“And what is really cool, what’s really impactful is the combination worked better than sertraline plus placebo on a brief inventory of psychosocial functioning,” study investigator Lori L. Davis, a senior research psychiatrist, Birmingham Veterans Affairs Health Care System in Alabama, said in an interview.

“We can treat symptoms but that’s where the rubber meets the road, in terms of are they functioning better,” added Davis, who is also an adjunct professor of psychiatry, Heersink School of Medicine, University of Alabama at Birmingham.

The findings were published online on December 18 in JAMA Psychiatry and reported in May 2024 as part of a trio of trials conducted by Otsuka Pharmaceutical and Lundbeck Pharmaceuticals, codevelopers of the drug.

 

Clinically Meaningful

The FDA accepted the companies’ supplemental new drug application in June with a decision on approval expected in early February 2025.

“This study provides promising results for a medication that may be an important new option for PTSD,” John Krystal, MD, director, Clinical Neuroscience Division, National Center for PTSD, US Department of Veterans Affairs, who was not involved in the research, said in an interview. “New PTSD treatments are a high priority.”

Currently, there are two FDA-approved medication treatments for PTSD — sertraline and paroxetine.

“They are helpful for many people, but patients are often left with residual symptoms or tolerability issues,” noted Krystal, who is also professor and chair of psychiatry, Yale University, New Haven, Connecticut.

“New medications that might address the important ‘effectiveness gap’ in PTSD could help to reduce the remaining distress, disability, and suicide risk associated with PTSD.” 

The double-blind, phase 3 trial included 416 adults aged 18-65 years with a DSM-5 diagnosis of PTSD and symptoms for at least 6 months prior to screening. Patients underwent a 1-week placebo-run in period followed by randomization to daily oral brexpiprazole 2-3 mg plus sertraline 150 mg or daily sertraline 150 mg plus placebo for 11 weeks.

Participants’ mean age was 37.4 years, 74.5% were women, and mean CAPS-5 total score was 38.4, suggesting moderate to high severity PTSD, Davis said. The average time from the index traumatic event was 4 years and three fourths had no prior exposure to PTSD prescription medications.

At week 10, the mean change in CAPS-5 score from randomization was –19.2 points in the brexpiprazole plus sertraline group and –13.6 points in the sertraline plus placebo group (95% CI, –8.79 to –2.38; P < .001).

Asked whether the 5.59-point treatment difference is clinically meaningful, Davis said there is no widely agreed definition for change in CAPS-5 total score but that a within-group reduction of more than 10-13 points is most-often cited as being clinically meaningful.

The key secondary endpoint of least square mean change in the patient-reported Brief Inventory of Psychosocial Function total score from baseline to week 12 was –33.8 with the combination vs –21.8 with sertraline plus placebo (95% CI, –19.4 to –4.62; P = .002).

“That’s clinically meaningful for me as a provider and a clinician and a researcher when you’re getting the PTSD symptom change differences in parallel with the improvement in functional outcome,” she said. “I see that as the clinically meaningful gauge.”

In terms of safety, 3.9% of the participants in the brexpiprazole/sertraline group and 10.2% of those in the sertraline/placebo group discontinued treatment because of adverse events.

In both the combination and control groups, the only treatment-emergent adverse event with an incidence of more than 10% was nausea (12.2% vs 11.7%, respectively).

At the last visit, the mean change in body weight from baseline was an increase of 1.3 kg for brexpiprazole plus sertraline vs 0 kg for sertraline alone. Rates of fatigue (6.8% vs 4.1%) and somnolence (5.4% vs 2.6%) were also higher with brexpiprazole plus sertraline.

 

A Trio of Clinical Trials

The findings are part of a larger program reported by the drug makers that includes a flexible-dose brexpiprazole phase 2 trial that met the same CAPS-5 primary endpoint and a second phase 3 trial (072 study) that did not.

“We’ve looked at that data and the sertraline/placebo response was a lot higher, so it was not due to a lack of response with the combination but due to a more robust response with the active control,” Davis said. “But we want to point out for that 072 study, there was still important separation between the combination and sertraline plus placebo on the functional outcome.”

All three trials ran for 12 weeks, so longer-term efficacy and safety data are needed, she said. Other limitations of the published phase 3 study are the patient eligibility criteria, restrictions on concomitant therapy, and lack of non-US sites, which many limit generalizability, the authors noted.

“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 PTSD),” they added.

 

Kudos, Caveats

Reached for comment, Vincent F. Capaldi, II, MD, ScM, professor and chair, department of psychiatry, Uniformed Services University of the Health Sciences School of Medicine, Bethesda, Maryland, said the exclusion of these patients is a limitation but that the study was well designed and conducted in a large sample across the United States.

“The findings suggest that brexpiprazole plus sertraline is a more effective treatment for PTSD than sertraline alone,” he said. “This finding is significant for our service members, who suffer from PTSD at higher rates than the general population.”

Additionally, the significant improvement in psychosocial functioning at week 12 “is important because PTSD is known to cause significant social and occupational disability, as well as quality-of-life issues,” he said.

Capaldi pointed out, however, that the study was conducted only at US sites and did not specifically target military/veteran persons, which may limit applicability to these unique populations.

“While subgroup analyses were generally consistent with the primary analysis, the study was not powered to detect differences between subgroups,” he added. “These subgroup analyses are quite important when considering military and veteran populations.”

Further research is needed to explore whether certain traumas are more responsive to combination treatment, the efficacy of augmenting existing sertraline therapy, and the specific mechanisms of brexpiprazole driving the improved outcomes, Capaldi said.

This study was funded by Otsuka Pharmaceutical Development & Commercialization, which was involved in the design, conduct, and data analysis. Davis reported receiving advisory board fees from Otsuka and Boehringer Ingelheim; lecture fees from Clinical Care Options; and grants from Alkermes, the Veterans Affairs, Patient-Centered Outcomes Research Institute, Department of Defense, and Social Finance. Several coauthors are employees of Otsuka. Krystal reported serving as a consultant for Otsuka America Pharmaceutical, Aptinyx, Biogen, IDEC, Bionomics, Boehringer Ingelheim International, Clearmind Medicine, Cybin IRL, Enveric Biosciences, Epiodyne, EpiVario, Janssen, Jazz Pharmaceuticals, Perception Neuroscience, Praxis Precision Medicines, Springcare, and Sunovion Pharmaceuticals. Krystal also reported serving as a scientific advisory board member for several companies and holding several patents.

A version of this article appeared on Medscape.com.

A drug that combines the atypical antipsychotic brexpiprazole and the selective serotonin reuptake inhibitor sertraline provides significantly greater relief of posttraumatic stress disorder (PTSD) symptoms than sertraline plus placebo, results of a phase 3 trial showed.

The medication is currently under review by the Food and Drug Administration (FDA) and if approved, will be the first pharmacologic option for PTSD in more than 20 years.

The trial met its primary endpoint of change in the Clinician Administered PTSD Scale for Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) (CAPS-5) total score at week 10 and secondary patient-reported outcomes of PTSD symptoms, anxiety, and depression.

“And what is really cool, what’s really impactful is the combination worked better than sertraline plus placebo on a brief inventory of psychosocial functioning,” study investigator Lori L. Davis, a senior research psychiatrist, Birmingham Veterans Affairs Health Care System in Alabama, said in an interview.

“We can treat symptoms but that’s where the rubber meets the road, in terms of are they functioning better,” added Davis, who is also an adjunct professor of psychiatry, Heersink School of Medicine, University of Alabama at Birmingham.

The findings were published online on December 18 in JAMA Psychiatry and reported in May 2024 as part of a trio of trials conducted by Otsuka Pharmaceutical and Lundbeck Pharmaceuticals, codevelopers of the drug.

 

Clinically Meaningful

The FDA accepted the companies’ supplemental new drug application in June with a decision on approval expected in early February 2025.

“This study provides promising results for a medication that may be an important new option for PTSD,” John Krystal, MD, director, Clinical Neuroscience Division, National Center for PTSD, US Department of Veterans Affairs, who was not involved in the research, said in an interview. “New PTSD treatments are a high priority.”

Currently, there are two FDA-approved medication treatments for PTSD — sertraline and paroxetine.

“They are helpful for many people, but patients are often left with residual symptoms or tolerability issues,” noted Krystal, who is also professor and chair of psychiatry, Yale University, New Haven, Connecticut.

“New medications that might address the important ‘effectiveness gap’ in PTSD could help to reduce the remaining distress, disability, and suicide risk associated with PTSD.” 

The double-blind, phase 3 trial included 416 adults aged 18-65 years with a DSM-5 diagnosis of PTSD and symptoms for at least 6 months prior to screening. Patients underwent a 1-week placebo-run in period followed by randomization to daily oral brexpiprazole 2-3 mg plus sertraline 150 mg or daily sertraline 150 mg plus placebo for 11 weeks.

Participants’ mean age was 37.4 years, 74.5% were women, and mean CAPS-5 total score was 38.4, suggesting moderate to high severity PTSD, Davis said. The average time from the index traumatic event was 4 years and three fourths had no prior exposure to PTSD prescription medications.

At week 10, the mean change in CAPS-5 score from randomization was –19.2 points in the brexpiprazole plus sertraline group and –13.6 points in the sertraline plus placebo group (95% CI, –8.79 to –2.38; P < .001).

Asked whether the 5.59-point treatment difference is clinically meaningful, Davis said there is no widely agreed definition for change in CAPS-5 total score but that a within-group reduction of more than 10-13 points is most-often cited as being clinically meaningful.

The key secondary endpoint of least square mean change in the patient-reported Brief Inventory of Psychosocial Function total score from baseline to week 12 was –33.8 with the combination vs –21.8 with sertraline plus placebo (95% CI, –19.4 to –4.62; P = .002).

“That’s clinically meaningful for me as a provider and a clinician and a researcher when you’re getting the PTSD symptom change differences in parallel with the improvement in functional outcome,” she said. “I see that as the clinically meaningful gauge.”

In terms of safety, 3.9% of the participants in the brexpiprazole/sertraline group and 10.2% of those in the sertraline/placebo group discontinued treatment because of adverse events.

In both the combination and control groups, the only treatment-emergent adverse event with an incidence of more than 10% was nausea (12.2% vs 11.7%, respectively).

At the last visit, the mean change in body weight from baseline was an increase of 1.3 kg for brexpiprazole plus sertraline vs 0 kg for sertraline alone. Rates of fatigue (6.8% vs 4.1%) and somnolence (5.4% vs 2.6%) were also higher with brexpiprazole plus sertraline.

 

A Trio of Clinical Trials

The findings are part of a larger program reported by the drug makers that includes a flexible-dose brexpiprazole phase 2 trial that met the same CAPS-5 primary endpoint and a second phase 3 trial (072 study) that did not.

“We’ve looked at that data and the sertraline/placebo response was a lot higher, so it was not due to a lack of response with the combination but due to a more robust response with the active control,” Davis said. “But we want to point out for that 072 study, there was still important separation between the combination and sertraline plus placebo on the functional outcome.”

All three trials ran for 12 weeks, so longer-term efficacy and safety data are needed, she said. Other limitations of the published phase 3 study are the patient eligibility criteria, restrictions on concomitant therapy, and lack of non-US sites, which many limit generalizability, the authors noted.

“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 PTSD),” they added.

 

Kudos, Caveats

Reached for comment, Vincent F. Capaldi, II, MD, ScM, professor and chair, department of psychiatry, Uniformed Services University of the Health Sciences School of Medicine, Bethesda, Maryland, said the exclusion of these patients is a limitation but that the study was well designed and conducted in a large sample across the United States.

“The findings suggest that brexpiprazole plus sertraline is a more effective treatment for PTSD than sertraline alone,” he said. “This finding is significant for our service members, who suffer from PTSD at higher rates than the general population.”

Additionally, the significant improvement in psychosocial functioning at week 12 “is important because PTSD is known to cause significant social and occupational disability, as well as quality-of-life issues,” he said.

Capaldi pointed out, however, that the study was conducted only at US sites and did not specifically target military/veteran persons, which may limit applicability to these unique populations.

“While subgroup analyses were generally consistent with the primary analysis, the study was not powered to detect differences between subgroups,” he added. “These subgroup analyses are quite important when considering military and veteran populations.”

Further research is needed to explore whether certain traumas are more responsive to combination treatment, the efficacy of augmenting existing sertraline therapy, and the specific mechanisms of brexpiprazole driving the improved outcomes, Capaldi said.

This study was funded by Otsuka Pharmaceutical Development & Commercialization, which was involved in the design, conduct, and data analysis. Davis reported receiving advisory board fees from Otsuka and Boehringer Ingelheim; lecture fees from Clinical Care Options; and grants from Alkermes, the Veterans Affairs, Patient-Centered Outcomes Research Institute, Department of Defense, and Social Finance. Several coauthors are employees of Otsuka. Krystal reported serving as a consultant for Otsuka America Pharmaceutical, Aptinyx, Biogen, IDEC, Bionomics, Boehringer Ingelheim International, Clearmind Medicine, Cybin IRL, Enveric Biosciences, Epiodyne, EpiVario, Janssen, Jazz Pharmaceuticals, Perception Neuroscience, Praxis Precision Medicines, Springcare, and Sunovion Pharmaceuticals. Krystal also reported serving as a scientific advisory board member for several companies and holding several patents.

A version of this article appeared on Medscape.com.

A drug that combines the atypical antipsychotic brexpiprazole and the selective serotonin reuptake inhibitor sertraline provides significantly greater relief of posttraumatic stress disorder (PTSD) symptoms than sertraline plus placebo, results of a phase 3 trial showed.

The medication is currently under review by the Food and Drug Administration (FDA) and if approved, will be the first pharmacologic option for PTSD in more than 20 years.

The trial met its primary endpoint of change in the Clinician Administered PTSD Scale for Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) (CAPS-5) total score at week 10 and secondary patient-reported outcomes of PTSD symptoms, anxiety, and depression.

“And what is really cool, what’s really impactful is the combination worked better than sertraline plus placebo on a brief inventory of psychosocial functioning,” study investigator Lori L. Davis, a senior research psychiatrist, Birmingham Veterans Affairs Health Care System in Alabama, said in an interview.

“We can treat symptoms but that’s where the rubber meets the road, in terms of are they functioning better,” added Davis, who is also an adjunct professor of psychiatry, Heersink School of Medicine, University of Alabama at Birmingham.

The findings were published online on December 18 in JAMA Psychiatry and reported in May 2024 as part of a trio of trials conducted by Otsuka Pharmaceutical and Lundbeck Pharmaceuticals, codevelopers of the drug.

 

Clinically Meaningful

The FDA accepted the companies’ supplemental new drug application in June with a decision on approval expected in early February 2025.

“This study provides promising results for a medication that may be an important new option for PTSD,” John Krystal, MD, director, Clinical Neuroscience Division, National Center for PTSD, US Department of Veterans Affairs, who was not involved in the research, said in an interview. “New PTSD treatments are a high priority.”

Currently, there are two FDA-approved medication treatments for PTSD — sertraline and paroxetine.

“They are helpful for many people, but patients are often left with residual symptoms or tolerability issues,” noted Krystal, who is also professor and chair of psychiatry, Yale University, New Haven, Connecticut.

“New medications that might address the important ‘effectiveness gap’ in PTSD could help to reduce the remaining distress, disability, and suicide risk associated with PTSD.” 

The double-blind, phase 3 trial included 416 adults aged 18-65 years with a DSM-5 diagnosis of PTSD and symptoms for at least 6 months prior to screening. Patients underwent a 1-week placebo-run in period followed by randomization to daily oral brexpiprazole 2-3 mg plus sertraline 150 mg or daily sertraline 150 mg plus placebo for 11 weeks.

Participants’ mean age was 37.4 years, 74.5% were women, and mean CAPS-5 total score was 38.4, suggesting moderate to high severity PTSD, Davis said. The average time from the index traumatic event was 4 years and three fourths had no prior exposure to PTSD prescription medications.

At week 10, the mean change in CAPS-5 score from randomization was –19.2 points in the brexpiprazole plus sertraline group and –13.6 points in the sertraline plus placebo group (95% CI, –8.79 to –2.38; P < .001).

Asked whether the 5.59-point treatment difference is clinically meaningful, Davis said there is no widely agreed definition for change in CAPS-5 total score but that a within-group reduction of more than 10-13 points is most-often cited as being clinically meaningful.

The key secondary endpoint of least square mean change in the patient-reported Brief Inventory of Psychosocial Function total score from baseline to week 12 was –33.8 with the combination vs –21.8 with sertraline plus placebo (95% CI, –19.4 to –4.62; P = .002).

“That’s clinically meaningful for me as a provider and a clinician and a researcher when you’re getting the PTSD symptom change differences in parallel with the improvement in functional outcome,” she said. “I see that as the clinically meaningful gauge.”

In terms of safety, 3.9% of the participants in the brexpiprazole/sertraline group and 10.2% of those in the sertraline/placebo group discontinued treatment because of adverse events.

In both the combination and control groups, the only treatment-emergent adverse event with an incidence of more than 10% was nausea (12.2% vs 11.7%, respectively).

At the last visit, the mean change in body weight from baseline was an increase of 1.3 kg for brexpiprazole plus sertraline vs 0 kg for sertraline alone. Rates of fatigue (6.8% vs 4.1%) and somnolence (5.4% vs 2.6%) were also higher with brexpiprazole plus sertraline.

 

A Trio of Clinical Trials

The findings are part of a larger program reported by the drug makers that includes a flexible-dose brexpiprazole phase 2 trial that met the same CAPS-5 primary endpoint and a second phase 3 trial (072 study) that did not.

“We’ve looked at that data and the sertraline/placebo response was a lot higher, so it was not due to a lack of response with the combination but due to a more robust response with the active control,” Davis said. “But we want to point out for that 072 study, there was still important separation between the combination and sertraline plus placebo on the functional outcome.”

All three trials ran for 12 weeks, so longer-term efficacy and safety data are needed, she said. Other limitations of the published phase 3 study are the patient eligibility criteria, restrictions on concomitant therapy, and lack of non-US sites, which many limit generalizability, the authors noted.

“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 PTSD),” they added.

 

Kudos, Caveats

Reached for comment, Vincent F. Capaldi, II, MD, ScM, professor and chair, department of psychiatry, Uniformed Services University of the Health Sciences School of Medicine, Bethesda, Maryland, said the exclusion of these patients is a limitation but that the study was well designed and conducted in a large sample across the United States.

“The findings suggest that brexpiprazole plus sertraline is a more effective treatment for PTSD than sertraline alone,” he said. “This finding is significant for our service members, who suffer from PTSD at higher rates than the general population.”

Additionally, the significant improvement in psychosocial functioning at week 12 “is important because PTSD is known to cause significant social and occupational disability, as well as quality-of-life issues,” he said.

Capaldi pointed out, however, that the study was conducted only at US sites and did not specifically target military/veteran persons, which may limit applicability to these unique populations.

“While subgroup analyses were generally consistent with the primary analysis, the study was not powered to detect differences between subgroups,” he added. “These subgroup analyses are quite important when considering military and veteran populations.”

Further research is needed to explore whether certain traumas are more responsive to combination treatment, the efficacy of augmenting existing sertraline therapy, and the specific mechanisms of brexpiprazole driving the improved outcomes, Capaldi said.

This study was funded by Otsuka Pharmaceutical Development & Commercialization, which was involved in the design, conduct, and data analysis. Davis reported receiving advisory board fees from Otsuka and Boehringer Ingelheim; lecture fees from Clinical Care Options; and grants from Alkermes, the Veterans Affairs, Patient-Centered Outcomes Research Institute, Department of Defense, and Social Finance. Several coauthors are employees of Otsuka. Krystal reported serving as a consultant for Otsuka America Pharmaceutical, Aptinyx, Biogen, IDEC, Bionomics, Boehringer Ingelheim International, Clearmind Medicine, Cybin IRL, Enveric Biosciences, Epiodyne, EpiVario, Janssen, Jazz Pharmaceuticals, Perception Neuroscience, Praxis Precision Medicines, Springcare, and Sunovion Pharmaceuticals. Krystal also reported serving as a scientific advisory board member for several companies and holding several patents.

A version of this article appeared on Medscape.com.

The first study funded by the US Department of Veterans Affairs (VA) for psychedelic-assisted therapy since the 1960s is currently enrolling veterans. Researchers are set to evaluate the potential of methylenedioxymethamphetamine (MDMA) for veterans with posttraumatic stress disorder (PTSD) and alcohol use disorder.   
 

The grant—about $1.5 million over 5 years—will fund a randomized, placebo-controlled trial at the Providence VA Medical Center in Rhode Island and the West Haven VA Medical Center in Connecticut by VA researchers affiliated with Brown University and Yale University. Pharmaceutical-grade MDMA will be used, and some participants will be randomly selected to receive an active placebo (lower dose of MDMA). MDMA is a psychedelic compound believed to increase emotional openness, reduce fear, and promote introspection during therapy. 
 

The study is part of the VA’s broader effort to gather definitive scientific evidence on the potential efficacy and safety of psychedelic compounds used in conjunction with psychotherapy to treat PTSD, depression, and related mental health conditions. Veterans service organizations like the American Legion and Disabled American Veterans in addition to mental health clinician groups have also called for expanded research into psychedelic compounds. The National Defense Authorization Act for fiscal year 2024 also authorized the US Department of Defense to perform research on psychedelics within military populations. 
 

In September 2023, VA and other federal clinicians, scientists, and policy makers assessed the state of scientific evidence regarding psychedelic-assisted therapies. The working groups provided advice to VA leadership, including the recommendation for the VA to begin funding its own research into these areas of care.  
 

The guidance was based on previously published studies that have found encouraging results but included few or no veteran participants. For example, a confirmatory phase 3 study by the MAPP2 Study Collaborator Group involved 104 patients, of whom only 16 were veterans.  
 

However, the findings of that study underscored the potential of the treatment: MDMA significantly improved PTSD symptoms and functional impairment, compared with placebo with therapy over 18 weeks. Notably, 45 of 52 (86%) participants treated with MDMA achieved a clinically meaningful benefit, and 37 of 52 (71%) participants no longer met criteria for PTSD by the end of the study. Consistent with an earlier study, no new major safety issues were reported. Common treatment-emergent adverse effects were like those of previous research and consistent with expected effects of MDMA. MDMA did not appear to increase the risk of suicidal ideation, and no suicidal behavior was observed. 
 

The VA researchers has conducted a limited number of small studies on psychedelics in VA facilities using non-VA funding. “VA is on the cutting edge of clinical research for veteran health, including in the investigation of psychedelics for mental health,” said Under Secretary for Health Shereef Elnahal, MD.  
 

The FDA granted breakthrough therapy status for MDMA in the treatment of PTSD and psilocybin for the treatment of depression in 2017 and 2018, respectively, based on promising preliminary research evidence. However, in June 2024 an FDA panel voted against approving a MDMA therapy for PTSD, citing concerns about research practices, a lack of diversity in the trials, and a failure to provide data on adverse effects such as potential for abuse.  
 

In August, the FDA formally rejected the treatment and called for another phase 3 study. “The FDA’s decision is disgraceful,” said Heroic Hearts Project, a veterans organization that had lobbied for FDA approval citing the many veteran suicides in a statement. “This is the epitome of bureaucratic red tape—and the result is people will keep dying.” 
 

Meanwhile, VA Press Secretary Terrence Hayes said in a statement: “VA is committed to high-quality research that safely promotes the health of our nation’s Veterans … VA anticipates that additional insights on the efficacy and safety of these therapies will add to the broader body of knowledge on MDMA-assisted psychotherapy.”

The first study funded by the US Department of Veterans Affairs (VA) for psychedelic-assisted therapy since the 1960s is currently enrolling veterans. Researchers are set to evaluate the potential of methylenedioxymethamphetamine (MDMA) for veterans with posttraumatic stress disorder (PTSD) and alcohol use disorder.   
 

The grant—about $1.5 million over 5 years—will fund a randomized, placebo-controlled trial at the Providence VA Medical Center in Rhode Island and the West Haven VA Medical Center in Connecticut by VA researchers affiliated with Brown University and Yale University. Pharmaceutical-grade MDMA will be used, and some participants will be randomly selected to receive an active placebo (lower dose of MDMA). MDMA is a psychedelic compound believed to increase emotional openness, reduce fear, and promote introspection during therapy. 
 

The study is part of the VA’s broader effort to gather definitive scientific evidence on the potential efficacy and safety of psychedelic compounds used in conjunction with psychotherapy to treat PTSD, depression, and related mental health conditions. Veterans service organizations like the American Legion and Disabled American Veterans in addition to mental health clinician groups have also called for expanded research into psychedelic compounds. The National Defense Authorization Act for fiscal year 2024 also authorized the US Department of Defense to perform research on psychedelics within military populations. 
 

In September 2023, VA and other federal clinicians, scientists, and policy makers assessed the state of scientific evidence regarding psychedelic-assisted therapies. The working groups provided advice to VA leadership, including the recommendation for the VA to begin funding its own research into these areas of care.  
 

The guidance was based on previously published studies that have found encouraging results but included few or no veteran participants. For example, a confirmatory phase 3 study by the MAPP2 Study Collaborator Group involved 104 patients, of whom only 16 were veterans.  
 

However, the findings of that study underscored the potential of the treatment: MDMA significantly improved PTSD symptoms and functional impairment, compared with placebo with therapy over 18 weeks. Notably, 45 of 52 (86%) participants treated with MDMA achieved a clinically meaningful benefit, and 37 of 52 (71%) participants no longer met criteria for PTSD by the end of the study. Consistent with an earlier study, no new major safety issues were reported. Common treatment-emergent adverse effects were like those of previous research and consistent with expected effects of MDMA. MDMA did not appear to increase the risk of suicidal ideation, and no suicidal behavior was observed. 
 

The VA researchers has conducted a limited number of small studies on psychedelics in VA facilities using non-VA funding. “VA is on the cutting edge of clinical research for veteran health, including in the investigation of psychedelics for mental health,” said Under Secretary for Health Shereef Elnahal, MD.  
 

The FDA granted breakthrough therapy status for MDMA in the treatment of PTSD and psilocybin for the treatment of depression in 2017 and 2018, respectively, based on promising preliminary research evidence. However, in June 2024 an FDA panel voted against approving a MDMA therapy for PTSD, citing concerns about research practices, a lack of diversity in the trials, and a failure to provide data on adverse effects such as potential for abuse.  
 

In August, the FDA formally rejected the treatment and called for another phase 3 study. “The FDA’s decision is disgraceful,” said Heroic Hearts Project, a veterans organization that had lobbied for FDA approval citing the many veteran suicides in a statement. “This is the epitome of bureaucratic red tape—and the result is people will keep dying.” 
 

Meanwhile, VA Press Secretary Terrence Hayes said in a statement: “VA is committed to high-quality research that safely promotes the health of our nation’s Veterans … VA anticipates that additional insights on the efficacy and safety of these therapies will add to the broader body of knowledge on MDMA-assisted psychotherapy.”

The first study funded by the US Department of Veterans Affairs (VA) for psychedelic-assisted therapy since the 1960s is currently enrolling veterans. Researchers are set to evaluate the potential of methylenedioxymethamphetamine (MDMA) for veterans with posttraumatic stress disorder (PTSD) and alcohol use disorder.   
 

The grant—about $1.5 million over 5 years—will fund a randomized, placebo-controlled trial at the Providence VA Medical Center in Rhode Island and the West Haven VA Medical Center in Connecticut by VA researchers affiliated with Brown University and Yale University. Pharmaceutical-grade MDMA will be used, and some participants will be randomly selected to receive an active placebo (lower dose of MDMA). MDMA is a psychedelic compound believed to increase emotional openness, reduce fear, and promote introspection during therapy. 
 

The study is part of the VA’s broader effort to gather definitive scientific evidence on the potential efficacy and safety of psychedelic compounds used in conjunction with psychotherapy to treat PTSD, depression, and related mental health conditions. Veterans service organizations like the American Legion and Disabled American Veterans in addition to mental health clinician groups have also called for expanded research into psychedelic compounds. The National Defense Authorization Act for fiscal year 2024 also authorized the US Department of Defense to perform research on psychedelics within military populations. 
 

In September 2023, VA and other federal clinicians, scientists, and policy makers assessed the state of scientific evidence regarding psychedelic-assisted therapies. The working groups provided advice to VA leadership, including the recommendation for the VA to begin funding its own research into these areas of care.  
 

The guidance was based on previously published studies that have found encouraging results but included few or no veteran participants. For example, a confirmatory phase 3 study by the MAPP2 Study Collaborator Group involved 104 patients, of whom only 16 were veterans.  
 

However, the findings of that study underscored the potential of the treatment: MDMA significantly improved PTSD symptoms and functional impairment, compared with placebo with therapy over 18 weeks. Notably, 45 of 52 (86%) participants treated with MDMA achieved a clinically meaningful benefit, and 37 of 52 (71%) participants no longer met criteria for PTSD by the end of the study. Consistent with an earlier study, no new major safety issues were reported. Common treatment-emergent adverse effects were like those of previous research and consistent with expected effects of MDMA. MDMA did not appear to increase the risk of suicidal ideation, and no suicidal behavior was observed. 
 

The VA researchers has conducted a limited number of small studies on psychedelics in VA facilities using non-VA funding. “VA is on the cutting edge of clinical research for veteran health, including in the investigation of psychedelics for mental health,” said Under Secretary for Health Shereef Elnahal, MD.  
 

The FDA granted breakthrough therapy status for MDMA in the treatment of PTSD and psilocybin for the treatment of depression in 2017 and 2018, respectively, based on promising preliminary research evidence. However, in June 2024 an FDA panel voted against approving a MDMA therapy for PTSD, citing concerns about research practices, a lack of diversity in the trials, and a failure to provide data on adverse effects such as potential for abuse.  
 

In August, the FDA formally rejected the treatment and called for another phase 3 study. “The FDA’s decision is disgraceful,” said Heroic Hearts Project, a veterans organization that had lobbied for FDA approval citing the many veteran suicides in a statement. “This is the epitome of bureaucratic red tape—and the result is people will keep dying.” 
 

Meanwhile, VA Press Secretary Terrence Hayes said in a statement: “VA is committed to high-quality research that safely promotes the health of our nation’s Veterans … VA anticipates that additional insights on the efficacy and safety of these therapies will add to the broader body of knowledge on MDMA-assisted psychotherapy.”

Posttraumatic stress disorder (PTSD) is the most likely diagnosis given the patient's symptoms — recurrent nightmares, flashbacks, and anxiety triggered by trauma-related noises, all of which are classic indicators of the disorder. His history of witnessing traumatic events at work, including a fatal accident, further reinforces this diagnosis and strongly suggests PTSD as the most fitting explanation. Although the brain scan does not diagnose PTSD directly, it plays an important role in ruling out other potential causes, such as structural brain damage, that could be contributing to his symptoms. Thus, the patient's symptoms are more likely a result of PTSD rather than an underlying organic brain injury.

Although major depressive disorder could explain some of the patient's symptoms, such as impaired daily functioning and withdrawal, the presence of recurrent nightmares, flashbacks, and trauma-specific triggers are more indicative of PTSD.

Generalized anxiety disorder might account for the patient's heightened anxiety, but it typically involves chronic, pervasive worry rather than the trauma-specific symptoms seen here.

Chronic traumatic encephalopathy (CTE) is a possible concern given the patient's occupation and the findings on the CT scan. However, CTE generally presents with cognitive and behavioral changes over time, such as memory loss and aggression, rather than the distinctive trauma-related symptoms characteristic of PTSD.

Individuals with PTSD often display heightened emotional, cognitive, and behavioral responses when exposed to trauma-related cues; these responses include severe anxiety, dissociative episodes, flashbacks, and heightened reactivity. To manage their increased arousal, individuals with PTSD frequently engage in avoidance behaviors, which can result in emotional numbing, diminished interest in daily activities, and, in more severe cases, social withdrawal.

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR), the diagnostic criteria for PTSD in individuals older than 6 years include (A) exposure to actual or threatened death, serious injury, or sexual violence; (B) the presence of one or more intrusion symptoms related to the trauma; (C) persistent avoidance of trauma-related stimuli; (D) negative changes in cognition and mood associated with the trauma; and (E) marked alterations in arousal and reactivity, with at least two specific symptoms.

Trauma-focused psychotherapy is generally recommended as the first-line treatment for most adults with PTSD, with exposure-based therapies often preferred over other therapeutic approaches or pharmacologic treatments, such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors. However, in patients with comorbid conditions such as depression or psychosis that hinder their ability to engage in trauma-focused therapy, initial pharmacologic management is recommended until symptoms stabilize, allowing for the later introduction of psychotherapy. Clinical trials and meta-analyses have demonstrated the effectiveness of various trauma-focused therapies, including trauma-focused cognitive-behavioral therapy, prolonged exposure therapy, and eye movement desensitization and reprocessing. Treatment selection should be made collaboratively, considering the patient's presentation and preferences and the therapist's expertise.

For effective management of PTSD, medication regimens should be maintained for at least 6 months to 1 year to prevent relapse or recurrence. Multiple clinical trials have shown that patients who continue SSRIs after acute treatment are less likely to experience a relapse than those who switch to placebo.

Heidi Moawad, MD, Clinical Assistant Professor, Department of Medical Education, Case Western Reserve University School of Medicine, Cleveland, Ohio.

Heidi Moawad, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

Posttraumatic stress disorder (PTSD) is the most likely diagnosis given the patient's symptoms — recurrent nightmares, flashbacks, and anxiety triggered by trauma-related noises, all of which are classic indicators of the disorder. His history of witnessing traumatic events at work, including a fatal accident, further reinforces this diagnosis and strongly suggests PTSD as the most fitting explanation. Although the brain scan does not diagnose PTSD directly, it plays an important role in ruling out other potential causes, such as structural brain damage, that could be contributing to his symptoms. Thus, the patient's symptoms are more likely a result of PTSD rather than an underlying organic brain injury.

Although major depressive disorder could explain some of the patient's symptoms, such as impaired daily functioning and withdrawal, the presence of recurrent nightmares, flashbacks, and trauma-specific triggers are more indicative of PTSD.

Generalized anxiety disorder might account for the patient's heightened anxiety, but it typically involves chronic, pervasive worry rather than the trauma-specific symptoms seen here.

Chronic traumatic encephalopathy (CTE) is a possible concern given the patient's occupation and the findings on the CT scan. However, CTE generally presents with cognitive and behavioral changes over time, such as memory loss and aggression, rather than the distinctive trauma-related symptoms characteristic of PTSD.

Individuals with PTSD often display heightened emotional, cognitive, and behavioral responses when exposed to trauma-related cues; these responses include severe anxiety, dissociative episodes, flashbacks, and heightened reactivity. To manage their increased arousal, individuals with PTSD frequently engage in avoidance behaviors, which can result in emotional numbing, diminished interest in daily activities, and, in more severe cases, social withdrawal.

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR), the diagnostic criteria for PTSD in individuals older than 6 years include (A) exposure to actual or threatened death, serious injury, or sexual violence; (B) the presence of one or more intrusion symptoms related to the trauma; (C) persistent avoidance of trauma-related stimuli; (D) negative changes in cognition and mood associated with the trauma; and (E) marked alterations in arousal and reactivity, with at least two specific symptoms.

Trauma-focused psychotherapy is generally recommended as the first-line treatment for most adults with PTSD, with exposure-based therapies often preferred over other therapeutic approaches or pharmacologic treatments, such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors. However, in patients with comorbid conditions such as depression or psychosis that hinder their ability to engage in trauma-focused therapy, initial pharmacologic management is recommended until symptoms stabilize, allowing for the later introduction of psychotherapy. Clinical trials and meta-analyses have demonstrated the effectiveness of various trauma-focused therapies, including trauma-focused cognitive-behavioral therapy, prolonged exposure therapy, and eye movement desensitization and reprocessing. Treatment selection should be made collaboratively, considering the patient's presentation and preferences and the therapist's expertise.

For effective management of PTSD, medication regimens should be maintained for at least 6 months to 1 year to prevent relapse or recurrence. Multiple clinical trials have shown that patients who continue SSRIs after acute treatment are less likely to experience a relapse than those who switch to placebo.

Heidi Moawad, MD, Clinical Assistant Professor, Department of Medical Education, Case Western Reserve University School of Medicine, Cleveland, Ohio.

Heidi Moawad, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

Posttraumatic stress disorder (PTSD) is the most likely diagnosis given the patient's symptoms — recurrent nightmares, flashbacks, and anxiety triggered by trauma-related noises, all of which are classic indicators of the disorder. His history of witnessing traumatic events at work, including a fatal accident, further reinforces this diagnosis and strongly suggests PTSD as the most fitting explanation. Although the brain scan does not diagnose PTSD directly, it plays an important role in ruling out other potential causes, such as structural brain damage, that could be contributing to his symptoms. Thus, the patient's symptoms are more likely a result of PTSD rather than an underlying organic brain injury.

Although major depressive disorder could explain some of the patient's symptoms, such as impaired daily functioning and withdrawal, the presence of recurrent nightmares, flashbacks, and trauma-specific triggers are more indicative of PTSD.

Generalized anxiety disorder might account for the patient's heightened anxiety, but it typically involves chronic, pervasive worry rather than the trauma-specific symptoms seen here.

Chronic traumatic encephalopathy (CTE) is a possible concern given the patient's occupation and the findings on the CT scan. However, CTE generally presents with cognitive and behavioral changes over time, such as memory loss and aggression, rather than the distinctive trauma-related symptoms characteristic of PTSD.

Individuals with PTSD often display heightened emotional, cognitive, and behavioral responses when exposed to trauma-related cues; these responses include severe anxiety, dissociative episodes, flashbacks, and heightened reactivity. To manage their increased arousal, individuals with PTSD frequently engage in avoidance behaviors, which can result in emotional numbing, diminished interest in daily activities, and, in more severe cases, social withdrawal.

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR), the diagnostic criteria for PTSD in individuals older than 6 years include (A) exposure to actual or threatened death, serious injury, or sexual violence; (B) the presence of one or more intrusion symptoms related to the trauma; (C) persistent avoidance of trauma-related stimuli; (D) negative changes in cognition and mood associated with the trauma; and (E) marked alterations in arousal and reactivity, with at least two specific symptoms.

Trauma-focused psychotherapy is generally recommended as the first-line treatment for most adults with PTSD, with exposure-based therapies often preferred over other therapeutic approaches or pharmacologic treatments, such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors. However, in patients with comorbid conditions such as depression or psychosis that hinder their ability to engage in trauma-focused therapy, initial pharmacologic management is recommended until symptoms stabilize, allowing for the later introduction of psychotherapy. Clinical trials and meta-analyses have demonstrated the effectiveness of various trauma-focused therapies, including trauma-focused cognitive-behavioral therapy, prolonged exposure therapy, and eye movement desensitization and reprocessing. Treatment selection should be made collaboratively, considering the patient's presentation and preferences and the therapist's expertise.

For effective management of PTSD, medication regimens should be maintained for at least 6 months to 1 year to prevent relapse or recurrence. Multiple clinical trials have shown that patients who continue SSRIs after acute treatment are less likely to experience a relapse than those who switch to placebo.

Heidi Moawad, MD, Clinical Assistant Professor, Department of Medical Education, Case Western Reserve University School of Medicine, Cleveland, Ohio.

Heidi Moawad, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

Editor's Note: This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

Editor's Note: This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

Editor's Note: This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.